ZINC DEFICIENCY - Jeremy Golding, MD
BASICS
DESCRIPTION
• Condition whose manifestations may involve growth retardation, hypogonadism, cell-mediated immune dysfunction, and skin changes related to decreased zinc levels
• System(s) Affected: Endocrine/metabolic; Nervous; Skin/exocrine
ALERT
Geriatric Considerations
• Zinc deficiency may cause poor night vision, leading to falls; poor wound healing or chronic ulcer; or loss of smell and taste, which may cause worsening nutrition.
• Elderly persons living in institutions may have low zinc intake.
Pediatric Considerations
Zinc deficiency may cause failure to thrive, and impair growth and development of secondary sexual characteristics.
Pregnancy Considerations
Requirements increase; deficiency may cause spontaneous abortion, inadequate weight gain.
GENERAL PREVENTION
• Adequate diet
• Supplementation when indicated (see "Medication")
EPIDEMIOLOGY
• Predominate age: All ages
• Predominant sex: Male = Female
Prevalence
In the US: Unknown
RISK FACTORS
• High milk consumption
• Low socioeconomic status
• Malabsorption syndromes
• Living in developing nations
• Strict vegetarian diet
Genetics
Usually acquired, but rarely caused by acrodermatitis enteropathica (autosomal recessive) and associated with sickle cell anemia (autosomal recessive).
ETIOLOGY
• Increased requirements
- Pregnancy
- Lactation
- Rapid growth phase in childhood
- Burns
- Major trauma
• Increased losses
- Diabetes
- Cirrhosis
- Renal disease
- Malabsorption states (e.g., inflammatory bowel diseases)
- Sickle cell anemia
• Decreased absorption
- Acrodermatitis enteropathica, an autosomal recessive deficiency in the enzyme required for intestinal absorption
- Geophagia
- Chelating agents
- Parasitism
- Diet high in phytates (plant fiber)
• Insufficient dietary intake
- Vegetarianism
- Parenteral hyperalimentation without supplementation
- Breast-feeding
- Suboptimal zinc conditions in diet (rare)
- Alcoholism
ASSOCIATED CONDITIONS
• Sickle cell anemia
• Malabsorption
• Parenteral hyperalimentation
• In the older patient, diabetes, cirrhosis, those taking diuretics
DIAGNOSIS
SIGNS AND SYMPTOMS
• Mild deficiency
- Hypogeusia
- Decreased dark adaptation
- Decreased lean body mass
• Moderate deficiency
- All the above
- Diarrhea
- Growth retardation
- Hypogonadism (especially male)
- Mental lethargy
- Anergy
- Rough skin
- Delayed wound healing
- Glucose intolerance
- Impaired cell-mediated immunity
• Severe deficiency
- All the above
- Bullous pustular dermatitis
- Weight loss
- Dwarfism
- Emotional instability
- Tremors
- Ataxia
- Alopecia
- Death
TESTS
Lab
• Plasma zinc levels decreased (in moderate to severe zinc deficiency). Levels 60 ug/L are strongly suggestive, but correction may be needed for low albumin, because most serum zinc is bound to albumin.
• Erythrocyte or leukocyte zinc levels more adequately assess tissue stores, but these are more costly and not widely available.
• Hair and fingernail levels are not useful.
DIFFERENTIAL DIAGNOSIS
• Congenital dwarfism
• Failure to thrive in infants
• Multiple micronutrient deficiencies
• Primary hypogonadism
• Mental retardation
TREATMENT
GENERAL MEASURES
Diet
• Balanced omnivorous diet, or vegetarian diet with supplementation
• Avoid excessive intake of foods with high phytate content (e.g., raw cereals, but ready-to-eat cereal may be the richest source of zinc from a plant product).
• Meat, seafood, milk, eggs, grains, legumes, nuts, and seeds are rich in zinc.
Activity
Full activity
MEDICATION (DRUGS)
• Zinc gluconate or zinc sulfate 25-50 mg PO q.i.d. for 6-9 months
• In adult patient, 4-6 mg of elemental zinc daily added to hyperalimentation, may increase to 12 mg q.i.d. if suspect ongoing heavy zinc losses (e.g., burns or major trauma)
• In pediatric patients, 0.02-0.04 mg zinc/kg/d in hyperalimentation
• Prenatal vitamins with minerals during pregnancy and lactation to prevent deficiency
• Precautions: Avoid large (>20 mg elemental zinc) parenteral doses
• Recommended daily intake is 15 mg, assuming no excessive losses
FOLLOW-UP
PROGNOSIS
Immediate improvement in clinical status with treatment. Full resolution in signs and symptoms
PATIENT MONITORING
Clinical status such as improved energy, weight gain, resolution of symptoms
REFERENCES
1. Abrams S. zinc deficiency and supplementation in children and adolescents. UpToDate; 2006.
2. Ronaghy H. The role of zinc in human nutrition. World Rev Nutr Diet. 1987;54:237-254.
3. Tasman-Jones C. Disturbances of trace mineral metabolism. In: Wyngaarden JB, Smith LH Jr, Bennet JC, eds. Cecil Textbook of Medicine, 19th ed. Philadelphia: WB Saunders, 1992.
MISCELLANEOUS
See also: Alcohol use disorders; Anemia, sickle cell; Failure to thrive (FTT)
Friday, January 16, 2009
WISKOTT-ALDRICH SYNDROME
WISKOTT-ALDRICH SYNDROME - PatriciaBorman, MD
BASICS
DESCRIPTION
• Males affected by this rare X-linked genetic disorder display combined immunodeficiency, microcytic thrombocytosis, and eczema leading to life-threatening infections and bleeding complications. Average life span is 11 years. The syndrome has variable expression. X-linked thrombocytopenia (XLT) is a related but milder form with mostly platelet defects.
• System(s) Affected: Hemic/Lymphatic/Immunologic; Skin/Exocrine
• Synonym(s): Aldrich syndrome; Immunodeficiency-2
ALERT
Geriatric Considerations
None have survived this long.
Pediatric Considerations
• Onset at birth
• 1st-year infections with encapsulated bacteria: respiratory, meningitis, sepsis
• Later infections occur with opportunistic organisms and virus.
GENERAL PREVENTION
Genetics counseling
• Identify carriers
• Prenatal diagnosis
EPIDEMIOLOGY
• Predominant age: Onset at birth, most diagnosed by 24 months of age
• Predominant sex: Male > Female
- Females rarely develop Wiskott-Aldrich syndrome (WAS). Some carriers express disease; others have different but related gene defect.
Incidence
In the US: 1 in 4 million live male births
RISK FACTORS
• Family history of WAS
• History of congenital defects
Genetics
• Family history in >60%
• X-linked recessive trait
• Wiskott-Aldrich syndrome protein (WASP) and XLT genes located at X/11.22
- Codes for cytoplasmic protein that signals cell membrane structure changes required for activation of blood cells
ETIOLOGY
• Hematopoietic cells express WASP.
- Defective WASP fails to organize membrane activation.
- Membranes do not form normal actin cytoskeletons.
- Altered motility and inability to change cell shapes inhibit normal functions.
• Platelets are intrinsically abnormal.
- Accelerated destruction, sequestered in spleen
• T cells show decreased responsiveness to antigens.
• B cells show abnormal antibody production.
ASSOCIATED CONDITIONS
Lymphomas, brain is primary site in 50%; nephropathy, other lymphoreticular tumors
DIAGNOSIS
SIGNS AND SYMPTOMS
Physical Exam
• Neonatal
- Excessive bleeding from circumcision
- Bloody diarrhea
- Petechiae and purpura
• Childhood
- Eczema with secondary skin infections
- Recurrent bacterial infections
- Viral infections
- Hepatosplenomegaly
- Autoimmune vasculitis and hemolytic anemia
TESTS
Lab
• Platelets abnormal at birth
- 30,000 mean platelet volume, 2/3 normal
• B-cell and T-cell changes over time
- White blood cell count fall by age 6 years
- Low IgM, normal IgG, high IgA and IgE
- Decreased response to capsular antigens
- Low CD 8 counts in 61%
- Decreased delayed hypersensitivity responses
- Decreased mitogenic responses
• Special tests
- Genetic testing for WASP
- Carrier identification
• Drugs that may alter lab results: Antibiotics
• Disorders that may alter lab results: Infections
Imaging
Not helpful
Diagnostic Procedures/Surgery
• Bone marrow aspiration to exclude leukemia and aplastic conditions and to HLA type for bone marrow transplantation
• Gene mapping of mutation in affected or female carriers
• Chorionic villus sampling for in utero diagnosis
Pathological Findings
• Hyperplasia of lymphoreticular system
• Vasculitic changes with multiple thromboses of small arterioles of kidney, lung, pancreas, brain
DIFFERENTIAL DIAGNOSIS
• May be difficult in infancy, before immune changes present
• Idiopathic thrombocytopenic purpura; other causes of thrombocytopenia
• Severe atopic disease
• Acute lymphoblastic anemia
• Other causes of immunodeficiency: Severe combined immunodeficiency, HIV
• Leukemias or marrow aplasias
TREATMENT
STABILIZATION
• Inpatient for acute infections
• No live virus vaccination
GENERAL MEASURES
• Cross-matched platelets
• Irradiated, cytomegalovirus-negative blood products
• Aggressive antibiotic therapy for infections
• Prophylactic antibiotics
Diet
No special diet
Activity
• Plan activities to help normal development.
• Avoid contact sports and prevent head injuries.
• Avoid crowds.
MEDICATION (DRUGS) (1)[B]
• Immunoglobulin infusions
• Prophylactic penicillin after splenectomy
• Antibiotics as indicated by culture
• Topical steroids for eczema
• Parenteral steroids, vincristine, or plasmapheresis for autoimmune complications
• Interleukin-2 can increase platelet counts while awaiting stem cell transplantation.
• Contraindications: Refer to the manufacturer's literature for each drug.
• Precautions: Corticosteroids in immunosuppressed patients. Refer to the manufacturer's literature for each drug.
• Significant possible interactions: Refer to the manufacturer's literature for each drug.
First Line
HLA-typed bone marrow or umbilical cord blood stem cell transplant restores all abnormalities with an 85% cure rate. (2)[B]
SURGERY
Splenectomy can transiently improve thrombocytopenia but increases the risk of infection.
FOLLOW-UP
PROGNOSIS
• Usual course is acute and chronic infections with progressive decrease in immune status.
• Average life expectancy is 11 years, with more living past 20 with stem cell transplant. Transplant therapy can restore all abnormalities. Causes of death have been infection (50%), bleeding (27%), and malignancies (12%).
COMPLICATIONS
• Severe infections, especially after splenectomy
• Hemorrhage, cerebral common
• Malignancies (lymphoreticular, leukemia, Kaposi)
• Nephropathy
• Autoimmune disease in 40%, can be aggressive
• Malabsorption syndrome
PATIENT MONITORING
As needed for therapy; monitor for infections, for progression of disease, complications
REFERENCES
1. Ochs HD. The Wiskott-Aldrich syndrome. Isr Med Assoc J. 2002;4(5):379-384.
2. Tsuji Y, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. 2006;1-9.
3. Klein C, et al. Gene therapy for Wiskott-Aldrich syndrome: Rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood. 2003;101(6):2159-2166.
4. Braithwaite K, Abu-Ghosh A, Anderson L, Cairo MS. Treatment of severe thrombocytopenia with IL-11 in children with Wiskott-Aldrich syndrome. J Pediatr Hematol Oncol. 2002;24(4):323-326.
5. Ming JE. Syndromic immunodeficiencies with humoral defects. Immunol Allergy Clin North Am. 2001;21(1):91-111.
MISCELLANEOUS
See also: Idiopathic Thrombocytopenic Purpura (ITP); Immunodeficiency Diseases; Leukemia
BASICS
DESCRIPTION
• Males affected by this rare X-linked genetic disorder display combined immunodeficiency, microcytic thrombocytosis, and eczema leading to life-threatening infections and bleeding complications. Average life span is 11 years. The syndrome has variable expression. X-linked thrombocytopenia (XLT) is a related but milder form with mostly platelet defects.
• System(s) Affected: Hemic/Lymphatic/Immunologic; Skin/Exocrine
• Synonym(s): Aldrich syndrome; Immunodeficiency-2
ALERT
Geriatric Considerations
None have survived this long.
Pediatric Considerations
• Onset at birth
• 1st-year infections with encapsulated bacteria: respiratory, meningitis, sepsis
• Later infections occur with opportunistic organisms and virus.
GENERAL PREVENTION
Genetics counseling
• Identify carriers
• Prenatal diagnosis
EPIDEMIOLOGY
• Predominant age: Onset at birth, most diagnosed by 24 months of age
• Predominant sex: Male > Female
- Females rarely develop Wiskott-Aldrich syndrome (WAS). Some carriers express disease; others have different but related gene defect.
Incidence
In the US: 1 in 4 million live male births
RISK FACTORS
• Family history of WAS
• History of congenital defects
Genetics
• Family history in >60%
• X-linked recessive trait
• Wiskott-Aldrich syndrome protein (WASP) and XLT genes located at X/11.22
- Codes for cytoplasmic protein that signals cell membrane structure changes required for activation of blood cells
ETIOLOGY
• Hematopoietic cells express WASP.
- Defective WASP fails to organize membrane activation.
- Membranes do not form normal actin cytoskeletons.
- Altered motility and inability to change cell shapes inhibit normal functions.
• Platelets are intrinsically abnormal.
- Accelerated destruction, sequestered in spleen
• T cells show decreased responsiveness to antigens.
• B cells show abnormal antibody production.
ASSOCIATED CONDITIONS
Lymphomas, brain is primary site in 50%; nephropathy, other lymphoreticular tumors
DIAGNOSIS
SIGNS AND SYMPTOMS
Physical Exam
• Neonatal
- Excessive bleeding from circumcision
- Bloody diarrhea
- Petechiae and purpura
• Childhood
- Eczema with secondary skin infections
- Recurrent bacterial infections
- Viral infections
- Hepatosplenomegaly
- Autoimmune vasculitis and hemolytic anemia
TESTS
Lab
• Platelets abnormal at birth
- 30,000 mean platelet volume, 2/3 normal
• B-cell and T-cell changes over time
- White blood cell count fall by age 6 years
- Low IgM, normal IgG, high IgA and IgE
- Decreased response to capsular antigens
- Low CD 8 counts in 61%
- Decreased delayed hypersensitivity responses
- Decreased mitogenic responses
• Special tests
- Genetic testing for WASP
- Carrier identification
• Drugs that may alter lab results: Antibiotics
• Disorders that may alter lab results: Infections
Imaging
Not helpful
Diagnostic Procedures/Surgery
• Bone marrow aspiration to exclude leukemia and aplastic conditions and to HLA type for bone marrow transplantation
• Gene mapping of mutation in affected or female carriers
• Chorionic villus sampling for in utero diagnosis
Pathological Findings
• Hyperplasia of lymphoreticular system
• Vasculitic changes with multiple thromboses of small arterioles of kidney, lung, pancreas, brain
DIFFERENTIAL DIAGNOSIS
• May be difficult in infancy, before immune changes present
• Idiopathic thrombocytopenic purpura; other causes of thrombocytopenia
• Severe atopic disease
• Acute lymphoblastic anemia
• Other causes of immunodeficiency: Severe combined immunodeficiency, HIV
• Leukemias or marrow aplasias
TREATMENT
STABILIZATION
• Inpatient for acute infections
• No live virus vaccination
GENERAL MEASURES
• Cross-matched platelets
• Irradiated, cytomegalovirus-negative blood products
• Aggressive antibiotic therapy for infections
• Prophylactic antibiotics
Diet
No special diet
Activity
• Plan activities to help normal development.
• Avoid contact sports and prevent head injuries.
• Avoid crowds.
MEDICATION (DRUGS) (1)[B]
• Immunoglobulin infusions
• Prophylactic penicillin after splenectomy
• Antibiotics as indicated by culture
• Topical steroids for eczema
• Parenteral steroids, vincristine, or plasmapheresis for autoimmune complications
• Interleukin-2 can increase platelet counts while awaiting stem cell transplantation.
• Contraindications: Refer to the manufacturer's literature for each drug.
• Precautions: Corticosteroids in immunosuppressed patients. Refer to the manufacturer's literature for each drug.
• Significant possible interactions: Refer to the manufacturer's literature for each drug.
First Line
HLA-typed bone marrow or umbilical cord blood stem cell transplant restores all abnormalities with an 85% cure rate. (2)[B]
SURGERY
Splenectomy can transiently improve thrombocytopenia but increases the risk of infection.
FOLLOW-UP
PROGNOSIS
• Usual course is acute and chronic infections with progressive decrease in immune status.
• Average life expectancy is 11 years, with more living past 20 with stem cell transplant. Transplant therapy can restore all abnormalities. Causes of death have been infection (50%), bleeding (27%), and malignancies (12%).
COMPLICATIONS
• Severe infections, especially after splenectomy
• Hemorrhage, cerebral common
• Malignancies (lymphoreticular, leukemia, Kaposi)
• Nephropathy
• Autoimmune disease in 40%, can be aggressive
• Malabsorption syndrome
PATIENT MONITORING
As needed for therapy; monitor for infections, for progression of disease, complications
REFERENCES
1. Ochs HD. The Wiskott-Aldrich syndrome. Isr Med Assoc J. 2002;4(5):379-384.
2. Tsuji Y, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. 2006;1-9.
3. Klein C, et al. Gene therapy for Wiskott-Aldrich syndrome: Rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood. 2003;101(6):2159-2166.
4. Braithwaite K, Abu-Ghosh A, Anderson L, Cairo MS. Treatment of severe thrombocytopenia with IL-11 in children with Wiskott-Aldrich syndrome. J Pediatr Hematol Oncol. 2002;24(4):323-326.
5. Ming JE. Syndromic immunodeficiencies with humoral defects. Immunol Allergy Clin North Am. 2001;21(1):91-111.
MISCELLANEOUS
See also: Idiopathic Thrombocytopenic Purpura (ITP); Immunodeficiency Diseases; Leukemia
WILMS TUMOR
WILMS TUMOR - Timothy L.Black, MD
BASICS
DESCRIPTION
• An embryonal renal neoplasm containing blastema, stromal, or epithelial cell types, usually affecting children before age 5 years.
• For staging, see "Prognosis" section.
• System(s) Affected: Renal/Urologic
• Synonym(s): Nephroblastoma
ALERT
Pediatric Considerations
• Occurs only in children
• Most common renal malignancy in childhood
EPIDEMIOLOGY
• Predominant age: Median age of 36.5 months
• Predominant sex: Female > Male (1.1:1)
Incidence
• Frequency rarer in East Asian populations than whites (1)[C]
• Frequency higher in black children than whites (1)[C]
Prevalence
US: 0.69/100,000. 7.6 cases/1 million children under 15 years of age
RISK FACTORS
• Aniridia (partial or complete absence of iris) 600 times greater than normal risk
• Hemihypertrophy (100 times greater than normal risk)
• Cryptorchidism
• Hypospadias
• Duplicated renal collecting systems
• Wiedemann-Beckwith syndrome
• Denys-Drash syndrome (nephropathy, renal failure, male pseudohermaphroditism, Wilms tumor)
• Klippel-Trenaunay syndrome
• WAGR complex (Wilms tumor, aniridia, genitourinary malformations, and mental retardation)
• Beckwith-Wiedemann syndrome (visceromegaly, macroglossia, omphalocele, hyperinsulinemic hypoclycemia)
• Familial occurrence (1-2%)
• Paternal occupation (see "Etiology")
Genetics
• Several congenital anomalies are known to be associated with Wilms tumor. A 2-stage mutational model has been proposed: Occurrence in either hereditary form or sporadic form. Patients with aniridia have a deletion of the short arm of chromosome 11 (11p13).
• Abnormalities of chromosome 11 at the 11p15 locus are associated with Beckwith-Wiedemann syndrome
• Wilms tumor suppressor gene (WT1) has been identified as well as additional candidates for another suppressor gene (WT2) (1)[C]
• Chromosome band 17q12-21 has been linked to two kindreds with Wilms tumor and other kindreds are associated with a Wilms tumor predisposition gene at 19q13.3-q13.4 (1)[C]
ETIOLOGY
• Hereditary or sporadic forms of genetic mutation
• Familial form: autosomal dominant trait with incomplete penetrance (1%)
• Potential of paternal occupational exposure (machinists, welders, motor vehicle mechanics, auto body repairmen)
ASSOCIATED CONDITIONS
See "Risk Factors."
DIAGNOSIS
SIGNS AND SYMPTOMS
• Usually asymptomatic
• Palpable upper abdominal mass
• Abdominal pain
• Fever
• Anemia
• Rarely, signs of acute abdomen with free intraperitoneal rupture
• Cardiac murmur
• Hepatosplenomegaly
• Ascites
• Prominent abdominal wall veins
• Varicocele
• Gonadal metastases
• Aniridia
History
History of increasing abdominal size
Physical Exam
Palpable abdominal mass
TESTS
Lab
• Urinalysis (occasional hematuria)
• CBC (anemia)
• Lactate dehydrogenase
• Plasma renin (rarely helpful)
• Urine catecholamines
Imaging
• Chest x-ray
• Kidney, ureter, bladder (presence of linear calcifications)
• Abdominal ultrasound: Gives best information about tumor extension into inferior vena cava
• CT (with IV and oral contrast) of chest and abdomen
• IV pyelogram rarely helpful
Diagnostic Procedures/Surgery
Occasionally, bone marrow aspiration necessary to distinguish from neuroblastoma
Pathological Findings
• Favorable findings (mortality of 7%)
- Bulky lesion, well encapsulated
- Focal areas of hemorrhage and necrosis
- Absence of anaplasia and sarcomatous cell types
- Presence of blastema, stomal, and epithelial elements
• Unfavorable histology (mortality rate of 57%)
- Anaplasia: Markedly enlarged and multipolar mitotic figures, 3-fold enlargement of nuclei in comparison with adjacent similar nuclei, hyperchromasia of enlarge nuclei. Anaplasia may be diffuse or focal.
- Sarcomatous changes: Now considered to be separate from Wilms, not subtypes (mortality 64%)
• Nephroblastomatosis: Considered premalignant
DIFFERENTIAL DIAGNOSIS
• Neuroblastoma
• Hepatic tumor
• Sarcoma
• Rhabdoid tumor
• Cystic nephroma
• Mesoblastic nephroma
• Renal cell carcinoma (generally occurs in older children)
TREATMENT
GENERAL MEASURES
• Appropriate health care: Inpatient workup and treatment until stable postoperative and induction chemotherapy completed
• Chemotherapy
• Radiation therapy in Stage II, unfavorable histology, Stage II and Stage IV
Diet
No special diet
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Dactinomycin (actinomycin-D)
• Vincristine
• Doxorubicin
• Cyclophosphamide (Cytoxan)
• Ifosphamide
• Etoposide
• Contraindications: Refer to the manufacturer's literature for each drug.
• Precautions: Refer to the manufacturer's literature for each drug.
• Significant possible interactions: Refer to the manufacturer's literature for each drug.
Second Line
• Doxorubicin (Adriamycin)
• Cyclophosphamide
SURGERY
• Examination (visual and manual) of contralateral kidney
• Radical nephroureterectomy and biopsies as needed to provide precise staging information
• Sampling of any enlarged lymph nodes
• Identification of any retained tumor with titanium clips
• Tumor should be given to pathologist fresh, not in formalin.
• Vertical midline incision if tumor extension to right atrium present (possible use of cardiopulmonary bypass)
• With bilateral Wilms tumors, biopsy, then chemotherapy and 2nd-look operation 6 weeks to 6 months later for partial bilateral nephrectomy if possible
- Preopoerative treatment also generally accepted in a solitary kidney, horseshoe kidneys, intravascular extension of tumor above the intrahepatic vena cava, and in the case of respiratory distress from extensive metastatic tumor
FOLLOW-UP
DISPOSITION
Issues for Referral
Surgical complications have been found to be significantly higher if the radical nephrectomy is done by a general surgeon rather than an pediatric surgeon or a pediatric urologist. (2)[B]
PROGNOSIS
• With favorable histology, 91% survival
• With diffuse anaplasia, 20% survival
• With focal anaplasia, 64% survival
• With rhabdoid features, 19% 3-year survival
• Staging
- I: Tumor limited to kidney, completely excised
- II: Tumor extends beyond kidney, completely excised
- III: Residual nonhematogenous tumor confined to abdomen (lymph nodes positive, spillage of tumor, peritoneal implants, extension beyond resection region)
- IV: Hematogenous metastases
- V: Bilateral renal involvement
COMPLICATIONS
• 1-2% will develop second malignant neoplasms (leukemia, lymphoma, hepatocellular carcinoma, soft tissue sarcoma)
• High risk of low-birth-weight infants, perinatal mortality in offspring of female survivors of Wilms tumor
• Chest is usual site of recurrence.
• Occurrence of second malignant neoplasms in 2% of patients 7-34 years after treatment
• Surgical complications: (2)[B]
- Postoperative hemorrhage
- Postoperative small bowel obstruction (5-7%)
- Tumor rupture with spillage in 19%. This may be spontaneous or surgical and results in upstaging the tumor. Only 2.7% of spills are considered avoidable. (3)[B]
• Local tumor recurrence
PATIENT MONITORING
• Multidrug chemotherapy every 3-4 weeks for 16 weeks: 15 months depending on stage
• Every 4 months for 1 year, every 6 months for 2nd to 3rd year, yearly after that
• Complete blood count, CT of chest and abdomen with each visit
REFERENCES
1. Ashcraft KW, Holcomb GW, Murphy JP, eds. Pediatric Surgery, 4th ed. Philadelphia, PA: Elsevier Saunders; 2005.
2. Ritchey ML, et al. Surgical complications after primary nephrectomy for Wilms tumor: Report from the national Wilms tumor study group. J Am Coll Surg. 2001;192:63-68.
3. Ehrlich PF, et al. Quality assessment for Wilms tumor: A report from the national Wilms study-5. J Ped Surg. 2005;40:208-210.
MISCELLANEOUS
Other notes
• Mesoblastic nephroma: Distinguished only by histology. Age usually 6 months. Essentially benign, although metastases have been reported; tends to be locally invasive. Operative spillage may lead to recurrence. No chemotherapy or radiotherapy needed with complete excision.
• Nephroblastomatosis: Considered premalignant; may present as nodularity of one or both kidneys; treated with biopsy and local excision (renal tissue sparing)
BASICS
DESCRIPTION
• An embryonal renal neoplasm containing blastema, stromal, or epithelial cell types, usually affecting children before age 5 years.
• For staging, see "Prognosis" section.
• System(s) Affected: Renal/Urologic
• Synonym(s): Nephroblastoma
ALERT
Pediatric Considerations
• Occurs only in children
• Most common renal malignancy in childhood
EPIDEMIOLOGY
• Predominant age: Median age of 36.5 months
• Predominant sex: Female > Male (1.1:1)
Incidence
• Frequency rarer in East Asian populations than whites (1)[C]
• Frequency higher in black children than whites (1)[C]
Prevalence
US: 0.69/100,000. 7.6 cases/1 million children under 15 years of age
RISK FACTORS
• Aniridia (partial or complete absence of iris) 600 times greater than normal risk
• Hemihypertrophy (100 times greater than normal risk)
• Cryptorchidism
• Hypospadias
• Duplicated renal collecting systems
• Wiedemann-Beckwith syndrome
• Denys-Drash syndrome (nephropathy, renal failure, male pseudohermaphroditism, Wilms tumor)
• Klippel-Trenaunay syndrome
• WAGR complex (Wilms tumor, aniridia, genitourinary malformations, and mental retardation)
• Beckwith-Wiedemann syndrome (visceromegaly, macroglossia, omphalocele, hyperinsulinemic hypoclycemia)
• Familial occurrence (1-2%)
• Paternal occupation (see "Etiology")
Genetics
• Several congenital anomalies are known to be associated with Wilms tumor. A 2-stage mutational model has been proposed: Occurrence in either hereditary form or sporadic form. Patients with aniridia have a deletion of the short arm of chromosome 11 (11p13).
• Abnormalities of chromosome 11 at the 11p15 locus are associated with Beckwith-Wiedemann syndrome
• Wilms tumor suppressor gene (WT1) has been identified as well as additional candidates for another suppressor gene (WT2) (1)[C]
• Chromosome band 17q12-21 has been linked to two kindreds with Wilms tumor and other kindreds are associated with a Wilms tumor predisposition gene at 19q13.3-q13.4 (1)[C]
ETIOLOGY
• Hereditary or sporadic forms of genetic mutation
• Familial form: autosomal dominant trait with incomplete penetrance (1%)
• Potential of paternal occupational exposure (machinists, welders, motor vehicle mechanics, auto body repairmen)
ASSOCIATED CONDITIONS
See "Risk Factors."
DIAGNOSIS
SIGNS AND SYMPTOMS
• Usually asymptomatic
• Palpable upper abdominal mass
• Abdominal pain
• Fever
• Anemia
• Rarely, signs of acute abdomen with free intraperitoneal rupture
• Cardiac murmur
• Hepatosplenomegaly
• Ascites
• Prominent abdominal wall veins
• Varicocele
• Gonadal metastases
• Aniridia
History
History of increasing abdominal size
Physical Exam
Palpable abdominal mass
TESTS
Lab
• Urinalysis (occasional hematuria)
• CBC (anemia)
• Lactate dehydrogenase
• Plasma renin (rarely helpful)
• Urine catecholamines
Imaging
• Chest x-ray
• Kidney, ureter, bladder (presence of linear calcifications)
• Abdominal ultrasound: Gives best information about tumor extension into inferior vena cava
• CT (with IV and oral contrast) of chest and abdomen
• IV pyelogram rarely helpful
Diagnostic Procedures/Surgery
Occasionally, bone marrow aspiration necessary to distinguish from neuroblastoma
Pathological Findings
• Favorable findings (mortality of 7%)
- Bulky lesion, well encapsulated
- Focal areas of hemorrhage and necrosis
- Absence of anaplasia and sarcomatous cell types
- Presence of blastema, stomal, and epithelial elements
• Unfavorable histology (mortality rate of 57%)
- Anaplasia: Markedly enlarged and multipolar mitotic figures, 3-fold enlargement of nuclei in comparison with adjacent similar nuclei, hyperchromasia of enlarge nuclei. Anaplasia may be diffuse or focal.
- Sarcomatous changes: Now considered to be separate from Wilms, not subtypes (mortality 64%)
• Nephroblastomatosis: Considered premalignant
DIFFERENTIAL DIAGNOSIS
• Neuroblastoma
• Hepatic tumor
• Sarcoma
• Rhabdoid tumor
• Cystic nephroma
• Mesoblastic nephroma
• Renal cell carcinoma (generally occurs in older children)
TREATMENT
GENERAL MEASURES
• Appropriate health care: Inpatient workup and treatment until stable postoperative and induction chemotherapy completed
• Chemotherapy
• Radiation therapy in Stage II, unfavorable histology, Stage II and Stage IV
Diet
No special diet
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Dactinomycin (actinomycin-D)
• Vincristine
• Doxorubicin
• Cyclophosphamide (Cytoxan)
• Ifosphamide
• Etoposide
• Contraindications: Refer to the manufacturer's literature for each drug.
• Precautions: Refer to the manufacturer's literature for each drug.
• Significant possible interactions: Refer to the manufacturer's literature for each drug.
Second Line
• Doxorubicin (Adriamycin)
• Cyclophosphamide
SURGERY
• Examination (visual and manual) of contralateral kidney
• Radical nephroureterectomy and biopsies as needed to provide precise staging information
• Sampling of any enlarged lymph nodes
• Identification of any retained tumor with titanium clips
• Tumor should be given to pathologist fresh, not in formalin.
• Vertical midline incision if tumor extension to right atrium present (possible use of cardiopulmonary bypass)
• With bilateral Wilms tumors, biopsy, then chemotherapy and 2nd-look operation 6 weeks to 6 months later for partial bilateral nephrectomy if possible
- Preopoerative treatment also generally accepted in a solitary kidney, horseshoe kidneys, intravascular extension of tumor above the intrahepatic vena cava, and in the case of respiratory distress from extensive metastatic tumor
FOLLOW-UP
DISPOSITION
Issues for Referral
Surgical complications have been found to be significantly higher if the radical nephrectomy is done by a general surgeon rather than an pediatric surgeon or a pediatric urologist. (2)[B]
PROGNOSIS
• With favorable histology, 91% survival
• With diffuse anaplasia, 20% survival
• With focal anaplasia, 64% survival
• With rhabdoid features, 19% 3-year survival
• Staging
- I: Tumor limited to kidney, completely excised
- II: Tumor extends beyond kidney, completely excised
- III: Residual nonhematogenous tumor confined to abdomen (lymph nodes positive, spillage of tumor, peritoneal implants, extension beyond resection region)
- IV: Hematogenous metastases
- V: Bilateral renal involvement
COMPLICATIONS
• 1-2% will develop second malignant neoplasms (leukemia, lymphoma, hepatocellular carcinoma, soft tissue sarcoma)
• High risk of low-birth-weight infants, perinatal mortality in offspring of female survivors of Wilms tumor
• Chest is usual site of recurrence.
• Occurrence of second malignant neoplasms in 2% of patients 7-34 years after treatment
• Surgical complications: (2)[B]
- Postoperative hemorrhage
- Postoperative small bowel obstruction (5-7%)
- Tumor rupture with spillage in 19%. This may be spontaneous or surgical and results in upstaging the tumor. Only 2.7% of spills are considered avoidable. (3)[B]
• Local tumor recurrence
PATIENT MONITORING
• Multidrug chemotherapy every 3-4 weeks for 16 weeks: 15 months depending on stage
• Every 4 months for 1 year, every 6 months for 2nd to 3rd year, yearly after that
• Complete blood count, CT of chest and abdomen with each visit
REFERENCES
1. Ashcraft KW, Holcomb GW, Murphy JP, eds. Pediatric Surgery, 4th ed. Philadelphia, PA: Elsevier Saunders; 2005.
2. Ritchey ML, et al. Surgical complications after primary nephrectomy for Wilms tumor: Report from the national Wilms tumor study group. J Am Coll Surg. 2001;192:63-68.
3. Ehrlich PF, et al. Quality assessment for Wilms tumor: A report from the national Wilms study-5. J Ped Surg. 2005;40:208-210.
MISCELLANEOUS
Other notes
• Mesoblastic nephroma: Distinguished only by histology. Age usually 6 months. Essentially benign, although metastases have been reported; tends to be locally invasive. Operative spillage may lead to recurrence. No chemotherapy or radiotherapy needed with complete excision.
• Nephroblastomatosis: Considered premalignant; may present as nodularity of one or both kidneys; treated with biopsy and local excision (renal tissue sparing)
WILLIAMS SYNDROME
WILLIAMS SYNDROME - Gene S.Fisch, PhD
BASICS
DESCRIPTION
• Williams syndrome is an unusual multisystem neurodevelopmental disorder typified by characteristic craniofacial features, mild microcephaly, mild to moderate mental retardation with a distinctive cognitive-behavioral profile, connective tissue abnormalities, growth retardation, supravalvular aortic stenosis, peripheral pulmonary stenosis, renal artery stenosis, limited joint movement, and transient hypercalcemia.
• Occurrence is sporadic, although familial autosomal dominant cases have been infrequently reported.
• System(s) Affected: Cardiovascular; Endocrine/Metabolic; Musculoskeletal; Nervous; Renal/Urologic
• Synonym(s): Williams-Beuren syndrome; Fanconi-type idiopathic infantile hypercalcemia; Elfin facies syndrome
ALERT
Pediatric Considerations
Infantile hypercalcemia
Pregnancy Considerations
Patient and family should receive genetic evaluation and counseling, as prenatal diagnosis is available.
GENERAL PREVENTION
Genetic counseling and evaluation, especially among high-functioning patients, about pregnancies. Prenatal diagnosis is available.
EPIDEMIOLOGY
• Predominant age: Life-long condition
• Predominant sex: Male = Female
Incidence
In the US: Affected individuals have been estimated at 1:20,000 live births.
RISK FACTORS
Possible familial transmission as an autosomal dominant mutation
Genetics
The pattern of occurrence is nearly always sporadic and is observed in both sexes, although there are several reported cases of familial transmission as an autosomal dominant mutation. The phenotypic expression is somewhat varied and associated with a hemizygous microdeletion of ~1.6 Mb in the 7q11.23 region which includes the elastin (ELN) and LIM-kinase (LIMK) gene.
ETIOLOGY
Microdeletion in the 7q11.23 region produced by unequal crossing over
ASSOCIATED CONDITIONS
• Developmental delay
• Growth retardation
• Cardiovascular dysfunction
• Renal dysfunction
• Attention deficit disorder (ADD)
- Frequently associated with neuropsychologic dysfunction
- Treatment for ADD is similar to methods used in the general population.
DIAGNOSIS
SIGNS AND SYMPTOMS
• The signs and symptoms observed in the classic case of Williams syndrome may be diagnostic, but the clinical presentation is somewhat varied.
• Early childhood: global developmental delay, albeit with seemingly normal speech and expressive language
- Hyperacusis
- Characteristic craniofacial features: Elfin-like facial appearance; medial eyebrow flare and stellate irises; wide mouth; long flat philtrum; upturned nose with a flat nasal bridge; dental anomalies; mild microcephaly
- Characteristic clinical features: Supravalvula aortic stenosis; peripheral pulmonary stenosis; renal artery stenosis; infantile hypercalcemia; growth retardation and short stature; slender limbs and trunk
- Characteristic cognitive/behavioral features: Weakness in abstract/visual reasoning; highly developed expressive language skills; low levels of daily living skills; age-related decreases in IQ scores
• Postpubertal males and females
- Characteristic clinical features: Hypertension; lordosis, and/or limited joint movement
- Characteristic behavioral features: Anxiety, depression, and suicidal ideation
TESTS
Lab
• Molecular-genetic (DNA) evaluation is the diagnostic test of choice and can determine the size of the deletion.
• Special tests: Affected individuals require cognitive, behavioral, psychologic, and educational evaluations to develop individual education programs.
DIFFERENTIAL DIAGNOSIS
Rule out uncomplicated hypercalcemia or supravalvular aortic stenosis.
TREATMENT
GENERAL MEASURES
• Appropriate health care: Affected individuals will generally need life-long adult supervision. Early intensive educational intervention and behavior modification should be implemented.
• Early detection will permit early intervention and intensive behavioral training.
• Treatment for hypercalcemia by controlling dietary intake of calcium and vitamin D
• Ophthalmologic evaluations are recommended for problems associated with visual acuity.
• Preventive dentistry to reduce risk of malocclusion
• Continual monitoring of cardiovascular anomalies and for hypertension
• Filtered ear protection for hyperacusis
Diet
For hypercalcemia, control intake of calcium and vitamin D.
Activity
Full activity unless cardiovascular stenoses are problematic
MEDICATION (DRUGS)
Medication for hypertension and for hyperparathyroidism
SURGERY
Treatment for aortic, pulmonary, or renal artery stenoses if needed
FOLLOW-UP
PROGNOSIS
• Individuals may need life-long supervision.
• Life span may be affected by renal dysfunction or hypertension resulting from supravalvuar stenosis and/or peripheral pulmonary stenosis
COMPLICATIONS
• Learning problems, especially in abstract/visual reasoning
• Behavioral problems concerning indifference to personal safety
• Postpubescent anxiety and depression
• Risk of cardiovascular disease and/or renal dysfunction
PATIENT MONITORING
Regular pediatric care and general health maintenance with particular attention to endocrine, renal, and cardiovascular function
REFERENCES
1. Anderson PE, Rourke BP. Williams syndrome. In: White BP, ed. Syndrome of Nonverbal Learning Disabilities. New York: Guilford Press; 1995.
2. Bayes M, Perez-Juardo LA. Williams-Beuren syndrome. In: Fisch GS, ed. Genetics and Genomics of Neurobehavioral Disorders. Totowa, NJ: Humana Press; 2003.
MISCELLANEOUS
See also: Attention Deficit/Hyperactivity Disorder; Down Syndrome; Fragile X Syndrome; Hyperparathyroidism; Hypertension, Essential; Mental Retardation
BASICS
DESCRIPTION
• Williams syndrome is an unusual multisystem neurodevelopmental disorder typified by characteristic craniofacial features, mild microcephaly, mild to moderate mental retardation with a distinctive cognitive-behavioral profile, connective tissue abnormalities, growth retardation, supravalvular aortic stenosis, peripheral pulmonary stenosis, renal artery stenosis, limited joint movement, and transient hypercalcemia.
• Occurrence is sporadic, although familial autosomal dominant cases have been infrequently reported.
• System(s) Affected: Cardiovascular; Endocrine/Metabolic; Musculoskeletal; Nervous; Renal/Urologic
• Synonym(s): Williams-Beuren syndrome; Fanconi-type idiopathic infantile hypercalcemia; Elfin facies syndrome
ALERT
Pediatric Considerations
Infantile hypercalcemia
Pregnancy Considerations
Patient and family should receive genetic evaluation and counseling, as prenatal diagnosis is available.
GENERAL PREVENTION
Genetic counseling and evaluation, especially among high-functioning patients, about pregnancies. Prenatal diagnosis is available.
EPIDEMIOLOGY
• Predominant age: Life-long condition
• Predominant sex: Male = Female
Incidence
In the US: Affected individuals have been estimated at 1:20,000 live births.
RISK FACTORS
Possible familial transmission as an autosomal dominant mutation
Genetics
The pattern of occurrence is nearly always sporadic and is observed in both sexes, although there are several reported cases of familial transmission as an autosomal dominant mutation. The phenotypic expression is somewhat varied and associated with a hemizygous microdeletion of ~1.6 Mb in the 7q11.23 region which includes the elastin (ELN) and LIM-kinase (LIMK) gene.
ETIOLOGY
Microdeletion in the 7q11.23 region produced by unequal crossing over
ASSOCIATED CONDITIONS
• Developmental delay
• Growth retardation
• Cardiovascular dysfunction
• Renal dysfunction
• Attention deficit disorder (ADD)
- Frequently associated with neuropsychologic dysfunction
- Treatment for ADD is similar to methods used in the general population.
DIAGNOSIS
SIGNS AND SYMPTOMS
• The signs and symptoms observed in the classic case of Williams syndrome may be diagnostic, but the clinical presentation is somewhat varied.
• Early childhood: global developmental delay, albeit with seemingly normal speech and expressive language
- Hyperacusis
- Characteristic craniofacial features: Elfin-like facial appearance; medial eyebrow flare and stellate irises; wide mouth; long flat philtrum; upturned nose with a flat nasal bridge; dental anomalies; mild microcephaly
- Characteristic clinical features: Supravalvula aortic stenosis; peripheral pulmonary stenosis; renal artery stenosis; infantile hypercalcemia; growth retardation and short stature; slender limbs and trunk
- Characteristic cognitive/behavioral features: Weakness in abstract/visual reasoning; highly developed expressive language skills; low levels of daily living skills; age-related decreases in IQ scores
• Postpubertal males and females
- Characteristic clinical features: Hypertension; lordosis, and/or limited joint movement
- Characteristic behavioral features: Anxiety, depression, and suicidal ideation
TESTS
Lab
• Molecular-genetic (DNA) evaluation is the diagnostic test of choice and can determine the size of the deletion.
• Special tests: Affected individuals require cognitive, behavioral, psychologic, and educational evaluations to develop individual education programs.
DIFFERENTIAL DIAGNOSIS
Rule out uncomplicated hypercalcemia or supravalvular aortic stenosis.
TREATMENT
GENERAL MEASURES
• Appropriate health care: Affected individuals will generally need life-long adult supervision. Early intensive educational intervention and behavior modification should be implemented.
• Early detection will permit early intervention and intensive behavioral training.
• Treatment for hypercalcemia by controlling dietary intake of calcium and vitamin D
• Ophthalmologic evaluations are recommended for problems associated with visual acuity.
• Preventive dentistry to reduce risk of malocclusion
• Continual monitoring of cardiovascular anomalies and for hypertension
• Filtered ear protection for hyperacusis
Diet
For hypercalcemia, control intake of calcium and vitamin D.
Activity
Full activity unless cardiovascular stenoses are problematic
MEDICATION (DRUGS)
Medication for hypertension and for hyperparathyroidism
SURGERY
Treatment for aortic, pulmonary, or renal artery stenoses if needed
FOLLOW-UP
PROGNOSIS
• Individuals may need life-long supervision.
• Life span may be affected by renal dysfunction or hypertension resulting from supravalvuar stenosis and/or peripheral pulmonary stenosis
COMPLICATIONS
• Learning problems, especially in abstract/visual reasoning
• Behavioral problems concerning indifference to personal safety
• Postpubescent anxiety and depression
• Risk of cardiovascular disease and/or renal dysfunction
PATIENT MONITORING
Regular pediatric care and general health maintenance with particular attention to endocrine, renal, and cardiovascular function
REFERENCES
1. Anderson PE, Rourke BP. Williams syndrome. In: White BP, ed. Syndrome of Nonverbal Learning Disabilities. New York: Guilford Press; 1995.
2. Bayes M, Perez-Juardo LA. Williams-Beuren syndrome. In: Fisch GS, ed. Genetics and Genomics of Neurobehavioral Disorders. Totowa, NJ: Humana Press; 2003.
MISCELLANEOUS
See also: Attention Deficit/Hyperactivity Disorder; Down Syndrome; Fragile X Syndrome; Hyperparathyroidism; Hypertension, Essential; Mental Retardation
WEGENER GRANULOMATOSIS
WEGENER GRANULOMATOSIS - Christopher M.Wise, MD
BASICS
DESCRIPTION
A disease characterized by granulomatous vasculitis involving multiple organs. The characteristic "triad" of involvement includes the upper airway (otitis, sinusitis, nasal mucosa), lungs, and kidneys. Other organ systems involved include the skin, joints, and nervous system (peripheral or central).
• As the condition progresses untreated, upper airway erosions, necrotic pulmonary nodules, and renal failure are common; without treatment, mortality rate is high.
• System(s) Affected: Upper Airways (sinusitis, otitis); Cardiovascular; Gastrointestinal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
ALERT
Pregnancy Considerations
• Rarely reported
• Should be considered only when patient is disease-free and off therapy
• Cyclophosphamide often causes sterility and is potentially teratogenic.
EPIDEMIOLOGY
• Predominant age: mean age of onset in mid-40s, but has been described in all age groups
• Predominant sex: Male > Female (3:2)
Incidence
Estimated at ~0.4/100,000
Prevalence
Three per 100,000
RISK FACTORS
None identified
Genetics
Increased presence in HLA-B8 and HLA-DR2
ETIOLOGY
The etiology is unknown; the autoimmune phenomena and immune complex deposition in arterial walls are implicated. Triggering infectious agents, yet unidentified, may be involved.
ASSOCIATED CONDITIONS
None
DIAGNOSIS
SIGNS AND SYMPTOMS
• Pulmonary infiltrates: 71%
• Sinusitis: 67%
• Arthralgia/arthritis: 44%
• Fever: 34%
• Cough: 34%
• Otitis: 25%
• Rhinitis: 22%
• Hemoptysis: 18%
• Ocular inflammation: 16%
• Weight loss: 16%
• Skin rash: 13%
• Epistaxis: 11%
• Renal failure: 11%
• Chest pain, anorexia, proptosis, dyspnea, oral ulcers, hearing loss, headache (all 10%)
TESTS
Lab
• Anemia, leukocytosis, and thrombocytosis common during active phases of disease
• Erythrocyte sedimentation rate usually markedly elevated (75%)
• Rheumatoid factor present in low to moderate titer in up to 50%
• Hematuria and/or cellular casts with moderate range proteinuria
• Renal insufficiency, mild to moderate at 1st, frequently progresses to end-stage renal disease.
• Antibodies to neutrophilic cytoplasmic antigens with a cytoplasmic pattern of staining (c-ANCA) are detected in 60-90% of patients. c-ANCA is highly specific (90+%); immunoblotting techniques or enzyme-linked immunoassay may detect antibodies to PR3 or MPO (anti-PR3 antibodies are more specific)
• Perinuclear staining (p-ANCA), is nonspecific and seen with other vasculitic syndromes or isolated necrotizing glomerulonephritis.
• Drugs that may alter lab results: Corticosteroids and cytotoxic drugs, used to treat the disease, may cause normalization of most abnormal laboratory findings.
• Disorders that may alter lab results: See disorders listed under "Differential Diagnosis."
Imaging
• Upper airways: Chronic otitis and sinusitis, often with evidence of erosion into bony structuresseen on plain radiographs
• CT scans of sinuses may show mucosal and bony involvement.
• Lungs: Radiographs show nodular pulmonary densities, often with central necrosis and cavitation. Local infiltrates or more diffuse interstitial involvement are also described, as are radiographic findings of pulmonary hemorrhage.
Diagnostic Procedures/Surgery
• Open lung biopsy is most likely to confirm granulomatous arteritis.
• Renal biopsy may give findings consistent with diagnosis, although findings are not always definitive.
• Sinus or upper airway mucosal biopsy is often helpful, although findings are often nonspecific.
• Diagnosis is best made by demonstration of granulomatous arteritis of involved organ, although compatible renal lesion in setting of chronic destructive sinusitis and/or pulmonary nodules may make a presumptive diagnosis.
• A positive serologic test for c-ANCA in the proper clinical setting is often diagnostic.
Pathological Findings
• Upper airways: Granulomatous inflammation frequently seen, although not specific unless showing actual vasculitis
• Lung: Granulomatous arteritis involving vessels; classically medium-sized arteries
• Kidney: Necrotizing and crescentic glomerulonephritis without immunofluorescent staining (pauci-immune) is common; granulomatous vasculitis rarely seen
• Skin: Vasculitic lesions, from leukocytoclastic vasculitis of small vessels; granulomatous arteritis seen occasionally
DIFFERENTIAL DIAGNOSIS
• Infectious otitis and sinusitis (bacterial or fungal)
• Midline granuloma or other upper airway malignancy
• Relapsing polychondritis
• Fungal or tuberculous pulmonary infections (Goodpasture syndrome)
• Other vasculitic syndromes (including polyarteritis nodosa, lymphomatoid granulomatosis, Churg-Strauss vasculitis, and overlap vasculitis syndromes)
• Any disease associated with necrotizing and crescentic glomerulonephritis, sarcoidosis
TREATMENT
STABILIZATION
• Patients are usually ill enough with fever, sinus or pulmonary involvement, or renal disease to require hospitalization for diagnostic tests (to rule out infectious causes) and appropriate biopsies.
• An occasional patient can be managed as an outpatient.
GENERAL MEASURES
• Careful attention to upper airway drainage
• Supportive measures for pulmonary, renal, or neurologic involvement
Diet
• Vigorous nutritional support may be needed early in the illness.
• Reduce calories salt in patients on prednisone.
• High fluid intake prevents hemorrhagic cystitis from cyclophosphamide.
Activity
There are no specific restrictions; fatigue, fever, and weight loss usually limit activity.
MEDICATION (DRUGS)
First Line
• Prednisone (1)[C]
- Given initially in high doses (60-100 mg/d)
- After the initial 2-4 weeks, may be tapered to alternate-day regimen then gradually discontinued over 2-6 months in most patients, depending on clinical course
• Cyclophosphamide (2,3)[A]
- In critically ill patient, may be given initially at a dose of 4 mg/kg/d IV for 2-3 days then at 2 mg/kg/d PO
- In stable patient, start at 2 mg/kg/d PO
- Dosage may need to be adjusted based on patient response and toxicity (usually bone marrow suppression)
- Usually continued for 1-2 years after patient is felt to be in remission, then tapered slowly, with careful monitoring for reactivation of disease
- Give dose in morning to decrease amount of drug present overnight in bladder
• Methotrexate 15-25 g/wk PO has been shown in a recent trial to be successful in maintaining remission in patients treated with cyclophosphamide. Methotrexate may be used in place of cyclophosphamide in some patients without pulmonary or renal involvement. (1,3)[B]
• There are no absolute contraindications, although diabetes, hypertension, and metabolic bone disease are relative contraindications to prednisone.
• Precautions
- Carefully monitor a patient taking corticosteroids.
- Consider reducing dose of cyclophosphamide with baseline leukopenia or renal insufficiency.
• Significant possible interactions
- Prednisone may interfere with hypoglycemics and antihypertensives.
- Cyclophosphamide may increase risk of other drugs with potential for bone marrow toxicity.
Second Line
• Azathioprine: For patients with history of severe bone marrow toxicity or hemorrhagic cystitis from cyclophosphamide
• Trimethoprim-sulfamethoxazole (TMP-SMX) has been used alone with success in some patients with limited (usually upper airway) disease, and has some potential as an adjunctive therapy with prednisone and cyclophosphamide.
• Methotrexate: For some patients without renal involvement; may be useful in maintaining remission in patients with stable disease, as an alternative to chronic cyclophosphamide therapy
• Rituximab has been reported to be useful in isolated cases or small series of patients.
• Etanercept does not appear to be of benefit, based on information from a recent clinical trial.
FOLLOW-UP
PROGNOSIS
• Without treatment, almost uniformly fatal, with a 10% 2-year survival; mean survival of 5 months
• With aggressive treatment, survival improved to 75-90% at 5 years.
• Treatment-related toxicity is significant, especially from long-term cyclophosphamide. After 1 year of diseasefree interval, cyclophosphamide is usually changed to methotrexate or tapered, although some patients may demonstrate disease reactivation. (4)[A]
COMPLICATIONS
• Disease related
- Destructive nasal lesions with "saddle nose" deformity
- Deafness from refractory otitis
- Necrotic pulmonary nodules with hemoptysis
- Interstitial lung disease
- Renal failure
- Foot drop from peripheral nerve disease
- Skin ulcers, digital and limb gangrene from peripheral vascular involvement
• Drug related
- Prednisone: Weight gain, hyperglycemia, hypertension, hypokalemia, skin thinning and bruising, infection, osteoporosis
- Cyclophosphamide: Bone marrow suppression (especially leukopenia, neutropenia), alopecia, hemorrhagic cystitis, mucosal membrane irritation, sterility and premature gonadal failure, secondary malignancies (especially leukemias) with long-term therapy. Risk of bladder cancer is 5% (10 years) and 16% (15 years) after first treatment, and is related to previous cystitis.
PATIENT MONITORING
• Early, careful monitoring of upper airway, pulmonary, and renal manifestations
• Blood pressure, glucose, potassium for steroid effects
• Frequent (every 2-4 weeks) complete blood count with differential to monitor for bone marrow toxicity from cyclophosphamide. Leukopenia is most common. Dose needs to be reduced if peripheral white blood cell count 3000/mm3.
• Urinalysis for potential of hemorrhagic cystitis from cyclophosphamide. Consider cystoscopy for persistent or recurrent hematuria.
• Acute phase reactants (ESR, CRP) and serum c-ANCA levels may be useful in monitoring disease activity during follow-up. (5)[A]
REFERENCES
1. Specks U. Methotrexate for Wegener's granulomatosis: What is the evidence? Arthritis Rheum. 2005;52:2237-2242.
2. Goek ON, Stone ON. Randomized controlled trials in vasculitis associated with anti-neutrophil cytoplasmic antibodies. Curr Opin Rheumatol. 2005;17:257-264.
3. DeGroot K, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52:2461-2469.
4. Seo P, et al. Damage caused by Wegeneris granulomatosis and its treatment: Prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 2005;52:2168-2178.
5. Hogan SL, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med. 2005;143:621-631.
MISCELLANEOUS
See also: Polyarteritis Nodosa
BASICS
DESCRIPTION
A disease characterized by granulomatous vasculitis involving multiple organs. The characteristic "triad" of involvement includes the upper airway (otitis, sinusitis, nasal mucosa), lungs, and kidneys. Other organ systems involved include the skin, joints, and nervous system (peripheral or central).
• As the condition progresses untreated, upper airway erosions, necrotic pulmonary nodules, and renal failure are common; without treatment, mortality rate is high.
• System(s) Affected: Upper Airways (sinusitis, otitis); Cardiovascular; Gastrointestinal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
ALERT
Pregnancy Considerations
• Rarely reported
• Should be considered only when patient is disease-free and off therapy
• Cyclophosphamide often causes sterility and is potentially teratogenic.
EPIDEMIOLOGY
• Predominant age: mean age of onset in mid-40s, but has been described in all age groups
• Predominant sex: Male > Female (3:2)
Incidence
Estimated at ~0.4/100,000
Prevalence
Three per 100,000
RISK FACTORS
None identified
Genetics
Increased presence in HLA-B8 and HLA-DR2
ETIOLOGY
The etiology is unknown; the autoimmune phenomena and immune complex deposition in arterial walls are implicated. Triggering infectious agents, yet unidentified, may be involved.
ASSOCIATED CONDITIONS
None
DIAGNOSIS
SIGNS AND SYMPTOMS
• Pulmonary infiltrates: 71%
• Sinusitis: 67%
• Arthralgia/arthritis: 44%
• Fever: 34%
• Cough: 34%
• Otitis: 25%
• Rhinitis: 22%
• Hemoptysis: 18%
• Ocular inflammation: 16%
• Weight loss: 16%
• Skin rash: 13%
• Epistaxis: 11%
• Renal failure: 11%
• Chest pain, anorexia, proptosis, dyspnea, oral ulcers, hearing loss, headache (all 10%)
TESTS
Lab
• Anemia, leukocytosis, and thrombocytosis common during active phases of disease
• Erythrocyte sedimentation rate usually markedly elevated (75%)
• Rheumatoid factor present in low to moderate titer in up to 50%
• Hematuria and/or cellular casts with moderate range proteinuria
• Renal insufficiency, mild to moderate at 1st, frequently progresses to end-stage renal disease.
• Antibodies to neutrophilic cytoplasmic antigens with a cytoplasmic pattern of staining (c-ANCA) are detected in 60-90% of patients. c-ANCA is highly specific (90+%); immunoblotting techniques or enzyme-linked immunoassay may detect antibodies to PR3 or MPO (anti-PR3 antibodies are more specific)
• Perinuclear staining (p-ANCA), is nonspecific and seen with other vasculitic syndromes or isolated necrotizing glomerulonephritis.
• Drugs that may alter lab results: Corticosteroids and cytotoxic drugs, used to treat the disease, may cause normalization of most abnormal laboratory findings.
• Disorders that may alter lab results: See disorders listed under "Differential Diagnosis."
Imaging
• Upper airways: Chronic otitis and sinusitis, often with evidence of erosion into bony structuresseen on plain radiographs
• CT scans of sinuses may show mucosal and bony involvement.
• Lungs: Radiographs show nodular pulmonary densities, often with central necrosis and cavitation. Local infiltrates or more diffuse interstitial involvement are also described, as are radiographic findings of pulmonary hemorrhage.
Diagnostic Procedures/Surgery
• Open lung biopsy is most likely to confirm granulomatous arteritis.
• Renal biopsy may give findings consistent with diagnosis, although findings are not always definitive.
• Sinus or upper airway mucosal biopsy is often helpful, although findings are often nonspecific.
• Diagnosis is best made by demonstration of granulomatous arteritis of involved organ, although compatible renal lesion in setting of chronic destructive sinusitis and/or pulmonary nodules may make a presumptive diagnosis.
• A positive serologic test for c-ANCA in the proper clinical setting is often diagnostic.
Pathological Findings
• Upper airways: Granulomatous inflammation frequently seen, although not specific unless showing actual vasculitis
• Lung: Granulomatous arteritis involving vessels; classically medium-sized arteries
• Kidney: Necrotizing and crescentic glomerulonephritis without immunofluorescent staining (pauci-immune) is common; granulomatous vasculitis rarely seen
• Skin: Vasculitic lesions, from leukocytoclastic vasculitis of small vessels; granulomatous arteritis seen occasionally
DIFFERENTIAL DIAGNOSIS
• Infectious otitis and sinusitis (bacterial or fungal)
• Midline granuloma or other upper airway malignancy
• Relapsing polychondritis
• Fungal or tuberculous pulmonary infections (Goodpasture syndrome)
• Other vasculitic syndromes (including polyarteritis nodosa, lymphomatoid granulomatosis, Churg-Strauss vasculitis, and overlap vasculitis syndromes)
• Any disease associated with necrotizing and crescentic glomerulonephritis, sarcoidosis
TREATMENT
STABILIZATION
• Patients are usually ill enough with fever, sinus or pulmonary involvement, or renal disease to require hospitalization for diagnostic tests (to rule out infectious causes) and appropriate biopsies.
• An occasional patient can be managed as an outpatient.
GENERAL MEASURES
• Careful attention to upper airway drainage
• Supportive measures for pulmonary, renal, or neurologic involvement
Diet
• Vigorous nutritional support may be needed early in the illness.
• Reduce calories salt in patients on prednisone.
• High fluid intake prevents hemorrhagic cystitis from cyclophosphamide.
Activity
There are no specific restrictions; fatigue, fever, and weight loss usually limit activity.
MEDICATION (DRUGS)
First Line
• Prednisone (1)[C]
- Given initially in high doses (60-100 mg/d)
- After the initial 2-4 weeks, may be tapered to alternate-day regimen then gradually discontinued over 2-6 months in most patients, depending on clinical course
• Cyclophosphamide (2,3)[A]
- In critically ill patient, may be given initially at a dose of 4 mg/kg/d IV for 2-3 days then at 2 mg/kg/d PO
- In stable patient, start at 2 mg/kg/d PO
- Dosage may need to be adjusted based on patient response and toxicity (usually bone marrow suppression)
- Usually continued for 1-2 years after patient is felt to be in remission, then tapered slowly, with careful monitoring for reactivation of disease
- Give dose in morning to decrease amount of drug present overnight in bladder
• Methotrexate 15-25 g/wk PO has been shown in a recent trial to be successful in maintaining remission in patients treated with cyclophosphamide. Methotrexate may be used in place of cyclophosphamide in some patients without pulmonary or renal involvement. (1,3)[B]
• There are no absolute contraindications, although diabetes, hypertension, and metabolic bone disease are relative contraindications to prednisone.
• Precautions
- Carefully monitor a patient taking corticosteroids.
- Consider reducing dose of cyclophosphamide with baseline leukopenia or renal insufficiency.
• Significant possible interactions
- Prednisone may interfere with hypoglycemics and antihypertensives.
- Cyclophosphamide may increase risk of other drugs with potential for bone marrow toxicity.
Second Line
• Azathioprine: For patients with history of severe bone marrow toxicity or hemorrhagic cystitis from cyclophosphamide
• Trimethoprim-sulfamethoxazole (TMP-SMX) has been used alone with success in some patients with limited (usually upper airway) disease, and has some potential as an adjunctive therapy with prednisone and cyclophosphamide.
• Methotrexate: For some patients without renal involvement; may be useful in maintaining remission in patients with stable disease, as an alternative to chronic cyclophosphamide therapy
• Rituximab has been reported to be useful in isolated cases or small series of patients.
• Etanercept does not appear to be of benefit, based on information from a recent clinical trial.
FOLLOW-UP
PROGNOSIS
• Without treatment, almost uniformly fatal, with a 10% 2-year survival; mean survival of 5 months
• With aggressive treatment, survival improved to 75-90% at 5 years.
• Treatment-related toxicity is significant, especially from long-term cyclophosphamide. After 1 year of diseasefree interval, cyclophosphamide is usually changed to methotrexate or tapered, although some patients may demonstrate disease reactivation. (4)[A]
COMPLICATIONS
• Disease related
- Destructive nasal lesions with "saddle nose" deformity
- Deafness from refractory otitis
- Necrotic pulmonary nodules with hemoptysis
- Interstitial lung disease
- Renal failure
- Foot drop from peripheral nerve disease
- Skin ulcers, digital and limb gangrene from peripheral vascular involvement
• Drug related
- Prednisone: Weight gain, hyperglycemia, hypertension, hypokalemia, skin thinning and bruising, infection, osteoporosis
- Cyclophosphamide: Bone marrow suppression (especially leukopenia, neutropenia), alopecia, hemorrhagic cystitis, mucosal membrane irritation, sterility and premature gonadal failure, secondary malignancies (especially leukemias) with long-term therapy. Risk of bladder cancer is 5% (10 years) and 16% (15 years) after first treatment, and is related to previous cystitis.
PATIENT MONITORING
• Early, careful monitoring of upper airway, pulmonary, and renal manifestations
• Blood pressure, glucose, potassium for steroid effects
• Frequent (every 2-4 weeks) complete blood count with differential to monitor for bone marrow toxicity from cyclophosphamide. Leukopenia is most common. Dose needs to be reduced if peripheral white blood cell count 3000/mm3.
• Urinalysis for potential of hemorrhagic cystitis from cyclophosphamide. Consider cystoscopy for persistent or recurrent hematuria.
• Acute phase reactants (ESR, CRP) and serum c-ANCA levels may be useful in monitoring disease activity during follow-up. (5)[A]
REFERENCES
1. Specks U. Methotrexate for Wegener's granulomatosis: What is the evidence? Arthritis Rheum. 2005;52:2237-2242.
2. Goek ON, Stone ON. Randomized controlled trials in vasculitis associated with anti-neutrophil cytoplasmic antibodies. Curr Opin Rheumatol. 2005;17:257-264.
3. DeGroot K, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52:2461-2469.
4. Seo P, et al. Damage caused by Wegeneris granulomatosis and its treatment: Prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 2005;52:2168-2178.
5. Hogan SL, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med. 2005;143:621-631.
MISCELLANEOUS
See also: Polyarteritis Nodosa
WARTS
WARTS - Herbert P.Goodheart, MD
BASICS
DESCRIPTION
Warts (verrucae) are benign growths that are confined to the epidermis. All warts are caused by the human papillomavirus (HPV).
• Warts often vary widely in shape, size, and appearance, and the different names for them generally reflect their clinical appearance, location, or both.
• For example, filiform warts are threadlike, planar warts are flat, and plantar warts are located on the soles of the feet.
• Genital warts, or condyloma acuminatum, may be large and cauliflowerlike, or they may consist of small papules.
• 5 types of warts are caused by specific genotypes of HPV
- Common wart (verruca vulgaris)
- Plantar wart (verruca plantaris)
- Flat wart (verruca plana)
- Venereal wart (condyloma acuminatum); see separate topic in this volume
• Epidermodysplasia verruciformis is a very rare, lifelong, hereditary disorder characterized by chronic infection with HPV.
• System(s) Affected: Skin/Exocrine
EPIDEMIOLOGY
• Predominant age: Young adults and children
• Predominant sex: Female = Male
Incidence
An estimated 20% of school-age children will at some time have at least one wart.
Prevalence
• ~7-10% of the US population
• Common warts appear ~2 times as frequently in whites as in African Americans or Asians.
RISK FACTORS
• AIDS and other immunosuppressive diseases (e.g., lymphomas)
• Immunosuppressive drugs that decrease cell-mediated immunity (e.g., prednisone, cyclosporine, and chemotherapeutic agents)
• Pregnancy
• Handling raw meat, fish, or other types of animal matter in one's occupation, e.g., butchers
ETIOLOGY
• Various strains of a DNA HPV virus: To date, >150 different subtypes have been identified.
• Common warts: HPV types 2 and 4 (most common), followed by types 1, 3, 27, 29, and 57
• Palmoplantar warts: HPV type 1 (most common), followed by types 2, 3, 4, 27, 29, and 57
• Flat warts: HPV types 3, 10, and 28
• Butcher warts: HPV type 7
• The virus is passed primarily through skin-to-skin contact or from the recently shed virus kept intact in a moist, warm environment.
• HPV infects epidermal keratinocytes, which stimulates cell proliferation.
DIAGNOSIS
• Most often made on clinical appearance
• Skin biopsy, if necessary
SIGNS AND SYMPTOMS
Common wart: Rough-surfaced, hyperkeratotic, papillomatous, raised, skin-colored to tan papules 5-10 mm in diameter; may coalesce into a mosaic 1-3 cm in diameter
• Most frequently seen on hands, knees, and elbows
• Usually asymptomatic, but may cause cosmetic disfigurement or tenderness
Variant
• Filiform warts: These are long, slender, delicate, fingerlike growths, usually seen on the face around the lips, eyelids, or nares.
• Plantar warts appear on the plantar surface of the feet in children and young adults.
- Can be tender and painful, and extensive involvement on the sole of the foot may impair ambulation, particularly when present on a weight-bearing surface
- Most often seen on the metatarsal area, heels, and toes in an asymmetric distribution
- Frequently attain 2-3 cm in diameter
- Pathognomonic "black dots" (thrombosed dermal capillaries). Punctate bleeding becomes more evident after paring with a #15 blade.
- Both common and plantar warts generally demonstrate the following clinical findings:
- A loss of normal skin markings (dermatoglyphics) such as finger, foot, and hand prints
- Lesions may be solitary or multiple, or they may appear in clusters (mosaic warts)
• Flat wart: Slightly elevated, flat-topped, skin-colored or tan papules, small (1-3 mm) in diameter
- Commonly found on the face, arms, dorsa of hands, shins (women)
- Sometimes exhibit a linear configuration caused by autoinoculation
- In men, shaving spreads flat warts
- In women, they often occur on the shins, where leg shaving spreads lesions.
• Epidermodysplasia verruciformis: Widespread flat, reddish-brown pigmented papules and plaques that present in childhood with lifelong persistence on the trunk, the hands, the upper and lower extremities, and the face, are characteristic.
- Lesions may transform into carcinomas, usually after age 30 years. Skin cancers initially appear on sun-exposed areas.
Physical Exam
Warts may develop anywhere on the body, but they are most often found at sites subject to frequent trauma, such as the hands and feet.
• Distribution is generally asymmetric, and lesions are often clustered.
TESTS
Lab
• HPV cannot be cultured.
• Definitive diagnosis can be achieved by
- Electron microscopy
- Viral DNA identification using Southern blot hybridization used to identify the specific HPV type present in tissue
- Polymerase chain reaction may be used to amplify viral DNA for testing.
Pathological Findings
• Histopathologic features of common warts include digitated epidermal hyperplasia, acanthosis, papillomatosis, compact orthokeratosis, hypergranulosis, dilated tortuous capillaries within the dermal papillae, and vertical tiers of parakeratotic cells with entrapped red blood cells above the tips of the digitations.
• In the granular layer, HPV-infected cells may have coarse keratohyaline granules and vacuoles surrounding wrinkled-appearing nuclei. These koilocytic (vacuolated) cells are pathognomonic for warts.
DIFFERENTIAL DIAGNOSIS
Pediatric
Molluscum contagiosum
Adults/Elderly
• Seborrheic keratosis
• Acrochordon (skin tag)
• Solar keratosis and cutaneous horn
• Squamous cell carcinoma
• Keratoacanthoma
• Subungual squamous cell carcinoma can easily be misdiagnosed as a subungual wart or onychomycosis.
• Plantar warts
• Corns (clavi) are sometimes difficult to distinguish from warts. Like calluses, corns are thickened areas of the skin and most commonly develop at sites subjected to repeated friction and pressure, such as the tops and the tips of toes and along the sides of the feet.
- They are usually hard and circular-shaped, with a polished or central translucent core, like the kernel of corn from which they take their name.
- Corns do not have "black dots,"and skin markings are retained except for the area of the central core.
ALERT
• Melanoma can mimic a plantar wart.
• Verrucous carcinoma, a slow growing, locally invasive, well-differentiated squamous cell carcinoma, may also be easily mistaken for a common or plantar wart.
TREATMENT
GENERAL MEASURES
• The clinical management of verrucae vulgaris is often challenging, and there is no ideal treatment.
• In children, most warts tend to regress spontaneously, which is probably related to a host immune response.
• In many adults and immunocompromised patients, however, warts often prove difficult to eradicate.
• Painful, aggressive therapy should be avoided unless there is a pressing need to eliminate the wart(s).
• For surgical procedures, especially in anxious children, pretreatment with anesthetic cream such as EMLA (emulsion of lidocaine and prilocaine):
- Benign neglect: Providing no treatment at all is certainly safe and cost effective as most may regress spontaneously within 2 years.
- If warts are extensive, spreading, or symptomatic, the method of treatment will depend upon the age of the patient, the patient's pain threshold, the type of wart, and its location.
- A cure is achieved when the skin lines are restored to a normal pattern and there is no recurrence.
Complementary and Alternative Medicine
• Occlusion: Easiest and least expensive. Cover wart with waterproof tape (e.g., duct tape) and leave on for 6 days, then soak, pare with emery board, leave uncovered overnight, then reapply tape cyclically for 8 cycles
• Hyperthermia: Safe and inexpensive approach; immerse affected area into 45C water bath for 30 minutes 3 times per week
ALERT
Pregnancy Considerations
• The use of many of the following topical chemical approaches may be contraindicated during pregnancy or in women who are likely to become pregnant during the treatment period.
• Refer to the manufacturer's profile of each drug.
MEDICATION (DRUGS)
First Line
The abundance of treatment modalities described below is a reflection of the fact that none of them is uniformly effective.
• Keratolytic (peeling) agents, primarily containing salicylic or salicylic acid plus lactic acid, are available in numerous OTC preparations that are self-administered. Best treatment for small children in whom warts are usually self-limiting. For best results and increased penetration with any of following keratolytic agents, the affected area should be hydrated 1st by soaking it in warm water for 5 minutes before application.
• Duofilm
• Occlusal-HP
• Trans-Ver-Sal
- Office-based and prescription treatment
• Combination cantharidin; 30% salicylic acid, 2% podophyllin, and 19% cantharidin in flexible collodion: Applied in a thin coat, occluded 4-6 hours, then washed off
• Aldara (imiquimod) 5% cream, a local inducer of interferon, is applied at home by the patient. It is approved for external genital and perianal warts and is used "off-label" and applied under duct tape occlusion applied at bedtime and washed off after 6-10 hours.
• Aldara is applied to flat warts without occlusion.
Second Line
Immunotherapy: Induction of delayed-type hypersensitivity with
• Diphencyprone
• Dinitrochlorobenzene (DNCB)
• Squaric acid dibutylester (SADBE)
• Possible mutagenicity and side effects with these agents
• Bleomycin: Intradermal injection is expensive and causes severe pain.
- Alpha-2 interferon
- Intralesional mumps or candida antigen
- Oral high dose cimetidine: Possibly works better in children
- Topical retinoids for facial flat warts
- Acitretin (an oral retinoid)
- Others: Dichloroacetic acid, trichloroacetic acid, podophyllin, formic acid, 5-fluorouracil, silver nitrate, formaldehyde, levamisole, topical or IV cidofovir for recalcitrant warts in the setting of HIV, glutaraldehyde, have all been used with varying results
SURGERY
• Duct tape: Cover wart with waterproof tape (e.g., duct tape) and leave on for 6 days, then soak, pare with emery board, leave uncovered overnight, then reapply tape cyclically for 8 cycles; 85% resolved compared to 60% efficacy with cryotherapy
• Cryotherapy with liquid nitrogen (LN2) may be applied with a cotton swab or with a cryotherapy gun (Cryogun).
- Best for warts on hands.
- Fast; can treat many lesions per visit
- Painful; not tolerated well by young children
- Freezing periungual warts may result in nail deformation.
- In darkly pigmented skin, treatment can result in hypo- or hyperpigmentation.
• Light electrocautery with or without curettage:
- Best for warts on the knees, elbows, and dorsa of hands
- Also good for filiform warts
- Tolerable in most adults
- Requires local anesthesia
- May cause scarring
• Photodynamic therapy
• CO2 or pulse-dye laser ablation: Expensive and requires local anesthesia
• Filifarm warts
- An almost painless method is to dip a hemostat into LN2 for 10 seconds and then gently grasp the wart for ~5-10 seconds. The frozen wart is generally shed in 7-10 days.
FOLLOW-UP
COMPLICATIONS
• Autoinoculation ("pseudo Koebner") reaction
• Scar formation
• Chronic pain after plantar wart removal or scar formation
• Nail deformity after injury to nail matrix
PATIENT MONITORING
One third of the warts of epidermodysplasia may become malignant.
REFERENCES
1. Micali G et al. Use of squaric acid dibutylester (SADBE) for cutaneous warts in children. Pediatr Dermatol. 2000;17:315-318.
2. Rogers J, et al. Cimetidine therapy for recalcitrant warts in adults: Is it any better than placebo? J Am Acad Dermatol. 1999;41:123-127.
3. Robson KJ, et al. Pulsed-dye laser versus conventional therapy in the treatment of warts: A prospective randomized trial. J Am Acad Dermatol. 2000;43(2 pt 1):275-280.
4. Silverberg NB, Lim JK, Paller AS, Mancini AJ. Squaric acid immunotherapy for warts in children. J Am Acad Dermatol. 2000;42(5 pt 1):803-808.
5. Stender IM et. al. Photodynamic therapy with 5-aminolevulinic acid or placebo for recalcitrant foot and hand warts: Randomized double-blind trial. Lancet. 2000;355:963-966.
BASICS
DESCRIPTION
Warts (verrucae) are benign growths that are confined to the epidermis. All warts are caused by the human papillomavirus (HPV).
• Warts often vary widely in shape, size, and appearance, and the different names for them generally reflect their clinical appearance, location, or both.
• For example, filiform warts are threadlike, planar warts are flat, and plantar warts are located on the soles of the feet.
• Genital warts, or condyloma acuminatum, may be large and cauliflowerlike, or they may consist of small papules.
• 5 types of warts are caused by specific genotypes of HPV
- Common wart (verruca vulgaris)
- Plantar wart (verruca plantaris)
- Flat wart (verruca plana)
- Venereal wart (condyloma acuminatum); see separate topic in this volume
• Epidermodysplasia verruciformis is a very rare, lifelong, hereditary disorder characterized by chronic infection with HPV.
• System(s) Affected: Skin/Exocrine
EPIDEMIOLOGY
• Predominant age: Young adults and children
• Predominant sex: Female = Male
Incidence
An estimated 20% of school-age children will at some time have at least one wart.
Prevalence
• ~7-10% of the US population
• Common warts appear ~2 times as frequently in whites as in African Americans or Asians.
RISK FACTORS
• AIDS and other immunosuppressive diseases (e.g., lymphomas)
• Immunosuppressive drugs that decrease cell-mediated immunity (e.g., prednisone, cyclosporine, and chemotherapeutic agents)
• Pregnancy
• Handling raw meat, fish, or other types of animal matter in one's occupation, e.g., butchers
ETIOLOGY
• Various strains of a DNA HPV virus: To date, >150 different subtypes have been identified.
• Common warts: HPV types 2 and 4 (most common), followed by types 1, 3, 27, 29, and 57
• Palmoplantar warts: HPV type 1 (most common), followed by types 2, 3, 4, 27, 29, and 57
• Flat warts: HPV types 3, 10, and 28
• Butcher warts: HPV type 7
• The virus is passed primarily through skin-to-skin contact or from the recently shed virus kept intact in a moist, warm environment.
• HPV infects epidermal keratinocytes, which stimulates cell proliferation.
DIAGNOSIS
• Most often made on clinical appearance
• Skin biopsy, if necessary
SIGNS AND SYMPTOMS
Common wart: Rough-surfaced, hyperkeratotic, papillomatous, raised, skin-colored to tan papules 5-10 mm in diameter; may coalesce into a mosaic 1-3 cm in diameter
• Most frequently seen on hands, knees, and elbows
• Usually asymptomatic, but may cause cosmetic disfigurement or tenderness
Variant
• Filiform warts: These are long, slender, delicate, fingerlike growths, usually seen on the face around the lips, eyelids, or nares.
• Plantar warts appear on the plantar surface of the feet in children and young adults.
- Can be tender and painful, and extensive involvement on the sole of the foot may impair ambulation, particularly when present on a weight-bearing surface
- Most often seen on the metatarsal area, heels, and toes in an asymmetric distribution
- Frequently attain 2-3 cm in diameter
- Pathognomonic "black dots" (thrombosed dermal capillaries). Punctate bleeding becomes more evident after paring with a #15 blade.
- Both common and plantar warts generally demonstrate the following clinical findings:
- A loss of normal skin markings (dermatoglyphics) such as finger, foot, and hand prints
- Lesions may be solitary or multiple, or they may appear in clusters (mosaic warts)
• Flat wart: Slightly elevated, flat-topped, skin-colored or tan papules, small (1-3 mm) in diameter
- Commonly found on the face, arms, dorsa of hands, shins (women)
- Sometimes exhibit a linear configuration caused by autoinoculation
- In men, shaving spreads flat warts
- In women, they often occur on the shins, where leg shaving spreads lesions.
• Epidermodysplasia verruciformis: Widespread flat, reddish-brown pigmented papules and plaques that present in childhood with lifelong persistence on the trunk, the hands, the upper and lower extremities, and the face, are characteristic.
- Lesions may transform into carcinomas, usually after age 30 years. Skin cancers initially appear on sun-exposed areas.
Physical Exam
Warts may develop anywhere on the body, but they are most often found at sites subject to frequent trauma, such as the hands and feet.
• Distribution is generally asymmetric, and lesions are often clustered.
TESTS
Lab
• HPV cannot be cultured.
• Definitive diagnosis can be achieved by
- Electron microscopy
- Viral DNA identification using Southern blot hybridization used to identify the specific HPV type present in tissue
- Polymerase chain reaction may be used to amplify viral DNA for testing.
Pathological Findings
• Histopathologic features of common warts include digitated epidermal hyperplasia, acanthosis, papillomatosis, compact orthokeratosis, hypergranulosis, dilated tortuous capillaries within the dermal papillae, and vertical tiers of parakeratotic cells with entrapped red blood cells above the tips of the digitations.
• In the granular layer, HPV-infected cells may have coarse keratohyaline granules and vacuoles surrounding wrinkled-appearing nuclei. These koilocytic (vacuolated) cells are pathognomonic for warts.
DIFFERENTIAL DIAGNOSIS
Pediatric
Molluscum contagiosum
Adults/Elderly
• Seborrheic keratosis
• Acrochordon (skin tag)
• Solar keratosis and cutaneous horn
• Squamous cell carcinoma
• Keratoacanthoma
• Subungual squamous cell carcinoma can easily be misdiagnosed as a subungual wart or onychomycosis.
• Plantar warts
• Corns (clavi) are sometimes difficult to distinguish from warts. Like calluses, corns are thickened areas of the skin and most commonly develop at sites subjected to repeated friction and pressure, such as the tops and the tips of toes and along the sides of the feet.
- They are usually hard and circular-shaped, with a polished or central translucent core, like the kernel of corn from which they take their name.
- Corns do not have "black dots,"and skin markings are retained except for the area of the central core.
ALERT
• Melanoma can mimic a plantar wart.
• Verrucous carcinoma, a slow growing, locally invasive, well-differentiated squamous cell carcinoma, may also be easily mistaken for a common or plantar wart.
TREATMENT
GENERAL MEASURES
• The clinical management of verrucae vulgaris is often challenging, and there is no ideal treatment.
• In children, most warts tend to regress spontaneously, which is probably related to a host immune response.
• In many adults and immunocompromised patients, however, warts often prove difficult to eradicate.
• Painful, aggressive therapy should be avoided unless there is a pressing need to eliminate the wart(s).
• For surgical procedures, especially in anxious children, pretreatment with anesthetic cream such as EMLA (emulsion of lidocaine and prilocaine):
- Benign neglect: Providing no treatment at all is certainly safe and cost effective as most may regress spontaneously within 2 years.
- If warts are extensive, spreading, or symptomatic, the method of treatment will depend upon the age of the patient, the patient's pain threshold, the type of wart, and its location.
- A cure is achieved when the skin lines are restored to a normal pattern and there is no recurrence.
Complementary and Alternative Medicine
• Occlusion: Easiest and least expensive. Cover wart with waterproof tape (e.g., duct tape) and leave on for 6 days, then soak, pare with emery board, leave uncovered overnight, then reapply tape cyclically for 8 cycles
• Hyperthermia: Safe and inexpensive approach; immerse affected area into 45C water bath for 30 minutes 3 times per week
ALERT
Pregnancy Considerations
• The use of many of the following topical chemical approaches may be contraindicated during pregnancy or in women who are likely to become pregnant during the treatment period.
• Refer to the manufacturer's profile of each drug.
MEDICATION (DRUGS)
First Line
The abundance of treatment modalities described below is a reflection of the fact that none of them is uniformly effective.
• Keratolytic (peeling) agents, primarily containing salicylic or salicylic acid plus lactic acid, are available in numerous OTC preparations that are self-administered. Best treatment for small children in whom warts are usually self-limiting. For best results and increased penetration with any of following keratolytic agents, the affected area should be hydrated 1st by soaking it in warm water for 5 minutes before application.
• Duofilm
• Occlusal-HP
• Trans-Ver-Sal
- Office-based and prescription treatment
• Combination cantharidin; 30% salicylic acid, 2% podophyllin, and 19% cantharidin in flexible collodion: Applied in a thin coat, occluded 4-6 hours, then washed off
• Aldara (imiquimod) 5% cream, a local inducer of interferon, is applied at home by the patient. It is approved for external genital and perianal warts and is used "off-label" and applied under duct tape occlusion applied at bedtime and washed off after 6-10 hours.
• Aldara is applied to flat warts without occlusion.
Second Line
Immunotherapy: Induction of delayed-type hypersensitivity with
• Diphencyprone
• Dinitrochlorobenzene (DNCB)
• Squaric acid dibutylester (SADBE)
• Possible mutagenicity and side effects with these agents
• Bleomycin: Intradermal injection is expensive and causes severe pain.
- Alpha-2 interferon
- Intralesional mumps or candida antigen
- Oral high dose cimetidine: Possibly works better in children
- Topical retinoids for facial flat warts
- Acitretin (an oral retinoid)
- Others: Dichloroacetic acid, trichloroacetic acid, podophyllin, formic acid, 5-fluorouracil, silver nitrate, formaldehyde, levamisole, topical or IV cidofovir for recalcitrant warts in the setting of HIV, glutaraldehyde, have all been used with varying results
SURGERY
• Duct tape: Cover wart with waterproof tape (e.g., duct tape) and leave on for 6 days, then soak, pare with emery board, leave uncovered overnight, then reapply tape cyclically for 8 cycles; 85% resolved compared to 60% efficacy with cryotherapy
• Cryotherapy with liquid nitrogen (LN2) may be applied with a cotton swab or with a cryotherapy gun (Cryogun).
- Best for warts on hands.
- Fast; can treat many lesions per visit
- Painful; not tolerated well by young children
- Freezing periungual warts may result in nail deformation.
- In darkly pigmented skin, treatment can result in hypo- or hyperpigmentation.
• Light electrocautery with or without curettage:
- Best for warts on the knees, elbows, and dorsa of hands
- Also good for filiform warts
- Tolerable in most adults
- Requires local anesthesia
- May cause scarring
• Photodynamic therapy
• CO2 or pulse-dye laser ablation: Expensive and requires local anesthesia
• Filifarm warts
- An almost painless method is to dip a hemostat into LN2 for 10 seconds and then gently grasp the wart for ~5-10 seconds. The frozen wart is generally shed in 7-10 days.
FOLLOW-UP
COMPLICATIONS
• Autoinoculation ("pseudo Koebner") reaction
• Scar formation
• Chronic pain after plantar wart removal or scar formation
• Nail deformity after injury to nail matrix
PATIENT MONITORING
One third of the warts of epidermodysplasia may become malignant.
REFERENCES
1. Micali G et al. Use of squaric acid dibutylester (SADBE) for cutaneous warts in children. Pediatr Dermatol. 2000;17:315-318.
2. Rogers J, et al. Cimetidine therapy for recalcitrant warts in adults: Is it any better than placebo? J Am Acad Dermatol. 1999;41:123-127.
3. Robson KJ, et al. Pulsed-dye laser versus conventional therapy in the treatment of warts: A prospective randomized trial. J Am Acad Dermatol. 2000;43(2 pt 1):275-280.
4. Silverberg NB, Lim JK, Paller AS, Mancini AJ. Squaric acid immunotherapy for warts in children. J Am Acad Dermatol. 2000;42(5 pt 1):803-808.
5. Stender IM et. al. Photodynamic therapy with 5-aminolevulinic acid or placebo for recalcitrant foot and hand warts: Randomized double-blind trial. Lancet. 2000;355:963-966.
WARTS, PLANTAR
WARTS, PLANTAR - Gary J.Silko, MD, MS
BASICS
DESCRIPTION
• Discrete or grouped firm keratotic masses on the sole of the foot initiated by a viral infection of keratinocytes
• System(s) Affected: Skin/Exocrine
• Synonym(s): Verruca plantaris
ALERT
Pediatric Considerations
Duration of warts is generally shorter in children than in adults.
Pregnancy Considerations
Avoid bleomycin treatments.
GENERAL PREVENTION
Use rubber footwear in communal shower areas.
EPIDEMIOLOGY
• Predominant age: Any age, although more common in children and young adults
• Predominant sex: Female > Male (slightly)
Incidence
In the US: Widespread; 2,000/100,000
RISK FACTORS
• AIDS
• Atopic dermatitis
• Lymphomas
• Patient taking immunosuppressive drugs
Genetics
Unknown
ETIOLOGY
Human papillomavirus type 1; less commonly types 2, 4, 27, and 57
DIAGNOSIS
TESTS
• Foot pain
• Discrete or grouped masses on sole of foot with disruption of normal skin markings
• Generally occur at pressure points
• Rough, hyperkeratotic surface with brown-black dots (thrombosed capillaries)
• Callus formation
• Leg or back pain (distortion of posture)
Diagnostic Procedures/Surgery
• Inspection usually confirms the diagnosis.
• If cannot distinguish between callus and wart, can examine with a magnifying lens. The wart should demonstrate a highly organized mosaic pattern.
• When pared down, have a soft central core and bleeding points (unlike calluses)
Pathological Findings
Acanthotic epidermis with hyperkeratosis, papillomatosis, and parakeratosis
DIFFERENTIAL DIAGNOSIS
• Corns (clavi)
• Calluses
• Black heel (ruptured capillaries)
TREATMENT
STABILIZATION
• Outpatient cryotherapy at weekly intervals
• Repeated parings at weekly intervals with or without use of a keratolytic is also an option. Most successful appears to be curettage and chemical cautery (with phenol or trichloroacetic acid) or light electrocautery. (Note: Extreme care must be exercised with this procedure, because excessive cautery or curettage can cause a painful scar.)
GENERAL MEASURES
• If warts are asymptomatic, no treatment is necessary. However, patient may be at risk for spread of warts.
• Warm soaks followed by patient's paring of the top layer of skin on repeated occasions may speed disappearance.
• Patient may use pumice stone, emery board. or a blade.
• OTC keratolytics containing salicylic acid in liquid or film may help. The advised procedure is paring of skin followed by warm soaks, and finally application of a few drops of keratolytic daily.
• Hyperthermia: Hot water immersion (113F) 1/2-3/4 hour 2-3 times per week for 16 treatments is effective for some patients.
• Duct tape: Cut a piece to the size of the wart and apply continuously for 6 days, remove and repeat for up to 2 months. (5)[B]
• Other measures include use of a heel bar or appropriate padding to relieve pressure points where warts tend to aggregate. (1)[C]
Diet
No special diet
Activity
Ambulatory unless warts or treatment are painful
MEDICATION (DRUGS)
First Line
• No effective antiviral wart medications currently exist. Keratolytics (OTC or prescription) and a variety of chemotherapeutic acids may be used.
• Salicylic acid: See "General Measures" for instructions.
• 40% salicylic acid plasters: available as Mediplast. It is supplied in 3 4 in sheets which are cut to the size of the wart, and the sticky surface is applied to the wart. They are removed every 1-2 days, the white keratin peeled, and a fresh plaster applied.
• Chemotherapy dichloroacetic acid and trichloroacetic acid kits are available. Callus is pared and the surrounding skin is protected by a ring of petrolatum. The wart(s) are coated with acid, which is then worked into the wart with a sharp toothpick. Procedure should be repeated at weekly intervals.
• Transdermal salicylates (Trans-Plantar)
• Vesicants containing cantharidin (Cantharone, Verrusol), applied in the office, allowed to dry, and are then covered with occlusive tape for 24 hours.
• Contraindications: Infection, vascular insufficiency
• Precautions
- If the dermis is damaged with any of the above procedures, a scar may result which can be permanently painful.
- Care should be taken to avoid excessive contact with normal skin when using keratolytics or chemotherapy.
- Avoid bleomycin treatment during pregnancy.
- Imiquimod has not been studied in patients 18 years. (1)[C]
Second Line
• Bleomycin injected intralesionally every 2 weeks
• Imiquimod (Aldara) 5% cream applied daily after soaking. It appears to be more effective when occluded and when in combination with other treatments such as cryotherapy or keratolytics.
• Alternative procedures include laser therapies (various).
SURGERY
• Cryotherapy: Application of liquid nitrogen is often effective. It usually requires at least four applications at weekly or biweekly intervals. Aggressive cryotherapy may cause blistering or even scarring, so light applications with 2 freeze-thaw cycles is preferred.
• Blunt dissection: A simple surgical procedure is effective and usually nonscarring. It requires inserting a blunt dissector between the wart and normal skin and separating the wart using short, firm stroke.
• Carbon dioxide laser surgery: used for recalcitrant warts (1)[C]
FOLLOW-UP
PROGNOSIS
The course of plantar warts is like that of other varieties of warts (i.e., highly variable). Most resolve spontaneously in weeks to months.
COMPLICATIONS
• Scarring with overly aggressive treatment
• A rare type of verrucous carcinoma, epithelioma cuniculatum, is thought to arise from these warts.
PATIENT MONITORING
With any treatment modality, follow-up weekly.
REFERENCES
1. Habif TP. Clinical Dermatology. 4th ed. New York, NY: Mosby; 2004: 374-377.
2. Epstein E. Common Skin Disorders. 5th ed. Philadelphia, PA: WB Saunders; 2001.
3. Freedberg IM et al. Fitzpatrick's Dermatology in General Medicine, 6th ed. New York, NY: McGraw-Hill; 2003;2120-2123, 2129.
4. James WD, Berger TG, Elston DM. Andrews' Diseases of the Skin, 10th ed. Philadephia, PA: WB Saunders; 2006;405-407.
5. Focht DR, Spicer C, Fairchok MP. The efficacy of duct tape vs cryotherapy in the treatment of verruca vulgaris. Arch Pedatr Adolesc Med. 2002;156:971-974.
MISCELLANEOUS
See also: Condyloma Acuminata; Warts
BASICS
DESCRIPTION
• Discrete or grouped firm keratotic masses on the sole of the foot initiated by a viral infection of keratinocytes
• System(s) Affected: Skin/Exocrine
• Synonym(s): Verruca plantaris
ALERT
Pediatric Considerations
Duration of warts is generally shorter in children than in adults.
Pregnancy Considerations
Avoid bleomycin treatments.
GENERAL PREVENTION
Use rubber footwear in communal shower areas.
EPIDEMIOLOGY
• Predominant age: Any age, although more common in children and young adults
• Predominant sex: Female > Male (slightly)
Incidence
In the US: Widespread; 2,000/100,000
RISK FACTORS
• AIDS
• Atopic dermatitis
• Lymphomas
• Patient taking immunosuppressive drugs
Genetics
Unknown
ETIOLOGY
Human papillomavirus type 1; less commonly types 2, 4, 27, and 57
DIAGNOSIS
TESTS
• Foot pain
• Discrete or grouped masses on sole of foot with disruption of normal skin markings
• Generally occur at pressure points
• Rough, hyperkeratotic surface with brown-black dots (thrombosed capillaries)
• Callus formation
• Leg or back pain (distortion of posture)
Diagnostic Procedures/Surgery
• Inspection usually confirms the diagnosis.
• If cannot distinguish between callus and wart, can examine with a magnifying lens. The wart should demonstrate a highly organized mosaic pattern.
• When pared down, have a soft central core and bleeding points (unlike calluses)
Pathological Findings
Acanthotic epidermis with hyperkeratosis, papillomatosis, and parakeratosis
DIFFERENTIAL DIAGNOSIS
• Corns (clavi)
• Calluses
• Black heel (ruptured capillaries)
TREATMENT
STABILIZATION
• Outpatient cryotherapy at weekly intervals
• Repeated parings at weekly intervals with or without use of a keratolytic is also an option. Most successful appears to be curettage and chemical cautery (with phenol or trichloroacetic acid) or light electrocautery. (Note: Extreme care must be exercised with this procedure, because excessive cautery or curettage can cause a painful scar.)
GENERAL MEASURES
• If warts are asymptomatic, no treatment is necessary. However, patient may be at risk for spread of warts.
• Warm soaks followed by patient's paring of the top layer of skin on repeated occasions may speed disappearance.
• Patient may use pumice stone, emery board. or a blade.
• OTC keratolytics containing salicylic acid in liquid or film may help. The advised procedure is paring of skin followed by warm soaks, and finally application of a few drops of keratolytic daily.
• Hyperthermia: Hot water immersion (113F) 1/2-3/4 hour 2-3 times per week for 16 treatments is effective for some patients.
• Duct tape: Cut a piece to the size of the wart and apply continuously for 6 days, remove and repeat for up to 2 months. (5)[B]
• Other measures include use of a heel bar or appropriate padding to relieve pressure points where warts tend to aggregate. (1)[C]
Diet
No special diet
Activity
Ambulatory unless warts or treatment are painful
MEDICATION (DRUGS)
First Line
• No effective antiviral wart medications currently exist. Keratolytics (OTC or prescription) and a variety of chemotherapeutic acids may be used.
• Salicylic acid: See "General Measures" for instructions.
• 40% salicylic acid plasters: available as Mediplast. It is supplied in 3 4 in sheets which are cut to the size of the wart, and the sticky surface is applied to the wart. They are removed every 1-2 days, the white keratin peeled, and a fresh plaster applied.
• Chemotherapy dichloroacetic acid and trichloroacetic acid kits are available. Callus is pared and the surrounding skin is protected by a ring of petrolatum. The wart(s) are coated with acid, which is then worked into the wart with a sharp toothpick. Procedure should be repeated at weekly intervals.
• Transdermal salicylates (Trans-Plantar)
• Vesicants containing cantharidin (Cantharone, Verrusol), applied in the office, allowed to dry, and are then covered with occlusive tape for 24 hours.
• Contraindications: Infection, vascular insufficiency
• Precautions
- If the dermis is damaged with any of the above procedures, a scar may result which can be permanently painful.
- Care should be taken to avoid excessive contact with normal skin when using keratolytics or chemotherapy.
- Avoid bleomycin treatment during pregnancy.
- Imiquimod has not been studied in patients 18 years. (1)[C]
Second Line
• Bleomycin injected intralesionally every 2 weeks
• Imiquimod (Aldara) 5% cream applied daily after soaking. It appears to be more effective when occluded and when in combination with other treatments such as cryotherapy or keratolytics.
• Alternative procedures include laser therapies (various).
SURGERY
• Cryotherapy: Application of liquid nitrogen is often effective. It usually requires at least four applications at weekly or biweekly intervals. Aggressive cryotherapy may cause blistering or even scarring, so light applications with 2 freeze-thaw cycles is preferred.
• Blunt dissection: A simple surgical procedure is effective and usually nonscarring. It requires inserting a blunt dissector between the wart and normal skin and separating the wart using short, firm stroke.
• Carbon dioxide laser surgery: used for recalcitrant warts (1)[C]
FOLLOW-UP
PROGNOSIS
The course of plantar warts is like that of other varieties of warts (i.e., highly variable). Most resolve spontaneously in weeks to months.
COMPLICATIONS
• Scarring with overly aggressive treatment
• A rare type of verrucous carcinoma, epithelioma cuniculatum, is thought to arise from these warts.
PATIENT MONITORING
With any treatment modality, follow-up weekly.
REFERENCES
1. Habif TP. Clinical Dermatology. 4th ed. New York, NY: Mosby; 2004: 374-377.
2. Epstein E. Common Skin Disorders. 5th ed. Philadelphia, PA: WB Saunders; 2001.
3. Freedberg IM et al. Fitzpatrick's Dermatology in General Medicine, 6th ed. New York, NY: McGraw-Hill; 2003;2120-2123, 2129.
4. James WD, Berger TG, Elston DM. Andrews' Diseases of the Skin, 10th ed. Philadephia, PA: WB Saunders; 2006;405-407.
5. Focht DR, Spicer C, Fairchok MP. The efficacy of duct tape vs cryotherapy in the treatment of verruca vulgaris. Arch Pedatr Adolesc Med. 2002;156:971-974.
MISCELLANEOUS
See also: Condyloma Acuminata; Warts
VULVOVAGINITIS, ESTROGEN DEFICIENT
VULVOVAGINITIS, ESTROGEN DEFICIENT - Michael P. Hopkins, MD, Med; Jamie Byler, MD; Eric L. Jenison, MD
BASICS
DESCRIPTION
• Decreased blood flow with thinning and atrophy of the female genital tissue
• Changes from estrogen deficiency occur throughout the body; the genital tissues are especially hormone responsive.
• Estrogen-deficient vulvovaginitis is frequently associated with urinary incontinence.
• System(s) Affected: Reproductive
EPIDEMIOLOGY
• Predominant age: Predominantly a problem of the postmenopausal female. The average age of menopause in the US is 52.5 years.
• Predominant sex: Female only
Prevalence
This disorder will affect all women to some degree unless estrogen replacement therapy (ERT) is provided.
RISK FACTORS
• Estrogen-deficient states accompanying metabolic disorders
• Vaginal infections with bacteria and fungi
Genetics
No known pattern
ETIOLOGY
Estrogen deficiency due to
• Menopause (surgical or natural)
• Ovariectomy
• Radiation of the pelvis
ASSOCIATED CONDITIONS
• Incontinence
• Pelvic organ prolapse
• Frequent urinary tract infections
DIAGNOSIS
SIGNS AND SYMPTOMS
• Vaginal dryness
• Decreased vaginal secretions
• Dyspareunia
• Vulva undergoes a thinning of the epidermis along with decreased integrity of the supporting structures; the thinning and atrophy often produce pruritus.
• Obese patients, especially those weighing >100 lb (45 kg) over an ideal body weight, have higher levels of circulating estrogen and thus may have fewer symptoms. (Androstenedione is converted to estrone in peripheral adipose tissue, and when there is an abundance of adipose, higher estrone levels are present.)
Physical Exam
Examination of the vagina and the vulva for maturation index
TESTS
Lab
• Cytology for maturation index will show a low maturation index, signifying a decreased turnover of the cells from the decreased estrogen effect.
• Check the follicle-stimulating hormone (FSH) level to confirm menopause. In the perimenopausal or menopausal female, FSH will be elevated and estradiol will be decreased.
• Estradiol level to evaluate circulating estrogen level
• Drugs that may alter lab results
- Estrogen therapy will alter the maturation index.
- Digoxin has estrogenlike properties.
- Tamoxifen (Nolvadex) may produce menopausal-type symptoms, but may also act on genital tissues as a weak estrogen agonist. Symptoms may vary.
- Drugs used to treat endometriosis or uterine bleeding, such as progestins, danazol, or gonadotropin-releasing hormone agonists, may produce a pseudomenopause, which is reversible.
Pathological Findings
Thinning of the cornified squamous layer of both the vulva and the vagina
DIFFERENTIAL DIAGNOSIS
• Malignancy
• Vulvar dystrophies
TREATMENT
STABILIZATION
Outpatient treatment
GENERAL MEASURES
• ERT will alleviate and reverse the symptoms and the thinning of the squamous epithelial layer. Replacement therapy leads to an increased blood supply to the genital tissues.
• OTC vaginal lubricants
• Symptomatic relief if needed, e.g., cool baths or compresses
Diet
No special diet
Activity
No restriction
MEDICATION (DRUGS)
First Line (1,2)[A]
• A wide variety of preparations are available.
• Progesterone should be used in women with an intact uterus when given estrogen to decrease risk of endometrial carcinoma.
- Estrogen, conjugated: 0.625 mg/d
- Estradiol: 1 mg/d
- Estradiol patch: 0.05 mg, changed twice weekly
- Estrogen vaginal preparations
Cream
Tablet
Ring
• Contraindications
- Estrogen therapy is contraindicated in patients with a history of breast cancer with estrogen-positive tumor receptors.
- Undiagnosed uterine bleeding
- A history of uterine malignancy is a relative contraindication.
• Precautions: Refer to the manufacturer's literature.
• Significant possible interactions: Refer to the manufacturer's literature.
FOLLOW-UP
PROGNOSIS
The prognosis is excellent. The vast majority of symptoms will be relieved with ERT.
COMPLICATIONS (2)[A]
Those associated with estrogen replacement
• Postmenopausal bleeding
• Nausea
• Headache
• Libido changes
• Thrombophlebitis
• Thromboembolic events (coronary, stroke)
• Breast cancer
• Gallbladder disease
• Uterine cancer
PATIENT MONITORING
The patient should be instructed that symptoms should resolve within 30-60 days. If they do not, reevaluation and reexamination for other causes should be undertaken.
REFERENCES
1. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2003;4:CD001500.
2. Farquhar CM, et al. Cochrane HT Study Group. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2005;3:CD004143.
BASICS
DESCRIPTION
• Decreased blood flow with thinning and atrophy of the female genital tissue
• Changes from estrogen deficiency occur throughout the body; the genital tissues are especially hormone responsive.
• Estrogen-deficient vulvovaginitis is frequently associated with urinary incontinence.
• System(s) Affected: Reproductive
EPIDEMIOLOGY
• Predominant age: Predominantly a problem of the postmenopausal female. The average age of menopause in the US is 52.5 years.
• Predominant sex: Female only
Prevalence
This disorder will affect all women to some degree unless estrogen replacement therapy (ERT) is provided.
RISK FACTORS
• Estrogen-deficient states accompanying metabolic disorders
• Vaginal infections with bacteria and fungi
Genetics
No known pattern
ETIOLOGY
Estrogen deficiency due to
• Menopause (surgical or natural)
• Ovariectomy
• Radiation of the pelvis
ASSOCIATED CONDITIONS
• Incontinence
• Pelvic organ prolapse
• Frequent urinary tract infections
DIAGNOSIS
SIGNS AND SYMPTOMS
• Vaginal dryness
• Decreased vaginal secretions
• Dyspareunia
• Vulva undergoes a thinning of the epidermis along with decreased integrity of the supporting structures; the thinning and atrophy often produce pruritus.
• Obese patients, especially those weighing >100 lb (45 kg) over an ideal body weight, have higher levels of circulating estrogen and thus may have fewer symptoms. (Androstenedione is converted to estrone in peripheral adipose tissue, and when there is an abundance of adipose, higher estrone levels are present.)
Physical Exam
Examination of the vagina and the vulva for maturation index
TESTS
Lab
• Cytology for maturation index will show a low maturation index, signifying a decreased turnover of the cells from the decreased estrogen effect.
• Check the follicle-stimulating hormone (FSH) level to confirm menopause. In the perimenopausal or menopausal female, FSH will be elevated and estradiol will be decreased.
• Estradiol level to evaluate circulating estrogen level
• Drugs that may alter lab results
- Estrogen therapy will alter the maturation index.
- Digoxin has estrogenlike properties.
- Tamoxifen (Nolvadex) may produce menopausal-type symptoms, but may also act on genital tissues as a weak estrogen agonist. Symptoms may vary.
- Drugs used to treat endometriosis or uterine bleeding, such as progestins, danazol, or gonadotropin-releasing hormone agonists, may produce a pseudomenopause, which is reversible.
Pathological Findings
Thinning of the cornified squamous layer of both the vulva and the vagina
DIFFERENTIAL DIAGNOSIS
• Malignancy
• Vulvar dystrophies
TREATMENT
STABILIZATION
Outpatient treatment
GENERAL MEASURES
• ERT will alleviate and reverse the symptoms and the thinning of the squamous epithelial layer. Replacement therapy leads to an increased blood supply to the genital tissues.
• OTC vaginal lubricants
• Symptomatic relief if needed, e.g., cool baths or compresses
Diet
No special diet
Activity
No restriction
MEDICATION (DRUGS)
First Line (1,2)[A]
• A wide variety of preparations are available.
• Progesterone should be used in women with an intact uterus when given estrogen to decrease risk of endometrial carcinoma.
- Estrogen, conjugated: 0.625 mg/d
- Estradiol: 1 mg/d
- Estradiol patch: 0.05 mg, changed twice weekly
- Estrogen vaginal preparations
Cream
Tablet
Ring
• Contraindications
- Estrogen therapy is contraindicated in patients with a history of breast cancer with estrogen-positive tumor receptors.
- Undiagnosed uterine bleeding
- A history of uterine malignancy is a relative contraindication.
• Precautions: Refer to the manufacturer's literature.
• Significant possible interactions: Refer to the manufacturer's literature.
FOLLOW-UP
PROGNOSIS
The prognosis is excellent. The vast majority of symptoms will be relieved with ERT.
COMPLICATIONS (2)[A]
Those associated with estrogen replacement
• Postmenopausal bleeding
• Nausea
• Headache
• Libido changes
• Thrombophlebitis
• Thromboembolic events (coronary, stroke)
• Breast cancer
• Gallbladder disease
• Uterine cancer
PATIENT MONITORING
The patient should be instructed that symptoms should resolve within 30-60 days. If they do not, reevaluation and reexamination for other causes should be undertaken.
REFERENCES
1. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2003;4:CD001500.
2. Farquhar CM, et al. Cochrane HT Study Group. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2005;3:CD004143.
VULVOVAGINITIS, PREPUBESCENT
VULVOVAGINITIS, PREPUBESCENT - Theresa N. Grabo, PhD, APRN, BC, FNP
BASICS
DESCRIPTION
• Irritation and/or inflammation of the vulva and/or vagina, associated with vaginal discharge
• In children, the vulva usually becomes inflamed first, with the vagina either not involved, or affected secondarily.
• System(s) Affected: Reproductive; Skin/exocrine
• Synonym(s): Vaginitis; Vulvitis
ALERT
Pediatric Considerations
• Usual adult vulvitis/vaginitis organisms are rare in the prepubertal child.
• Lack of estrogen causes thin vaginal mucosa, which is more susceptible to trauma and infection.
GENERAL PREVENTION
• Perineal hygiene
• Avoidance of irritants and tight or occlusive, nonbreathable clothing
• White, unscented toilet paper
EPIDEMIOLOGY
• Predominant age: Toddlers to menarche
• Predominant sex: Female only
Incidence
Unknown
Prevalence
Common in the US
RISK FACTORS
• Coexisting pharyngitis or other systemic conditions
• Faulty hygiene
• Trauma
Genetics
Not well studied
ETIOLOGY
• Most often due to
- Poor hygiene, may lead to labial agglutination
- Primary infection elsewhere (e.g., otitis media, pharyngitis)
• Most common specific organisms
- Group A -hemolytic streptococci; Streptococcus pyogenes, S. pneumoniae
- Escherichia coli
- Staphylococcus aureus
- Haemophilus influenzae
• Less common specific organisms
- Pinworms
- Sarcoptes scabiei (scabies)
- Candida spp: most common with immunocompromised, antibiotic therapy, or diapers
- Shigella flexneri
• Systemic illnesses
- Measles
- Chickenpox
- Stevens-Johnson syndrome
- Inflammatory conditions (e.g., Reiter syndrome)
• Localized vulvar disease
- Seborrheic dermatitis
- Psoriasis
- Atopic dermatitis
- Contact dermatitis
- Lichen sclerosus et atrophicus
• Other
- Urethral prolapse
- Ectopic ureter
- Sexual abuse (gonorrhea, chlamydia, trichomoniasis, herpes). In 1 study, 4% of girls not suspected to have sexual abuse had positive cultures for gonorrhea.
- Other trauma
- Foreign body
- Tumors or polyps
- Masturbation
- Genital tract malformations
- Polyps or tumors
DIAGNOSIS
SIGNS AND SYMPTOMS
• Irritation and erythema of vulva
• Vaginal discharge
• Unpleasant odor
• Itching
• Excoriation of the genital area
• Bleeding
• Dysuria
• Inflammation of the introitus
• Soreness
Physical Exam
• See "Diagnostic Procedures."
• Look for evidence of chronic illness or dermatologic disease
• Inspection of the genital area in the supine position
• Inspection of the vagina and cervix in the knee-chest position
• Rectal examination if vaginal bleeding or abdominal pain
TESTS
Lab
• Culture for bacteria, fungi, or viruses
• Gram stain
• Tape examination for pinworms
• Potassium hydroxide and saline smears
• Special tests: Exploration of vagina for foreign body may be necessary in long-standing foul vaginal discharge.
Diagnostic Procedures/Surgery
Visualization of the vagina may be necessary using a nasal speculum or infant laryngoscope. If blood or foul-smelling discharge is present, visualization is mandatory. Place child in knee-chest position for best result. Hold buttocks apart and slightly upward.
DIFFERENTIAL DIAGNOSIS
• Contact dermatitis
• Eczema
• Psoriasis
• Shigella vulvovaginitis
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient (except where systemic illness requires hospital care)
• Hygiene
- Wipe front-to-back after elimination.
- Avoid bubble baths and other irritating products.
- Clean daily with mild soap and water and dry gently with soft towel or cool hair dryer.
- Apply bland ointments for protection of the skin, if necessary.
Diet
Healthy balanced diet, high in fiber to prevent constipation; adequate fluid intake.
Activity
Normal with regular exercise
MEDICATION (DRUGS)
First Line
• For empiric treatment, amoxicillin 20 mg/kg/d for 7 days; in areas of high prevalence of resistant H. influenzae, amoxicillin-clavulanate (Augmentin) 20 mg/kg/d
• Estrogen deficiency with labial adhesion/agglutination: Estrogen, conjugated cream to fused area nightly for 2 weeks
• Specific organisms on culture
- Group A -streptococcus, Streptococcus pneumoniae: Penicillin V (Pen Vee K)25-50 mg/kg/d, maximum of 3 g/d, divided q.i.d., for 10 days
- H. influenzae:Amoxicillin 20-40 mg/kg/d for 7 days; amoxicillin-clavulanate 20 mg/kg/d
- Staphylococcus aureus:Cephalexin 25-50 mg/kg/d, divided q.i.d., for 7-10 days; or dicloxacillin 12.5-25 mg/kg/d for 7-10 days
- Candida spp: Topical nystatin (Mycostatin), miconazole, clotrimazole, or terconazole
• Contraindications: Allergy to proposed treatment
• Precautions: Avoid potential allergens and topical sensitizers if possible.
• Significant possible interactions: See the manufacturer's profile for each drug.
Second Line
Topical corticosteroids for pruritus; avoid long-term use
FOLLOW-UP
Recurring vulvovaginitis that does not respond to treatment should be referred to a specialist for further evaluation
PROGNOSIS
Usually clears with appropriate treatment with no permanent sequelae (if not due to underlying disease such as psoriasis, etc.)
COMPLICATIONS
Labial agglutination or adhesions
PATIENT MONITORING
Only if symptoms do not respond to treatment
REFERENCES
1. Jones R. Childhood vulvovaginitis and vaginal discharge in general practice. Fam Pract. 1996;13(4):369-372.
2. Paek SC, Merritt D, Mallory SB. Pruritus vulvae in prepubertal children. J Am Acad Dermatol. 2001;44:795-802.
3. Pierce AM, Hart CA. Vulvovaginitis: Causes and management. Arch Dis Child. 1992;67:509-512.
4. Shapiro RA, Schubert CJ, Siegel RM. Neisseria gonorrhea infections in girls younger than 12 years of age evaluated for vaginitis. Pediatrics. 1999;104(6):e72.
5. Vandeven AM, Emans SJ. Vulvovaginitis in the child and adolescent. Pediatr Rev. 1993;14:141-147.
6. Jasper JM, Ward MA. Shigella vulvovaginitis in a prepubertal child. Pediatr Emerg Care. 2006;22(8):585-6. (3) [C].
7. Emans SJ, Goldstein DP. Pediatrics. The gynecologic examination of the prepubertal child with vulvovaginitis: Use of the knee-chest position. Pediatrics. 1980;65(4):758-760.
8. Joishy M, Ashtekar CS, Jain A, Gonsalves R. Do we need to treat vulvovaginitis in prepubertal girls? Br Med J. 2005;22:330(7484):186-188.
9. Stricker T, Navratil F, Sennhauser FH. BMJ. 2002. Archives of Disease in Childhood. 2003;88:324-326. (2) [B].
ADDITIONAL READING
• Sultan C, ed. Pediatric and adolescent gynecology. evidence-based clinical practice. Endocr Dev. 2004;7:1-8.
• Farrington PF. Pediatric Vulvo-Vaginitis. Clinical Obstetrics Gynecology. Thyroid Diseases in Pregnancy. 1997;40(1):135-140.
• Merkley K. Vulvovaginitis and vaginal discharge in the pediatric patient. J Emerg Nurs. 2005;31(4):400-402.
BASICS
DESCRIPTION
• Irritation and/or inflammation of the vulva and/or vagina, associated with vaginal discharge
• In children, the vulva usually becomes inflamed first, with the vagina either not involved, or affected secondarily.
• System(s) Affected: Reproductive; Skin/exocrine
• Synonym(s): Vaginitis; Vulvitis
ALERT
Pediatric Considerations
• Usual adult vulvitis/vaginitis organisms are rare in the prepubertal child.
• Lack of estrogen causes thin vaginal mucosa, which is more susceptible to trauma and infection.
GENERAL PREVENTION
• Perineal hygiene
• Avoidance of irritants and tight or occlusive, nonbreathable clothing
• White, unscented toilet paper
EPIDEMIOLOGY
• Predominant age: Toddlers to menarche
• Predominant sex: Female only
Incidence
Unknown
Prevalence
Common in the US
RISK FACTORS
• Coexisting pharyngitis or other systemic conditions
• Faulty hygiene
• Trauma
Genetics
Not well studied
ETIOLOGY
• Most often due to
- Poor hygiene, may lead to labial agglutination
- Primary infection elsewhere (e.g., otitis media, pharyngitis)
• Most common specific organisms
- Group A -hemolytic streptococci; Streptococcus pyogenes, S. pneumoniae
- Escherichia coli
- Staphylococcus aureus
- Haemophilus influenzae
• Less common specific organisms
- Pinworms
- Sarcoptes scabiei (scabies)
- Candida spp: most common with immunocompromised, antibiotic therapy, or diapers
- Shigella flexneri
• Systemic illnesses
- Measles
- Chickenpox
- Stevens-Johnson syndrome
- Inflammatory conditions (e.g., Reiter syndrome)
• Localized vulvar disease
- Seborrheic dermatitis
- Psoriasis
- Atopic dermatitis
- Contact dermatitis
- Lichen sclerosus et atrophicus
• Other
- Urethral prolapse
- Ectopic ureter
- Sexual abuse (gonorrhea, chlamydia, trichomoniasis, herpes). In 1 study, 4% of girls not suspected to have sexual abuse had positive cultures for gonorrhea.
- Other trauma
- Foreign body
- Tumors or polyps
- Masturbation
- Genital tract malformations
- Polyps or tumors
DIAGNOSIS
SIGNS AND SYMPTOMS
• Irritation and erythema of vulva
• Vaginal discharge
• Unpleasant odor
• Itching
• Excoriation of the genital area
• Bleeding
• Dysuria
• Inflammation of the introitus
• Soreness
Physical Exam
• See "Diagnostic Procedures."
• Look for evidence of chronic illness or dermatologic disease
• Inspection of the genital area in the supine position
• Inspection of the vagina and cervix in the knee-chest position
• Rectal examination if vaginal bleeding or abdominal pain
TESTS
Lab
• Culture for bacteria, fungi, or viruses
• Gram stain
• Tape examination for pinworms
• Potassium hydroxide and saline smears
• Special tests: Exploration of vagina for foreign body may be necessary in long-standing foul vaginal discharge.
Diagnostic Procedures/Surgery
Visualization of the vagina may be necessary using a nasal speculum or infant laryngoscope. If blood or foul-smelling discharge is present, visualization is mandatory. Place child in knee-chest position for best result. Hold buttocks apart and slightly upward.
DIFFERENTIAL DIAGNOSIS
• Contact dermatitis
• Eczema
• Psoriasis
• Shigella vulvovaginitis
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient (except where systemic illness requires hospital care)
• Hygiene
- Wipe front-to-back after elimination.
- Avoid bubble baths and other irritating products.
- Clean daily with mild soap and water and dry gently with soft towel or cool hair dryer.
- Apply bland ointments for protection of the skin, if necessary.
Diet
Healthy balanced diet, high in fiber to prevent constipation; adequate fluid intake.
Activity
Normal with regular exercise
MEDICATION (DRUGS)
First Line
• For empiric treatment, amoxicillin 20 mg/kg/d for 7 days; in areas of high prevalence of resistant H. influenzae, amoxicillin-clavulanate (Augmentin) 20 mg/kg/d
• Estrogen deficiency with labial adhesion/agglutination: Estrogen, conjugated cream to fused area nightly for 2 weeks
• Specific organisms on culture
- Group A -streptococcus, Streptococcus pneumoniae: Penicillin V (Pen Vee K)25-50 mg/kg/d, maximum of 3 g/d, divided q.i.d., for 10 days
- H. influenzae:Amoxicillin 20-40 mg/kg/d for 7 days; amoxicillin-clavulanate 20 mg/kg/d
- Staphylococcus aureus:Cephalexin 25-50 mg/kg/d, divided q.i.d., for 7-10 days; or dicloxacillin 12.5-25 mg/kg/d for 7-10 days
- Candida spp: Topical nystatin (Mycostatin), miconazole, clotrimazole, or terconazole
• Contraindications: Allergy to proposed treatment
• Precautions: Avoid potential allergens and topical sensitizers if possible.
• Significant possible interactions: See the manufacturer's profile for each drug.
Second Line
Topical corticosteroids for pruritus; avoid long-term use
FOLLOW-UP
Recurring vulvovaginitis that does not respond to treatment should be referred to a specialist for further evaluation
PROGNOSIS
Usually clears with appropriate treatment with no permanent sequelae (if not due to underlying disease such as psoriasis, etc.)
COMPLICATIONS
Labial agglutination or adhesions
PATIENT MONITORING
Only if symptoms do not respond to treatment
REFERENCES
1. Jones R. Childhood vulvovaginitis and vaginal discharge in general practice. Fam Pract. 1996;13(4):369-372.
2. Paek SC, Merritt D, Mallory SB. Pruritus vulvae in prepubertal children. J Am Acad Dermatol. 2001;44:795-802.
3. Pierce AM, Hart CA. Vulvovaginitis: Causes and management. Arch Dis Child. 1992;67:509-512.
4. Shapiro RA, Schubert CJ, Siegel RM. Neisseria gonorrhea infections in girls younger than 12 years of age evaluated for vaginitis. Pediatrics. 1999;104(6):e72.
5. Vandeven AM, Emans SJ. Vulvovaginitis in the child and adolescent. Pediatr Rev. 1993;14:141-147.
6. Jasper JM, Ward MA. Shigella vulvovaginitis in a prepubertal child. Pediatr Emerg Care. 2006;22(8):585-6. (3) [C].
7. Emans SJ, Goldstein DP. Pediatrics. The gynecologic examination of the prepubertal child with vulvovaginitis: Use of the knee-chest position. Pediatrics. 1980;65(4):758-760.
8. Joishy M, Ashtekar CS, Jain A, Gonsalves R. Do we need to treat vulvovaginitis in prepubertal girls? Br Med J. 2005;22:330(7484):186-188.
9. Stricker T, Navratil F, Sennhauser FH. BMJ. 2002. Archives of Disease in Childhood. 2003;88:324-326. (2) [B].
ADDITIONAL READING
• Sultan C, ed. Pediatric and adolescent gynecology. evidence-based clinical practice. Endocr Dev. 2004;7:1-8.
• Farrington PF. Pediatric Vulvo-Vaginitis. Clinical Obstetrics Gynecology. Thyroid Diseases in Pregnancy. 1997;40(1):135-140.
• Merkley K. Vulvovaginitis and vaginal discharge in the pediatric patient. J Emerg Nurs. 2005;31(4):400-402.
VULVOVAGINITIS, CANDIDAL
VULVOVAGINITIS, CANDIDAL - Martha H. McLoughlin, MD
BASICS
DESCRIPTION
Vulvar pruritus and/or burning, often with abnormal vaginal discharge
• System(s) Affected: Reproductive; Skin/Exocrine
• Synonym(s): Monilial vulvovaginitis
GENERAL PREVENTION
• Follow instructions under "Patient Teaching".
• For recurrences, consider reinfection from sexual partner(s). Examine and treat the sex partner for Candida balanitis and oral Candida if vaginitis recurs.
• Review "Risk Factors."
EPIDEMIOLOGY
• Predominant age: Menarche to menopause
• Predominant sex: Female only
Prevalence
• 10-20% of nonpregnant premenopausal women are asymptomatic carriers
• Common in pregnancy
ALERT
Pediatric Considerations
Less common before puberty
RISK FACTORS
• Pregnancy
• Diabetes mellitus
• Antibiotic therapy
• Corticosteroid therapy
• Immunosuppressed states
• HIV infection
• Occlusive synthetic underpants and undergarments
• Hypothyroidism
• Oral contraceptive medications (low dose formulations usually not a cause of increased infection risk)
• Anemia
• Zinc deficiency
• Other contraceptives: Sponge, diaphragms, intrauterine devices
ETIOLOGY
• 40% of vulvovaginitis is caused by Candida.
• Overgrowth of Candida species (C. albicans, C. glabrata, C. tropicalis) in vagina
ASSOCIATED CONDITIONS
Sexually transmitted diseases
DIAGNOSIS
SIGNS AND SYMPTOMS
• Intense vulvar pruritis
• Thick curdlike vaginal discharge
• Dyspareunia at times
• Erythema and/or edema of vulva
• Erythema, pain, and pruritus of crural and perineal area
• Thick white patches appear attached to vaginal mucosa.
• Inflamed vulvar skin
TESTS
Lab
• Yeast, spores, and/or pseudohyphae on smear with 10% potassium hydroxide (KOH) solution
• Vaginal pH 4.5
• Culture findings on Nickerson or Sabouraud medium; usually only indicated for recurrent infections
• Pap smear
DIFFERENTIAL DIAGNOSIS
• Trichomonas vaginitis
• Gonorrheal vaginitisin prepubertal girls
• Pinworm vaginitis
• Contact dermatitis/vaginitis
• Allergic vulvitis/hypersensitivity
• Mechanical/chemical irritation
TREATMENT
STABILIZATION
Outpatient treatment
GENERAL MEASURES
• Remove foreign body if one present
• Consider recommending that the patient use a povidone-iodine (Betadine, Operand) douche (15-30 mL/L [2 tbsp/qt] of water) for symptomatic relief until the specific therapy is effective.
• If urination causes burning, have the patient
- Urinate through a tubular device such as a toilet-paper roll or plastic cup with the end cut out
- Pour warm water over vaginal area while urinating
• Insist on strict diabetic control if patient is diabetic.
Diet
Limit sweets (sucrose) and dairy products (lactose for a patient with recurrent infections.
Activity
• Avoid overexertion, heat, and excessive sweating.
• Delay sexual relations until the symptoms clear/discomfort resolves.
MEDICATION (DRUGS)
First Line
• Fluconazole (Diflucan): 150 mg PO once; use with caution in patients with liver disease.
• Miconazole nitrate (Monistat): 1 200 mg suppository at bedtime for 3 days or miconazole vaginal cream at bedtime for 7 days, or
• Butoconazole nitrate (Femstat): 2% vaginal cream at bedtime for 3 days, or
• Terconazole (Terazol): 1 suppository or 0.8% vaginal cream at bedtime for 3 days, or
• Clotrimazole (Gyne-Lotrimin): 2 100 mg tablets intravaginally for 3 days or cream at bedtime for 7-14 days
• Significant possible interactions: Refer to the manufacturer's profile of each drug.
Second Line
• Retreat with different agent, if recurrence
• Course of oral nystatin; 100,000 units t.i.d. for 2 weeks
• Topical gentian violet 1% aqueous solution painted onto vagina weekly until infection resolves (usually 2-3 weeks)
• Boric acid 600 mg in gelatin capsule inserted vaginally daily for 2 weeks
ALERT
Pregnancy Considerations
Oral azoles are contraindicated in pregnancy. A topical azole may be used with no adverse outcomes.
FOLLOW-UP
PROGNOSIS
• Complete cure with vigorous treatment
• Recurrences are common.
COMPLICATIONS
Secondary bacterial infections of the vagina or vulva
PATIENT MONITORING
Generally no specific follow-up is needed. If symptoms persist, repeat pelvic exam and culture.
REFERENCES
1. Fong IW. The value of treating the sexual partners of women with recurrent vaginal candidiasis with ketoconazole. Genitourin Med. 1992;68:174.
2. Jones HW, Wentz-Colston A, eds. Novak's Textbook of Gynecology.11th ed. Baltimore, MD: Williams Wilkins Co.; 1988.
3. Kaufman RH, Faro S, eds. Benign Diseases of the Vulva and Vagina.4th ed. St. Louis, MO: Mosby-Year Book; 1994.
4. National guideline for the management of vulvovaginal candidiasis. Sex Transm Infect. 1999;75(Suppl 1):S19.
5. Sobel J. Vulvovaginitis, when candida becomes a problem. Clin Dermatol. 1998;16:763-769.
6. Spinillo A, Carratta L, Pizzoli G. Recurrent vaginal candidiasis. J Reprod Med. 1992;37:343.
BASICS
DESCRIPTION
Vulvar pruritus and/or burning, often with abnormal vaginal discharge
• System(s) Affected: Reproductive; Skin/Exocrine
• Synonym(s): Monilial vulvovaginitis
GENERAL PREVENTION
• Follow instructions under "Patient Teaching".
• For recurrences, consider reinfection from sexual partner(s). Examine and treat the sex partner for Candida balanitis and oral Candida if vaginitis recurs.
• Review "Risk Factors."
EPIDEMIOLOGY
• Predominant age: Menarche to menopause
• Predominant sex: Female only
Prevalence
• 10-20% of nonpregnant premenopausal women are asymptomatic carriers
• Common in pregnancy
ALERT
Pediatric Considerations
Less common before puberty
RISK FACTORS
• Pregnancy
• Diabetes mellitus
• Antibiotic therapy
• Corticosteroid therapy
• Immunosuppressed states
• HIV infection
• Occlusive synthetic underpants and undergarments
• Hypothyroidism
• Oral contraceptive medications (low dose formulations usually not a cause of increased infection risk)
• Anemia
• Zinc deficiency
• Other contraceptives: Sponge, diaphragms, intrauterine devices
ETIOLOGY
• 40% of vulvovaginitis is caused by Candida.
• Overgrowth of Candida species (C. albicans, C. glabrata, C. tropicalis) in vagina
ASSOCIATED CONDITIONS
Sexually transmitted diseases
DIAGNOSIS
SIGNS AND SYMPTOMS
• Intense vulvar pruritis
• Thick curdlike vaginal discharge
• Dyspareunia at times
• Erythema and/or edema of vulva
• Erythema, pain, and pruritus of crural and perineal area
• Thick white patches appear attached to vaginal mucosa.
• Inflamed vulvar skin
TESTS
Lab
• Yeast, spores, and/or pseudohyphae on smear with 10% potassium hydroxide (KOH) solution
• Vaginal pH 4.5
• Culture findings on Nickerson or Sabouraud medium; usually only indicated for recurrent infections
• Pap smear
DIFFERENTIAL DIAGNOSIS
• Trichomonas vaginitis
• Gonorrheal vaginitisin prepubertal girls
• Pinworm vaginitis
• Contact dermatitis/vaginitis
• Allergic vulvitis/hypersensitivity
• Mechanical/chemical irritation
TREATMENT
STABILIZATION
Outpatient treatment
GENERAL MEASURES
• Remove foreign body if one present
• Consider recommending that the patient use a povidone-iodine (Betadine, Operand) douche (15-30 mL/L [2 tbsp/qt] of water) for symptomatic relief until the specific therapy is effective.
• If urination causes burning, have the patient
- Urinate through a tubular device such as a toilet-paper roll or plastic cup with the end cut out
- Pour warm water over vaginal area while urinating
• Insist on strict diabetic control if patient is diabetic.
Diet
Limit sweets (sucrose) and dairy products (lactose for a patient with recurrent infections.
Activity
• Avoid overexertion, heat, and excessive sweating.
• Delay sexual relations until the symptoms clear/discomfort resolves.
MEDICATION (DRUGS)
First Line
• Fluconazole (Diflucan): 150 mg PO once; use with caution in patients with liver disease.
• Miconazole nitrate (Monistat): 1 200 mg suppository at bedtime for 3 days or miconazole vaginal cream at bedtime for 7 days, or
• Butoconazole nitrate (Femstat): 2% vaginal cream at bedtime for 3 days, or
• Terconazole (Terazol): 1 suppository or 0.8% vaginal cream at bedtime for 3 days, or
• Clotrimazole (Gyne-Lotrimin): 2 100 mg tablets intravaginally for 3 days or cream at bedtime for 7-14 days
• Significant possible interactions: Refer to the manufacturer's profile of each drug.
Second Line
• Retreat with different agent, if recurrence
• Course of oral nystatin; 100,000 units t.i.d. for 2 weeks
• Topical gentian violet 1% aqueous solution painted onto vagina weekly until infection resolves (usually 2-3 weeks)
• Boric acid 600 mg in gelatin capsule inserted vaginally daily for 2 weeks
ALERT
Pregnancy Considerations
Oral azoles are contraindicated in pregnancy. A topical azole may be used with no adverse outcomes.
FOLLOW-UP
PROGNOSIS
• Complete cure with vigorous treatment
• Recurrences are common.
COMPLICATIONS
Secondary bacterial infections of the vagina or vulva
PATIENT MONITORING
Generally no specific follow-up is needed. If symptoms persist, repeat pelvic exam and culture.
REFERENCES
1. Fong IW. The value of treating the sexual partners of women with recurrent vaginal candidiasis with ketoconazole. Genitourin Med. 1992;68:174.
2. Jones HW, Wentz-Colston A, eds. Novak's Textbook of Gynecology.11th ed. Baltimore, MD: Williams Wilkins Co.; 1988.
3. Kaufman RH, Faro S, eds. Benign Diseases of the Vulva and Vagina.4th ed. St. Louis, MO: Mosby-Year Book; 1994.
4. National guideline for the management of vulvovaginal candidiasis. Sex Transm Infect. 1999;75(Suppl 1):S19.
5. Sobel J. Vulvovaginitis, when candida becomes a problem. Clin Dermatol. 1998;16:763-769.
6. Spinillo A, Carratta L, Pizzoli G. Recurrent vaginal candidiasis. J Reprod Med. 1992;37:343.
VULVOVAGINITIS, BACTERIAL
VULVOVAGINITIS, BACTERIAL - J. C.Chava-Zimmerman, MD
BASICS
DESCRIPTION
A syndrome in which H2O2-producing lactobacilli are replaced by anaerobic bacteria
• System(s) Affected: Reproductive
• Synonym(s): Gardnerella vaginosis; Bacterial vaginosis; Nonspecific vaginitis; Haemophilus vaginitis; Corynebacterium vaginitis
GENERAL PREVENTION
• Good hygiene
• Use of condoms for sexual intercourse
EPIDEMIOLOGY
Predominant sex: Female
Prevalence
• As low as 4% in unselected populations
• Up to 33% in sexually transmitted disease clinics
• Up to 44% in patients with vaginitis
RISK FACTORS
• Controversial regarding multiple sexual partners
• Intrauterine device use
ETIOLOGY
• Polymicrobial: Gardnerella vaginalis, Mobiluncus species, Mycoplasma hominis, Peptostreptococcus, other various anaerobes, including Prevotella, Bacteroides, and Fusobacterium
• Shift from a healthy lactobacilli-based endogenous flora to an anaerobically based endogenous flora
• Rectal reservoir of organisms leading to autoinfection
DIAGNOSIS
SIGNS AND SYMPTOMS
• Unpleasant musty or fishy vaginal odor, exacerbated immediately after intercourse
• Thin gray-white vaginal discharge, mildly adherent to vaginal walls
• 10-30% with vaginal/vulvar irritation
• 10% with frothy discharge
TESTS
Lab
• Affirm VP Microbial Identification Test
• pH paper test (pH >4.5)
• Wet prep: Clue cells in >10-20% of epithelial cells; fewer white blood cells than epithelial cells
• 10% potassium hydroxide (KOH); "whiff test" transient but potent amine or fishy odor
• Gram stain indicating absence of lactobacilli
• May be seen on cytology
• Culture difficult for mycoplasma; not useful
• Lab results may be altered by recent douching
DIFFERENTIAL DIAGNOSIS
• Gonorrhea
• Chlamydial infection
• Trichomoniasis
• Escherichia coli vaginitis
• Staphylococcal vaginitis
• Fungal vaginitis
• Atrophic vaginitis
TREATMENT
STABILIZATION
Outpatient treatment
GENERAL MEASURES
Consider repletion of lactobacilli.
Diet
No restrictions
Activity
No restrictions
MEDICATION (DRUGS)
First Line
• Metronidazole (Flagyl): 500 mg PO 2 b.i.d. for 7 days, or
• Metronidazole vaginal gel: 0.75% 5 g intravaginally daily for 7 days, or
• Clindamycin: 2% vaginal cream 5 g intravaginally daily for 7 days
• Contraindications: Refer to the manufacturer's literature.
• Precautions: Refer to the manufacturer's literature.
• Significant possible interactions: Metronidazole and alcohol
ALERT
Pregnancy Considerations
All symptomatic women and those who have had preterm delivery should be treated. Avoid creams; Metronidazole 250 mg PO t.i.d. for 7 days or clindamycin 300 mg PO 2 b.i.d. for 7 days
Second Line
• Metronidazole: 2 g PO single dose
• Clindamycin: 300 mg PO daily for 7 days
• Clindamycin ovules: 100 g intravaginally at bedtime for 3 days (clindamycin creams are less effective than metronidazole)
FOLLOW-UP
PROGNOSIS
Relapses are fairly common; may be decreased by increased colonization of lactobacilli
COMPLICATIONS
• Uncommon but include:
- Adnexal tenderness
- Pelvic inflammatory disease (PID)
- Intrauterine infections
- Chorioamnionitis
- Postabortion PID
- Postpartum endometritis
- Pelvic abscesses
- Vaginitis emphysematosa
- Rare extravaginal disease
- Preterm labor
- Premature rupture of membranes
- Chorioamnionitis
- Newborn infections, including scalp electrode sites, abscesses, and one reported case of meningitis
- Fetal loss
• Posthysterectomy infection, septicemia, gaseous crepitation in wound
PATIENT MONITORING
None indicated
REFERENCES
1. Briselden AM, Hillier SL. Evaluation of affirm VP microbial identification test for Gardnerella vaginalis and Trichomonas vaginalis. J Clin Microbiol. 1994;32:148-152.
2. Caitlin BW. Gardnerella vaginalis: Characteristics, clinical considerations and controversies. Clin Microbiol Rev. 1992;5:213-217.
3. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2002. MMWR Recomm Rep. 2002;51(RR-06):1-80.
4. Curry SL, Barclay DL. Benign disorders of the vulva-vagina. In: DeCherney AH, Perroll ML, eds. Current Obstetric and Gynecologic Diagnosis and Treatment. 8th ed. Norwalk, CT: Appleton Lang; 1994.
5. Herbst A, Mishell D Jr, Stenchever A, Droegemueller W. Comprehensive Gynecology. 2nd ed. St. Louis, MO: Mosby-Year Book; 1992.
6. Kharsany AB, Hosen AA, Vanden Ende J. Antimicrobial susceptibility of Gardnerella vaginalis. Antimicrob Agents Chemother. 1993;37:2733-2735.
7. Majeroni BA. Bacterial vaginosis: An update. Am Fam Physician. 1998;57:1285-1289.
8. Ray A, Gulati AK, Pandey LK, Pandey S. Non-specific vaginitis vis-a-vis Gardnerella vaginalis. J Commun Dis. 1990;22:274-276.
9. Reed B, Eyler A. Vaginal infections: Diagnosis and management. Am Fam Physician. 1993;47:1805-1818.
BASICS
DESCRIPTION
A syndrome in which H2O2-producing lactobacilli are replaced by anaerobic bacteria
• System(s) Affected: Reproductive
• Synonym(s): Gardnerella vaginosis; Bacterial vaginosis; Nonspecific vaginitis; Haemophilus vaginitis; Corynebacterium vaginitis
GENERAL PREVENTION
• Good hygiene
• Use of condoms for sexual intercourse
EPIDEMIOLOGY
Predominant sex: Female
Prevalence
• As low as 4% in unselected populations
• Up to 33% in sexually transmitted disease clinics
• Up to 44% in patients with vaginitis
RISK FACTORS
• Controversial regarding multiple sexual partners
• Intrauterine device use
ETIOLOGY
• Polymicrobial: Gardnerella vaginalis, Mobiluncus species, Mycoplasma hominis, Peptostreptococcus, other various anaerobes, including Prevotella, Bacteroides, and Fusobacterium
• Shift from a healthy lactobacilli-based endogenous flora to an anaerobically based endogenous flora
• Rectal reservoir of organisms leading to autoinfection
DIAGNOSIS
SIGNS AND SYMPTOMS
• Unpleasant musty or fishy vaginal odor, exacerbated immediately after intercourse
• Thin gray-white vaginal discharge, mildly adherent to vaginal walls
• 10-30% with vaginal/vulvar irritation
• 10% with frothy discharge
TESTS
Lab
• Affirm VP Microbial Identification Test
• pH paper test (pH >4.5)
• Wet prep: Clue cells in >10-20% of epithelial cells; fewer white blood cells than epithelial cells
• 10% potassium hydroxide (KOH); "whiff test" transient but potent amine or fishy odor
• Gram stain indicating absence of lactobacilli
• May be seen on cytology
• Culture difficult for mycoplasma; not useful
• Lab results may be altered by recent douching
DIFFERENTIAL DIAGNOSIS
• Gonorrhea
• Chlamydial infection
• Trichomoniasis
• Escherichia coli vaginitis
• Staphylococcal vaginitis
• Fungal vaginitis
• Atrophic vaginitis
TREATMENT
STABILIZATION
Outpatient treatment
GENERAL MEASURES
Consider repletion of lactobacilli.
Diet
No restrictions
Activity
No restrictions
MEDICATION (DRUGS)
First Line
• Metronidazole (Flagyl): 500 mg PO 2 b.i.d. for 7 days, or
• Metronidazole vaginal gel: 0.75% 5 g intravaginally daily for 7 days, or
• Clindamycin: 2% vaginal cream 5 g intravaginally daily for 7 days
• Contraindications: Refer to the manufacturer's literature.
• Precautions: Refer to the manufacturer's literature.
• Significant possible interactions: Metronidazole and alcohol
ALERT
Pregnancy Considerations
All symptomatic women and those who have had preterm delivery should be treated. Avoid creams; Metronidazole 250 mg PO t.i.d. for 7 days or clindamycin 300 mg PO 2 b.i.d. for 7 days
Second Line
• Metronidazole: 2 g PO single dose
• Clindamycin: 300 mg PO daily for 7 days
• Clindamycin ovules: 100 g intravaginally at bedtime for 3 days (clindamycin creams are less effective than metronidazole)
FOLLOW-UP
PROGNOSIS
Relapses are fairly common; may be decreased by increased colonization of lactobacilli
COMPLICATIONS
• Uncommon but include:
- Adnexal tenderness
- Pelvic inflammatory disease (PID)
- Intrauterine infections
- Chorioamnionitis
- Postabortion PID
- Postpartum endometritis
- Pelvic abscesses
- Vaginitis emphysematosa
- Rare extravaginal disease
- Preterm labor
- Premature rupture of membranes
- Chorioamnionitis
- Newborn infections, including scalp electrode sites, abscesses, and one reported case of meningitis
- Fetal loss
• Posthysterectomy infection, septicemia, gaseous crepitation in wound
PATIENT MONITORING
None indicated
REFERENCES
1. Briselden AM, Hillier SL. Evaluation of affirm VP microbial identification test for Gardnerella vaginalis and Trichomonas vaginalis. J Clin Microbiol. 1994;32:148-152.
2. Caitlin BW. Gardnerella vaginalis: Characteristics, clinical considerations and controversies. Clin Microbiol Rev. 1992;5:213-217.
3. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2002. MMWR Recomm Rep. 2002;51(RR-06):1-80.
4. Curry SL, Barclay DL. Benign disorders of the vulva-vagina. In: DeCherney AH, Perroll ML, eds. Current Obstetric and Gynecologic Diagnosis and Treatment. 8th ed. Norwalk, CT: Appleton Lang; 1994.
5. Herbst A, Mishell D Jr, Stenchever A, Droegemueller W. Comprehensive Gynecology. 2nd ed. St. Louis, MO: Mosby-Year Book; 1992.
6. Kharsany AB, Hosen AA, Vanden Ende J. Antimicrobial susceptibility of Gardnerella vaginalis. Antimicrob Agents Chemother. 1993;37:2733-2735.
7. Majeroni BA. Bacterial vaginosis: An update. Am Fam Physician. 1998;57:1285-1289.
8. Ray A, Gulati AK, Pandey LK, Pandey S. Non-specific vaginitis vis-a-vis Gardnerella vaginalis. J Commun Dis. 1990;22:274-276.
9. Reed B, Eyler A. Vaginal infections: Diagnosis and management. Am Fam Physician. 1993;47:1805-1818.
VULVAR MALIGNANCY
VULVAR MALIGNANCY - Michael P. Hopkins, MD, MEd; Noridelle Gilo, MD; Eric L. Jenison, MD
BASICS
DESCRIPTION
• Carcinoma in situ (Bowen disease): Premalignant changes involving the squamous epithelium of the vulva
• Squamous cell carcinoma: Invasive squamous cell carcinoma is the most common malignancy involving the vulva (85% of the patients). The malignancy can be well, moderately, or poorly differentiated.
• Other invasive cell types include melanoma, Paget disease, adenocarcinoma, adenocystic carcinoma, small cell carcinoma, and sarcomas. Sarcomas are usually leiomyosarcoma and probably arise at the insertion of the round ligament in the labium majus.
• System(s) Affected: Reproductive
• Synonym(s): Bowen disease; Vulvar cancer
ALERT
Geriatric Considerations
• Older patients with associated medical problems are at high risk for radical surgery. The surgery, however, is external, usually well tolerated, and is the treatment of choice.
• In the very elderly, palliative vulvectomy provides relief of symptoms for ulcerating symptomatic advanced disease.
Pregnancy Considerations
This malignancy is not associated with pregnancy.
GENERAL PREVENTION
• Any woman complaining of symptoms related to the vulva should have a close examination and biopsies made of appropriate areas.
• The vulva can be washed with 3% acetic acid to highlight areas. Areas of white raised epithelium should be biopsied.
• Patients with new onset of pruritus should be biopsied in the area of pruritus.
• Liberal biopsy must be used to diagnose in situ disease prior to invasion and to diagnose early invasive disease.
• The patient should not be treated for presumed benign conditions of the vulva without full examination and biopsy.
• When symptoms persist, re-examination and rebiopsy should be undertaken.
• The treatment of benign condyloma of the vulva has not been shown to decrease the eventual incidence of in situ or invasive disease of the vulva.
EPIDEMIOLOGY
• Predominant age
- In situ disease: Mean age, 40s
- Invasive malignancy: Mean age, 60s, with a range of 20s-90s
• Predominant sex: Female only
Incidence
In the US: Invasive vulvar malignancy is a rare gynecologic malignancy, accounting for ~2,000 new cases per year.
RISK FACTORS
• Old age: Invasive disease is rarely seen before age 40 years, and the majority of patients are elderly.
• In situ disease can occur at any age but is rarely seen before the age of 25 years.
• Human papilloma virus (HPV)
• Immunosuppression
Genetics
No known genetic pattern
ETIOLOGY
• Patients with cervical cancer are more likely to develop vulvar cancer at a later date. This is due to the so-called field effect with a carcinogen involving the lower genital tract.
• HPV has been associated with squamous cell abnormalities of the cervix, vagina, and vulva but has not been proven to be the causative agent.
• Smoking is associated with squamous cell disease of the vulva, possibly from direct irritation of the vulva by the transfer of tars and nicotine on the patient's hands or from systemic absorption of carcinogen.
ASSOCIATED CONDITIONS
• Patients with invasive vulvar cancer are often elderly and have associated medical conditions.
• High rate of other gynecologic malignancies. Patients should be evaluated for these.
DIAGNOSIS
SIGNS AND SYMPTOMS
• In situ disease: A small raised area associated with pruritus
• Invasive malignancy: An ulcerated, nonhealing area; as lesions become large, bleeding occurs with associated pain and foul-smelling discharge
• In far advanced disease: The patients can develop rectal bleeding or urethral obstruction.
• Large involved inguinal lymph nodes are also associated with advanced disease.
TESTS
Lab
• Squamous cell antigen can be elevated with invasive disease.
• Hypercalcemia can occur when metastatic disease is present.
Imaging
• Chest x-ray to evaluate for metastatic disease to lungs
• CAT scan to evaluate pelvic lymph node status and periaortic lymph node status
Diagnostic Procedures/Surgery
• Office vulvar biopsy. Vulvar punch biopsy should be done to establish the diagnosis.
• Wide excision can be performed for carcinoma in situ, and any lesion about which there is doubt should be further excised for definitive diagnosis to ensure that invasive disease is not coexistent with the carcinoma in situ.
• Cystoscopy and sigmoidoscopy should be performed if there is a question of invasion into the urethra, bladder, or rectum.
Pathological Findings
• A surgical staging system is used for vulvar cancer: TNM classification = tumor, node, and metastases
- T1: Tumor 2.0 cm
- T2: Tumor >2.0 cm
- T3: Lower urethra or vagina involved
- T4: Upper urethra, bladder, or rectum involved
- N0: Nodes negative
- N1: Unilateral positive lymph nodes
- N2: Bilateral positive lymph nodes
- M0: No metastatic disease
- M1: Distant metastatic disease, positive pelvic lymph node
• International Federation of Obstetrics and Gynecology Classification using TNM
- Stage I: T1, N0, M0
Stage IA: T1a: 1 mm stromal invasion
Stage IB: T1b: > 1 mm stromal invasion
- Stage II: T2, N0, M0
- Stage III: T1-3, N1, M0; T3, N0-l, M0
- Stage IVA: T1-3, N2, M0
- Stage IVB: Any T, any N, any M
DIFFERENTIAL DIAGNOSIS
• The definitive diagnosis for vulvar lesions is made by biopsy. Infectious processes can present as ulcerative lesions and include syphilis, lymphogranuloma venereum, and granuloma inguinale.
• Crohn disease can present as an ulcerative area on the vulva.
• Rarely, lesions can metastasize to the vulva.
TREATMENT
GENERAL MEASURES
• Appropriate health care: Inpatient for treatment
• In advanced malignancy involving the urethra and rectum, concomitant cisplatin/5-fluorouracil (5-FU) chemotherapy with radiation produces significant decrease in size of the primary tumor, usually obviating the need for pelvic exenteration.
Diet
Unrestricted, unless undergoing radiation
Activity
Patients are usually ambulatory and able to resume full activities by 6 weeks after surgery unless wound breakdown occurs.
SPECIAL THERAPY
Radiotherapy
• Radiation therapy is used as adjuvant therapy for patients with positive inguinal lymph nodes.
• Pre-operative radiation may allow for a less radical surgical procedure in patients with advanced disease. [B]
• Postoperative radiation as an adjuvant treatment in early/intermediate stage disease decreases recurrence frequency and may improve survival. [B]
MEDICATION (DRUGS)
• There are no curative drugs.
• As an adjuvant therapy, fluorouracil (Efudex) cream for in situ disease can produce occasional results, but the regimen is not well tolerated because of the excoriation and irritation of the vulva. Adjuvant chemotherapy has not proven to be effective in this disease.
• Chemoradiotherapy has been successful in limiting spread of locally advanced or recurrent disease, though local morbidity is increased.
• Metastatic disease, especially in the subcutaneous tissues of the leg or abdomen, will produce hypercalcemia, which is treated in the usual medical fashion for hypercalcemia.
• Contraindications
- Elderly patients: If chemotherapeutic agents are used, pay close attention to the patient's performance status and ability to tolerate aggressive chemotherapy.
• Precautions: The usual precautions for chemotherapy agents. Refer to the manufacturer's literature for each drug.
• Significant possible interactions: Refer to the manufacturer's literature for each drug.
Second Line
• Surgery: In situ disease can be treated with wide excision or laser vaporization of the affected area. Laser vaporization is preferable in the younger patient, where as wide excision is preferable in the elderly patient, in whom the risk of invasive disease is also higher.
• 0.5 mm of negative margin is adequate for in situ disease.
• Invasive disease is treated primarily by radical vulvectomy and bilateral groin node dissection.
• Pelvic exenteration after radiation provides effective therapy for advanced or recurrent malignancies involving the bladder or rectum.
• More limited surgery
- Has been undertaken for invasive lesions, especially in young patients, to preserve the clitoris and sexual function
- Radical vulvectomy with bilateral groin node dissection through separate incisions provides better cosmetic results than the en bloc technique.
- Radical hemivulvectomy and unilateral groin node dissection can also be utilized for smaller lesions.
FOLLOW-UP
PROGNOSIS
The 5-year survival is based on stages
• Stage I: 90%
• Stage II: 85%
• Stage III: 70%
• Stage IVA: 25%
• Stage IVB: 5%
COMPLICATIONS
The major complications from radical vulvectomy and groin node dissection are wound breakdown, lymphedema, and urinary stress incontinence.
PATIENT MONITORING
• Clinical examination of the groin nodes and vulvar area every 3 months for 2 years, then every 6 months for 3 years.
• Chest x-ray should be obtained once a year.
REFERENCES
1. Cardosi RJ, Bomalaski JJ, Hoffman MS. Diagnosis and management of vulvar and vaginal intraepithelial neoplasia. Obstet Gynecol Clin North Am. 2001;28:685-702.
2. Montana GS. Carcinoma of the vulva: Combined modality treatment. Curr Treat Options Oncol. 2004;5:85-95.
3. Tyring SK. Vulvar squamous cell carcinoma: Guidelines for early diagnosis and treatment. Am J Obstet Gynecol. 2003;189(3 Suppl):S17-S23.
4. Hoffman MS. Squamous-cell carcinoma of the vulva: Locally advanced disease. Best Pract Res Clin Obstet Gynaecol. 2003;17:635-647.
5. Hopkins MP, Reid GC, Vettrano I, Morley GW. Squamous cell carcinoma of the vulva: Prognostic factors influencing survival. Gynecol Oncol. 1991;43:113-117.
BASICS
DESCRIPTION
• Carcinoma in situ (Bowen disease): Premalignant changes involving the squamous epithelium of the vulva
• Squamous cell carcinoma: Invasive squamous cell carcinoma is the most common malignancy involving the vulva (85% of the patients). The malignancy can be well, moderately, or poorly differentiated.
• Other invasive cell types include melanoma, Paget disease, adenocarcinoma, adenocystic carcinoma, small cell carcinoma, and sarcomas. Sarcomas are usually leiomyosarcoma and probably arise at the insertion of the round ligament in the labium majus.
• System(s) Affected: Reproductive
• Synonym(s): Bowen disease; Vulvar cancer
ALERT
Geriatric Considerations
• Older patients with associated medical problems are at high risk for radical surgery. The surgery, however, is external, usually well tolerated, and is the treatment of choice.
• In the very elderly, palliative vulvectomy provides relief of symptoms for ulcerating symptomatic advanced disease.
Pregnancy Considerations
This malignancy is not associated with pregnancy.
GENERAL PREVENTION
• Any woman complaining of symptoms related to the vulva should have a close examination and biopsies made of appropriate areas.
• The vulva can be washed with 3% acetic acid to highlight areas. Areas of white raised epithelium should be biopsied.
• Patients with new onset of pruritus should be biopsied in the area of pruritus.
• Liberal biopsy must be used to diagnose in situ disease prior to invasion and to diagnose early invasive disease.
• The patient should not be treated for presumed benign conditions of the vulva without full examination and biopsy.
• When symptoms persist, re-examination and rebiopsy should be undertaken.
• The treatment of benign condyloma of the vulva has not been shown to decrease the eventual incidence of in situ or invasive disease of the vulva.
EPIDEMIOLOGY
• Predominant age
- In situ disease: Mean age, 40s
- Invasive malignancy: Mean age, 60s, with a range of 20s-90s
• Predominant sex: Female only
Incidence
In the US: Invasive vulvar malignancy is a rare gynecologic malignancy, accounting for ~2,000 new cases per year.
RISK FACTORS
• Old age: Invasive disease is rarely seen before age 40 years, and the majority of patients are elderly.
• In situ disease can occur at any age but is rarely seen before the age of 25 years.
• Human papilloma virus (HPV)
• Immunosuppression
Genetics
No known genetic pattern
ETIOLOGY
• Patients with cervical cancer are more likely to develop vulvar cancer at a later date. This is due to the so-called field effect with a carcinogen involving the lower genital tract.
• HPV has been associated with squamous cell abnormalities of the cervix, vagina, and vulva but has not been proven to be the causative agent.
• Smoking is associated with squamous cell disease of the vulva, possibly from direct irritation of the vulva by the transfer of tars and nicotine on the patient's hands or from systemic absorption of carcinogen.
ASSOCIATED CONDITIONS
• Patients with invasive vulvar cancer are often elderly and have associated medical conditions.
• High rate of other gynecologic malignancies. Patients should be evaluated for these.
DIAGNOSIS
SIGNS AND SYMPTOMS
• In situ disease: A small raised area associated with pruritus
• Invasive malignancy: An ulcerated, nonhealing area; as lesions become large, bleeding occurs with associated pain and foul-smelling discharge
• In far advanced disease: The patients can develop rectal bleeding or urethral obstruction.
• Large involved inguinal lymph nodes are also associated with advanced disease.
TESTS
Lab
• Squamous cell antigen can be elevated with invasive disease.
• Hypercalcemia can occur when metastatic disease is present.
Imaging
• Chest x-ray to evaluate for metastatic disease to lungs
• CAT scan to evaluate pelvic lymph node status and periaortic lymph node status
Diagnostic Procedures/Surgery
• Office vulvar biopsy. Vulvar punch biopsy should be done to establish the diagnosis.
• Wide excision can be performed for carcinoma in situ, and any lesion about which there is doubt should be further excised for definitive diagnosis to ensure that invasive disease is not coexistent with the carcinoma in situ.
• Cystoscopy and sigmoidoscopy should be performed if there is a question of invasion into the urethra, bladder, or rectum.
Pathological Findings
• A surgical staging system is used for vulvar cancer: TNM classification = tumor, node, and metastases
- T1: Tumor 2.0 cm
- T2: Tumor >2.0 cm
- T3: Lower urethra or vagina involved
- T4: Upper urethra, bladder, or rectum involved
- N0: Nodes negative
- N1: Unilateral positive lymph nodes
- N2: Bilateral positive lymph nodes
- M0: No metastatic disease
- M1: Distant metastatic disease, positive pelvic lymph node
• International Federation of Obstetrics and Gynecology Classification using TNM
- Stage I: T1, N0, M0
Stage IA: T1a: 1 mm stromal invasion
Stage IB: T1b: > 1 mm stromal invasion
- Stage II: T2, N0, M0
- Stage III: T1-3, N1, M0; T3, N0-l, M0
- Stage IVA: T1-3, N2, M0
- Stage IVB: Any T, any N, any M
DIFFERENTIAL DIAGNOSIS
• The definitive diagnosis for vulvar lesions is made by biopsy. Infectious processes can present as ulcerative lesions and include syphilis, lymphogranuloma venereum, and granuloma inguinale.
• Crohn disease can present as an ulcerative area on the vulva.
• Rarely, lesions can metastasize to the vulva.
TREATMENT
GENERAL MEASURES
• Appropriate health care: Inpatient for treatment
• In advanced malignancy involving the urethra and rectum, concomitant cisplatin/5-fluorouracil (5-FU) chemotherapy with radiation produces significant decrease in size of the primary tumor, usually obviating the need for pelvic exenteration.
Diet
Unrestricted, unless undergoing radiation
Activity
Patients are usually ambulatory and able to resume full activities by 6 weeks after surgery unless wound breakdown occurs.
SPECIAL THERAPY
Radiotherapy
• Radiation therapy is used as adjuvant therapy for patients with positive inguinal lymph nodes.
• Pre-operative radiation may allow for a less radical surgical procedure in patients with advanced disease. [B]
• Postoperative radiation as an adjuvant treatment in early/intermediate stage disease decreases recurrence frequency and may improve survival. [B]
MEDICATION (DRUGS)
• There are no curative drugs.
• As an adjuvant therapy, fluorouracil (Efudex) cream for in situ disease can produce occasional results, but the regimen is not well tolerated because of the excoriation and irritation of the vulva. Adjuvant chemotherapy has not proven to be effective in this disease.
• Chemoradiotherapy has been successful in limiting spread of locally advanced or recurrent disease, though local morbidity is increased.
• Metastatic disease, especially in the subcutaneous tissues of the leg or abdomen, will produce hypercalcemia, which is treated in the usual medical fashion for hypercalcemia.
• Contraindications
- Elderly patients: If chemotherapeutic agents are used, pay close attention to the patient's performance status and ability to tolerate aggressive chemotherapy.
• Precautions: The usual precautions for chemotherapy agents. Refer to the manufacturer's literature for each drug.
• Significant possible interactions: Refer to the manufacturer's literature for each drug.
Second Line
• Surgery: In situ disease can be treated with wide excision or laser vaporization of the affected area. Laser vaporization is preferable in the younger patient, where as wide excision is preferable in the elderly patient, in whom the risk of invasive disease is also higher.
• 0.5 mm of negative margin is adequate for in situ disease.
• Invasive disease is treated primarily by radical vulvectomy and bilateral groin node dissection.
• Pelvic exenteration after radiation provides effective therapy for advanced or recurrent malignancies involving the bladder or rectum.
• More limited surgery
- Has been undertaken for invasive lesions, especially in young patients, to preserve the clitoris and sexual function
- Radical vulvectomy with bilateral groin node dissection through separate incisions provides better cosmetic results than the en bloc technique.
- Radical hemivulvectomy and unilateral groin node dissection can also be utilized for smaller lesions.
FOLLOW-UP
PROGNOSIS
The 5-year survival is based on stages
• Stage I: 90%
• Stage II: 85%
• Stage III: 70%
• Stage IVA: 25%
• Stage IVB: 5%
COMPLICATIONS
The major complications from radical vulvectomy and groin node dissection are wound breakdown, lymphedema, and urinary stress incontinence.
PATIENT MONITORING
• Clinical examination of the groin nodes and vulvar area every 3 months for 2 years, then every 6 months for 3 years.
• Chest x-ray should be obtained once a year.
REFERENCES
1. Cardosi RJ, Bomalaski JJ, Hoffman MS. Diagnosis and management of vulvar and vaginal intraepithelial neoplasia. Obstet Gynecol Clin North Am. 2001;28:685-702.
2. Montana GS. Carcinoma of the vulva: Combined modality treatment. Curr Treat Options Oncol. 2004;5:85-95.
3. Tyring SK. Vulvar squamous cell carcinoma: Guidelines for early diagnosis and treatment. Am J Obstet Gynecol. 2003;189(3 Suppl):S17-S23.
4. Hoffman MS. Squamous-cell carcinoma of the vulva: Locally advanced disease. Best Pract Res Clin Obstet Gynaecol. 2003;17:635-647.
5. Hopkins MP, Reid GC, Vettrano I, Morley GW. Squamous cell carcinoma of the vulva: Prognostic factors influencing survival. Gynecol Oncol. 1991;43:113-117.
VITILIGO
VITILIGO - Gary J. Silko, MD, MS
BASICS
DESCRIPTION
• An acquired, slowly progressive depigmenting condition in small or large areas of the skin due to the disappearance of previously active melanocytes
- Focal (including segmental) vitiligo: 1 to a few scattered macules, occasionally in a dermatomal distribution
- Generalized vitiligo: Many widespread macules (most common form)
- Universal vitiligo: Little remaining normal pigment
- Acrofacial: Affects distal fingers and facial orifices
• System(s) Affected: Skin/Exocrine
• Synonym(s): Hypomelanosis; Depigmentation
ALERT
Pediatric Considerations
Childhood vitiligo is a distinct subset of vitiligo. Higher incidence of focal vitiligo. Also higher incidence of autoimmune and endocrine disease. Response is poor to topical psoralen plus ultraviolet exposure (PUVA) therapy, but can be tried. Topical steroids may be prescribed (e.g., desonide 0.05% cream every day for 4 months).
Pregnancy Considerations
Treatment with topical or oral psoralens is contraindicated.
GENERAL PREVENTION
While undergoing all therapies, avoid excessive sun exposure.
EPIDEMIOLOGY
• Predominant age: All ages: 50% begin before age 20 years.
• Predominant sex: Male = Female
Incidence
In the US: 500-1,000/100,000
RISK FACTORS
• Positive family history
• Autoimmune disorders including hemolytic anemia and adrenal insufficiency
• Major life crisis or illness
Genetics
Autosomal dominant with variable expression and incomplete penetrance. Positive family history in 30% of cases
ETIOLOGY
Etiology unclear, but thought to be an autoimmune reaction to preexisting melanocytes
ASSOCIATED CONDITIONS
• Addison disease
• Alopecia areata
• Chronic mucocutaneous candidiasis
• Diabetes mellitus (insulin dependent)
• Hypoparathyroidism
• Melanoma
• Pernicious anemia
• Polyglandular autoimmune syndrome
• Thyroid disorders (hyperthyroidism and hypothyroidism), 30% of patients with vitiligo
• Uveitis
• Halo nevi
DIAGNOSIS
SIGNS AND SYMPTOMS
• Loss of pigment
• Locally increased sunburning
• Predilection for acral areas and around orifices such as eyes, mouth, anus
• Pruritus (10%)
• Premature graying (35%)
• Koebner phenomenon (aggravation by trauma)
TESTS
Lab
• Routine blood and urine studies are usually normal in the absence of associated diseases in adults.
• In children, screen for autoimmune diseases with thyroid-stimulating hormone, CBC, and fasting glucose.
Diagnostic Procedures/Surgery
• Examination under Wood light accentuates the hypopigmented areas, especially in light-skinned individuals.
• Skin scraping and a potassium hydroxide (KOH) preparation can be examined microscopically to rule out tinea versicolor.
Pathological Findings
Complete absence of melanocytes in skin biopsy. At the margins one may see a few lymphocytes and large melanocytes with abnormal melanosomes.
DIFFERENTIAL DIAGNOSIS
Any condition that causes acquired hypomelanosis
• Tinea versicolor
• Leprosy
• Lupus erythematosus
• Pityriasis alba
• Atopic dermatitis
• Albinism
• Alopecia areata
• Chemical exposure (phenols, arsenic, chloroquine, hydroquinone)
• Steroid exposure
• Retinoic acid use
• Tuberous sclerosis
• Neurofibromatosis
• Melanocytic nevi (halo nevi)
• Tumor regression of malignant melanoma
• Piebaldism
• Hypopituitarism
• Hyperthyroidism
• Morphea
• Lichen sclerosis
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient except in rare cases of surgical skin grafting or transplantation
• Sun exposure can accentuate the difference between normal and abnormal skin, so for cosmetic reasons patients may wish to avoid this.
• Skin dyes and cosmetics may be used as cover-ups.
Diet
No special diet
Activity
Full activity
MEDICATION (DRUGS)
First Line
• Focal or segmental vitiligo
- A midpotency steroid cream can be applied daily for 3-4 months. If no response, advance to high-potency steroids. Clobetasol (Temovate) cream applied daily for 2 months (every other day on the face). Treatment may be resumed following a 1-4-month respite.
- Phototherapy with narrow band UVB 2 times per week. (1)[C]
• Generalized vitiligo:
- Oral systemic steroids, e.g., betamethasone 5 mg given 2 days in a row, then held the remainder of the week. This pattern continued for 2-4 months minimizes side effects and is effective in arresting the disease in many patients.
- Narrow-band UVB therapy is the preferred initial phototherapy, given 2 times per week.
- Oral trimethylpsoralen or methoxsalen (Oxsoralen-Ultra, 8-MOP) and UVA over a 12-24-month period
- Alternatively, depigmenting the remaining normal skin with monobenzone, a hydroquinone derivative, 20% cream may be elected. It should be applied b.i.d. for 3-6 months. (1)[C]
• Contraindications
- Absolute contraindications to use of psoralen compounds: Idiosyncratic reaction to psoralens, photosensitive disease (e.g., systemic lupus erythematosus, albinism, porphyria), invasive squamous cell carcinoma, melanoma, aphakia
- Relative contraindications to use of psoralen compounds: Cardiac disease, hepatic dysfunction, multiple basal cell carcinomas, prior radiation therapy, prior arsenic therapy
• Precautions
- Watch for skin atrophy and telangiectasias when using topical steroids, especially on the face.
- Watch for photosensitizers with UVA treatment.
- Severe burns possible with topical psoralens. Partially avoided with: 1:10 or 1:50 dilution of psoralens
- PUVA cannot be used for children 12 years of age due to immaturity of the ocular lens.
- Patients undergoing PUVA therapy should have a screening ophthalmologic examination to rule out subclinical retinal pigmentary disease, which is frequently associated with vitiligo.
• Significant possible interactions: Other photosensitizers, e.g., tetracyclines and retinoic acid
Second Line
• Patients with unresponsive focal vitiligo may be candidates for minigrafting with or without PUVA therapy.
• Levamisole 150 mg 2 days a week for several months has been effective in patients with limited or slowly spreading disease.
FOLLOW-UP
DISPOSITION
Issues for Referral
Dermatology consultation should be considered for facial or widespread vitiligo or when PUVA therapy may be necessary.
PROGNOSIS
• Only 5% repigment spontaneously.
• Best results are with PUVA therapy, with which 70% have repigmentation of head and neck area, less in other body areas. Lower percentages respond to topical therapy.
• There is no response in at least 20% of cases, especially long-standing cases.
• Once repigmentation occurs, it usually persists.
COMPLICATIONS
• Phototoxic reactions ranging from mild to severe with PUVA
• Skin atrophy and telangiectasias with topical steroids
• Contact dermatitis can occur with use of depigmenting agents and cosmetic covers.
PATIENT MONITORING
• With PUVA therapy, complete blood count, liver, renal function tests, and an antinuclear antibody should be done every 6 months.
• With topical steroids, follow at monthly intervals to avoid steroid-atrophy of the skin.
REFERENCES
1. James WD, Berger TG, Elston DM. Andrews' Diseases of the Skin. 10th ed. Philadephia, PA: WB Saunders; 2006: 860-863.
2. Freedberg IM, et al. Fitzpatrick's Dermatology in General Medicine, 6th ed. New York, NY: McGraw-Hill; 2003: 839-847.
3. Habif TP. Clinical Dermatology. 4th ed. New York, NY: Mosby; 2004.
MISCELLANEOUS
See also: Hyperthyroidism; Hypothyroidism, Adult; Pityriasis Alba; Tinea Versicolor
BASICS
DESCRIPTION
• An acquired, slowly progressive depigmenting condition in small or large areas of the skin due to the disappearance of previously active melanocytes
- Focal (including segmental) vitiligo: 1 to a few scattered macules, occasionally in a dermatomal distribution
- Generalized vitiligo: Many widespread macules (most common form)
- Universal vitiligo: Little remaining normal pigment
- Acrofacial: Affects distal fingers and facial orifices
• System(s) Affected: Skin/Exocrine
• Synonym(s): Hypomelanosis; Depigmentation
ALERT
Pediatric Considerations
Childhood vitiligo is a distinct subset of vitiligo. Higher incidence of focal vitiligo. Also higher incidence of autoimmune and endocrine disease. Response is poor to topical psoralen plus ultraviolet exposure (PUVA) therapy, but can be tried. Topical steroids may be prescribed (e.g., desonide 0.05% cream every day for 4 months).
Pregnancy Considerations
Treatment with topical or oral psoralens is contraindicated.
GENERAL PREVENTION
While undergoing all therapies, avoid excessive sun exposure.
EPIDEMIOLOGY
• Predominant age: All ages: 50% begin before age 20 years.
• Predominant sex: Male = Female
Incidence
In the US: 500-1,000/100,000
RISK FACTORS
• Positive family history
• Autoimmune disorders including hemolytic anemia and adrenal insufficiency
• Major life crisis or illness
Genetics
Autosomal dominant with variable expression and incomplete penetrance. Positive family history in 30% of cases
ETIOLOGY
Etiology unclear, but thought to be an autoimmune reaction to preexisting melanocytes
ASSOCIATED CONDITIONS
• Addison disease
• Alopecia areata
• Chronic mucocutaneous candidiasis
• Diabetes mellitus (insulin dependent)
• Hypoparathyroidism
• Melanoma
• Pernicious anemia
• Polyglandular autoimmune syndrome
• Thyroid disorders (hyperthyroidism and hypothyroidism), 30% of patients with vitiligo
• Uveitis
• Halo nevi
DIAGNOSIS
SIGNS AND SYMPTOMS
• Loss of pigment
• Locally increased sunburning
• Predilection for acral areas and around orifices such as eyes, mouth, anus
• Pruritus (10%)
• Premature graying (35%)
• Koebner phenomenon (aggravation by trauma)
TESTS
Lab
• Routine blood and urine studies are usually normal in the absence of associated diseases in adults.
• In children, screen for autoimmune diseases with thyroid-stimulating hormone, CBC, and fasting glucose.
Diagnostic Procedures/Surgery
• Examination under Wood light accentuates the hypopigmented areas, especially in light-skinned individuals.
• Skin scraping and a potassium hydroxide (KOH) preparation can be examined microscopically to rule out tinea versicolor.
Pathological Findings
Complete absence of melanocytes in skin biopsy. At the margins one may see a few lymphocytes and large melanocytes with abnormal melanosomes.
DIFFERENTIAL DIAGNOSIS
Any condition that causes acquired hypomelanosis
• Tinea versicolor
• Leprosy
• Lupus erythematosus
• Pityriasis alba
• Atopic dermatitis
• Albinism
• Alopecia areata
• Chemical exposure (phenols, arsenic, chloroquine, hydroquinone)
• Steroid exposure
• Retinoic acid use
• Tuberous sclerosis
• Neurofibromatosis
• Melanocytic nevi (halo nevi)
• Tumor regression of malignant melanoma
• Piebaldism
• Hypopituitarism
• Hyperthyroidism
• Morphea
• Lichen sclerosis
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient except in rare cases of surgical skin grafting or transplantation
• Sun exposure can accentuate the difference between normal and abnormal skin, so for cosmetic reasons patients may wish to avoid this.
• Skin dyes and cosmetics may be used as cover-ups.
Diet
No special diet
Activity
Full activity
MEDICATION (DRUGS)
First Line
• Focal or segmental vitiligo
- A midpotency steroid cream can be applied daily for 3-4 months. If no response, advance to high-potency steroids. Clobetasol (Temovate) cream applied daily for 2 months (every other day on the face). Treatment may be resumed following a 1-4-month respite.
- Phototherapy with narrow band UVB 2 times per week. (1)[C]
• Generalized vitiligo:
- Oral systemic steroids, e.g., betamethasone 5 mg given 2 days in a row, then held the remainder of the week. This pattern continued for 2-4 months minimizes side effects and is effective in arresting the disease in many patients.
- Narrow-band UVB therapy is the preferred initial phototherapy, given 2 times per week.
- Oral trimethylpsoralen or methoxsalen (Oxsoralen-Ultra, 8-MOP) and UVA over a 12-24-month period
- Alternatively, depigmenting the remaining normal skin with monobenzone, a hydroquinone derivative, 20% cream may be elected. It should be applied b.i.d. for 3-6 months. (1)[C]
• Contraindications
- Absolute contraindications to use of psoralen compounds: Idiosyncratic reaction to psoralens, photosensitive disease (e.g., systemic lupus erythematosus, albinism, porphyria), invasive squamous cell carcinoma, melanoma, aphakia
- Relative contraindications to use of psoralen compounds: Cardiac disease, hepatic dysfunction, multiple basal cell carcinomas, prior radiation therapy, prior arsenic therapy
• Precautions
- Watch for skin atrophy and telangiectasias when using topical steroids, especially on the face.
- Watch for photosensitizers with UVA treatment.
- Severe burns possible with topical psoralens. Partially avoided with: 1:10 or 1:50 dilution of psoralens
- PUVA cannot be used for children 12 years of age due to immaturity of the ocular lens.
- Patients undergoing PUVA therapy should have a screening ophthalmologic examination to rule out subclinical retinal pigmentary disease, which is frequently associated with vitiligo.
• Significant possible interactions: Other photosensitizers, e.g., tetracyclines and retinoic acid
Second Line
• Patients with unresponsive focal vitiligo may be candidates for minigrafting with or without PUVA therapy.
• Levamisole 150 mg 2 days a week for several months has been effective in patients with limited or slowly spreading disease.
FOLLOW-UP
DISPOSITION
Issues for Referral
Dermatology consultation should be considered for facial or widespread vitiligo or when PUVA therapy may be necessary.
PROGNOSIS
• Only 5% repigment spontaneously.
• Best results are with PUVA therapy, with which 70% have repigmentation of head and neck area, less in other body areas. Lower percentages respond to topical therapy.
• There is no response in at least 20% of cases, especially long-standing cases.
• Once repigmentation occurs, it usually persists.
COMPLICATIONS
• Phototoxic reactions ranging from mild to severe with PUVA
• Skin atrophy and telangiectasias with topical steroids
• Contact dermatitis can occur with use of depigmenting agents and cosmetic covers.
PATIENT MONITORING
• With PUVA therapy, complete blood count, liver, renal function tests, and an antinuclear antibody should be done every 6 months.
• With topical steroids, follow at monthly intervals to avoid steroid-atrophy of the skin.
REFERENCES
1. James WD, Berger TG, Elston DM. Andrews' Diseases of the Skin. 10th ed. Philadephia, PA: WB Saunders; 2006: 860-863.
2. Freedberg IM, et al. Fitzpatrick's Dermatology in General Medicine, 6th ed. New York, NY: McGraw-Hill; 2003: 839-847.
3. Habif TP. Clinical Dermatology. 4th ed. New York, NY: Mosby; 2004.
MISCELLANEOUS
See also: Hyperthyroidism; Hypothyroidism, Adult; Pityriasis Alba; Tinea Versicolor
VITAMIN DEFICIENCY
VITAMIN DEFICIENCY - Samuel N. Grief, MD, FCFP
BASICS
DESCRIPTION
Vitamin deficiencies
• Vitamins are essential micronutrients required for normal metabolism, growth, and development.
• Deficiencies usually related to disease can occur under healthy conditions. NOTE: Deficiencies are rarely diagnosed or documented in the western world. Regulations mandating vitamin supplementation in food products, adequate food supply, availability of vitamin supplements, and lack of physician awareness all play a role.
GENERAL PREVENTION
• Adequate intake of an appropriately balanced diet containing carbohydrates, proteins, and fats
• Avoidance of fad diets
• Vitamin or nutrition supplementation when appropriate
EPIDEMIOLOGY
• Affects mainly geriatric population
• Occurs in select adult demographics: Pregnant women, chronic disease states (see "Etiology")
• Travelers spending extended time in developing nations
Incidence
• Very low for isolated vitamin deficiencies in western world; true incidence unknown
• Vitamin levels rarely measured (exceptions include vitamin B12-incidence increases over age 50; and folate-incidence increases with specific states: Pregnancy, antiepileptic drugs, neoplastic processes, alcoholism)
Prevalence
Varies by
• Age groups (1)[C]
• Comorbid conditions
• Geography
• Setting (i.e., urban, rural)
RISK FACTORS
Poverty, malnutrition, chronic disease states, advanced age
Genetics
• Cystic fibrosis
• Rare genetic predisposition
- Autoimmune disease (e.g., pernicious anemia)
- Congenital enzyme deficiencies (e.g., biotinidase deficiency)
- Transcobalamin II deficiency
- Ataxia and vitamin E deficiency (AVED)
- A--lipoproteinemia
PATHOPHYSIOLOGY
Various mechanisms, including
• Bleeding diathesis
• Bone disruption
• Cognitive impairment
• Visual distortion
• Skin breakdown
• Anemia
• Alopecia
• Cardiovascular compromise
ETIOLOGY
• Chronic disease states: (e.g., HIV, malabsorption, chronic liver and kidney disease, alcoholism, pernicious anemia)
• Gastric surgeries: (e.g., gastric bypass, gastrectomy, small or large bowel resection)
• Predisposition related to certain medicines: (e.g., prednisone, phenytoin, isoniazid, protease inhibitors, proton pump inhibitors, chronic antibiotic use, penicillamine, hydralazine)
• Malnutrition, imbalanced nutrition, eating disorders: Obesity, bulimia/anorexia, fad diets, extreme vegetarianism
• Dialysis
• Parasitic infestation
ASSOCIATED CONDITIONS
• Osteoporosis, anemia, neuropathies
• Hartnup disease
DIAGNOSIS
SIGNS AND SYMPTOMS
• Night blindness
• Macular degeneration
• Decreased visual acuity
• Poor wound
• Healing
• Hyperkeratosis of skin
• Neuropathy
• Abnormal food cravings (pica)
• Osteomalacia
• Spina bifida
History
• Previous gastrointestinal or gastric bypass surgery
• Prior or current medical conditions
- TB
- HIV
- Hepatitis
- Neoplastic condition
- Hypermetabolic state
Thyrotoxicosis
Second or third degree burns
Wound healing
Any other systemic infection
- Any chronic disease requiring steroids or immunosuppressants
- Any malabsorption or chronic gastrointestinal disorder
Celiac disease, sprue, Crohn, ulcerative colitis
• Parenteral or enteral nutrition via tube feeding (2)[C]
• Pregnancy
• Medications
• Supplements
• Food allergies or intolerances
Physical Exam
• Breakdown of skin integrity
• Coarse or thinning hair
• Reduced visual acuity
• Beefy red tongue
• Angular cheilitis (perleche)
• Poor dentition and gingivitis
• Cognitive impairment
• Bruising and/or petechiae
• Sensory and motor neuropathies
• Ataxic gait
TESTS
• CBC
• If clinical characteristics are present, consider
- Prothrombin and partial thromboplastin times
- Vitamin B12 and folate levels
- Consider serum homocysteine level if suspect vitamin B12, folate deficiency, and normal serum levels (3)[C]
• Specific vitamin level of choice
Lab
Ancillary tests include
• Blood urea nitrogen
• Albumin
• Pre-albumin
• Calcium
• Phosphorous
• Magnesium
• Liver function tests
Imaging
• X-ray of long bones and spine
• Bone densitometry: Indicated in
- Women over age 65 years
- Patients with chronic disease requiring long-standing steroids or immunosuppressants
- Patients on thyroid medicine
- Patients on antiepileptic drugs
Pathological Findings
• Rickets/Osteomalacia
- Osteoid demineralization
- Osteoporosis
• Scurvy
- Ecchymoses
- Bleeding gums
• Beriberi
- Muscle wasting
- Neuropathy
- CHF
• Korsakoff syndrome
- Confabulation
- Memory disturbance
• Wernicke encephalopathy: Cognitive impairment
• Macular degeneration: Decreased visual acuity
• Pellagra
- Dermatitis
- Diarrhea
- Dementia
- Death
• Pernicious anemia
- Subacute combined degeneration
- Gait disturbance
- Cognitive impairment
- Alopecia
ALERT
Pediatric Considerations
• Hemorrhagic disease of the newborn
- Deficiency of vitamin K is seen in neonates as they require 1 week of life to establish their intestinal flora (intestinal bacteria manufacture vitamin K) and as breast milk is a poor source of vitamin K.
- Peaks 2-10 days after birth. Presents with bleeding from the umbilical stump and/or circumcision site along with generalized bruising and gastrointestinal hemorrhage. Routine injection of newborns with vitamin K (1 mg) prevents hemorrhagic disease.
• Vitamin D deficiency: Vitamin D supplementation (200 IU/day) is recommended in all exclusively breast-fed infants for the 1st 2 months of life (AAP recommendations) to prevent rickets.
• Many vitamin deficiencies lead to developmental delay in children.
• Supplemental vitamins in otherwise healthy children, although encouraged, are not mandated by medical authorities.
Pregnancy Considerations
Folate deficiency
- All pregnant women, and women of childbearing age considering pregnancy, should be strongly encouraged to take a multivitamin containing 0.8 mg of folic acid daily.
Geriatric Considerations
• Vitamin B12 deficiency: 25% of the general population age 65 and older has borderline or low levels of vitamin B12 necessitating supplementation. Method of administration for maximum B12 absorption is via sublingual route.
• Concurrent deficiency of other B vitamins often co-exists.
DIFFERENTIAL DIAGNOSIS
Many medical conditions may lead to symptoms and signs that mimic vitamin deficiencies, including
• Diabetes mellitus types 1 and 2
• Hyperparathyroidism
• Thyroid disorders
• Alzheimer disease
• Multiple sclerosis
• Substance abuse
• Toxic ingestion/overdose
• Hematologic malignancies/disorders
TREATMENT
PRE-HOSPITAL
• Obtain prior medical records
• Nutrition history focusing on any food allergies, aversions, or intolerances
STABILIZATION
Provide daily B-vitamin complex (folate, B6, B12), including thiamine supplementation (dose = 100 mg) via oral or parenteral route, to all patients with chronic medical conditions admitted to hospital or in postoperative state. (4)[B], (5)[C], (6)[A]
GENERAL MEASURES
Diet
• Obtain dietetics/nutrition consult.
• Monitor nutrient intake.
• Tailor diet to underlying chronic medical condition, such as
- Diabetes: Carbohydrate counting required
- Hypertension: DASH diet
- Obesity: Calorie-controlled diet
- Chronic kidney disease: Appropriate protein intake and balanced diet
- Congestive heart failure: Low-salt, free-water restricted diet
- Inflammatory bowel disease: Low-residue diet
- Osteoporosis: Calcium-laden diet
• Supplemental enteral nutrition (i.e., Ensure, Boost, Sustacal, etc.) if anorexic or if difficulty eating solids
MEDICATION (DRUGS)
• The abundance of multivitamin formulations makes it very difficult for the medical provider to advise use or avoidance of each product.
• Encourage patients to bring in multivitamin bottle for personal review by a physician or knowledgeable health care practitioner or pharmacist.
FOLLOW-UP
PROGNOSIS
• Most vitamin deficiencies are fully reversible if treated without undue delay.
• Vitamin repletion or supplementation may be required short term (3 months) or long term (>3 months) dependent upon cause of deficiency
COMPLICATIONS
Vitamin toxicities
• Liver failure (vitamins A, D, E, K)
• Desquamation of skin (vitamin A)
• Kidney stones (vitamin C)
• Hypercoagulability (vitamin K)
• Facial flushing (vitamin B3)
• Pseudohyperparathyroidism (vitamin D)
• Masking of pernicious anemia (folic acid) NOTE: Any vitamin can be taken to excess; refer to the Recommended Dietary Allowance (RDA) for specific intake guidelines.
PATIENT MONITORING
• Symptomatic observation needed in majority of cases
• Semi-annual to annual monitoring of pertinent lab tests, as needed
REFERENCES
1. Van Wayenburg CAM, et al. Nutritional deficiency in Dutch primary care: Data from general practice research and registration networks. Clin Nutr. 2005;59(suppl):187-194.
2. Skelton JA, Havens PL, Werlin SL. Nutrient deficiencies in tube-fed children. Clin Pediatrics. 2006;45:37-41.
3. Hankey GJ. Is plasma homocysteine a modifiable risk factor for stroke? Nat Clin Pract Neurol. 2006;2:26-33.
4. Thomson AD, Marshall EJ. The treatment of patients at risk of developing Wernicke's encephalopathy in the community. Alcohol Alcoholism. 2006;41:159-167.
5. Parsons JP, Marsh CB, Mastronade JG. Wernicke's encephalopathy in a patient after gastric bypass surgery. Chest. 2005;128(suppl):453-454.
6. Jacques JND. Nutritional implications of weight loss surgery. Nutrition the MD. 2005;31:1-6.
BASICS
DESCRIPTION
Vitamin deficiencies
• Vitamins are essential micronutrients required for normal metabolism, growth, and development.
• Deficiencies usually related to disease can occur under healthy conditions. NOTE: Deficiencies are rarely diagnosed or documented in the western world. Regulations mandating vitamin supplementation in food products, adequate food supply, availability of vitamin supplements, and lack of physician awareness all play a role.
GENERAL PREVENTION
• Adequate intake of an appropriately balanced diet containing carbohydrates, proteins, and fats
• Avoidance of fad diets
• Vitamin or nutrition supplementation when appropriate
EPIDEMIOLOGY
• Affects mainly geriatric population
• Occurs in select adult demographics: Pregnant women, chronic disease states (see "Etiology")
• Travelers spending extended time in developing nations
Incidence
• Very low for isolated vitamin deficiencies in western world; true incidence unknown
• Vitamin levels rarely measured (exceptions include vitamin B12-incidence increases over age 50; and folate-incidence increases with specific states: Pregnancy, antiepileptic drugs, neoplastic processes, alcoholism)
Prevalence
Varies by
• Age groups (1)[C]
• Comorbid conditions
• Geography
• Setting (i.e., urban, rural)
RISK FACTORS
Poverty, malnutrition, chronic disease states, advanced age
Genetics
• Cystic fibrosis
• Rare genetic predisposition
- Autoimmune disease (e.g., pernicious anemia)
- Congenital enzyme deficiencies (e.g., biotinidase deficiency)
- Transcobalamin II deficiency
- Ataxia and vitamin E deficiency (AVED)
- A--lipoproteinemia
PATHOPHYSIOLOGY
Various mechanisms, including
• Bleeding diathesis
• Bone disruption
• Cognitive impairment
• Visual distortion
• Skin breakdown
• Anemia
• Alopecia
• Cardiovascular compromise
ETIOLOGY
• Chronic disease states: (e.g., HIV, malabsorption, chronic liver and kidney disease, alcoholism, pernicious anemia)
• Gastric surgeries: (e.g., gastric bypass, gastrectomy, small or large bowel resection)
• Predisposition related to certain medicines: (e.g., prednisone, phenytoin, isoniazid, protease inhibitors, proton pump inhibitors, chronic antibiotic use, penicillamine, hydralazine)
• Malnutrition, imbalanced nutrition, eating disorders: Obesity, bulimia/anorexia, fad diets, extreme vegetarianism
• Dialysis
• Parasitic infestation
ASSOCIATED CONDITIONS
• Osteoporosis, anemia, neuropathies
• Hartnup disease
DIAGNOSIS
SIGNS AND SYMPTOMS
• Night blindness
• Macular degeneration
• Decreased visual acuity
• Poor wound
• Healing
• Hyperkeratosis of skin
• Neuropathy
• Abnormal food cravings (pica)
• Osteomalacia
• Spina bifida
History
• Previous gastrointestinal or gastric bypass surgery
• Prior or current medical conditions
- TB
- HIV
- Hepatitis
- Neoplastic condition
- Hypermetabolic state
Thyrotoxicosis
Second or third degree burns
Wound healing
Any other systemic infection
- Any chronic disease requiring steroids or immunosuppressants
- Any malabsorption or chronic gastrointestinal disorder
Celiac disease, sprue, Crohn, ulcerative colitis
• Parenteral or enteral nutrition via tube feeding (2)[C]
• Pregnancy
• Medications
• Supplements
• Food allergies or intolerances
Physical Exam
• Breakdown of skin integrity
• Coarse or thinning hair
• Reduced visual acuity
• Beefy red tongue
• Angular cheilitis (perleche)
• Poor dentition and gingivitis
• Cognitive impairment
• Bruising and/or petechiae
• Sensory and motor neuropathies
• Ataxic gait
TESTS
• CBC
• If clinical characteristics are present, consider
- Prothrombin and partial thromboplastin times
- Vitamin B12 and folate levels
- Consider serum homocysteine level if suspect vitamin B12, folate deficiency, and normal serum levels (3)[C]
• Specific vitamin level of choice
Lab
Ancillary tests include
• Blood urea nitrogen
• Albumin
• Pre-albumin
• Calcium
• Phosphorous
• Magnesium
• Liver function tests
Imaging
• X-ray of long bones and spine
• Bone densitometry: Indicated in
- Women over age 65 years
- Patients with chronic disease requiring long-standing steroids or immunosuppressants
- Patients on thyroid medicine
- Patients on antiepileptic drugs
Pathological Findings
• Rickets/Osteomalacia
- Osteoid demineralization
- Osteoporosis
• Scurvy
- Ecchymoses
- Bleeding gums
• Beriberi
- Muscle wasting
- Neuropathy
- CHF
• Korsakoff syndrome
- Confabulation
- Memory disturbance
• Wernicke encephalopathy: Cognitive impairment
• Macular degeneration: Decreased visual acuity
• Pellagra
- Dermatitis
- Diarrhea
- Dementia
- Death
• Pernicious anemia
- Subacute combined degeneration
- Gait disturbance
- Cognitive impairment
- Alopecia
ALERT
Pediatric Considerations
• Hemorrhagic disease of the newborn
- Deficiency of vitamin K is seen in neonates as they require 1 week of life to establish their intestinal flora (intestinal bacteria manufacture vitamin K) and as breast milk is a poor source of vitamin K.
- Peaks 2-10 days after birth. Presents with bleeding from the umbilical stump and/or circumcision site along with generalized bruising and gastrointestinal hemorrhage. Routine injection of newborns with vitamin K (1 mg) prevents hemorrhagic disease.
• Vitamin D deficiency: Vitamin D supplementation (200 IU/day) is recommended in all exclusively breast-fed infants for the 1st 2 months of life (AAP recommendations) to prevent rickets.
• Many vitamin deficiencies lead to developmental delay in children.
• Supplemental vitamins in otherwise healthy children, although encouraged, are not mandated by medical authorities.
Pregnancy Considerations
Folate deficiency
- All pregnant women, and women of childbearing age considering pregnancy, should be strongly encouraged to take a multivitamin containing 0.8 mg of folic acid daily.
Geriatric Considerations
• Vitamin B12 deficiency: 25% of the general population age 65 and older has borderline or low levels of vitamin B12 necessitating supplementation. Method of administration for maximum B12 absorption is via sublingual route.
• Concurrent deficiency of other B vitamins often co-exists.
DIFFERENTIAL DIAGNOSIS
Many medical conditions may lead to symptoms and signs that mimic vitamin deficiencies, including
• Diabetes mellitus types 1 and 2
• Hyperparathyroidism
• Thyroid disorders
• Alzheimer disease
• Multiple sclerosis
• Substance abuse
• Toxic ingestion/overdose
• Hematologic malignancies/disorders
TREATMENT
PRE-HOSPITAL
• Obtain prior medical records
• Nutrition history focusing on any food allergies, aversions, or intolerances
STABILIZATION
Provide daily B-vitamin complex (folate, B6, B12), including thiamine supplementation (dose = 100 mg) via oral or parenteral route, to all patients with chronic medical conditions admitted to hospital or in postoperative state. (4)[B], (5)[C], (6)[A]
GENERAL MEASURES
Diet
• Obtain dietetics/nutrition consult.
• Monitor nutrient intake.
• Tailor diet to underlying chronic medical condition, such as
- Diabetes: Carbohydrate counting required
- Hypertension: DASH diet
- Obesity: Calorie-controlled diet
- Chronic kidney disease: Appropriate protein intake and balanced diet
- Congestive heart failure: Low-salt, free-water restricted diet
- Inflammatory bowel disease: Low-residue diet
- Osteoporosis: Calcium-laden diet
• Supplemental enteral nutrition (i.e., Ensure, Boost, Sustacal, etc.) if anorexic or if difficulty eating solids
MEDICATION (DRUGS)
• The abundance of multivitamin formulations makes it very difficult for the medical provider to advise use or avoidance of each product.
• Encourage patients to bring in multivitamin bottle for personal review by a physician or knowledgeable health care practitioner or pharmacist.
FOLLOW-UP
PROGNOSIS
• Most vitamin deficiencies are fully reversible if treated without undue delay.
• Vitamin repletion or supplementation may be required short term (3 months) or long term (>3 months) dependent upon cause of deficiency
COMPLICATIONS
Vitamin toxicities
• Liver failure (vitamins A, D, E, K)
• Desquamation of skin (vitamin A)
• Kidney stones (vitamin C)
• Hypercoagulability (vitamin K)
• Facial flushing (vitamin B3)
• Pseudohyperparathyroidism (vitamin D)
• Masking of pernicious anemia (folic acid) NOTE: Any vitamin can be taken to excess; refer to the Recommended Dietary Allowance (RDA) for specific intake guidelines.
PATIENT MONITORING
• Symptomatic observation needed in majority of cases
• Semi-annual to annual monitoring of pertinent lab tests, as needed
REFERENCES
1. Van Wayenburg CAM, et al. Nutritional deficiency in Dutch primary care: Data from general practice research and registration networks. Clin Nutr. 2005;59(suppl):187-194.
2. Skelton JA, Havens PL, Werlin SL. Nutrient deficiencies in tube-fed children. Clin Pediatrics. 2006;45:37-41.
3. Hankey GJ. Is plasma homocysteine a modifiable risk factor for stroke? Nat Clin Pract Neurol. 2006;2:26-33.
4. Thomson AD, Marshall EJ. The treatment of patients at risk of developing Wernicke's encephalopathy in the community. Alcohol Alcoholism. 2006;41:159-167.
5. Parsons JP, Marsh CB, Mastronade JG. Wernicke's encephalopathy in a patient after gastric bypass surgery. Chest. 2005;128(suppl):453-454.
6. Jacques JND. Nutritional implications of weight loss surgery. Nutrition the MD. 2005;31:1-6.
VITAMIN D DEFICIENCY
VITAMIN D DEFICIENCY - Frank J. Domino, MD; Samir Malkani, MD
BASICS
This topic covers the commonly acquired vitamin D Deficiency and not type II vitamin D-resistant rickets or type I pseudo-vitamin D resistant rickets (both rare autosomal recessive disorders).
DESCRIPTION
• Vitamin D is both a hormone and a vitamin. Cholecalciferol (D3) is synthesized in the skin by exposure to ultraviolet B (UVB) radiation. Ergocalciferol (D2) and D3 are present in foods.
• D2 and D3 are hydroxylated in the liver to 25 vitamin D (calcidiol), which is the major circulating form.
• This is further hydroxylated in the kidney to the active metabolite 1,25 vitamin D (calcitriol). Any insult to this production can result in deficiency.
GENERAL PREVENTION
• Adequate exposure to sunlight and dietary sources of vitamin D (plants, fish). Many foods are fortified with D2 and D3.
• Higher intake of vitamin D recommended for ages >50.
• For age 51-70, recommended intake is 400 IU/day; for 71, 600 IU/day.
ALERT
Pediatric Considerations
The American Academy of Pediatrics recommends all breast-fed babies receive 200 I.U. of vitamin D per day.
EPIDEMIOLOGY
• Unclear in general population.
• In the community, a cohort study of asymptomatic adolescents in Boston found 24.1% were deficient, with 4.6% severely deficient. (1)
• A study of hospitalized patients in Massachusetts found 57% vitamin D deficient. (2)
• Women with history of osteoporosis or osteoporotic fracture have high prevalence of vitamin D deficiency. (3)[A]
• A cross-sectional study of patients with persistent, nonspecific pain in an urban Minneapolis primary care clinic found 93% deficient and 28% severely deficient. (4)
RISK FACTORS
• Inadequate sun exposure
• Female
• Dark skin
• Immigrant populations
• Low socioeconomic status
• Latitudes higher than 38
• Elderly
• Institutionalized
• Medications (phenobarbital, phenytoin)
Genetics
Numerous rare genetic disorders can induce hypoparathyroidism (DiGeorge syndrome)
PATHOPHYSIOLOGY
• Insufficient dietary intake of vitamin D and/or lack of UVB exposure results in low levels of vitamin D; this limits calcium absorption, causing excess parathyroid hormone (PTH) to be released.
• PTH stimulates osteoclast activity, which raises calcium and phosphorous, but results in osteomalacia.
ETIOLOGY
• Dietary deficiency
- Inadequate vitamin D intake
- Macrobiotic diet
• Inadequate sunlight exposure
- Institutionalized patients
- Hospitalized patients
- Chronic illness
- Liver or kidney disease
- Malabsorptive states
ASSOCIATED CONDITIONS
• Osteomalacia, osteoporosis
• Rickets
• Celiac disease
• Gastric bypass
• Chronic renal disease
DIAGNOSIS
SIGNS AND SYMPTOMS
• Nonspecific musculoskeletal complaints
• Weak antigravity muscles
History
• Renal disease
• Gastrointestinal (malabsorption) disorders
• Liver dysfunction
• Immigration from tropical to colder climates
Physical Exam
• Numerous neurologic signs: Numbness, proximal myopathy, paresthesias, muscle cramps, laryngospasm
• Chvostek sign: Contraction of the muscles of the eye, mouth or nose, by tapping along the facial nerve
• Trousseau phenomenon: Carpal spasms and paraesthesia produced by pressure upon nerves and vessels of the upper arm
• Tetany
• Seizures
TESTS
Lab
• 25 vitamin D (most sensitive vitamin D status)
• Vitamin D Insufficiency
- 25 D is 15-40 ng/mL
• Vitamin D deficiency
- 15 ng/mL
• PTH elevation (normal in early vitamin D deficiency)
• Low calcium and phosphorous
• Elevated alkaline phosphatase (in later disease)
Imaging
• Plain radiographs: If atypical fracture, radiographs may show osteomalacia (pseudofractures or Looser zones) in pelvis, femur, and fibula.
• Osteoporosis Screen (5)[C]
- Women 65 years with no risk factors
- Women 60 years at risk: Body weight 70 kg (best predictor); less evidence smoking, low body mass index (BMI), family history, decreased activity, alcohol, or caffeine use.
- African American women have higher bone density than Caucasians; thus, rarely screen 65
TREATMENT
GENERAL MEASURES
Diet
• Fatty fish (tuna, salmon)
• Fortified milk, cereal, and foods
Activity
Weightbearing exercise
SPECIAL THERAPY
Aggressive calcium in ICU patients with ionized calcium 3.2 mg/dL or if symptomatic (tetany, seizures, QT prolongation, bradycardia, or hypotension, or ventilated patient with decreased diaphragmatic function)
MEDICATION (DRUGS)
First Line
• Vitamin D Insufficiency
- Vitamin D 800 IU/d plus
- Elemental calcium 1,200 mg/d Or
• Ergocalciferol 50,000 IU/wk for 8 weeks plus
• Elemental calcium 1,200 mg/d
Second Line
Vitamin D deficiency
• Ergocalciferol 50,000 IU daily for 3 weeks, followed by 50,000 IU/week plus
• Elemental calcium 1,200 mg/d
• Patients with no sun exposure, malabsorption syndromes, and antiepileptic drugs may require more replacement
FOLLOW-UP
Repeat abnormal 25 vitamin D and other abnormal labs at 8 weeks.
DISPOSITION
Admission Criteria
• Symptoms of severe hypocalcemia or
• Malabsorption syndromes
Issues for Referral
Endocrinology if no response to treatment
REFERENCES
1. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med.
2. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-783.
3. QJM. 2005;98(9):667-676. Epub 2005 Jul 8.
4. Mayo Clin Proc. 2003;78(12):1463-1470. 2004;158:531-537.
5. www.ahrq.gov
ADDITIONAL READING
Undiagnosed vitamin D deficiency in the hospitalized patient: http://www.aafp.org/afp/20050115/299.html
BASICS
This topic covers the commonly acquired vitamin D Deficiency and not type II vitamin D-resistant rickets or type I pseudo-vitamin D resistant rickets (both rare autosomal recessive disorders).
DESCRIPTION
• Vitamin D is both a hormone and a vitamin. Cholecalciferol (D3) is synthesized in the skin by exposure to ultraviolet B (UVB) radiation. Ergocalciferol (D2) and D3 are present in foods.
• D2 and D3 are hydroxylated in the liver to 25 vitamin D (calcidiol), which is the major circulating form.
• This is further hydroxylated in the kidney to the active metabolite 1,25 vitamin D (calcitriol). Any insult to this production can result in deficiency.
GENERAL PREVENTION
• Adequate exposure to sunlight and dietary sources of vitamin D (plants, fish). Many foods are fortified with D2 and D3.
• Higher intake of vitamin D recommended for ages >50.
• For age 51-70, recommended intake is 400 IU/day; for 71, 600 IU/day.
ALERT
Pediatric Considerations
The American Academy of Pediatrics recommends all breast-fed babies receive 200 I.U. of vitamin D per day.
EPIDEMIOLOGY
• Unclear in general population.
• In the community, a cohort study of asymptomatic adolescents in Boston found 24.1% were deficient, with 4.6% severely deficient. (1)
• A study of hospitalized patients in Massachusetts found 57% vitamin D deficient. (2)
• Women with history of osteoporosis or osteoporotic fracture have high prevalence of vitamin D deficiency. (3)[A]
• A cross-sectional study of patients with persistent, nonspecific pain in an urban Minneapolis primary care clinic found 93% deficient and 28% severely deficient. (4)
RISK FACTORS
• Inadequate sun exposure
• Female
• Dark skin
• Immigrant populations
• Low socioeconomic status
• Latitudes higher than 38
• Elderly
• Institutionalized
• Medications (phenobarbital, phenytoin)
Genetics
Numerous rare genetic disorders can induce hypoparathyroidism (DiGeorge syndrome)
PATHOPHYSIOLOGY
• Insufficient dietary intake of vitamin D and/or lack of UVB exposure results in low levels of vitamin D; this limits calcium absorption, causing excess parathyroid hormone (PTH) to be released.
• PTH stimulates osteoclast activity, which raises calcium and phosphorous, but results in osteomalacia.
ETIOLOGY
• Dietary deficiency
- Inadequate vitamin D intake
- Macrobiotic diet
• Inadequate sunlight exposure
- Institutionalized patients
- Hospitalized patients
- Chronic illness
- Liver or kidney disease
- Malabsorptive states
ASSOCIATED CONDITIONS
• Osteomalacia, osteoporosis
• Rickets
• Celiac disease
• Gastric bypass
• Chronic renal disease
DIAGNOSIS
SIGNS AND SYMPTOMS
• Nonspecific musculoskeletal complaints
• Weak antigravity muscles
History
• Renal disease
• Gastrointestinal (malabsorption) disorders
• Liver dysfunction
• Immigration from tropical to colder climates
Physical Exam
• Numerous neurologic signs: Numbness, proximal myopathy, paresthesias, muscle cramps, laryngospasm
• Chvostek sign: Contraction of the muscles of the eye, mouth or nose, by tapping along the facial nerve
• Trousseau phenomenon: Carpal spasms and paraesthesia produced by pressure upon nerves and vessels of the upper arm
• Tetany
• Seizures
TESTS
Lab
• 25 vitamin D (most sensitive vitamin D status)
• Vitamin D Insufficiency
- 25 D is 15-40 ng/mL
• Vitamin D deficiency
- 15 ng/mL
• PTH elevation (normal in early vitamin D deficiency)
• Low calcium and phosphorous
• Elevated alkaline phosphatase (in later disease)
Imaging
• Plain radiographs: If atypical fracture, radiographs may show osteomalacia (pseudofractures or Looser zones) in pelvis, femur, and fibula.
• Osteoporosis Screen (5)[C]
- Women 65 years with no risk factors
- Women 60 years at risk: Body weight 70 kg (best predictor); less evidence smoking, low body mass index (BMI), family history, decreased activity, alcohol, or caffeine use.
- African American women have higher bone density than Caucasians; thus, rarely screen 65
TREATMENT
GENERAL MEASURES
Diet
• Fatty fish (tuna, salmon)
• Fortified milk, cereal, and foods
Activity
Weightbearing exercise
SPECIAL THERAPY
Aggressive calcium in ICU patients with ionized calcium 3.2 mg/dL or if symptomatic (tetany, seizures, QT prolongation, bradycardia, or hypotension, or ventilated patient with decreased diaphragmatic function)
MEDICATION (DRUGS)
First Line
• Vitamin D Insufficiency
- Vitamin D 800 IU/d plus
- Elemental calcium 1,200 mg/d Or
• Ergocalciferol 50,000 IU/wk for 8 weeks plus
• Elemental calcium 1,200 mg/d
Second Line
Vitamin D deficiency
• Ergocalciferol 50,000 IU daily for 3 weeks, followed by 50,000 IU/week plus
• Elemental calcium 1,200 mg/d
• Patients with no sun exposure, malabsorption syndromes, and antiepileptic drugs may require more replacement
FOLLOW-UP
Repeat abnormal 25 vitamin D and other abnormal labs at 8 weeks.
DISPOSITION
Admission Criteria
• Symptoms of severe hypocalcemia or
• Malabsorption syndromes
Issues for Referral
Endocrinology if no response to treatment
REFERENCES
1. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med.
2. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-783.
3. QJM. 2005;98(9):667-676. Epub 2005 Jul 8.
4. Mayo Clin Proc. 2003;78(12):1463-1470. 2004;158:531-537.
5. www.ahrq.gov
ADDITIONAL READING
Undiagnosed vitamin D deficiency in the hospitalized patient: http://www.aafp.org/afp/20050115/299.html
VERTIGO
VERTIGO - Michele Matthews, PharmD; Kristy Kedian, DO
BASICS
DESCRIPTION
• Sensation of movement when no movement is actually occurring. Results from peripheral or central causes or, in some instances, may be induced by medications or anxiety disorders.
• System(s) Affected: Nervous
• Synonym(s): Dizziness; Acute vestibular neuronitis; Labyrinthitis; Benign paroxysmal positional vertigo (BPPV)
GENERAL PREVENTION
• Precautions to avoid injuries from falls that may occur secondary to imbalance
• If due to motion sickness, pretreatment with anticholinergics such as scopolamine
EPIDEMIOLOGY
• Women are more likely to experience central causes, particularly vertiginous migraine.
• Patients who are elderly and have risk factors for cerebrovascular disease (CVD) are more likely to experience central causes.
Incidence
Accounts for 54% of cases of dizziness reported in primary care:
• >90% of these patients are diagnosed with peripheral causes, such as BPPV.
Prevalence
Ranges from 5-10% within the general population
RISK FACTORS
• History of migraines
• History of CVD or risk factors for CVD
• Use of ototoxic medications
• Trauma or barotrauma
• Perilymphatic fistula
• Heavy weightbearing
• Psychosocial stress
• Exposure to toxins
Genetics
Family history of CVD or migraines may indicate higher risk of central causes.
PATHOPHYSIOLOGY
Caused by dysfunction of the rotational velocity sensors of the inner ear. Results in asymmetrical central processing. Related to the combination of sensory disturbance of motion and the malfunction of the central vestibular apparatus.
ETIOLOGY
• Peripheral causes
- Acute labyrinthitis, acute vestibular neuronitis, BPPV, cholesteatoma, herpes zoster oticus, Meniere disease, otosclerosis
• Central causes
- Cerebellar tumor, CVD, migraine, multiple sclerosis
• Other causes
- Cervical, drug-induced, psychological
ASSOCIATED CONDITIONS
See "Etiology."
DIAGNOSIS
SIGNS AND SYMPTOMS
• Dizziness
• Rotary illusions
• Nystagmus
• Nausea and vomiting
• Hearing loss
• Pallor
• Diaphoresis
• Pain
• Neurologic symptoms (i.e., ataxia)
History
• Determine if true vertigo exists versus other causes of dizziness by asking the patient if they feel lightheaded or if they see the world spinning around them during a dizzy spell. (1)
- Affirmative answer to spinning is indicative of true vertigo
• Distinguish between peripheral and central causes.
- Timing and duration
Seconds to minutes: Peripheral
Minutes to hours: Peripheral or central
Days: Peripheral or central
Weeks: Central or psychological
- Provoking factors
Changes in head position: Peripheral or central
Spontaneous episodes: Peripheral or central
Recent upper viral respiratory infection: Peripheral
Stress: Central or psychological
Immunosuppression: Peripheral
Changes in ear pressure: Peripheral
- Associated symptoms
Rotary illusions with nausea and vomiting: Peripheral
Horizontal and rotational nystagmus: Peripheral
Horizontal, vertical, or rotational nystagmus: Central
Hearing loss: Peripheral
Neurologic symptoms: Central
• Obtain medical and medication history
- Recent use of ototoxic medications
- History of CVD or risk factors for CVD
Physical Exam
• Neurologic (1)
- Cranial nerves for signs of palsies, nystagmus
- Balance
Peripheral: Mild to moderate, able to walk
Central: Severe, unable to walk
- Dix-Hallpike maneuver (PPV = 83%, NPV = 52%)
If induced symptoms subside after repeated maneuvers, consider peripheral causes.
If induced symptoms do not subside, consider central causes.
• Head and neck (1)
- Tympanic membranes
Vesicles: Herpes zoster oticus
Cholesteatoma
• Cardiovascular (1)
- Orthostatic changes in BP: Dehydration or autonomic dysfunction
TESTS
Lab
Audiometry if acoustic neuroma or Meniere disease is suspected
Imaging
Consider MRI in the presence of neurologic symptoms, risk factors for CVD, or progressive unilateral hearing loss.
DIFFERENTIAL DIAGNOSIS
• Acoustic neuroma
• Anxiety disorder
• BPPV
• Cerebellar degeneration
• Cerebellar tumor
• Labyrinthine concussion
• Labyrinthitis
• Meniere disease
• Multiple sclerosis
• Perilymphatic fistula
• Syphilis
• Vascular ischemia
• Vertiginous migraine
• Vestibular neuronitis
• Vestibular ototoxicity
TREATMENT
• Epley maneuver for BPPV (2)[A]
• Modified Epley maneuver for BPPV (3)[B]
• Vestibular exercises for acute vestibular neuronitis (3)[B]
• Low-salt diet and diuretics for Meniere disease (3)[B]
• Migraine prophylaxis, migraine abortive medications, and vestibular exercises for vertiginous migraines (3)[B]
• Selective serotonin reuptake inhibitors (SSRIs) when associated with anxiety disorders (3)[B]
• Vestibular suppressant medications for symptom relief in acute vestibular neuronitis (3,4)[C]
GENERAL MEASURES
• Provide an explanation and offer assurance to avoid anxiety that may exacerbate vertigo.
• Treatments depend on cause
- BPPV: Epley maneuver or modified Epley maneuver (2)[A] (see "Special Therapy")
- Vestibular neuronitis and labyrinthitis
Vestibular suppressant medications (3,4)[C] (see "Medications")
Vestibular rehabilitation exercises (3)[B] (see "Physical Therapy")
- Meniere disease:
Low-salt diet (1-2 g/d) (3)[B]
Diuretics such as hydrochlorothiazide (3)[B]
- Vascular ischemia
Prevention of future events through blood pressure reduction, lipid lowering, smoking cessation, antiplatelet therapy, and anticoagulation if necessary
- Vertiginous migraines
Dietary and lifestyle modifications, vestibular rehabilitation exercises, prophylactic and migraine abortive medications (3)[B]
- Drug-induced vertigo
Discontinue causative agent
- Psychological
SSRIs (3)[B]
Diet
• Restricted salt intake for Meniere disease
• Dietary modifications for vertiginous migraine
SPECIAL THERAPY
Epley maneuver or modified Epley maneuver for BPPV to displace calcium deposits in the semicircular canals (2)[A]
• Improves symptoms and converts patient from positive to negative Dix-Hallpike maneuver
• Contraindications: Carotid stenosis, unstable cardiac disease, severe neck disease
Physical Therapy
Vestibular rehabilitation exercises (3)[B]
• Ball toss
• Lying-to-standing
• Target-change
• Thumb-tracking
• Tightrope
• Walking turns
MEDICATION (DRUGS)
First Line
• Meclizine (Antivert): 12.5-50 mg PO q4-8h (3,4)[C]
• Dimenhydrinate (Dramamine): 25-100 mg PO, IM, or IV q4-8h (3,4)[C]
- Precautions: Concomitant use of CNS depressants, prostatic hyperplasia, glaucoma
- Adverse effects: Sedation, xerostomia
- Interactions: CNS depressants
• Prochlorperazine (Compazine): 5-10 mg PO or IM q6-8h; 25 mg rectally q12h; 5-10 mg by slow IV over 2 minutes (3,4)[C]
- Contraindications: Blood dyscrasias, age 2 years, severe hypotension
- Precautions: Children with acute illness; glaucoma, history of breast cancer, impaired cardiovascular function, pregnancy, prostatic hyperplasia
- Adverse effects: Sedation, xerostomia, hypotension, extrapyramidal effects
- Interactions: Phenothiazines, tricyclic antidepressants
• Metoclopramide (Reglan): 5-10 mg PO q6h, 5-10 mg slow IV q6h
- Contraindications: Concomitant use of drugs with extrapyramidal effects, seizure disorders
- Precautions: History of depression, Parkinson disease, hypertension
- Adverse effects: Sedation, fluid retention, constipation
- Interactions: Linezolid, cyclosporine, digoxin, levodopa
• Benzodiazepines (3,4)[C]
- Diazepam (Valium): 2-10 mg PO or IV q4-8h
- Lorazepam (Ativan): 0.5-2 mg PO, IM, or IV q4-8h
Contraindications: Glaucoma, age 6 months
Precautions: Concomitant use of CNS depressants, hepatic insufficiency, pregnancy
Adverse effects: Sedation, respiratory depression, hypotension
Interactions: CNS depressants
ALERT
Geriatric Considerations
Use vestibular suppressant medications with caution
- Increased risk of falls
- Urinary retention
Pregnancy Considerations
Meclizine and dimenhydrinate are Pregnancy Category B
FOLLOW-UP
DISPOSITION
Issues for Referral
Consider referral to otolaryngologist, ENT specialist, or neurologist if patient requires further care.
PROGNOSIS
Depends on diagnosis and response to treatment
COMPLICATIONS
• Anxiety
• Depression
• Disability
• Injuries from falls
PATIENT MONITORING
After 1-2 weeks, assess for
• Recurrence of symptoms
• New-onset symptoms
• Medication-related adverse effects
• Relief from vestibular rehabilitation exercises
REFERENCES
1. Labuguen RH. Initial evaluation of vertigo. Am Fam Physician. 2006;73:244-251.
2. Hilton M, Pinder D. The Epley (canalith repositioning) maneuver for benign paroxysmal positional vertigo. Cochrane Database Syst Rev. 2004;(3):CD003162.
3. Swartz R, Longwell P. Treatment of vertigo. Am Fam Physician. 2005;71:1115-1122.
4. Hain TC, Uddin M. Pharmacological treatment of vertigo. CNS Drugs. 2003;(2):85-100.
MISCELLANEOUS
See also BPPV, Meniere disease, Motion sickness
BASICS
DESCRIPTION
• Sensation of movement when no movement is actually occurring. Results from peripheral or central causes or, in some instances, may be induced by medications or anxiety disorders.
• System(s) Affected: Nervous
• Synonym(s): Dizziness; Acute vestibular neuronitis; Labyrinthitis; Benign paroxysmal positional vertigo (BPPV)
GENERAL PREVENTION
• Precautions to avoid injuries from falls that may occur secondary to imbalance
• If due to motion sickness, pretreatment with anticholinergics such as scopolamine
EPIDEMIOLOGY
• Women are more likely to experience central causes, particularly vertiginous migraine.
• Patients who are elderly and have risk factors for cerebrovascular disease (CVD) are more likely to experience central causes.
Incidence
Accounts for 54% of cases of dizziness reported in primary care:
• >90% of these patients are diagnosed with peripheral causes, such as BPPV.
Prevalence
Ranges from 5-10% within the general population
RISK FACTORS
• History of migraines
• History of CVD or risk factors for CVD
• Use of ototoxic medications
• Trauma or barotrauma
• Perilymphatic fistula
• Heavy weightbearing
• Psychosocial stress
• Exposure to toxins
Genetics
Family history of CVD or migraines may indicate higher risk of central causes.
PATHOPHYSIOLOGY
Caused by dysfunction of the rotational velocity sensors of the inner ear. Results in asymmetrical central processing. Related to the combination of sensory disturbance of motion and the malfunction of the central vestibular apparatus.
ETIOLOGY
• Peripheral causes
- Acute labyrinthitis, acute vestibular neuronitis, BPPV, cholesteatoma, herpes zoster oticus, Meniere disease, otosclerosis
• Central causes
- Cerebellar tumor, CVD, migraine, multiple sclerosis
• Other causes
- Cervical, drug-induced, psychological
ASSOCIATED CONDITIONS
See "Etiology."
DIAGNOSIS
SIGNS AND SYMPTOMS
• Dizziness
• Rotary illusions
• Nystagmus
• Nausea and vomiting
• Hearing loss
• Pallor
• Diaphoresis
• Pain
• Neurologic symptoms (i.e., ataxia)
History
• Determine if true vertigo exists versus other causes of dizziness by asking the patient if they feel lightheaded or if they see the world spinning around them during a dizzy spell. (1)
- Affirmative answer to spinning is indicative of true vertigo
• Distinguish between peripheral and central causes.
- Timing and duration
Seconds to minutes: Peripheral
Minutes to hours: Peripheral or central
Days: Peripheral or central
Weeks: Central or psychological
- Provoking factors
Changes in head position: Peripheral or central
Spontaneous episodes: Peripheral or central
Recent upper viral respiratory infection: Peripheral
Stress: Central or psychological
Immunosuppression: Peripheral
Changes in ear pressure: Peripheral
- Associated symptoms
Rotary illusions with nausea and vomiting: Peripheral
Horizontal and rotational nystagmus: Peripheral
Horizontal, vertical, or rotational nystagmus: Central
Hearing loss: Peripheral
Neurologic symptoms: Central
• Obtain medical and medication history
- Recent use of ototoxic medications
- History of CVD or risk factors for CVD
Physical Exam
• Neurologic (1)
- Cranial nerves for signs of palsies, nystagmus
- Balance
Peripheral: Mild to moderate, able to walk
Central: Severe, unable to walk
- Dix-Hallpike maneuver (PPV = 83%, NPV = 52%)
If induced symptoms subside after repeated maneuvers, consider peripheral causes.
If induced symptoms do not subside, consider central causes.
• Head and neck (1)
- Tympanic membranes
Vesicles: Herpes zoster oticus
Cholesteatoma
• Cardiovascular (1)
- Orthostatic changes in BP: Dehydration or autonomic dysfunction
TESTS
Lab
Audiometry if acoustic neuroma or Meniere disease is suspected
Imaging
Consider MRI in the presence of neurologic symptoms, risk factors for CVD, or progressive unilateral hearing loss.
DIFFERENTIAL DIAGNOSIS
• Acoustic neuroma
• Anxiety disorder
• BPPV
• Cerebellar degeneration
• Cerebellar tumor
• Labyrinthine concussion
• Labyrinthitis
• Meniere disease
• Multiple sclerosis
• Perilymphatic fistula
• Syphilis
• Vascular ischemia
• Vertiginous migraine
• Vestibular neuronitis
• Vestibular ototoxicity
TREATMENT
• Epley maneuver for BPPV (2)[A]
• Modified Epley maneuver for BPPV (3)[B]
• Vestibular exercises for acute vestibular neuronitis (3)[B]
• Low-salt diet and diuretics for Meniere disease (3)[B]
• Migraine prophylaxis, migraine abortive medications, and vestibular exercises for vertiginous migraines (3)[B]
• Selective serotonin reuptake inhibitors (SSRIs) when associated with anxiety disorders (3)[B]
• Vestibular suppressant medications for symptom relief in acute vestibular neuronitis (3,4)[C]
GENERAL MEASURES
• Provide an explanation and offer assurance to avoid anxiety that may exacerbate vertigo.
• Treatments depend on cause
- BPPV: Epley maneuver or modified Epley maneuver (2)[A] (see "Special Therapy")
- Vestibular neuronitis and labyrinthitis
Vestibular suppressant medications (3,4)[C] (see "Medications")
Vestibular rehabilitation exercises (3)[B] (see "Physical Therapy")
- Meniere disease:
Low-salt diet (1-2 g/d) (3)[B]
Diuretics such as hydrochlorothiazide (3)[B]
- Vascular ischemia
Prevention of future events through blood pressure reduction, lipid lowering, smoking cessation, antiplatelet therapy, and anticoagulation if necessary
- Vertiginous migraines
Dietary and lifestyle modifications, vestibular rehabilitation exercises, prophylactic and migraine abortive medications (3)[B]
- Drug-induced vertigo
Discontinue causative agent
- Psychological
SSRIs (3)[B]
Diet
• Restricted salt intake for Meniere disease
• Dietary modifications for vertiginous migraine
SPECIAL THERAPY
Epley maneuver or modified Epley maneuver for BPPV to displace calcium deposits in the semicircular canals (2)[A]
• Improves symptoms and converts patient from positive to negative Dix-Hallpike maneuver
• Contraindications: Carotid stenosis, unstable cardiac disease, severe neck disease
Physical Therapy
Vestibular rehabilitation exercises (3)[B]
• Ball toss
• Lying-to-standing
• Target-change
• Thumb-tracking
• Tightrope
• Walking turns
MEDICATION (DRUGS)
First Line
• Meclizine (Antivert): 12.5-50 mg PO q4-8h (3,4)[C]
• Dimenhydrinate (Dramamine): 25-100 mg PO, IM, or IV q4-8h (3,4)[C]
- Precautions: Concomitant use of CNS depressants, prostatic hyperplasia, glaucoma
- Adverse effects: Sedation, xerostomia
- Interactions: CNS depressants
• Prochlorperazine (Compazine): 5-10 mg PO or IM q6-8h; 25 mg rectally q12h; 5-10 mg by slow IV over 2 minutes (3,4)[C]
- Contraindications: Blood dyscrasias, age 2 years, severe hypotension
- Precautions: Children with acute illness; glaucoma, history of breast cancer, impaired cardiovascular function, pregnancy, prostatic hyperplasia
- Adverse effects: Sedation, xerostomia, hypotension, extrapyramidal effects
- Interactions: Phenothiazines, tricyclic antidepressants
• Metoclopramide (Reglan): 5-10 mg PO q6h, 5-10 mg slow IV q6h
- Contraindications: Concomitant use of drugs with extrapyramidal effects, seizure disorders
- Precautions: History of depression, Parkinson disease, hypertension
- Adverse effects: Sedation, fluid retention, constipation
- Interactions: Linezolid, cyclosporine, digoxin, levodopa
• Benzodiazepines (3,4)[C]
- Diazepam (Valium): 2-10 mg PO or IV q4-8h
- Lorazepam (Ativan): 0.5-2 mg PO, IM, or IV q4-8h
Contraindications: Glaucoma, age 6 months
Precautions: Concomitant use of CNS depressants, hepatic insufficiency, pregnancy
Adverse effects: Sedation, respiratory depression, hypotension
Interactions: CNS depressants
ALERT
Geriatric Considerations
Use vestibular suppressant medications with caution
- Increased risk of falls
- Urinary retention
Pregnancy Considerations
Meclizine and dimenhydrinate are Pregnancy Category B
FOLLOW-UP
DISPOSITION
Issues for Referral
Consider referral to otolaryngologist, ENT specialist, or neurologist if patient requires further care.
PROGNOSIS
Depends on diagnosis and response to treatment
COMPLICATIONS
• Anxiety
• Depression
• Disability
• Injuries from falls
PATIENT MONITORING
After 1-2 weeks, assess for
• Recurrence of symptoms
• New-onset symptoms
• Medication-related adverse effects
• Relief from vestibular rehabilitation exercises
REFERENCES
1. Labuguen RH. Initial evaluation of vertigo. Am Fam Physician. 2006;73:244-251.
2. Hilton M, Pinder D. The Epley (canalith repositioning) maneuver for benign paroxysmal positional vertigo. Cochrane Database Syst Rev. 2004;(3):CD003162.
3. Swartz R, Longwell P. Treatment of vertigo. Am Fam Physician. 2005;71:1115-1122.
4. Hain TC, Uddin M. Pharmacological treatment of vertigo. CNS Drugs. 2003;(2):85-100.
MISCELLANEOUS
See also BPPV, Meniere disease, Motion sickness
VARICOSE VEINS
VARICOSE VEINS - Joseph A. Florence, MD
BASICS
DESCRIPTION
• Permanent dilation and tortuosity of superficial veins usually occurring in the legs and feet. May result from congenitally incomplete valves, or valves that have become incompetent. Affects legs where reverse flow occurs when dependent.
• System(s) Affected: Cardiovascular; Skin/Exocrine
ALERT
Ulceration of varicose veins has a high rate of infection which can lead to sepsis.
Geriatric Considerations
• More common, usually valvular degeneration, but may be secondary to chronic venous deficiency
• Recommended therapy: Elastic support hose and frequent rests with legs elevated rather than ligation and stripping
Pregnancy Considerations
• Frequent problem
• Use of elastic stockings recommended for individuals who have a history of varicosities or when activities involve a great deal of standing
EPIDEMIOLOGY
• Predominant age: Middle age
• Predominant sex: Female > Male (5:1)
Incidence
• 45 per 1,000 (National Health Interview Survey NHIS95)
• The National Women's Health Information Center (NWHIC) estimates that 50% of all women are affected by varicose veins.
RISK FACTORS
• Increasing age
• Pregnancy, especially multiple pregnancies
• Occupations requiring prolonged standing, restrictive clothing (e.g., very tight girdles)
• Obesity
• History of phlebitis
• Family history
Genetics
Familial, dominant, X-linked
PATHOPHYSIOLOGY
• Varicose veins are caused by venous insufficiency from faulty valves in 1 or more perforator veins in the lower leg, causing secondary incompetence at the saphenofemoral junction (valvular reflux).
• Valvular dysfunction causing venous reflux and subsequently venous hypertension
• Failed valves allow blood to flow in the reverse direction (away from the heart) from deep to superficial and from proximal to distal veins.
• Deep thrombophlebitis
• Increased venous pressure from any cause
• Congenital valvular incompetence
• Trauma (should consider AV fistula: Listen for bruit)
• In many individuals, no cause or precipitating factor found
• Presumed to be due to a loss in vein wall elasticity with failure of the valve leaflets to coapt (1)[C]
ASSOCIATED CONDITIONS
• Stasis dermatitis
• Stasis ulcer, venous ulcer (large varicose veins may lead to skin changes and eventual ulceration (2)
DIAGNOSIS
SIGNS AND SYMPTOMS
History
Symptoms range from minor annoyance or cosmetic problem to a lifestyle-limiting problem.
• Localized symptoms
- Sometimes asymptomatic or minimal symptoms
- Pain
- Burning
- Itching
• Generalized symptoms
- Leg muscular cramp, aching
- Leg fatigue or swelling
• Pain if varicose ulcer develops
• Symptoms often worse at the end of the day, especially with prolonged standing
• Women are more prone to symptoms due to hormonal influences: Symptoms worse during menses (3)[B]
• There is no direct correlation with the severity of the varicose veins and the severity of symptoms.
Physical Exam
• Inspect lower extremities with patient standing. Varicose veins in the proximal femoral ring and distal portion of the legs may not be visible when the patient is supine.
• Varicose veins are
- Dilatated, tortuose superficial veins, chiefly in the lower extremities
- Dark purple or blue in color and are raised above the surface of the skin.
- Often twisted and bulging and can look like cords.
- Most commonly found on the posterior or medial lower extremity
• Edema of affected limb may be present.
• Skin changes may include
- Eczema
- Hyperpigmentation
- Lipodermatosclerosis
• Spider veins (idiopathic telangiectases)
- Fine intracutaneous angiectasis
- May be extensive/unsightly
• Documentation to help with differential diagnosis should include
- The extent and location of varicose veins
- Description of the skin including hair distribution
- Neurological-especially sensory and motor
- Periferial arterial vasculature-pulses
- Musculoskeletal system to document associated rheumatologic or orthopedic issues
TESTS
Special tests
• Trendelenburg test (4): Test for varicose veins. Patient lies on his back and raises his leg to empty the veins. A tourniquet is applied just below the saphenous opening. The patient is then stood up and the tourniquet removed in 60 seconds. Normally the vein should fill from below within 35 seconds with the tourniquet in situ. Earlier filling indicates incompetence of a communicating vein. If on release the veins fill rapidly from above it is due to incompetent sapheno-femoral valves.
• Perthes test (5): A clinical test for assessing the patency of the deep femoral veins, used in preparations for operation for varicose veins. With the patient standing and veins filled, a tourniquet is placed around the mid-thigh, and the patient walks for 5 minutes. If the saphenous veins collapse below the tourniquet, the deep veins are patent and the communicating veins are competent; if unchanged, both saphenous and communicating veins are incompetent, and if the veins increase in prominence and pain occurs the deep veins are occluded.
Imaging
• Duplex ultrasound-formal noninvasive imaging of the venous system with duplex ultrasound will confirm the etiology, anatomy, and pathophysiology of segmental venous reflux.
• Duplex scanning, venous Doppler study, photoplethysmography, light-reflection rheography, air plethysmography, and other vascular testing should be reserved for those patients who have venous symptoms and/or large (>4 mm in diameter) vessels or large numbers of spider telangiectasia indicating venous hypertension.
Pathological Findings
• Elongation and tortuosity of veins
• Medial fibrosis of veins
• Disappearance or atrophy of valves
DIFFERENTIAL DIAGNOSIS
• Nerve root compression
• Arthritis
• Peripheral neuritis
• Telangiectasia: Smaller, visible blood vessels that are permanently dilated
• Deep vein thrombosis
TREATMENT
Patients with unsightly varicose veins seek treatment for cosmetic reasons.
GENERAL MEASURES
• Appropriate health care: Outpatient
• Conservative methods
- Frequent rest periods with legs elevated
- Lightweight, elastic compression hosiery. Best put on before getting out of bed
- Graduated compressing stockings are considered 1st-line therapy.
- Avoid girdles and other restrictive clothing.
- If stasis ulcers present, use warm, wet dressings
SURGERY
• Challenge to balance a cosmetically acceptable result with a low incidence of recurrence and complications
• Surgery is indicated if there is pain, recurrent phlebitis, skin changes/ulceration, or for cosmetic improvement for severe cases.
• Minimally invasive techniques include (6)[C]
- Radiofrequency ablation (RFA)
- Endovenous laser therapy (EVLT)
- Transilluminated power phlebectomy (TIPP)
- Foam sclerotherapy is more powerful than a liquid sclerosant. (7)[A]
- Ambulatory phlebectomy-has a lower risk of recurrence than with sclerotherapy. (7)[A]
• Traditional surgical methods include
- Ligation and stripping of the varicose vein (Sclerotherapy: Sclerosing solution is injected into varicosities causing vein walls to swell, adhere, and scar. 50-90% improvement expected [American Academy of Dermatology])
- Stab avulsion phlebectomy
• For extensive fibrosis: Excision of the entire area, followed by skin graft, may be necessary.
• Surgical treatment of clinically symptomatic varicose veins involves treatment of the saphenous vein reflux as well as the varicosities.
PROGNOSIS
• Usual course: Chronic
• Favorable with appropriate treatment
• Quality of surgical treatment is less satisfactory if significant deep venous reflux, history of ulceration, or congenital arteriovenous malformation exists. (6)
COMPLICATIONS
• Petechial hemorrhages
• Chronic edema
• Superimposed infection
• Varicose ulcers
• Pigmentation
• Eczema
• Recurrence after surgical treatment
• Scarring or nerve damage from stripping technique
PATIENT MONITORING
Until surgery or conservative therapy brings maximal benefit
REFERENCES
1. Clarke GH, Vasdekis SN, Hobbs JT, Nicolaides AN. Venous wall function in the pathogenesis of varicose veins. Surgery. 1992;111(4):402-408.
2. Hanrahan LM, et al. Distribution of valvular incompetence in patients with venous stasis ulceration. J Vasc Surg. 1991;13(6):805-811.
3. Fegan WG, Lambe R, Henry M. Steroid hormones and varicose veins. Lancet. 1967;2:1070-1071.
4. Trendelenburg F. Uber die Unterbindung der Vena saphena magna bei Unterschenkelvaricen. [Brun's] Beitrage zur klinischen Chirurgie,1891;7:195-210.
5. Perthes GC. Uber die Operation der Unterschenkelvarizen nach Trendelenburg. Deutsche medizinische Wochenschrift. Berlin,1895;16:253-257.
6. Teruya TH, Ballard JL. New approaches for the treatment of varicose veins. Surg Clin North Am. 2004;84(5):1397-1417.
7. Sadick NS. Advances in the treatment of varicose veins: Ambulatory phlebectomy, foam sclerotherapy, endovascular laser, and radiofrequency closure. Dermatol Clin. 2005;23(3):443-455.
ADDITIONAL READING
• Callam MJ. Epidemiology of varicose veins. Br J Surg. 1994;81:167-173.
• Ellis H, Taylor P. Varicose Veins. 3rd ed. London: Greenwich Medical Media; 1999.
MISCELLANEOUS
See also: Hemorrhoids; Dermatitis, Stasis
BASICS
DESCRIPTION
• Permanent dilation and tortuosity of superficial veins usually occurring in the legs and feet. May result from congenitally incomplete valves, or valves that have become incompetent. Affects legs where reverse flow occurs when dependent.
• System(s) Affected: Cardiovascular; Skin/Exocrine
ALERT
Ulceration of varicose veins has a high rate of infection which can lead to sepsis.
Geriatric Considerations
• More common, usually valvular degeneration, but may be secondary to chronic venous deficiency
• Recommended therapy: Elastic support hose and frequent rests with legs elevated rather than ligation and stripping
Pregnancy Considerations
• Frequent problem
• Use of elastic stockings recommended for individuals who have a history of varicosities or when activities involve a great deal of standing
EPIDEMIOLOGY
• Predominant age: Middle age
• Predominant sex: Female > Male (5:1)
Incidence
• 45 per 1,000 (National Health Interview Survey NHIS95)
• The National Women's Health Information Center (NWHIC) estimates that 50% of all women are affected by varicose veins.
RISK FACTORS
• Increasing age
• Pregnancy, especially multiple pregnancies
• Occupations requiring prolonged standing, restrictive clothing (e.g., very tight girdles)
• Obesity
• History of phlebitis
• Family history
Genetics
Familial, dominant, X-linked
PATHOPHYSIOLOGY
• Varicose veins are caused by venous insufficiency from faulty valves in 1 or more perforator veins in the lower leg, causing secondary incompetence at the saphenofemoral junction (valvular reflux).
• Valvular dysfunction causing venous reflux and subsequently venous hypertension
• Failed valves allow blood to flow in the reverse direction (away from the heart) from deep to superficial and from proximal to distal veins.
• Deep thrombophlebitis
• Increased venous pressure from any cause
• Congenital valvular incompetence
• Trauma (should consider AV fistula: Listen for bruit)
• In many individuals, no cause or precipitating factor found
• Presumed to be due to a loss in vein wall elasticity with failure of the valve leaflets to coapt (1)[C]
ASSOCIATED CONDITIONS
• Stasis dermatitis
• Stasis ulcer, venous ulcer (large varicose veins may lead to skin changes and eventual ulceration (2)
DIAGNOSIS
SIGNS AND SYMPTOMS
History
Symptoms range from minor annoyance or cosmetic problem to a lifestyle-limiting problem.
• Localized symptoms
- Sometimes asymptomatic or minimal symptoms
- Pain
- Burning
- Itching
• Generalized symptoms
- Leg muscular cramp, aching
- Leg fatigue or swelling
• Pain if varicose ulcer develops
• Symptoms often worse at the end of the day, especially with prolonged standing
• Women are more prone to symptoms due to hormonal influences: Symptoms worse during menses (3)[B]
• There is no direct correlation with the severity of the varicose veins and the severity of symptoms.
Physical Exam
• Inspect lower extremities with patient standing. Varicose veins in the proximal femoral ring and distal portion of the legs may not be visible when the patient is supine.
• Varicose veins are
- Dilatated, tortuose superficial veins, chiefly in the lower extremities
- Dark purple or blue in color and are raised above the surface of the skin.
- Often twisted and bulging and can look like cords.
- Most commonly found on the posterior or medial lower extremity
• Edema of affected limb may be present.
• Skin changes may include
- Eczema
- Hyperpigmentation
- Lipodermatosclerosis
• Spider veins (idiopathic telangiectases)
- Fine intracutaneous angiectasis
- May be extensive/unsightly
• Documentation to help with differential diagnosis should include
- The extent and location of varicose veins
- Description of the skin including hair distribution
- Neurological-especially sensory and motor
- Periferial arterial vasculature-pulses
- Musculoskeletal system to document associated rheumatologic or orthopedic issues
TESTS
Special tests
• Trendelenburg test (4): Test for varicose veins. Patient lies on his back and raises his leg to empty the veins. A tourniquet is applied just below the saphenous opening. The patient is then stood up and the tourniquet removed in 60 seconds. Normally the vein should fill from below within 35 seconds with the tourniquet in situ. Earlier filling indicates incompetence of a communicating vein. If on release the veins fill rapidly from above it is due to incompetent sapheno-femoral valves.
• Perthes test (5): A clinical test for assessing the patency of the deep femoral veins, used in preparations for operation for varicose veins. With the patient standing and veins filled, a tourniquet is placed around the mid-thigh, and the patient walks for 5 minutes. If the saphenous veins collapse below the tourniquet, the deep veins are patent and the communicating veins are competent; if unchanged, both saphenous and communicating veins are incompetent, and if the veins increase in prominence and pain occurs the deep veins are occluded.
Imaging
• Duplex ultrasound-formal noninvasive imaging of the venous system with duplex ultrasound will confirm the etiology, anatomy, and pathophysiology of segmental venous reflux.
• Duplex scanning, venous Doppler study, photoplethysmography, light-reflection rheography, air plethysmography, and other vascular testing should be reserved for those patients who have venous symptoms and/or large (>4 mm in diameter) vessels or large numbers of spider telangiectasia indicating venous hypertension.
Pathological Findings
• Elongation and tortuosity of veins
• Medial fibrosis of veins
• Disappearance or atrophy of valves
DIFFERENTIAL DIAGNOSIS
• Nerve root compression
• Arthritis
• Peripheral neuritis
• Telangiectasia: Smaller, visible blood vessels that are permanently dilated
• Deep vein thrombosis
TREATMENT
Patients with unsightly varicose veins seek treatment for cosmetic reasons.
GENERAL MEASURES
• Appropriate health care: Outpatient
• Conservative methods
- Frequent rest periods with legs elevated
- Lightweight, elastic compression hosiery. Best put on before getting out of bed
- Graduated compressing stockings are considered 1st-line therapy.
- Avoid girdles and other restrictive clothing.
- If stasis ulcers present, use warm, wet dressings
SURGERY
• Challenge to balance a cosmetically acceptable result with a low incidence of recurrence and complications
• Surgery is indicated if there is pain, recurrent phlebitis, skin changes/ulceration, or for cosmetic improvement for severe cases.
• Minimally invasive techniques include (6)[C]
- Radiofrequency ablation (RFA)
- Endovenous laser therapy (EVLT)
- Transilluminated power phlebectomy (TIPP)
- Foam sclerotherapy is more powerful than a liquid sclerosant. (7)[A]
- Ambulatory phlebectomy-has a lower risk of recurrence than with sclerotherapy. (7)[A]
• Traditional surgical methods include
- Ligation and stripping of the varicose vein (Sclerotherapy: Sclerosing solution is injected into varicosities causing vein walls to swell, adhere, and scar. 50-90% improvement expected [American Academy of Dermatology])
- Stab avulsion phlebectomy
• For extensive fibrosis: Excision of the entire area, followed by skin graft, may be necessary.
• Surgical treatment of clinically symptomatic varicose veins involves treatment of the saphenous vein reflux as well as the varicosities.
PROGNOSIS
• Usual course: Chronic
• Favorable with appropriate treatment
• Quality of surgical treatment is less satisfactory if significant deep venous reflux, history of ulceration, or congenital arteriovenous malformation exists. (6)
COMPLICATIONS
• Petechial hemorrhages
• Chronic edema
• Superimposed infection
• Varicose ulcers
• Pigmentation
• Eczema
• Recurrence after surgical treatment
• Scarring or nerve damage from stripping technique
PATIENT MONITORING
Until surgery or conservative therapy brings maximal benefit
REFERENCES
1. Clarke GH, Vasdekis SN, Hobbs JT, Nicolaides AN. Venous wall function in the pathogenesis of varicose veins. Surgery. 1992;111(4):402-408.
2. Hanrahan LM, et al. Distribution of valvular incompetence in patients with venous stasis ulceration. J Vasc Surg. 1991;13(6):805-811.
3. Fegan WG, Lambe R, Henry M. Steroid hormones and varicose veins. Lancet. 1967;2:1070-1071.
4. Trendelenburg F. Uber die Unterbindung der Vena saphena magna bei Unterschenkelvaricen. [Brun's] Beitrage zur klinischen Chirurgie,1891;7:195-210.
5. Perthes GC. Uber die Operation der Unterschenkelvarizen nach Trendelenburg. Deutsche medizinische Wochenschrift. Berlin,1895;16:253-257.
6. Teruya TH, Ballard JL. New approaches for the treatment of varicose veins. Surg Clin North Am. 2004;84(5):1397-1417.
7. Sadick NS. Advances in the treatment of varicose veins: Ambulatory phlebectomy, foam sclerotherapy, endovascular laser, and radiofrequency closure. Dermatol Clin. 2005;23(3):443-455.
ADDITIONAL READING
• Callam MJ. Epidemiology of varicose veins. Br J Surg. 1994;81:167-173.
• Ellis H, Taylor P. Varicose Veins. 3rd ed. London: Greenwich Medical Media; 1999.
MISCELLANEOUS
See also: Hemorrhoids; Dermatitis, Stasis
VENTRICULAR SEPTAL DEFECT (VSD)
VENTRICULAR SEPTAL DEFECT (VSD) - Brent Barber, MD; Brad Friedman, MD
BASICS
DESCRIPTION
• Congenital or acquired defect of the interventricular septum that allows communication of blood between the left and right ventricles
• Other than bicuspid aortic valve, this is the most common congenital heart malformation reported in infants and children. It also occurs as a complication of acute myocardial infarctions (MI).
• Blood flow across the defect is typically left to right and depends on the size of the defect and the pulmonary vascular resistance (PVR).
• Prolonged shunting of blood can lead to pulmonary hypertension and eventually reversal of flow across the defect, and to cyanosis (Eisenmenger complex).
• System(s) Affected: Cardiovascular
ALERT
Geriatric Considerations
In this population, almost entirely associated with myocardial infarction
Pediatric Considerations
Congenital
Pregnancy Considerations
• Pregnancy may exacerbate symptoms and signs of a VSD.
• Tolerated during pregnancy if the septal defect is small
GENERAL PREVENTION
For adults, avoid risk factors for MI and obtain evaluation before pregnancy.
EPIDEMIOLOGY
• Predominant age: Infants and children
• Predominant sex: Male = Female (Male > Female if secondary to myocardial infarction)
Prevalence
In the US
• Congenital: 100-500 of 100,000 live births
• Acute myocardial infarctions: Estimated to complicate 1-3%
RISK FACTORS
• Congenital
- 4.2% risk of sibling being affected
- 4.0% of offspring being affected
• Post-acute MI
- 1st MI
- Limited coronary artery disease
- Hypertension
- Most frequent within 1st week after MI
- Occur in 1-2% of MI, most commonly after anterior MI
Genetics
Multifactorial etiology; autosomal dominant and recessive transmission have been reported.
ETIOLOGY
• Congenital
• In adults, secondary to MI
ASSOCIATED CONDITIONS
• Congenital
- Tetralogy of Fallot
- Aortic valvular deformities, especially aortic insufficiency
- Down syndrome (Trisomy 21), endocardial cushion defect
- Transposition of the great arteries
- Coarctation of the aorta
- Tricuspid atresia
- Truncus arteriosus
- Patent ductus arteriosus
- Atrial septal defect
- Pulmonic stenosis
- Subaortic stenosis
• Adult: Coronary artery disease
DIAGNOSIS
SIGNS AND SYMPTOMS
• Depend on the degree of shunting across the defect
• Respiratory distress, tachypnea, tachycardia
• Diaphoresis with feeds, poor weight gain in infants
• Forceful apical impulse
• Thrill along the left lower or midsternal borders
• High-frequency holosystolic murmur
• S3
• Increased intensity of P2
• Elevated jugular venous pressure
• Diastolic rumble due to increased flow across the mitral valve
• If pulmonary hypertension exists: Cyanosis with exertion
• If Eisenmenger complex is present: Cyanosis and clubbing
TESTS
Lab
Special tests
• ECG may suggest severity of VSD. Initially, left ventricular hypertrophy and left atrial enlargement may be evident. With pulmonary hypertension, right ventricular hypertrophy and right atrial enlargement may be seen.
• After surgical repair, right bundle branch block and left anterior hemi-block are common.
Imaging
• Chest x-ray may demonstrate increased pulmonary vascularity and/or cardiomegaly.
• 2-dimensional ECG for visualization and size of defect.
• Color-flow Doppler, for direction and velocity of ventricular septal defect jet. May be used to estimate right ventricular pressure
Diagnostic Procedures/Surgery
• Cardiac catheterization (left and right heart) can establish the diagnosis, and quantitate degree of shunting.
• Demonstration of an oxygen saturation step-up from the right atrium to the distal pulmonary artery
Pathological Findings
• Congenital VSDs (4 major anatomical types)
- Membranous (70%)
- Muscular (20%)
- Atrioventricular canal type (5%)
- Supracristal (5%; higher percentage in Asian populations)
• Post-MI VSDs: Involve predominantly the muscular septum
DIFFERENTIAL DIAGNOSIS
• Any defect with left to right shunt, such as patent ductus arteriosus, atrial septal defect
• Children: Tetralogy of Fallot
• Adults: Mitral regurgitation
TREATMENT
GENERAL MEASURES
Appropriate health care
• Outpatient, until surgical repair is indicated
• Inpatient in setting of acute MI
• Inpatient for treatment of severe congestive heart failure
Diet
Low sodium
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Endocarditis antibiotic prophylaxis (1)[A]
• Pediatric
- Furosemide 1-2 mg/kg PO/IV once to twice a day (2)[A]
- Digoxin: Infants 2 years old, 10 ug/kg/d PO divided b.i.d.; children 2-10 years old, 5-10 ug/kg/d PO divided b.i.d.; children >10 years old, 2-5 ug/kg/d PO divided b.i.d.
- Spironolactone: 1-2 mg/kg/d divided b.i.d.
- Captopril: 0.1-0.4 mg/kg PO given q6-24h (max 6 mg/kg per 24 hours)
• Adult: Digoxin and diuretics may be beneficial in some circumstances.
• Precautions
- Drugs that increase peripheral vascular resistance may increase left-to-right shunting and cause signs and symptoms of pulmonary overcirculation.
- Hypotension
• Significant possible interactions: Refer to manufacturer's profile for each drug.
SURGERY
• Surgical closure is generally indicated if the pulmonic-to-systemic flow is >1.5:1.
• Congenital VSD surgery is usually performed before the child enters school or earlier, if hemodynamically indicated. (3)[A]
• Percutaneous transcatheter device closure of muscular and perimembranous is an alternative to surgery which has shown promising results. (4)[B]
• In the post-MI setting, afterload reduction, inotropic support, and intra-aortic balloon pump may be used to stabilize the patient prior to surgery.
FOLLOW-UP
PROGNOSIS
• Congenital:
- Course is variable, depending on the size of the VSD.
- Small VSD: 25-45% will close spontaneously by age 3 years. Muscular defects are more likely to close spontaneously.
- Large VSD: CHF, failure to thrive in infancy, necessitating surgical repair
- 4% of patients with VSD develop infective endocarditis by the 3rd or 4th decade of life.
- Progressive pulmonary vascular disease and pulmonary hypertension are the most feared complications of VSD caused by left-to-right shunting, and may eventually lead to reversal of the shunt (Eisenmenger complex). Death usually occurs in the 4th decade of life if untreated.
• Post-MI:
- With medical management alone, 80-90% mortality in the 1st 2 weeks
- Prognosis worse with inferior MI compared to anterior MI
COMPLICATIONS
• CHF
• Infective endocarditis
• Aortic insufficiency
• Sudden death
• Hemoptysis
• Chest pain
• Cerebral abscess
• Paradoxical emboli
• Cardiogenic shock
• Heart block may rarely accompany surgical closure.
• Pulmonary hypertension
PATIENT MONITORING
Close follow-up of a congenital VSD is necessary until primary intracardiac repair is performed, to ensure that significant pulmonary hypertension does not develop.
REFERENCES
1. Glen S, Burns J, Bloomfield P. Prevalence and development of additional cardiac abnormalities in 1448 patients with congenital VSD. Heart. 2004;90(11):1321-1325.
2. Faris R, et al. Diuretics for heart failure. The Cochrane Database of Systemic Reviews: John Wiley and Sons; 2006.
3. Chang RK, Chen A, Klitzner TS. Factors associated with age at operation for children with congenital heart disease. Pediatrics. 2000;(105):1073-1081.
4. Hein R, et al. Atrial and septal defects can safely be closed by percutaneous intervention. J Interventional Cardiol. 2005;(18):515-522.
MISCELLANEOUS
See also: Down Syndrome; Myocardial Infarction; Tetralogy of Fallot
BASICS
DESCRIPTION
• Congenital or acquired defect of the interventricular septum that allows communication of blood between the left and right ventricles
• Other than bicuspid aortic valve, this is the most common congenital heart malformation reported in infants and children. It also occurs as a complication of acute myocardial infarctions (MI).
• Blood flow across the defect is typically left to right and depends on the size of the defect and the pulmonary vascular resistance (PVR).
• Prolonged shunting of blood can lead to pulmonary hypertension and eventually reversal of flow across the defect, and to cyanosis (Eisenmenger complex).
• System(s) Affected: Cardiovascular
ALERT
Geriatric Considerations
In this population, almost entirely associated with myocardial infarction
Pediatric Considerations
Congenital
Pregnancy Considerations
• Pregnancy may exacerbate symptoms and signs of a VSD.
• Tolerated during pregnancy if the septal defect is small
GENERAL PREVENTION
For adults, avoid risk factors for MI and obtain evaluation before pregnancy.
EPIDEMIOLOGY
• Predominant age: Infants and children
• Predominant sex: Male = Female (Male > Female if secondary to myocardial infarction)
Prevalence
In the US
• Congenital: 100-500 of 100,000 live births
• Acute myocardial infarctions: Estimated to complicate 1-3%
RISK FACTORS
• Congenital
- 4.2% risk of sibling being affected
- 4.0% of offspring being affected
• Post-acute MI
- 1st MI
- Limited coronary artery disease
- Hypertension
- Most frequent within 1st week after MI
- Occur in 1-2% of MI, most commonly after anterior MI
Genetics
Multifactorial etiology; autosomal dominant and recessive transmission have been reported.
ETIOLOGY
• Congenital
• In adults, secondary to MI
ASSOCIATED CONDITIONS
• Congenital
- Tetralogy of Fallot
- Aortic valvular deformities, especially aortic insufficiency
- Down syndrome (Trisomy 21), endocardial cushion defect
- Transposition of the great arteries
- Coarctation of the aorta
- Tricuspid atresia
- Truncus arteriosus
- Patent ductus arteriosus
- Atrial septal defect
- Pulmonic stenosis
- Subaortic stenosis
• Adult: Coronary artery disease
DIAGNOSIS
SIGNS AND SYMPTOMS
• Depend on the degree of shunting across the defect
• Respiratory distress, tachypnea, tachycardia
• Diaphoresis with feeds, poor weight gain in infants
• Forceful apical impulse
• Thrill along the left lower or midsternal borders
• High-frequency holosystolic murmur
• S3
• Increased intensity of P2
• Elevated jugular venous pressure
• Diastolic rumble due to increased flow across the mitral valve
• If pulmonary hypertension exists: Cyanosis with exertion
• If Eisenmenger complex is present: Cyanosis and clubbing
TESTS
Lab
Special tests
• ECG may suggest severity of VSD. Initially, left ventricular hypertrophy and left atrial enlargement may be evident. With pulmonary hypertension, right ventricular hypertrophy and right atrial enlargement may be seen.
• After surgical repair, right bundle branch block and left anterior hemi-block are common.
Imaging
• Chest x-ray may demonstrate increased pulmonary vascularity and/or cardiomegaly.
• 2-dimensional ECG for visualization and size of defect.
• Color-flow Doppler, for direction and velocity of ventricular septal defect jet. May be used to estimate right ventricular pressure
Diagnostic Procedures/Surgery
• Cardiac catheterization (left and right heart) can establish the diagnosis, and quantitate degree of shunting.
• Demonstration of an oxygen saturation step-up from the right atrium to the distal pulmonary artery
Pathological Findings
• Congenital VSDs (4 major anatomical types)
- Membranous (70%)
- Muscular (20%)
- Atrioventricular canal type (5%)
- Supracristal (5%; higher percentage in Asian populations)
• Post-MI VSDs: Involve predominantly the muscular septum
DIFFERENTIAL DIAGNOSIS
• Any defect with left to right shunt, such as patent ductus arteriosus, atrial septal defect
• Children: Tetralogy of Fallot
• Adults: Mitral regurgitation
TREATMENT
GENERAL MEASURES
Appropriate health care
• Outpatient, until surgical repair is indicated
• Inpatient in setting of acute MI
• Inpatient for treatment of severe congestive heart failure
Diet
Low sodium
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Endocarditis antibiotic prophylaxis (1)[A]
• Pediatric
- Furosemide 1-2 mg/kg PO/IV once to twice a day (2)[A]
- Digoxin: Infants 2 years old, 10 ug/kg/d PO divided b.i.d.; children 2-10 years old, 5-10 ug/kg/d PO divided b.i.d.; children >10 years old, 2-5 ug/kg/d PO divided b.i.d.
- Spironolactone: 1-2 mg/kg/d divided b.i.d.
- Captopril: 0.1-0.4 mg/kg PO given q6-24h (max 6 mg/kg per 24 hours)
• Adult: Digoxin and diuretics may be beneficial in some circumstances.
• Precautions
- Drugs that increase peripheral vascular resistance may increase left-to-right shunting and cause signs and symptoms of pulmonary overcirculation.
- Hypotension
• Significant possible interactions: Refer to manufacturer's profile for each drug.
SURGERY
• Surgical closure is generally indicated if the pulmonic-to-systemic flow is >1.5:1.
• Congenital VSD surgery is usually performed before the child enters school or earlier, if hemodynamically indicated. (3)[A]
• Percutaneous transcatheter device closure of muscular and perimembranous is an alternative to surgery which has shown promising results. (4)[B]
• In the post-MI setting, afterload reduction, inotropic support, and intra-aortic balloon pump may be used to stabilize the patient prior to surgery.
FOLLOW-UP
PROGNOSIS
• Congenital:
- Course is variable, depending on the size of the VSD.
- Small VSD: 25-45% will close spontaneously by age 3 years. Muscular defects are more likely to close spontaneously.
- Large VSD: CHF, failure to thrive in infancy, necessitating surgical repair
- 4% of patients with VSD develop infective endocarditis by the 3rd or 4th decade of life.
- Progressive pulmonary vascular disease and pulmonary hypertension are the most feared complications of VSD caused by left-to-right shunting, and may eventually lead to reversal of the shunt (Eisenmenger complex). Death usually occurs in the 4th decade of life if untreated.
• Post-MI:
- With medical management alone, 80-90% mortality in the 1st 2 weeks
- Prognosis worse with inferior MI compared to anterior MI
COMPLICATIONS
• CHF
• Infective endocarditis
• Aortic insufficiency
• Sudden death
• Hemoptysis
• Chest pain
• Cerebral abscess
• Paradoxical emboli
• Cardiogenic shock
• Heart block may rarely accompany surgical closure.
• Pulmonary hypertension
PATIENT MONITORING
Close follow-up of a congenital VSD is necessary until primary intracardiac repair is performed, to ensure that significant pulmonary hypertension does not develop.
REFERENCES
1. Glen S, Burns J, Bloomfield P. Prevalence and development of additional cardiac abnormalities in 1448 patients with congenital VSD. Heart. 2004;90(11):1321-1325.
2. Faris R, et al. Diuretics for heart failure. The Cochrane Database of Systemic Reviews: John Wiley and Sons; 2006.
3. Chang RK, Chen A, Klitzner TS. Factors associated with age at operation for children with congenital heart disease. Pediatrics. 2000;(105):1073-1081.
4. Hein R, et al. Atrial and septal defects can safely be closed by percutaneous intervention. J Interventional Cardiol. 2005;(18):515-522.
MISCELLANEOUS
See also: Down Syndrome; Myocardial Infarction; Tetralogy of Fallot
VAGINISMUS
VAGINISMUS - Leena Nathan, MD; Wendy Satmary, MD, FACOG
BASICS
DESCRIPTION
• Involuntary painful contraction of perineal muscles and levator ani prior to or during vaginal intercourse. The experience of or even the anticipation of pain on vaginal entry causes these muscles to contract, occluding the vaginal opening and causing further pain when penetration is attempted. Repeated dyspareunia (pain with intercourse) can cause vaginismus and vaginismus can cause dyspareunia.
• System(s) Affected: Reproductive
ALERT
Pregnancy Considerations
Pregnancy can occur in patients with vaginismus, via perineal ejaculation.
EPIDEMIOLOGY
Predominant age
• Postpubertal
Prevalence
In the US: 5.1-17% in females presenting to sexual dysfunction clinics. No incidence or prevalence data available for occurrence in general population.
RISK FACTORS
• Previous sexual trauma, but rates appear to be similar in abused and nonabused women
• Often associated with other sexual dysfunctions
ETIOLOGY
• Primary: Often multifactorial
- Negative messages about sex and sexual relations in upbringing may cause phobic reaction
- Poor body image of genital area
- History of sexual trauma, although rates of vaginismus appear to be similar in sexually abused and nonabused populations of women (studies show incidence of sexual abuse of women to be 12-40%)
• Secondary
- New onset of infection
- Surgical or postdelivery scarring
- Endometriosis
- Inadequate vaginal lubrication
• Can be complete (perineal spasm with attempts to insert anything into vagina) or situational (tampons or pelvic exams permitted)
ASSOCIATED CONDITIONS
• Marital stress, family dysfunction
• Dyspareunia
DIAGNOSIS
SIGNS AND SYMPTOMS
• Inability to allow entry for vaginal sexual intercourse secondary to involuntary muscle spasms
• Reluctance or avoidance of pelvic examination
• Relationship discord or difficulty
• Infertility
• Sexual satisfaction may be independent of sexual function.
History
General and sexual history
Physical Exam
• At some point, a careful pelvic examination to rule out medical cause
• Lamont classification of degree
- 1st degree: Perineal and levator spasm relieved with reassurance
- 2nd degree: Perineal spasm maintained throughout the pelvic exam
- 3rd degree: Levator spasm and elevation of buttocks
- 4th degree: Levator and perineal spasm and elevation with adduction and retreat
TESTS
Psychiatric consultation if not responsive to primary physician's therapy or if primary provider not comfortable with caring for sexual problems
Pathological Findings
Rarely found in primary vaginismus, but may be varied, such as endometriosis or scarring, in secondary vaginismus
DIFFERENTIAL DIAGNOSIS
Dyspareunia
TREATMENT
GENERAL MEASURES
• Outpatient care
• Can often treat vaginismus successfully without defining/treating its etiologies
• No published controlled studies on success of psychotherapy for vaginismus
• Patient education as noted on pelvic anatomy and sexual function
• Sexual cognitive behavioral therapy has been found to be very effective
• Kegel exercises to control perineal muscles
• Stepwise vaginal desensitization exercises
- With vaginal dilators (patient inserts/controls)
- With woman's own finger(s) (promotes sexual self-awareness)
• Valsalva can help with vaginal entry
• Advance to husband's fingers with patient's control
• Coitus after achieving largest vaginal dilator or 3 fingers; important to begin with sensate-focused exercises/sensual caressing without necessarily a demand for coitus
- Female superior at 1st; passive (nonthrusting); female directed
- Later, thrusting may be allowed
Diet
No special diet
Activity
Simple techniques of gentle, progressive, patient-controlled vaginal dilation
SPECIAL THERAPY
Complementary and Alternative Medicine
• Biofeedback
• Functional electrical stimulation
MEDICATION (DRUGS)
• Botulism toxin: 150-400 U of botulism toxin type A injected in the levator ani at 3 points on each side with 23-gauge needle is effective for 3rd- and 4th-degree disease but still experimental.
• Contraindications: Anxiolytics, especially benzodiazepines
SURGERY
Contraindicated
FOLLOW-UP
PROGNOSIS
• Some studies show high degrees of success (58-70%) with behavioral interventions.
• History of sexual abuse does not predict outcome negatively or positively.
PATIENT MONITORING
General preventive health care
REFERENCES
1. Lamont J. Vaginismus. Am J Obstet Gynecol 1978;131:632-636.
2. Spector IP, Carey MP. Incidence and prevalence of the sexual dysfunctions: A critical review of the empirical literature. Arch Sexual Behavior 1990;19:389-405.
3. Biswas A. Vaginismus and outcome of treatment. Ann Acad Med Singapore 1995;24:755-758.
4. Heiman JR. Evaluating sexual dysfunctions: Primary care of women. Norwalk, CT: Appleton Lange, 1995.
5. Read S, King M, Watson J. Sexual dysfunction in primary medical care. J Public Health Med 1997;19(4):387-391.
6. Sarwer D, Durlak J. A field trial of the effectiveness of behavioral treatment for sexual dysfunctions. J Sex Marital Ther 1997;23(2):87-97.
7. Ghazizadeh S, Nikzad M. Botulism toxin in the treatment of refractory vaginismus. Obstet Gynecol 2004;104:922-925.
MISCELLANEOUS
See also: Dyspareunia; Sexual Dysfunction in Women
BASICS
DESCRIPTION
• Involuntary painful contraction of perineal muscles and levator ani prior to or during vaginal intercourse. The experience of or even the anticipation of pain on vaginal entry causes these muscles to contract, occluding the vaginal opening and causing further pain when penetration is attempted. Repeated dyspareunia (pain with intercourse) can cause vaginismus and vaginismus can cause dyspareunia.
• System(s) Affected: Reproductive
ALERT
Pregnancy Considerations
Pregnancy can occur in patients with vaginismus, via perineal ejaculation.
EPIDEMIOLOGY
Predominant age
• Postpubertal
Prevalence
In the US: 5.1-17% in females presenting to sexual dysfunction clinics. No incidence or prevalence data available for occurrence in general population.
RISK FACTORS
• Previous sexual trauma, but rates appear to be similar in abused and nonabused women
• Often associated with other sexual dysfunctions
ETIOLOGY
• Primary: Often multifactorial
- Negative messages about sex and sexual relations in upbringing may cause phobic reaction
- Poor body image of genital area
- History of sexual trauma, although rates of vaginismus appear to be similar in sexually abused and nonabused populations of women (studies show incidence of sexual abuse of women to be 12-40%)
• Secondary
- New onset of infection
- Surgical or postdelivery scarring
- Endometriosis
- Inadequate vaginal lubrication
• Can be complete (perineal spasm with attempts to insert anything into vagina) or situational (tampons or pelvic exams permitted)
ASSOCIATED CONDITIONS
• Marital stress, family dysfunction
• Dyspareunia
DIAGNOSIS
SIGNS AND SYMPTOMS
• Inability to allow entry for vaginal sexual intercourse secondary to involuntary muscle spasms
• Reluctance or avoidance of pelvic examination
• Relationship discord or difficulty
• Infertility
• Sexual satisfaction may be independent of sexual function.
History
General and sexual history
Physical Exam
• At some point, a careful pelvic examination to rule out medical cause
• Lamont classification of degree
- 1st degree: Perineal and levator spasm relieved with reassurance
- 2nd degree: Perineal spasm maintained throughout the pelvic exam
- 3rd degree: Levator spasm and elevation of buttocks
- 4th degree: Levator and perineal spasm and elevation with adduction and retreat
TESTS
Psychiatric consultation if not responsive to primary physician's therapy or if primary provider not comfortable with caring for sexual problems
Pathological Findings
Rarely found in primary vaginismus, but may be varied, such as endometriosis or scarring, in secondary vaginismus
DIFFERENTIAL DIAGNOSIS
Dyspareunia
TREATMENT
GENERAL MEASURES
• Outpatient care
• Can often treat vaginismus successfully without defining/treating its etiologies
• No published controlled studies on success of psychotherapy for vaginismus
• Patient education as noted on pelvic anatomy and sexual function
• Sexual cognitive behavioral therapy has been found to be very effective
• Kegel exercises to control perineal muscles
• Stepwise vaginal desensitization exercises
- With vaginal dilators (patient inserts/controls)
- With woman's own finger(s) (promotes sexual self-awareness)
• Valsalva can help with vaginal entry
• Advance to husband's fingers with patient's control
• Coitus after achieving largest vaginal dilator or 3 fingers; important to begin with sensate-focused exercises/sensual caressing without necessarily a demand for coitus
- Female superior at 1st; passive (nonthrusting); female directed
- Later, thrusting may be allowed
Diet
No special diet
Activity
Simple techniques of gentle, progressive, patient-controlled vaginal dilation
SPECIAL THERAPY
Complementary and Alternative Medicine
• Biofeedback
• Functional electrical stimulation
MEDICATION (DRUGS)
• Botulism toxin: 150-400 U of botulism toxin type A injected in the levator ani at 3 points on each side with 23-gauge needle is effective for 3rd- and 4th-degree disease but still experimental.
• Contraindications: Anxiolytics, especially benzodiazepines
SURGERY
Contraindicated
FOLLOW-UP
PROGNOSIS
• Some studies show high degrees of success (58-70%) with behavioral interventions.
• History of sexual abuse does not predict outcome negatively or positively.
PATIENT MONITORING
General preventive health care
REFERENCES
1. Lamont J. Vaginismus. Am J Obstet Gynecol 1978;131:632-636.
2. Spector IP, Carey MP. Incidence and prevalence of the sexual dysfunctions: A critical review of the empirical literature. Arch Sexual Behavior 1990;19:389-405.
3. Biswas A. Vaginismus and outcome of treatment. Ann Acad Med Singapore 1995;24:755-758.
4. Heiman JR. Evaluating sexual dysfunctions: Primary care of women. Norwalk, CT: Appleton Lange, 1995.
5. Read S, King M, Watson J. Sexual dysfunction in primary medical care. J Public Health Med 1997;19(4):387-391.
6. Sarwer D, Durlak J. A field trial of the effectiveness of behavioral treatment for sexual dysfunctions. J Sex Marital Ther 1997;23(2):87-97.
7. Ghazizadeh S, Nikzad M. Botulism toxin in the treatment of refractory vaginismus. Obstet Gynecol 2004;104:922-925.
MISCELLANEOUS
See also: Dyspareunia; Sexual Dysfunction in Women
VAGINAL BLEEDING DURING PREGNANCY
VAGINAL BLEEDING DURING PREGNANCY - Kimberle Vore, MD
BASICS
DESCRIPTION
• Vaginal bleeding during pregnancy has many causes and ranges in severity from mild (with normal pregnancy outcome) to life threatening for both infant and mother.
• Bleeding can vary from scant to excessive, from brown to bright red, and can be painless or painful.
• Causes can be divided into vaginal, cervical, and uterine factors. The differential diagnosis is guided by the gestational age of the pregnancy.
• System(s) Affected: Cardiovascular; Reproductive
ALERT
Pregnancy Considerations
A complication of pregnancy
EPIDEMIOLOGY
• Predominant age: Childbearing
• Predominant sex: Female only
Prevalence
In the US: Common
RISK FACTORS
• Cervical or vaginal infections
- Multiple sexual partners
- Previous history of sexually transmitted disease or pelvic inflammatory disease
• Cervical dysplasia: Previous history of abnormal pap
• Placenta previa
- Previous history of previa
- Previous caesarean section
- History of uterine surgery including dilation and curettage (DC)
• Placental abruption
- Previous history of abruption (increases risk by 10%)
- Hypertension
- Preeclampsia
- Multiple gestation
- Smoking
- Cocaine use
Genetics
No known genetic pattern
ETIOLOGY
• Vaginal or cervical causes can occur throughout the pregnancy, and usually are no threat to the pregnancy. They include
- Vaginal infection or trauma
- Cervicitis (infections or noninfections)
- Cervical polyp
- Cervical neoplasia
- Hyperemia of cervix (increased blood flow from pregnancy)
- Postcoital bleeding: Usually cervical source
• Bleeding from above the cervix is a concern because it can be life threatening to mother and/or fetus. In determining the cause it is helpful to separate first-trimester bleeding from later-pregnancy bleeding.
- 1st-trimester bleeding causes include Implantation bleedingbenign; ectopic pregnancy; threatened or spontaneous abortion; molar pregnancy; subchorionic bleed
- 2nd- or 3rd-trimester bleeding causes include: Placenta previa (nonpainful); placenta abruption (painful, contraction usually present); subchorionic bleed
• Many times the cause is unknown. For up to 50% of 1st-trimester bleeding, no cause is ever found.
ASSOCIATED CONDITIONS
Depends on cause of vaginal bleeding
DIAGNOSIS
SIGNS AND SYMPTOMS
• Bleeding can vary from scant to excessive.
• Color of blood varies from brown to bright red.
• May be painless or painful
• Patient reports bleeding from vagina.
TESTS
Lab
• Blood work based on dating of pregnancy, previous tests, and need for further diagnosis
• Blood type and screen. If not known already, needs to be done on all women
• Rh-negative patients who bleed during pregnancy will need Rho(d) immune globulin (RhoGAM), to prevent mother from becoming sensitized if exposed to infant's Rh-positive blood. In 3rd-trimester bleeding, the mother may lose significant amounts of blood and require transfusion.
• Quantitative--human chorionic gonadotropin (Q hCG) can be used in early pregnancy when ultrasound is not able to diagnose cause. Ultrasound should be able to see an intrauterine pregnancy (IUP) when Q hCG >2,000.
• Levels can be followed serially every 2 days. Levels fall in spontaneous abortion, are extremely high in molar pregnancy, and rise gradually in ectopic or intrauterine pregnancy. This level usually doubles in 48 hours in normal pregnancy, and failure to increase by 50% is concerning for ectopic
• Once Q hCG level is >2,000, an ultrasound should be performed to confirm diagnosis. When spontaneous abortion is suspected but there is no definitive diagnosis by either ultrasound or pathology confirmation of products of conception, then following Q hCG weekly until level is 25 is advised to exclude possible undiagnosed ectopic pregnancy. If dropping levels start to rise, reconsider ectopic pregnancy. In molar pregnancy, after surgical evacuation of productions of conception, monthly Q hCG are followed for 1 year to rule out the possibility of choriocarcinoma. During this time the patient should be instructed not to get pregnant.
• Other labs are based on severity of bleeding:
- CBC: May be done to assess severity, when bleeding profuse
- Bleeding time, fibrinogen, fibrin split products: Rarely necessary. Disseminated intravascular coagulation (DIC) reported rarely in missed abortion.
Imaging
• Ultrasound (USN) is the diagnostic test of choice. A gestational sac can be seen at 5-6 weeks, fetal heart tone can be observed by 8-9 weeks. USN is diagnostic of molar pregnancy with 98% accuracy. In later pregnancy USN locates the placenta and may show degree of placental separation in abruption.
• Serial ultrasound may be required in early pregnancy.
Diagnostic Procedures/Surgery
• It is important to evaluate whether bleeding is coming from genital tract or from other nearby structures.
• Association of bleeding with other activities or symptoms may aid in the diagnosis (e.g., following bowel movement, after intercourse, associated with abdominal cramping).
• In 1st-trimester bleeding: Pelvic exam is performed to confirm bleeding from cervical os, and if any adnexal masses. If pregnancy is >8 weeks, USN should be done to confirm IUP. If no IUP and USN not confirmatory for ectopic, then serial Q hCG are followed. If pelvic pain and concern for ectopic pregnancy is high but not confirmed by USN, a laparoscopy or laparotomy may be performed to make a diagnosis.
• In 2nd- or 3rd-trimester bleeding: Locate placenta by ultrasound prior to pelvic exam. If placenta previa, do not perform bimanual or speculum exam unless set up for immediate caesarean delivery.
Pathological Findings
Dependent on cause
DIFFERENTIAL DIAGNOSIS
• Hematuria from urinary tract infection (UTI), kidney stones
• Bleeding hemorrhoids
• Rectal bleeding from lower gastrointestinal bleed: Extremely rare in pregnancy
TREATMENT
GENERAL MEASURES
• Appropriate health care
- In 1st-trimester bleeding, most, patients can be managed as outpatients.
- In late-pregnancy bleeding, most patients need inpatient monitoring.
• In late-pregnancy bleeding, the amount of bleeding and presence of maternal or fetal compromise indicates whether emergent caesarean section is performed or whether conservative measures are appropriate until greater fetal lung maturity can be obtained.
• Threatened abortion: Bed rest and nothing in the vagina. If bleeding is severe, hospitalization and close observation. Type and screen for possible transfusion.
Diet
No restrictions
Activity
Bed rest: no coitus, no douching
MEDICATION (DRUGS)
First Line
Rho(d) immune globulin (Rhogam) if mother Rh-negative and significant bleeding from uterus
Second Line
Tocolytics in suspected premature labor
SURGERY
• If ectopic or molar pregnancy is diagnosed, immediate surgical treatment may be needed in some cases.
• Some early ectopic pregnancies can be treated medically if certain criteria are met.
• Inevitable or incomplete abortion: DC (usually suction).
• If completeness of abortion is in doubt, then DC and removal of retained products
• Caesarean section for placenta previa or placental abruption
FOLLOW-UP
PROGNOSIS
• Depends on the cause of vaginal bleeding, the severity of bleeding, and the rapidity of diagnosis. Maternal mortality is 31.9 per 100,000 of ectopic pregnancies. (4)
• If fetal heart tones present in first trimester bleed, 10% chance of pregnancy loss
COMPLICATIONS
• Anemia
• Shock
• Fetal or maternal death
• Infection
• Choriocarcinoma or invasive mole in the case of hydatidiform mole
• Premature delivery of infant with associated complications
• Coagulopathy (extremely rare)
PATIENT MONITORING
Daily to weekly, depending on diagnosis and severity of bleeding
REFERENCES
1. American College of Emergency Physicians. Clinical policy for the initial approach to patients presenting with a chief complaint of vaginal bleeding. Ann Emerg Med. 1997;29(3):435-458.
2. Suspected ectopic pregnancy. Obstet Gynecol. 2006;107:399-413.
3. Signore CC. Second trimester vaginal bleeding: Correllation of ultrasonographic findings with perinatal outcome. Am J Obstet Gynecol. 1998;179(2):336-340.
4. Estimation of pregnancy-related mortality risk by pregnancy outcome, United States, 1991 to 1999. Am J Obstet Gynecol. 2006;194:92-94.
MISCELLANEOUS
See also: Abnormal Pap Smear; Abortion, Spontaneous; Abruptio Placentae; Cervical Dysplasia; Cervical Malignancy; Cervical Polyps; Cervicitis; Cervicitis, Ectropion and True Erosion; Chlamydial Sexually Transmitted Diseases; Ectopic Pregnancy; Placenta Previa; Preterm Labor; Trichomoniasis; Vaginal Malignancy; Vulvovaginitis, Bacterial; Vulvovaginitis, Candidal
BASICS
DESCRIPTION
• Vaginal bleeding during pregnancy has many causes and ranges in severity from mild (with normal pregnancy outcome) to life threatening for both infant and mother.
• Bleeding can vary from scant to excessive, from brown to bright red, and can be painless or painful.
• Causes can be divided into vaginal, cervical, and uterine factors. The differential diagnosis is guided by the gestational age of the pregnancy.
• System(s) Affected: Cardiovascular; Reproductive
ALERT
Pregnancy Considerations
A complication of pregnancy
EPIDEMIOLOGY
• Predominant age: Childbearing
• Predominant sex: Female only
Prevalence
In the US: Common
RISK FACTORS
• Cervical or vaginal infections
- Multiple sexual partners
- Previous history of sexually transmitted disease or pelvic inflammatory disease
• Cervical dysplasia: Previous history of abnormal pap
• Placenta previa
- Previous history of previa
- Previous caesarean section
- History of uterine surgery including dilation and curettage (DC)
• Placental abruption
- Previous history of abruption (increases risk by 10%)
- Hypertension
- Preeclampsia
- Multiple gestation
- Smoking
- Cocaine use
Genetics
No known genetic pattern
ETIOLOGY
• Vaginal or cervical causes can occur throughout the pregnancy, and usually are no threat to the pregnancy. They include
- Vaginal infection or trauma
- Cervicitis (infections or noninfections)
- Cervical polyp
- Cervical neoplasia
- Hyperemia of cervix (increased blood flow from pregnancy)
- Postcoital bleeding: Usually cervical source
• Bleeding from above the cervix is a concern because it can be life threatening to mother and/or fetus. In determining the cause it is helpful to separate first-trimester bleeding from later-pregnancy bleeding.
- 1st-trimester bleeding causes include Implantation bleedingbenign; ectopic pregnancy; threatened or spontaneous abortion; molar pregnancy; subchorionic bleed
- 2nd- or 3rd-trimester bleeding causes include: Placenta previa (nonpainful); placenta abruption (painful, contraction usually present); subchorionic bleed
• Many times the cause is unknown. For up to 50% of 1st-trimester bleeding, no cause is ever found.
ASSOCIATED CONDITIONS
Depends on cause of vaginal bleeding
DIAGNOSIS
SIGNS AND SYMPTOMS
• Bleeding can vary from scant to excessive.
• Color of blood varies from brown to bright red.
• May be painless or painful
• Patient reports bleeding from vagina.
TESTS
Lab
• Blood work based on dating of pregnancy, previous tests, and need for further diagnosis
• Blood type and screen. If not known already, needs to be done on all women
• Rh-negative patients who bleed during pregnancy will need Rho(d) immune globulin (RhoGAM), to prevent mother from becoming sensitized if exposed to infant's Rh-positive blood. In 3rd-trimester bleeding, the mother may lose significant amounts of blood and require transfusion.
• Quantitative--human chorionic gonadotropin (Q hCG) can be used in early pregnancy when ultrasound is not able to diagnose cause. Ultrasound should be able to see an intrauterine pregnancy (IUP) when Q hCG >2,000.
• Levels can be followed serially every 2 days. Levels fall in spontaneous abortion, are extremely high in molar pregnancy, and rise gradually in ectopic or intrauterine pregnancy. This level usually doubles in 48 hours in normal pregnancy, and failure to increase by 50% is concerning for ectopic
• Once Q hCG level is >2,000, an ultrasound should be performed to confirm diagnosis. When spontaneous abortion is suspected but there is no definitive diagnosis by either ultrasound or pathology confirmation of products of conception, then following Q hCG weekly until level is 25 is advised to exclude possible undiagnosed ectopic pregnancy. If dropping levels start to rise, reconsider ectopic pregnancy. In molar pregnancy, after surgical evacuation of productions of conception, monthly Q hCG are followed for 1 year to rule out the possibility of choriocarcinoma. During this time the patient should be instructed not to get pregnant.
• Other labs are based on severity of bleeding:
- CBC: May be done to assess severity, when bleeding profuse
- Bleeding time, fibrinogen, fibrin split products: Rarely necessary. Disseminated intravascular coagulation (DIC) reported rarely in missed abortion.
Imaging
• Ultrasound (USN) is the diagnostic test of choice. A gestational sac can be seen at 5-6 weeks, fetal heart tone can be observed by 8-9 weeks. USN is diagnostic of molar pregnancy with 98% accuracy. In later pregnancy USN locates the placenta and may show degree of placental separation in abruption.
• Serial ultrasound may be required in early pregnancy.
Diagnostic Procedures/Surgery
• It is important to evaluate whether bleeding is coming from genital tract or from other nearby structures.
• Association of bleeding with other activities or symptoms may aid in the diagnosis (e.g., following bowel movement, after intercourse, associated with abdominal cramping).
• In 1st-trimester bleeding: Pelvic exam is performed to confirm bleeding from cervical os, and if any adnexal masses. If pregnancy is >8 weeks, USN should be done to confirm IUP. If no IUP and USN not confirmatory for ectopic, then serial Q hCG are followed. If pelvic pain and concern for ectopic pregnancy is high but not confirmed by USN, a laparoscopy or laparotomy may be performed to make a diagnosis.
• In 2nd- or 3rd-trimester bleeding: Locate placenta by ultrasound prior to pelvic exam. If placenta previa, do not perform bimanual or speculum exam unless set up for immediate caesarean delivery.
Pathological Findings
Dependent on cause
DIFFERENTIAL DIAGNOSIS
• Hematuria from urinary tract infection (UTI), kidney stones
• Bleeding hemorrhoids
• Rectal bleeding from lower gastrointestinal bleed: Extremely rare in pregnancy
TREATMENT
GENERAL MEASURES
• Appropriate health care
- In 1st-trimester bleeding, most, patients can be managed as outpatients.
- In late-pregnancy bleeding, most patients need inpatient monitoring.
• In late-pregnancy bleeding, the amount of bleeding and presence of maternal or fetal compromise indicates whether emergent caesarean section is performed or whether conservative measures are appropriate until greater fetal lung maturity can be obtained.
• Threatened abortion: Bed rest and nothing in the vagina. If bleeding is severe, hospitalization and close observation. Type and screen for possible transfusion.
Diet
No restrictions
Activity
Bed rest: no coitus, no douching
MEDICATION (DRUGS)
First Line
Rho(d) immune globulin (Rhogam) if mother Rh-negative and significant bleeding from uterus
Second Line
Tocolytics in suspected premature labor
SURGERY
• If ectopic or molar pregnancy is diagnosed, immediate surgical treatment may be needed in some cases.
• Some early ectopic pregnancies can be treated medically if certain criteria are met.
• Inevitable or incomplete abortion: DC (usually suction).
• If completeness of abortion is in doubt, then DC and removal of retained products
• Caesarean section for placenta previa or placental abruption
FOLLOW-UP
PROGNOSIS
• Depends on the cause of vaginal bleeding, the severity of bleeding, and the rapidity of diagnosis. Maternal mortality is 31.9 per 100,000 of ectopic pregnancies. (4)
• If fetal heart tones present in first trimester bleed, 10% chance of pregnancy loss
COMPLICATIONS
• Anemia
• Shock
• Fetal or maternal death
• Infection
• Choriocarcinoma or invasive mole in the case of hydatidiform mole
• Premature delivery of infant with associated complications
• Coagulopathy (extremely rare)
PATIENT MONITORING
Daily to weekly, depending on diagnosis and severity of bleeding
REFERENCES
1. American College of Emergency Physicians. Clinical policy for the initial approach to patients presenting with a chief complaint of vaginal bleeding. Ann Emerg Med. 1997;29(3):435-458.
2. Suspected ectopic pregnancy. Obstet Gynecol. 2006;107:399-413.
3. Signore CC. Second trimester vaginal bleeding: Correllation of ultrasonographic findings with perinatal outcome. Am J Obstet Gynecol. 1998;179(2):336-340.
4. Estimation of pregnancy-related mortality risk by pregnancy outcome, United States, 1991 to 1999. Am J Obstet Gynecol. 2006;194:92-94.
MISCELLANEOUS
See also: Abnormal Pap Smear; Abortion, Spontaneous; Abruptio Placentae; Cervical Dysplasia; Cervical Malignancy; Cervical Polyps; Cervicitis; Cervicitis, Ectropion and True Erosion; Chlamydial Sexually Transmitted Diseases; Ectopic Pregnancy; Placenta Previa; Preterm Labor; Trichomoniasis; Vaginal Malignancy; Vulvovaginitis, Bacterial; Vulvovaginitis, Candidal
VAGINAL MALIGNANCY
VAGINAL MALIGNANCY - Michael P. Hopkins, MD, MEd; Ahntuan T. Huynh, DO; Eric L. Jenison, MD
BASICS
DESCRIPTION
• Vaginal intraepithelial neoplasia (carcinoma in situ): A premalignant phase with full-thickness neoplastic changes in the superficial epithelium. However, there is no invasion through the basement membrane.
• Invasive malignancies: Vaginal malignancies are squamous cell in 90% of patients; the remaining 10% are adenocarcinomas, sarcomas, and melanomas. The clear-cell carcinoma is a subtype of adenocarcinoma.
• To be classified as a vaginal malignancy, only the vagina can be involved. If the cervix or the vulva is involved, then the tumor is classified as a primary cancer arising from the cervix or the vulva.
• System(s) Affected: Reproductive
• Synonym(s): Bowen disease; Vaginal intraepithelial neoplasia (VAIN)
ALERT
Geriatric Considerations
Older patients, many with a long history of smoking, are at a higher risk for malignancies requiring surgical treatments.
Pediatric Considerations
Childhood sarcomas can be treated in a conservative fashion with multimodality therapy. This avoids the loss of the young child's bladder and/or rectum.
Pregnancy Considerations
This malignancy is not associated with pregnancy.
EPIDEMIOLOGY
Incidence
• Predominant age
- Carcinoma in situ: Mid-40s-60s
- Invasive squamous cell malignancy: Mid-60s-70s
- Adenocarcinoma: Any age range, 50s is mean age
- Mixed Mullerian sarcomas and leiomyosarcomas in the adult population: Mean age 60 years
- Sarcoma botryoides and embryonal sarcomas: Occur in the pediatric population
• Predominant sex: Female only
Prevalence
In the US: This is 1 of the rarest of all gynecologic malignancies.
RISK FACTORS
• History of squamous cell cancer of the cervix or vulva
• Smoking
• Multiple sex partners
• Age
• Vaginal adenosis
• HPV infection
• Daughters of mothers who took diethylstilbestrol (DES)
Genetics
No known genetic pattern
ETIOLOGY
• Women with a history of cervical malignancy have a higher probability of developing squamous cell malignancy in the vagina after hysterectomy.
• The human papilloma virus (HPV) has been associated with vulvovaginal, cervical, adenocarcinoma, and squamous cell carcinoma.
• Smokers have a higher incidence.
• Clear-cell adenocarcinoma of the vagina in young women has been associated with DES exposure. The incidence, however, is exceedingly rare, estimated at 1:1,000-1:10,000 DES-exposed females.
• Metastatic lesions can involve the vagina from the other gynecologic organs.
• Renal cell carcinoma and breast cancer can metastasize to the vagina (rarely).
ASSOCIATED CONDITIONS
Due to the field effect, patients with vaginal cancer are more likely to develop malignancy in the cervix or vulva and should be followed closely.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Abnormal bleeding is the most common symptom. This results from a fungating tumor present in the vagina.
• Dyspareunia
• Postcoital bleeding can result from direct trauma to the tumor.
• Pain along with symptoms and signs of hydroureter are late findings when the tumor has spread into the paravaginal tissues and extends to the pelvic side wall.
• In the pediatric population, sarcomas can present either as a mass protruding from the vagina or as abnormal genital bleeding.
TESTS
Lab
Cytology will usually be positive when an obvious lesion is present.
Imaging
• Chest x-ray: Lung metastases are a late finding.
• Intravenous pyelogram (IVP): To evaluate for ureteral obstruction
• CAT scan to evaluate the retroperitoneum and especially the lymph nodes in the pelvic and periaortic area
• Lymphangiography is also useful for evaluation of the lymph node status.
• Barium enema to rule out rectal invasion
Diagnostic Procedures/Surgery
• Colposcopy with directed biopsies for small lesions
• Wide excision under anesthesia of superficial disease may be necessary to ensure that invasive cancer is not present.
• Cystoscopy to rule out bladder invasion
• Sigmoidoscopy to rule out rectal invasion
Pathological Findings
• Stage 0: Carcinoma in situ
• Stage I: Infiltrative tumor not involving the paravaginal tissues
• Stage II: Paravaginal extension but not to the side wall
• Stage III: Paravaginal extension to the side wall
• Stage IVA: Tumor involving the bladder or the rectum
• Stage IVB: Distant metastatic disease
DIFFERENTIAL DIAGNOSIS
• VAIN involves premalignant changes that do not infiltrate beyond the basement membrane.
• Adequate biopsies ensure that invasive lesions are not overlooked. Invasive lesions penetrate the basement membrane and cannot be treated conservatively. Other malignancies such as endometrial, cervix, bladder, or colon cancer can invade directly into the vagina or metastasize to the vagina.
• In the childbearing ages, trophoblastic disease should be considered. The vagina is a common site of metastases. Biopsy will usually provide a clue to the primary site.
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient or inpatient, depending on treatment
• Carcinoma in situ can be treated by a variety of methods: Laser vaporization under microscopic guidance; fluorouracil (Efudex) intravaginal cream; partial vaginectomy
• In all tumor types, metastatic disease from the vagina to other sites is only minimally responsive to chemotherapy.
Diet
Unrestricted unless undergoing radiation
Activity
• Patients are usually ambulatory and able to resume full activity by 6 weeks after surgery.
• Most patients are fully active while receiving radiation therapy.
SPECIAL THERAPY
Radiotherapy
• Treatment with radiotherapy is dependent on the stage of disease. This treatment option should be discussed with physicians experienced with this malignancy. (1,2)[C]
MEDICATION (DRUGS)
First Line
• With 1 exception, there are no chemotherapeutic agents to which this tumor is responsive. The exception is the childhood sarcomas, which have been treated with combinations of
- Vincristine
- Dactinomycin (actinomycin-D)
- Cyclophosphamide (Cytoxan)
- Cisplatin
- Etoposide (VP-16)
• Patients with advanced cervical cancer receive concurrent irradiation and cisplatin-based chemotherapy. This may become a treatment option for advanced carcinoma of the vagina. (2)[C]
• Adjuvant chemotherapy has no proven benefit in squamous cell or adenocarcinoma of the vagina.
• Intraepithelial neoplasia of the vagina can be treated with topical chemotherapy (5-fluorouracil cream). (1,3)[C]
• Contraindications
- The diagnosis must be established with certainty prior to treatment.
- If there is any doubt that a process beyond in situ disease exists, vaginectomy must be performed. Because these patients are often elderly, aggressive therapy is limited by the patient's performance status and ability to tolerate radical surgery, chemotherapy, or radiation.
• Precautions: Refer to the manufacturer's literature.
• Significant possible interactions: Refer to the manufacturer's literature.
Second Line
Ondansetron (Zofran), dronabinol (Marinol), metoclopramide (Reglan), and others for nausea control
SURGERY
• Whenever there is a doubt as to the presence or absence of invasive disease, vaginectomy must be performed.
• Invasive lesions are usually treated by radiation therapy, but stage I lesions can be treated with radical hysterectomy, radical vaginectomy with pelvic lymph node dissection. (1)[C]
• If the lesion involves the lower vagina, inguinal node dissection must also be done, as cancer involving the lower vagina can metastasize to the groin region.
• Premenopausal women, who desire to retain ovarian function, are better candidates for radical surgery for early-stage disease.
• Younger patients, who have not completed their family, can occasionally be treated with limited resection and localized radiation to the area.
• Sarcomas are treated by radiation therapy followed by pelvic exenteration if persistent disease is present.
• Childhood sarcomas are treated with chemotherapy followed by local resection. Childhood sarcomas are responsive to multiagent combination chemotherapies.
FOLLOW-UP
PROGNOSIS
Stage and 5-year survival
• I: 60%
• II: 40%
• III: 20%
• IVA: 5%
• IVB: 0%
COMPLICATIONS
Those associated with major abdominal surgery or radiation therapy
PATIENT MONITORING
• Pelvic examination and Pap smear every 3 months for 2 years and then every 6 months for subsequent 3 years
• Chest x-ray once a year
REFERENCES
1. Creasman WT. Vaginal cancers. Curr Opin Obstet Gynecol. 2005;17:71-76.
2. Grigsby PW. Vaginal cancer. Curr Treat Options Oncol. 2002;3:125-130.
3. Cardosi RJ, Bomalaski JJ, Hoffman MS. Diagnosis and management of vulvar and vaginal intraepithelial neoplasia. Obstet Gynecol Clin North Am. 2001;28:685-702.
4. Yalcin OT, et al. Vaginal intraepithelial neoplasia: Treatment by carbon dioxide laser and risk factors for failure. Eur J Obstet Gynecol Reprod Biol. 2003;106:64-68.
MISCELLANEOUS
This is an uncommon malignancy, and patients should be treated by a physician familiar and experienced with this malignancy.
BASICS
DESCRIPTION
• Vaginal intraepithelial neoplasia (carcinoma in situ): A premalignant phase with full-thickness neoplastic changes in the superficial epithelium. However, there is no invasion through the basement membrane.
• Invasive malignancies: Vaginal malignancies are squamous cell in 90% of patients; the remaining 10% are adenocarcinomas, sarcomas, and melanomas. The clear-cell carcinoma is a subtype of adenocarcinoma.
• To be classified as a vaginal malignancy, only the vagina can be involved. If the cervix or the vulva is involved, then the tumor is classified as a primary cancer arising from the cervix or the vulva.
• System(s) Affected: Reproductive
• Synonym(s): Bowen disease; Vaginal intraepithelial neoplasia (VAIN)
ALERT
Geriatric Considerations
Older patients, many with a long history of smoking, are at a higher risk for malignancies requiring surgical treatments.
Pediatric Considerations
Childhood sarcomas can be treated in a conservative fashion with multimodality therapy. This avoids the loss of the young child's bladder and/or rectum.
Pregnancy Considerations
This malignancy is not associated with pregnancy.
EPIDEMIOLOGY
Incidence
• Predominant age
- Carcinoma in situ: Mid-40s-60s
- Invasive squamous cell malignancy: Mid-60s-70s
- Adenocarcinoma: Any age range, 50s is mean age
- Mixed Mullerian sarcomas and leiomyosarcomas in the adult population: Mean age 60 years
- Sarcoma botryoides and embryonal sarcomas: Occur in the pediatric population
• Predominant sex: Female only
Prevalence
In the US: This is 1 of the rarest of all gynecologic malignancies.
RISK FACTORS
• History of squamous cell cancer of the cervix or vulva
• Smoking
• Multiple sex partners
• Age
• Vaginal adenosis
• HPV infection
• Daughters of mothers who took diethylstilbestrol (DES)
Genetics
No known genetic pattern
ETIOLOGY
• Women with a history of cervical malignancy have a higher probability of developing squamous cell malignancy in the vagina after hysterectomy.
• The human papilloma virus (HPV) has been associated with vulvovaginal, cervical, adenocarcinoma, and squamous cell carcinoma.
• Smokers have a higher incidence.
• Clear-cell adenocarcinoma of the vagina in young women has been associated with DES exposure. The incidence, however, is exceedingly rare, estimated at 1:1,000-1:10,000 DES-exposed females.
• Metastatic lesions can involve the vagina from the other gynecologic organs.
• Renal cell carcinoma and breast cancer can metastasize to the vagina (rarely).
ASSOCIATED CONDITIONS
Due to the field effect, patients with vaginal cancer are more likely to develop malignancy in the cervix or vulva and should be followed closely.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Abnormal bleeding is the most common symptom. This results from a fungating tumor present in the vagina.
• Dyspareunia
• Postcoital bleeding can result from direct trauma to the tumor.
• Pain along with symptoms and signs of hydroureter are late findings when the tumor has spread into the paravaginal tissues and extends to the pelvic side wall.
• In the pediatric population, sarcomas can present either as a mass protruding from the vagina or as abnormal genital bleeding.
TESTS
Lab
Cytology will usually be positive when an obvious lesion is present.
Imaging
• Chest x-ray: Lung metastases are a late finding.
• Intravenous pyelogram (IVP): To evaluate for ureteral obstruction
• CAT scan to evaluate the retroperitoneum and especially the lymph nodes in the pelvic and periaortic area
• Lymphangiography is also useful for evaluation of the lymph node status.
• Barium enema to rule out rectal invasion
Diagnostic Procedures/Surgery
• Colposcopy with directed biopsies for small lesions
• Wide excision under anesthesia of superficial disease may be necessary to ensure that invasive cancer is not present.
• Cystoscopy to rule out bladder invasion
• Sigmoidoscopy to rule out rectal invasion
Pathological Findings
• Stage 0: Carcinoma in situ
• Stage I: Infiltrative tumor not involving the paravaginal tissues
• Stage II: Paravaginal extension but not to the side wall
• Stage III: Paravaginal extension to the side wall
• Stage IVA: Tumor involving the bladder or the rectum
• Stage IVB: Distant metastatic disease
DIFFERENTIAL DIAGNOSIS
• VAIN involves premalignant changes that do not infiltrate beyond the basement membrane.
• Adequate biopsies ensure that invasive lesions are not overlooked. Invasive lesions penetrate the basement membrane and cannot be treated conservatively. Other malignancies such as endometrial, cervix, bladder, or colon cancer can invade directly into the vagina or metastasize to the vagina.
• In the childbearing ages, trophoblastic disease should be considered. The vagina is a common site of metastases. Biopsy will usually provide a clue to the primary site.
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient or inpatient, depending on treatment
• Carcinoma in situ can be treated by a variety of methods: Laser vaporization under microscopic guidance; fluorouracil (Efudex) intravaginal cream; partial vaginectomy
• In all tumor types, metastatic disease from the vagina to other sites is only minimally responsive to chemotherapy.
Diet
Unrestricted unless undergoing radiation
Activity
• Patients are usually ambulatory and able to resume full activity by 6 weeks after surgery.
• Most patients are fully active while receiving radiation therapy.
SPECIAL THERAPY
Radiotherapy
• Treatment with radiotherapy is dependent on the stage of disease. This treatment option should be discussed with physicians experienced with this malignancy. (1,2)[C]
MEDICATION (DRUGS)
First Line
• With 1 exception, there are no chemotherapeutic agents to which this tumor is responsive. The exception is the childhood sarcomas, which have been treated with combinations of
- Vincristine
- Dactinomycin (actinomycin-D)
- Cyclophosphamide (Cytoxan)
- Cisplatin
- Etoposide (VP-16)
• Patients with advanced cervical cancer receive concurrent irradiation and cisplatin-based chemotherapy. This may become a treatment option for advanced carcinoma of the vagina. (2)[C]
• Adjuvant chemotherapy has no proven benefit in squamous cell or adenocarcinoma of the vagina.
• Intraepithelial neoplasia of the vagina can be treated with topical chemotherapy (5-fluorouracil cream). (1,3)[C]
• Contraindications
- The diagnosis must be established with certainty prior to treatment.
- If there is any doubt that a process beyond in situ disease exists, vaginectomy must be performed. Because these patients are often elderly, aggressive therapy is limited by the patient's performance status and ability to tolerate radical surgery, chemotherapy, or radiation.
• Precautions: Refer to the manufacturer's literature.
• Significant possible interactions: Refer to the manufacturer's literature.
Second Line
Ondansetron (Zofran), dronabinol (Marinol), metoclopramide (Reglan), and others for nausea control
SURGERY
• Whenever there is a doubt as to the presence or absence of invasive disease, vaginectomy must be performed.
• Invasive lesions are usually treated by radiation therapy, but stage I lesions can be treated with radical hysterectomy, radical vaginectomy with pelvic lymph node dissection. (1)[C]
• If the lesion involves the lower vagina, inguinal node dissection must also be done, as cancer involving the lower vagina can metastasize to the groin region.
• Premenopausal women, who desire to retain ovarian function, are better candidates for radical surgery for early-stage disease.
• Younger patients, who have not completed their family, can occasionally be treated with limited resection and localized radiation to the area.
• Sarcomas are treated by radiation therapy followed by pelvic exenteration if persistent disease is present.
• Childhood sarcomas are treated with chemotherapy followed by local resection. Childhood sarcomas are responsive to multiagent combination chemotherapies.
FOLLOW-UP
PROGNOSIS
Stage and 5-year survival
• I: 60%
• II: 40%
• III: 20%
• IVA: 5%
• IVB: 0%
COMPLICATIONS
Those associated with major abdominal surgery or radiation therapy
PATIENT MONITORING
• Pelvic examination and Pap smear every 3 months for 2 years and then every 6 months for subsequent 3 years
• Chest x-ray once a year
REFERENCES
1. Creasman WT. Vaginal cancers. Curr Opin Obstet Gynecol. 2005;17:71-76.
2. Grigsby PW. Vaginal cancer. Curr Treat Options Oncol. 2002;3:125-130.
3. Cardosi RJ, Bomalaski JJ, Hoffman MS. Diagnosis and management of vulvar and vaginal intraepithelial neoplasia. Obstet Gynecol Clin North Am. 2001;28:685-702.
4. Yalcin OT, et al. Vaginal intraepithelial neoplasia: Treatment by carbon dioxide laser and risk factors for failure. Eur J Obstet Gynecol Reprod Biol. 2003;106:64-68.
MISCELLANEOUS
This is an uncommon malignancy, and patients should be treated by a physician familiar and experienced with this malignancy.
VAGINAL ADENOSIS
VAGINAL ADENOSIS - Michael P. Hopkins, MD, MEd; Jennifer Savitski, MD; Eric L. Jenison, MD
BASICS
DESCRIPTION
• Adenosis is a term used to describe nonepithelialized columnar glandular epithelium in the vagina. At ~15th week of embryological development, the Mullerian system, which forms the upper 2/3 of the vagina, fuses with the invaginating cloaca, which forms the lower vagina. Squamous metaplasia from the cloacal region then produces a squamous epithelium through the vagina. Adenosis occurs when this squamous epithelium fails to completely epithelialize the vagina.
• System(s) Affected: Reproductive
ALERT
Geriatric Considerations
• Adenosis is a disorder of the young female. By the time of menopause the vagina and cervix should be completely epithelialized.
• The presence of glandular epithelium in the postmenopausal patient is an indication for excision and close evaluation for the possibility of a well-differentiated adenocarcinoma.
Pregnancy Considerations
Pregnancy produces a wide eversion of the transformation zone of the cervix. This will occasionally become so widely everted that it will extend onto the vaginal fornices, leading to the impression of adenosis. This will resolve after the pregnancy is completed.
EPIDEMIOLOGY
• Predominant age
- Teenage years: Epithelialization occurs from puberty to 20 years of age.
- By age 30 years, it is extremely rare for adenosis to be present.
• Predominant sex: Female only
Prevalence
In the US: Adenosis is relatively common, affecting 10-20% of young females studied. As maturation progresses with puberty, epithelialization occurs. (3)
RISK FACTORS
Diethylstilbestrol (DES)-exposed females
Genetics
Unknown
ETIOLOGY
• In the vast majority of young females, the etiology is incomplete squamous metaplasia. This occurs as a natural phenomenon and resolves with age.
• In DES-exposed females, the incidence of adenosis is higher and the etiology presumably is from the effect of the DES on the developing embryologic system.
ASSOCIATED CONDITIONS
DES exposure
• Adenosis from DES exposure should lead to an evaluation of other DES-related abnormalities.
• The greatest risk to the patient is from Mullerian tract anomalies. These include cervical abnormalities with cervical hood, ridges, shortened cervix, and incompetent cervix, T-shaped uterine cavity.
• Patients with known DES exposure should have the reproductive tract evaluated prior to conception.
• The vast majority of patients with adenosis have not been DES exposed and do not require evaluation of the reproductive system.
• DES was last used to prevent spontaneous abortion in ~1970. This is a problem of decreasing importance.
DIAGNOSIS
SIGNS AND SYMPTOMS
A clear, watery vaginal discharge, which is the glandular epithelium producing a small amount of mucus
TESTS
Diagnostic Procedures/Surgery
• 4-quadrant Pap smear should be utilized liberally, to isolate quadrants of the vagina which may contain abnormalities. This can be followed by colposcopy and biopsy.
• Colposcopy should be used to outline areas of adenosis and ensure that no malignancy is present.
Pathological Findings
Biopsy will show benign glandular epithelium, which has not yet undergone squamous metaplasia. Biopsies in the areas of ongoing squamous metaplasia will be typical for this process.
DIFFERENTIAL DIAGNOSIS
A thorough evaluation for adenocarcinoma of the vagina arising in adenosis should be done. A biopsy may be necessary to ensure that the process represents only benign adenosis. Colposcopy of the upper vagina aids in choosing the areas for biopsy. On visual inspection, adenosis appears as a fine, raised, reddened, granular-type tissue.
TREATMENT
STABILIZATION
Outpatient
GENERAL MEASURES
• Unless malignancy is present, conservative treatment is indicated.
• In the vast majority of young females with this condition, it will resolve with expectant management.
Diet
No special diet
Activity
• No limitations
• It is not necessary to avoid intercourse or placing objects in the vagina.
SURGERY
Aggressive therapy such as laser or surgical excision is necessary only if premalignant or malignant changes arise. (1)[C]
FOLLOW-UP
Yearly after a negative initial evaluation
PROGNOSIS
• It is expected that the vast majority of patients will have squamous metaplasia with complete resolution of the adenosis.
• The rare patient, 1:1,000-1:10,000, may develop adenocarcinoma in the adenosis and will require definitive therapy as for vaginal cancer.
COMPLICATIONS
Infertility, miscarriage, dysplasia, cancer
PATIENT MONITORING
• Initial evaluation consists of four-quadrant vaginal Pap smear, cervical Pap smear, and colposcopy of the upper vagina and cervix.
• If the initial colposcopy is normal, a yearly 4-quadrant Pap smear of the vagina and Pap smear of the cervix are all that is necessary.
REFERENCES
1. Chattopadhyay I, Cruickshank DJ, Packer M. Non diethylstilbesterol induced vaginal adenosis-A case series and review of literature. Eur J Gynaecol Oncol. 2001;22(4):260-262.
2. Herbst A. Behavior of estrogen-associated female genital tract cancer and its relation to neoplasia following intrauterine exposure to diethylstilbesterol (DES). Gynecol Oncol. 2000;76:147-156.
3. Sandberg EC. The incidence and distribution of occult vaginal adenosis. Am J Obstet Gynecol. 1968;101:322-334.
BASICS
DESCRIPTION
• Adenosis is a term used to describe nonepithelialized columnar glandular epithelium in the vagina. At ~15th week of embryological development, the Mullerian system, which forms the upper 2/3 of the vagina, fuses with the invaginating cloaca, which forms the lower vagina. Squamous metaplasia from the cloacal region then produces a squamous epithelium through the vagina. Adenosis occurs when this squamous epithelium fails to completely epithelialize the vagina.
• System(s) Affected: Reproductive
ALERT
Geriatric Considerations
• Adenosis is a disorder of the young female. By the time of menopause the vagina and cervix should be completely epithelialized.
• The presence of glandular epithelium in the postmenopausal patient is an indication for excision and close evaluation for the possibility of a well-differentiated adenocarcinoma.
Pregnancy Considerations
Pregnancy produces a wide eversion of the transformation zone of the cervix. This will occasionally become so widely everted that it will extend onto the vaginal fornices, leading to the impression of adenosis. This will resolve after the pregnancy is completed.
EPIDEMIOLOGY
• Predominant age
- Teenage years: Epithelialization occurs from puberty to 20 years of age.
- By age 30 years, it is extremely rare for adenosis to be present.
• Predominant sex: Female only
Prevalence
In the US: Adenosis is relatively common, affecting 10-20% of young females studied. As maturation progresses with puberty, epithelialization occurs. (3)
RISK FACTORS
Diethylstilbestrol (DES)-exposed females
Genetics
Unknown
ETIOLOGY
• In the vast majority of young females, the etiology is incomplete squamous metaplasia. This occurs as a natural phenomenon and resolves with age.
• In DES-exposed females, the incidence of adenosis is higher and the etiology presumably is from the effect of the DES on the developing embryologic system.
ASSOCIATED CONDITIONS
DES exposure
• Adenosis from DES exposure should lead to an evaluation of other DES-related abnormalities.
• The greatest risk to the patient is from Mullerian tract anomalies. These include cervical abnormalities with cervical hood, ridges, shortened cervix, and incompetent cervix, T-shaped uterine cavity.
• Patients with known DES exposure should have the reproductive tract evaluated prior to conception.
• The vast majority of patients with adenosis have not been DES exposed and do not require evaluation of the reproductive system.
• DES was last used to prevent spontaneous abortion in ~1970. This is a problem of decreasing importance.
DIAGNOSIS
SIGNS AND SYMPTOMS
A clear, watery vaginal discharge, which is the glandular epithelium producing a small amount of mucus
TESTS
Diagnostic Procedures/Surgery
• 4-quadrant Pap smear should be utilized liberally, to isolate quadrants of the vagina which may contain abnormalities. This can be followed by colposcopy and biopsy.
• Colposcopy should be used to outline areas of adenosis and ensure that no malignancy is present.
Pathological Findings
Biopsy will show benign glandular epithelium, which has not yet undergone squamous metaplasia. Biopsies in the areas of ongoing squamous metaplasia will be typical for this process.
DIFFERENTIAL DIAGNOSIS
A thorough evaluation for adenocarcinoma of the vagina arising in adenosis should be done. A biopsy may be necessary to ensure that the process represents only benign adenosis. Colposcopy of the upper vagina aids in choosing the areas for biopsy. On visual inspection, adenosis appears as a fine, raised, reddened, granular-type tissue.
TREATMENT
STABILIZATION
Outpatient
GENERAL MEASURES
• Unless malignancy is present, conservative treatment is indicated.
• In the vast majority of young females with this condition, it will resolve with expectant management.
Diet
No special diet
Activity
• No limitations
• It is not necessary to avoid intercourse or placing objects in the vagina.
SURGERY
Aggressive therapy such as laser or surgical excision is necessary only if premalignant or malignant changes arise. (1)[C]
FOLLOW-UP
Yearly after a negative initial evaluation
PROGNOSIS
• It is expected that the vast majority of patients will have squamous metaplasia with complete resolution of the adenosis.
• The rare patient, 1:1,000-1:10,000, may develop adenocarcinoma in the adenosis and will require definitive therapy as for vaginal cancer.
COMPLICATIONS
Infertility, miscarriage, dysplasia, cancer
PATIENT MONITORING
• Initial evaluation consists of four-quadrant vaginal Pap smear, cervical Pap smear, and colposcopy of the upper vagina and cervix.
• If the initial colposcopy is normal, a yearly 4-quadrant Pap smear of the vagina and Pap smear of the cervix are all that is necessary.
REFERENCES
1. Chattopadhyay I, Cruickshank DJ, Packer M. Non diethylstilbesterol induced vaginal adenosis-A case series and review of literature. Eur J Gynaecol Oncol. 2001;22(4):260-262.
2. Herbst A. Behavior of estrogen-associated female genital tract cancer and its relation to neoplasia following intrauterine exposure to diethylstilbesterol (DES). Gynecol Oncol. 2000;76:147-156.
3. Sandberg EC. The incidence and distribution of occult vaginal adenosis. Am J Obstet Gynecol. 1968;101:322-334.
UTERINE PROLAPSE
UTERINE PROLAPSE - Eric L. Jenison, MD; Michael P. Hopkins, MD, MEd; Jennifer L. Savitski, MD
BASICS
DESCRIPTION
• Uterine prolapse occurs when the integrity of supporting structures is lost. This allows the uterus to descend into the vagina. In advanced cases, complete protrusion with inversion of the vagina occurs.
• Before menopause, the degree and severity of prolapse are usually related to the number of children and the difficulty of childbirth. After menopause, atrophy and loss of tissue integrity lead to further prolapse.
• System(s) Affected: Gastrointestinal; Renal/Urologic; Reproductive
• Synonym(s): Uterine prolapse; Genital prolapse; Genital relaxation; Uterine descensus; Total or partial procidentia; Dropped uterus
ALERT
Geriatric Considerations
This is largely a disease of aging, and incidence will be much higher as the median age of the population increases.
Pediatric Considerations
Prolapse in newborns has been reported, but it is rare and usually associated with congenital disorders and neuropathies.
GENERAL PREVENTION
• Kegel exercises will increase the strength of the pelvic diaphragm muscles and may provide some pelvic support.
• Weight loss and proper management of conditions that would increase abdominal pressure help to prevent prolapse.
EPIDEMIOLOGY
• Predominant age: Perimenopausal and postmenopausal women
• Predominant sex: Female only
Prevalence
~30-50% of women experience some degree of prolapse.
RISK FACTORS
• Childbirth, particularly multiple parity
• Advancing age
• White race
• Various connective tissue and neurogenic disorders
• Conditions resulting in increased intra-abdominal pressure (e.g., obesity, abdominal or pelvic tumors, pulmonary disease with chronic coughing, chronic constipation)
• Occupations requiring heavy lifting
Genetics
• Common among white people
• Less common among Asians and African Americans and particularly uncommon in South African Bantus and in West Africans
ETIOLOGY
• Advancing age and vaginal childbirth are the most important factors.
• Incidence of prolapse increases with frequency and difficulty of vaginal deliveries; 2% of prolapse occurs in nulliparous women.
• Although this disorder in large part results from the distention and distortion of supporting tissues with vaginal childbirth, pregnancy regardless of mode of delivery may contribute to prolapse.
• Other causes of prolapse include connective tissue disorders with lax tissue (e.g., Marfan syndrome), neurogenic disorders (e.g., multiple sclerosis), cloacal agenesis, chronic constipation, pelvic tumors or ascites, and chronic coughing resulting from chronic lung disease.
• Patients who have undergone radical vulvectomy with loss of the external supporting structures have a higher rate of prolapse.
ASSOCIATED CONDITIONS
Cystocele, rectocele, enterocele, and vaginal vault prolapse are often associated with uterine prolapse.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Often asymptomatic
• Pelvic pressure and low back pain
• Bulging sensation in vagina or at introitus.
• Dyspareunia
• Difficulty with urination or defecation
History
• Number of pregnancies, mode of deliveries, episiotomies, extent and repair of vaginal/perineal lacerations.
• Previous pelvic surgery
• Congenital abnormalities
• Medical conditions that chronically increase intra-abdominal pressure (e.g., COPD)
Physical Exam
Diagnosis is confirmed by pelvic examination. With coughing and straining, the cervix will prolapse toward introitus or beyond. The patient may need to be examined standing as well as lying down to confirm diagnosis.
TESTS
Lab
• Evaluation of renal function to rule out ureteral obstruction
• Urinalysis to rule out urinary tract infection
Imaging
• Intravenous pyelogram to rule out ureteral obstruction in complete uterine prolapse (optional)
• Pelvic ultrasound or CT scan to rule out other pelvic pathology, if suspected (optional)
Diagnostic Procedures/Surgery
• If surgical correction is planned, urodynamic studies should be performed to evaluate for potential urinary incontinence masked by the prolapse. (1)[B]
• If ulceration or bleeding is present, Pap smears and appropriate cervical and endometrial biopsies should be done to rule out concomitant malignancies.
Pathological Findings
• Hyperkeratosis of the cervical and vaginal tissues occurs with prolapse beyond the introitus due to chronic irritation and drying. As the irritation becomes more pronounced, bleeding and ulceration occur.
• Degrees of prolapse
- 1st-degree prolapse: To the ischial spine
- 2nd-degree prolapse: To the introitus
- 3rd-degree prolapse: Just beyond the introitus
- 4th-degree prolapse: Complete uterine and vaginal inversion involving bladder and bowel
TREATMENT
STABILIZATION
• Outpatient
• Inpatient when surgery is necessary
GENERAL MEASURES
• Treatment depends on multiple variables including the severity of prolapse, age, sexual activity, associated pelvic pathology, and desire for future fertility.
• Treatment of 1st- and 2nd-degree prolapse is expectant unless patient is symptomatic.
• Conservative therapies include estrogen replacement (see below), pessary use, and physical therapy (see below).
• Pessaries are indicated for women who are unfit for or decline surgery. Proper fitting and maintenance are required. (2)[C]
• Pessaries may also be used in the preoperative evaluation of prolapse. (2)[C]
• Surgery is indicated for women who fail conservative therapies and/or desire definitive treatment. (1)[B]
Diet
Avoid constipation.
Activity
• Heavy lifting, sexual intercourse, and other activities that increase intra-abdominal pressure should be avoided for 6-12 weeks after surgical correction.
• Maintain ideal body weight.
SPECIAL THERAPY
Physical Therapy
Biofeedback and pelvic muscle training (Kegels) may be an option for women with mild prolapse and/or those wishing conservative therapy. (2)[C]
MEDICATION (DRUGS)
• Estrogen replacement therapy (oral or vaginal cream) can increase blood supply to vaginal tissues and supporting tissue strength. This is especially important in postmenopausal women using pessaries or undergoing reconstructive pelvic surgery. (1,3)[B]
• Contraindications: Those associated with the use of estrogen. Refer to the manufacturer's literature.
• Precautions: If estrogen therapy is used and the uterus is present, progesterone should be prescribed to offset the potential for endometrial carcinoma.
• Significant possible interactions: Refer to the manufacturer's literature.
SURGERY
• Surgically able patients without additional pelvic pathology: Vaginal hysterectomy with or without enterocele, cystocele, rectocele, paravaginal repair, culdoplasty, and vaginal vault suspension depending on coexisting pelvic organ prolapse. (1)[B]
• If vault suspension is necessary in conjunction with hysterectomy, abdominal approach has decreased risk of recurrent prolapse compared to vaginal approach. (4)[A]
• Uterine suspension is an option for patients who desire to maintain reproductive function. (1)[B]
• Older women who are not sexually active can be treated with a colpocleisis or vaginal obliteration procedure.
FOLLOW-UP
PROGNOSIS
• It is expected that the incidence and severity of prolapse will increase as patients age.
• Although surgical correction is usually successful initially, reoperation rate is ~29%. (1)
COMPLICATIONS
• Ureteral obstruction and renal failure
• Incarceration of bowel herniations
• Pessary use may not always be effective, and may cause discomfort, ulcers, and infection.
PATIENT MONITORING
• Expectant management is appropriate, with periodic follow-up examinations.
• If a pessary is placed, it should be removed, cleaned, and replaced every 3-6 months. (2)[C]
REFERENCES
1. Thakar R, Stanton S. Regular review: Management of genital prolapse. BMJ. 2002;324:1258-1262.
2. Trowbridge ER, Fenner DE. Conservative management of pelvic organ prolapse. Clin Obstet Gynecol. 2005;48(3):668-681.
3. Drutz HP, Alnaif B. Surgical management of pelvic organ prolapse and stress urinary incontinence. Clin Obstet Gynecol. 1998;41(3):786-793.
4. Maher C, et al. Surgical management of pelvic organ prolapse in women. Cochrane Database Syst Rev. 2006;1.
BASICS
DESCRIPTION
• Uterine prolapse occurs when the integrity of supporting structures is lost. This allows the uterus to descend into the vagina. In advanced cases, complete protrusion with inversion of the vagina occurs.
• Before menopause, the degree and severity of prolapse are usually related to the number of children and the difficulty of childbirth. After menopause, atrophy and loss of tissue integrity lead to further prolapse.
• System(s) Affected: Gastrointestinal; Renal/Urologic; Reproductive
• Synonym(s): Uterine prolapse; Genital prolapse; Genital relaxation; Uterine descensus; Total or partial procidentia; Dropped uterus
ALERT
Geriatric Considerations
This is largely a disease of aging, and incidence will be much higher as the median age of the population increases.
Pediatric Considerations
Prolapse in newborns has been reported, but it is rare and usually associated with congenital disorders and neuropathies.
GENERAL PREVENTION
• Kegel exercises will increase the strength of the pelvic diaphragm muscles and may provide some pelvic support.
• Weight loss and proper management of conditions that would increase abdominal pressure help to prevent prolapse.
EPIDEMIOLOGY
• Predominant age: Perimenopausal and postmenopausal women
• Predominant sex: Female only
Prevalence
~30-50% of women experience some degree of prolapse.
RISK FACTORS
• Childbirth, particularly multiple parity
• Advancing age
• White race
• Various connective tissue and neurogenic disorders
• Conditions resulting in increased intra-abdominal pressure (e.g., obesity, abdominal or pelvic tumors, pulmonary disease with chronic coughing, chronic constipation)
• Occupations requiring heavy lifting
Genetics
• Common among white people
• Less common among Asians and African Americans and particularly uncommon in South African Bantus and in West Africans
ETIOLOGY
• Advancing age and vaginal childbirth are the most important factors.
• Incidence of prolapse increases with frequency and difficulty of vaginal deliveries; 2% of prolapse occurs in nulliparous women.
• Although this disorder in large part results from the distention and distortion of supporting tissues with vaginal childbirth, pregnancy regardless of mode of delivery may contribute to prolapse.
• Other causes of prolapse include connective tissue disorders with lax tissue (e.g., Marfan syndrome), neurogenic disorders (e.g., multiple sclerosis), cloacal agenesis, chronic constipation, pelvic tumors or ascites, and chronic coughing resulting from chronic lung disease.
• Patients who have undergone radical vulvectomy with loss of the external supporting structures have a higher rate of prolapse.
ASSOCIATED CONDITIONS
Cystocele, rectocele, enterocele, and vaginal vault prolapse are often associated with uterine prolapse.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Often asymptomatic
• Pelvic pressure and low back pain
• Bulging sensation in vagina or at introitus.
• Dyspareunia
• Difficulty with urination or defecation
History
• Number of pregnancies, mode of deliveries, episiotomies, extent and repair of vaginal/perineal lacerations.
• Previous pelvic surgery
• Congenital abnormalities
• Medical conditions that chronically increase intra-abdominal pressure (e.g., COPD)
Physical Exam
Diagnosis is confirmed by pelvic examination. With coughing and straining, the cervix will prolapse toward introitus or beyond. The patient may need to be examined standing as well as lying down to confirm diagnosis.
TESTS
Lab
• Evaluation of renal function to rule out ureteral obstruction
• Urinalysis to rule out urinary tract infection
Imaging
• Intravenous pyelogram to rule out ureteral obstruction in complete uterine prolapse (optional)
• Pelvic ultrasound or CT scan to rule out other pelvic pathology, if suspected (optional)
Diagnostic Procedures/Surgery
• If surgical correction is planned, urodynamic studies should be performed to evaluate for potential urinary incontinence masked by the prolapse. (1)[B]
• If ulceration or bleeding is present, Pap smears and appropriate cervical and endometrial biopsies should be done to rule out concomitant malignancies.
Pathological Findings
• Hyperkeratosis of the cervical and vaginal tissues occurs with prolapse beyond the introitus due to chronic irritation and drying. As the irritation becomes more pronounced, bleeding and ulceration occur.
• Degrees of prolapse
- 1st-degree prolapse: To the ischial spine
- 2nd-degree prolapse: To the introitus
- 3rd-degree prolapse: Just beyond the introitus
- 4th-degree prolapse: Complete uterine and vaginal inversion involving bladder and bowel
TREATMENT
STABILIZATION
• Outpatient
• Inpatient when surgery is necessary
GENERAL MEASURES
• Treatment depends on multiple variables including the severity of prolapse, age, sexual activity, associated pelvic pathology, and desire for future fertility.
• Treatment of 1st- and 2nd-degree prolapse is expectant unless patient is symptomatic.
• Conservative therapies include estrogen replacement (see below), pessary use, and physical therapy (see below).
• Pessaries are indicated for women who are unfit for or decline surgery. Proper fitting and maintenance are required. (2)[C]
• Pessaries may also be used in the preoperative evaluation of prolapse. (2)[C]
• Surgery is indicated for women who fail conservative therapies and/or desire definitive treatment. (1)[B]
Diet
Avoid constipation.
Activity
• Heavy lifting, sexual intercourse, and other activities that increase intra-abdominal pressure should be avoided for 6-12 weeks after surgical correction.
• Maintain ideal body weight.
SPECIAL THERAPY
Physical Therapy
Biofeedback and pelvic muscle training (Kegels) may be an option for women with mild prolapse and/or those wishing conservative therapy. (2)[C]
MEDICATION (DRUGS)
• Estrogen replacement therapy (oral or vaginal cream) can increase blood supply to vaginal tissues and supporting tissue strength. This is especially important in postmenopausal women using pessaries or undergoing reconstructive pelvic surgery. (1,3)[B]
• Contraindications: Those associated with the use of estrogen. Refer to the manufacturer's literature.
• Precautions: If estrogen therapy is used and the uterus is present, progesterone should be prescribed to offset the potential for endometrial carcinoma.
• Significant possible interactions: Refer to the manufacturer's literature.
SURGERY
• Surgically able patients without additional pelvic pathology: Vaginal hysterectomy with or without enterocele, cystocele, rectocele, paravaginal repair, culdoplasty, and vaginal vault suspension depending on coexisting pelvic organ prolapse. (1)[B]
• If vault suspension is necessary in conjunction with hysterectomy, abdominal approach has decreased risk of recurrent prolapse compared to vaginal approach. (4)[A]
• Uterine suspension is an option for patients who desire to maintain reproductive function. (1)[B]
• Older women who are not sexually active can be treated with a colpocleisis or vaginal obliteration procedure.
FOLLOW-UP
PROGNOSIS
• It is expected that the incidence and severity of prolapse will increase as patients age.
• Although surgical correction is usually successful initially, reoperation rate is ~29%. (1)
COMPLICATIONS
• Ureteral obstruction and renal failure
• Incarceration of bowel herniations
• Pessary use may not always be effective, and may cause discomfort, ulcers, and infection.
PATIENT MONITORING
• Expectant management is appropriate, with periodic follow-up examinations.
• If a pessary is placed, it should be removed, cleaned, and replaced every 3-6 months. (2)[C]
REFERENCES
1. Thakar R, Stanton S. Regular review: Management of genital prolapse. BMJ. 2002;324:1258-1262.
2. Trowbridge ER, Fenner DE. Conservative management of pelvic organ prolapse. Clin Obstet Gynecol. 2005;48(3):668-681.
3. Drutz HP, Alnaif B. Surgical management of pelvic organ prolapse and stress urinary incontinence. Clin Obstet Gynecol. 1998;41(3):786-793.
4. Maher C, et al. Surgical management of pelvic organ prolapse in women. Cochrane Database Syst Rev. 2006;1.
UVEITIS
UVEITIS - Teresa A. Everson, MD; William L. Toffler, MD
BASICS
DESCRIPTION
• Uveitis is a nonspecific term used to describe any intraocular inflammatory disorder. Symptoms vary depending on depth of involvement and associated conditions.
- Anterior uveitis: Refers to ocular inflammation limited to the iris (iritis) alone or iris and ciliary body (iridocyclitis)
- Intermediate uveitis: Refers to inflammation of the structures just posterior to the lens (pars planitis or peripheral uveitis)
- Posterior uveitis: Refers to inflammation of the choroid (choroiditis), retina (retinitis), or vitreous near the optic nerve and macula
• System(s) Affected: Nervous
• Synonym(s): Iritis; Iridocyclitis; Choroiditis; Retinochoroiditis; Chorioretinitis; Anterior uveitis; Posterior uveitis; Pars planitis; Panuveitis
ALERT
Geriatric Considerations
The inflammatory response to systemic disease may be suppressed.
Pediatric Considerations
Infection should be the primary consideration. Allergies and psychologic factors (depression, stress) may serve as a triggers. Trauma is also a common cause in this population.
Pregnancy Considerations
May be of importance in the selection of medications
EPIDEMIOLOGY
• Predominant age: All ages
• Predominant sex: Male = Female (except for HLA-B27 anterior uveitis: Male > Female [2.5:1])
Incidence
Anterior uveitis most common (8.2 cases/100,000 annual incidence)
Prevalence
Iritis is 4 more prevalent than posterior uveitis.
RISK FACTORS
No specific risk factors. Higher incidence seen with specific associated conditions
Genetics
• No specific pattern for uveitis in general
• Iritis: Of patients, 50-70% are HLA-B27 positive.
ETIOLOGY
• Infectious: May result from viral, bacterial, parasitic, or fungal etiologies
• Suspected immune-mediated: Possible autoimmune or immune-complex-mediated mechanism postulated in association with systemic (especially rheumatologic) disorders
• Isolated eye disease
• Idiopathic (~25%)
• Masquerade syndromes: Diseases such as malignancies that may be mistaken for primary inflammation of the eye
ASSOCIATED CONDITIONS
• Viral infections: HIV, herpes simplex, herpes zoster, cytomegalovirus
• Bacterial infections: Tuberculosis, leprosy, propionibacterium infection, syphilis, leptospirosis, brucellosis, Lyme disease, Whipple disease
• Parasitic infections: Toxoplasmosis, acanthamebiasis, toxocariasis, cysticercosis, onchocerciasis
• Fungal infections: Histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, sporotrichosis, blastomycosis, cryptococcosis
• Suspected immune-mediated: Ankylosing spondylitis, Behccet disease, Crohn disease, drug or hypersensitivity reaction, interstitial nephritis, juvenile rheumatoid arthritis, Kawasaki disease, multiple sclerosis, psoriatic arthritis, Reiter syndrome, relapsing polychondritis, sarcoidosis, Sjogren syndrome, systemic lupus erythematosus, ulcerative colitis, vasculitis, vitiligo, Vogt-Koyanagi (Harada) syndrome
• Isolated eye disease: Acute multifocal placoid pigmentary epitheliopathy, acute retinal necrosis, bird-shot choroidopathy, Fuch heterochromatic cyclitis, glaucomatocyclitic crisis, lens-induced uveitis, multifocal choroiditis, pars planitis, serpiginous choroiditis, sympathetic ophthalmia, trauma
• Masquerade syndromes: Leukemia, lymphoma, retinitis pigmentosa, retinoblastoma
DIAGNOSIS
SIGNS AND SYMPTOMS
• Anterior uveitis (~80% of patients with uveitis)
- Decreased visual acuity
- Generally acute in onset
- Deep eye pain
- Photophobia (consensual)
- Conjunctival vessel dilation
- Perilimbal (circumcorneal) dilation of episcleral and scleral vessels (ciliary flush)
- Small pupillary size of affected eye
- Hypopyon or hyphema (white or red blood cells pooled in the anterior chamber)
- Frequently unilateral (95% of HLA-B27-associated cases)
- Bilateral involvement and systemic symptoms (fever, fatigue, abdominal pain) may be associated with interstitial nephritis.
- Systemic disease is most likely to be associated with anterior uveitis (in 1 study, 53% of patients found to have systemic disease).
• Intermediate and posterior uveitis
- Decreased visual acuity
- Unresolving floaters
- Generally insidious in onset
- More commonly bilateral
- Posterior inflammation will generally cause minimal pain or redness unless associated with an iritis.
Physical Exam
Slit-lamp examination and indirect ophthalmoscopy are necessary for precise diagnosis.
TESTS
Lab
• No specific test for the diagnosis of uveitis. Tests for etiologic factors or associated conditions should be based on history and physical examination.
• CBC, BUN, creatinine (interstitial nephritis)
• HLA-B27 typing (ankylosing spondylitis, Reiter syndrome)
• Antinuclear antibody, ESR (systemic lupus erythematosus, Sjogren syndrome)
• Venereal Disease Research Lab test, fluorescent titer antibody (syphilis)
• Purified protein derivative (PPD) tuberculin skin test (tuberculosis)
• Lyme serology (Lyme disease)
• Special tests
• Disorders that may alter lab results: Immune deficiency
Imaging
• Chest x-ray (sarcoidosis, histoplasmosis, tuberculosis, lymphoma)
• Sacroiliac x-ray (ankylosing spondylitis)
Diagnostic Procedures/Surgery
Slit-lamp examination
Pathological Findings
Keratic precipitates, inflammatory cells in anterior chamber or vitreous, synechiae (fibrous tissue scarring between iris and lens), macular edema, perivasculitis of retinal vessels
DIFFERENTIAL DIAGNOSIS
• Conjunctivitis
• Episcleritis
• Scleritis
• Keratitis
• Acute angle-closure glaucoma
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient with urgent ophthalmologic consultation
• Medical therapy best initiated following full ophthalmologic evaluation
• Treatment of underlying cause, if identified
• Cycloplegia
• Anti-inflammatory therapy
Diet
No special diet
Activity
Full activity
MEDICATION (DRUGS)
First Line
• Caution should be used when using empiric treatment; referral to an ophthalmologist is recommended in most cases.
• Homatropine hydrobromide (Isopto) 2% ophthalmic solution: 2 drops to the affected eye b.i.d., or as often as q3h if necessary; plus
• Prednisolone acetate 1% ophthalmic suspension: 2 drops to the affected eye q1h initially, tapering to once a day with improvement
• Contraindications
- Hypersensitivity to the medication or component of the preparation
- Cycloplegia is contraindicated in patients known to have, or be predisposed to, glaucoma.
- Topical corticosteroid therapy is contraindicated in uveitis secondary to infectious etiologies.
• Precautions
- Homatropine hydrobromide may produce adverse systemic antimuscarinic effects. Use extreme caution in infants and young children because of increased susceptibility to systemic effects.
- Topical corticosteroids may increase intraocular pressure. Prolonged use may cause cataract formation and exacerbate existing herpetic keratitis which may masquerade as iritis.
• Significant possible interactions
- Refer to manufacturer's profile for each drug.
Second Line
• Cycloplegia: Scopolamine hydrobromide 0.25% (Isopto Hyoscine) up to t.i.d. or cyclopentolate hydrochloride 1% (Cyclogyl)
• Anti-inflammatory: Prednisolone sodium phosphate 1% (Ocu-Pred Forte), dexamethasone sodium phosphate 0.1% (Ocu-Dex), and dexamethasone suspension
• Systemic NSAIDs may provide some benefit.
FOLLOW-UP
PROGNOSIS
• Dependent on the presence of causal diseases, or associated conditions
• Uveitis resulting from infections (systemic or local) tend to resolve with eradication of the underlying infection.
• Uveitis associated with seronegative arthropathies tend to be acute (lasting 3 months) and frequently recurrent.
COMPLICATIONS
Loss of vision as a result of the following
• Keratic precipitate deposition on the corneal or lens surfaces
• Increased intraocular pressure, acute angle-closure glaucoma
• Formation of synechiae
• Cataract formation
• Vasculitis with vascular occlusion, retinal infarction
• Macular edema
• Optic nerve damage
PATIENT MONITORING
• Ophthalmologic follow-up as recommended by consultant
• Schedule for complete history and physical to evaluate for associated systemic disease.
REFERENCES
1. McCluskey PJ, Towler HM, Lightman S. Management of chronic uveitis. BMJ. 2000;320(7234):555-558.
2. Schiffman RM, Jacobsen G, Whitcup SM. Visual functioning and general health status in patients with uveitis. Arch Ophthalmol. 2001;119(6):841-849.
3. Smith JR, Rosenbaum JT. Management of uveitis: A rheumatologic perspective. Arthritis Rheum. 2002;46(2):309-318.
4. Patel H, Goldstein D. Pediatric uveitis. Pediatr Clin North Am. 2003;50(1):125-136.
5. Lee AG, Beaver HA. Painful ophthalmologic disorders and eye pain for the neurologist. Neurol Clin. 2004;22(1):75-97.
MISCELLANEOUS
• See also: Conjunctivitis, acute; Glaucoma, primary angle-closure; Scleritis
• Other notes
- Synonyms are anatomic descriptions of the focus of the uveal inflammation.
- Severe or unresponsive uveitis may require therapy including periocular injection of corticosteroids, systemic corticosteroids, cytotoxic agents (azathioprine, cyclophosphamide, chlorambucil, and methotrexate), immunosuppressive agents (cyclosporine), immunomodulatory agents (sulfasalazine), or tumor necrosis factor inhibitors (infliximab, etanercept).
BASICS
DESCRIPTION
• Uveitis is a nonspecific term used to describe any intraocular inflammatory disorder. Symptoms vary depending on depth of involvement and associated conditions.
- Anterior uveitis: Refers to ocular inflammation limited to the iris (iritis) alone or iris and ciliary body (iridocyclitis)
- Intermediate uveitis: Refers to inflammation of the structures just posterior to the lens (pars planitis or peripheral uveitis)
- Posterior uveitis: Refers to inflammation of the choroid (choroiditis), retina (retinitis), or vitreous near the optic nerve and macula
• System(s) Affected: Nervous
• Synonym(s): Iritis; Iridocyclitis; Choroiditis; Retinochoroiditis; Chorioretinitis; Anterior uveitis; Posterior uveitis; Pars planitis; Panuveitis
ALERT
Geriatric Considerations
The inflammatory response to systemic disease may be suppressed.
Pediatric Considerations
Infection should be the primary consideration. Allergies and psychologic factors (depression, stress) may serve as a triggers. Trauma is also a common cause in this population.
Pregnancy Considerations
May be of importance in the selection of medications
EPIDEMIOLOGY
• Predominant age: All ages
• Predominant sex: Male = Female (except for HLA-B27 anterior uveitis: Male > Female [2.5:1])
Incidence
Anterior uveitis most common (8.2 cases/100,000 annual incidence)
Prevalence
Iritis is 4 more prevalent than posterior uveitis.
RISK FACTORS
No specific risk factors. Higher incidence seen with specific associated conditions
Genetics
• No specific pattern for uveitis in general
• Iritis: Of patients, 50-70% are HLA-B27 positive.
ETIOLOGY
• Infectious: May result from viral, bacterial, parasitic, or fungal etiologies
• Suspected immune-mediated: Possible autoimmune or immune-complex-mediated mechanism postulated in association with systemic (especially rheumatologic) disorders
• Isolated eye disease
• Idiopathic (~25%)
• Masquerade syndromes: Diseases such as malignancies that may be mistaken for primary inflammation of the eye
ASSOCIATED CONDITIONS
• Viral infections: HIV, herpes simplex, herpes zoster, cytomegalovirus
• Bacterial infections: Tuberculosis, leprosy, propionibacterium infection, syphilis, leptospirosis, brucellosis, Lyme disease, Whipple disease
• Parasitic infections: Toxoplasmosis, acanthamebiasis, toxocariasis, cysticercosis, onchocerciasis
• Fungal infections: Histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, sporotrichosis, blastomycosis, cryptococcosis
• Suspected immune-mediated: Ankylosing spondylitis, Behccet disease, Crohn disease, drug or hypersensitivity reaction, interstitial nephritis, juvenile rheumatoid arthritis, Kawasaki disease, multiple sclerosis, psoriatic arthritis, Reiter syndrome, relapsing polychondritis, sarcoidosis, Sjogren syndrome, systemic lupus erythematosus, ulcerative colitis, vasculitis, vitiligo, Vogt-Koyanagi (Harada) syndrome
• Isolated eye disease: Acute multifocal placoid pigmentary epitheliopathy, acute retinal necrosis, bird-shot choroidopathy, Fuch heterochromatic cyclitis, glaucomatocyclitic crisis, lens-induced uveitis, multifocal choroiditis, pars planitis, serpiginous choroiditis, sympathetic ophthalmia, trauma
• Masquerade syndromes: Leukemia, lymphoma, retinitis pigmentosa, retinoblastoma
DIAGNOSIS
SIGNS AND SYMPTOMS
• Anterior uveitis (~80% of patients with uveitis)
- Decreased visual acuity
- Generally acute in onset
- Deep eye pain
- Photophobia (consensual)
- Conjunctival vessel dilation
- Perilimbal (circumcorneal) dilation of episcleral and scleral vessels (ciliary flush)
- Small pupillary size of affected eye
- Hypopyon or hyphema (white or red blood cells pooled in the anterior chamber)
- Frequently unilateral (95% of HLA-B27-associated cases)
- Bilateral involvement and systemic symptoms (fever, fatigue, abdominal pain) may be associated with interstitial nephritis.
- Systemic disease is most likely to be associated with anterior uveitis (in 1 study, 53% of patients found to have systemic disease).
• Intermediate and posterior uveitis
- Decreased visual acuity
- Unresolving floaters
- Generally insidious in onset
- More commonly bilateral
- Posterior inflammation will generally cause minimal pain or redness unless associated with an iritis.
Physical Exam
Slit-lamp examination and indirect ophthalmoscopy are necessary for precise diagnosis.
TESTS
Lab
• No specific test for the diagnosis of uveitis. Tests for etiologic factors or associated conditions should be based on history and physical examination.
• CBC, BUN, creatinine (interstitial nephritis)
• HLA-B27 typing (ankylosing spondylitis, Reiter syndrome)
• Antinuclear antibody, ESR (systemic lupus erythematosus, Sjogren syndrome)
• Venereal Disease Research Lab test, fluorescent titer antibody (syphilis)
• Purified protein derivative (PPD) tuberculin skin test (tuberculosis)
• Lyme serology (Lyme disease)
• Special tests
• Disorders that may alter lab results: Immune deficiency
Imaging
• Chest x-ray (sarcoidosis, histoplasmosis, tuberculosis, lymphoma)
• Sacroiliac x-ray (ankylosing spondylitis)
Diagnostic Procedures/Surgery
Slit-lamp examination
Pathological Findings
Keratic precipitates, inflammatory cells in anterior chamber or vitreous, synechiae (fibrous tissue scarring between iris and lens), macular edema, perivasculitis of retinal vessels
DIFFERENTIAL DIAGNOSIS
• Conjunctivitis
• Episcleritis
• Scleritis
• Keratitis
• Acute angle-closure glaucoma
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient with urgent ophthalmologic consultation
• Medical therapy best initiated following full ophthalmologic evaluation
• Treatment of underlying cause, if identified
• Cycloplegia
• Anti-inflammatory therapy
Diet
No special diet
Activity
Full activity
MEDICATION (DRUGS)
First Line
• Caution should be used when using empiric treatment; referral to an ophthalmologist is recommended in most cases.
• Homatropine hydrobromide (Isopto) 2% ophthalmic solution: 2 drops to the affected eye b.i.d., or as often as q3h if necessary; plus
• Prednisolone acetate 1% ophthalmic suspension: 2 drops to the affected eye q1h initially, tapering to once a day with improvement
• Contraindications
- Hypersensitivity to the medication or component of the preparation
- Cycloplegia is contraindicated in patients known to have, or be predisposed to, glaucoma.
- Topical corticosteroid therapy is contraindicated in uveitis secondary to infectious etiologies.
• Precautions
- Homatropine hydrobromide may produce adverse systemic antimuscarinic effects. Use extreme caution in infants and young children because of increased susceptibility to systemic effects.
- Topical corticosteroids may increase intraocular pressure. Prolonged use may cause cataract formation and exacerbate existing herpetic keratitis which may masquerade as iritis.
• Significant possible interactions
- Refer to manufacturer's profile for each drug.
Second Line
• Cycloplegia: Scopolamine hydrobromide 0.25% (Isopto Hyoscine) up to t.i.d. or cyclopentolate hydrochloride 1% (Cyclogyl)
• Anti-inflammatory: Prednisolone sodium phosphate 1% (Ocu-Pred Forte), dexamethasone sodium phosphate 0.1% (Ocu-Dex), and dexamethasone suspension
• Systemic NSAIDs may provide some benefit.
FOLLOW-UP
PROGNOSIS
• Dependent on the presence of causal diseases, or associated conditions
• Uveitis resulting from infections (systemic or local) tend to resolve with eradication of the underlying infection.
• Uveitis associated with seronegative arthropathies tend to be acute (lasting 3 months) and frequently recurrent.
COMPLICATIONS
Loss of vision as a result of the following
• Keratic precipitate deposition on the corneal or lens surfaces
• Increased intraocular pressure, acute angle-closure glaucoma
• Formation of synechiae
• Cataract formation
• Vasculitis with vascular occlusion, retinal infarction
• Macular edema
• Optic nerve damage
PATIENT MONITORING
• Ophthalmologic follow-up as recommended by consultant
• Schedule for complete history and physical to evaluate for associated systemic disease.
REFERENCES
1. McCluskey PJ, Towler HM, Lightman S. Management of chronic uveitis. BMJ. 2000;320(7234):555-558.
2. Schiffman RM, Jacobsen G, Whitcup SM. Visual functioning and general health status in patients with uveitis. Arch Ophthalmol. 2001;119(6):841-849.
3. Smith JR, Rosenbaum JT. Management of uveitis: A rheumatologic perspective. Arthritis Rheum. 2002;46(2):309-318.
4. Patel H, Goldstein D. Pediatric uveitis. Pediatr Clin North Am. 2003;50(1):125-136.
5. Lee AG, Beaver HA. Painful ophthalmologic disorders and eye pain for the neurologist. Neurol Clin. 2004;22(1):75-97.
MISCELLANEOUS
• See also: Conjunctivitis, acute; Glaucoma, primary angle-closure; Scleritis
• Other notes
- Synonyms are anatomic descriptions of the focus of the uveal inflammation.
- Severe or unresponsive uveitis may require therapy including periocular injection of corticosteroids, systemic corticosteroids, cytotoxic agents (azathioprine, cyclophosphamide, chlorambucil, and methotrexate), immunosuppressive agents (cyclosporine), immunomodulatory agents (sulfasalazine), or tumor necrosis factor inhibitors (infliximab, etanercept).
UTERINE MYOMAS
UTERINE MYOMAS - Eric L. Jenison, MD; Michael P. Hopkins, MD, MEd; Summer L. James, MD
BASICS
DESCRIPTION
• Uterine leiomyomas are well-circumscribed, pseudo-encapsulated benign tumors composed mainly of smooth muscle but with varying amounts of fibrous connective tissue.
• 3 major types
- Submucous: ~5% of all cases, evincing abnormal uterine bleeding and infection, and do occasionally protrude from cervix
- Subserous: Common; may become pedunculated and rarely parasitic
- Intramural: Common; may cause marked uterine enlargement
• System(s) Affected: Reproductive
• Synonym(s): Fibroids; Myoma; Fibromyoma; Myofibroma; Fibroleiomyoma
ALERT
Geriatric Considerations
In postmenopausal patients with newly diagnosed uterine myoma or enlarging uterine myomas, high suspicion of uterine sarcoma or other gynecologic malignancy
Pregnancy Considerations
• Pregnant women may need additional fetal testing if placenta is located over or near a fibroid.
• Complications during pregnancy include abortion, premature labor, 2nd-trimester rapid myoma growth leading to degeneration and pain, and 3rd-trimester fetal malpresentation and dystocia during labor and delivery.
• Previous myomectomy patients may develop uterine rupture during labor. Caesarean section is recommended if endometrial cavity has been entered during myomectomy.
GENERAL PREVENTION
Excessive growth may occur with estrogen stimulation (i.e., estrogen-containing birth control, HRT, and pregnancy).
EPIDEMIOLOGY
• Predominant age: 4th and 5th decades
• Predominant sex: Female only
Incidence
• Incidence increases with each decade during reproductive years and is highest in perimenopausal age group.
• Not seen in premenarchal females.
Prevalence
• 4-11% of all women
• 20% of all women 35 years of age
• 40% of women 50 years of age
RISK FACTORS
• Later reproductive and perimenopausal age groups
• 3-9 times higher among African Americans
ETIOLOGY
• May arise from totipotential cells that normally give rise to muscle and connective tissue cells
• May arise from small immature smooth muscle cell nests
• Positive correlation with estrogen stimulation (i.e., not seen before menarche), may grow rapidly during pregnancy, with use of oral estrogen, and with estrogen-producing tumors
• Myomas usually regress after pregnancy and menopause.
ASSOCIATED CONDITIONS
Endometrial carcinoma is also associated with high unopposed estrogen stimulation.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Most affected patients: Asymptomatic disease only becomes suspected based on results of pelvic examination.
• Most common symptom is abnormal uterine bleeding. Hypermenorrhea is most common. Symptoms of secondary anemia may result.
• Pressure on bladder may result in suprapubic discomfort, urinary frequency.
• Pressure on rectosigmoid may result in low back pain.
• Edema and varicosities of the lower extremities may result from large tumors.
• Pain may result from twisted, pedunculated myomas or degenerating, hemorrhagic, or infected myomas.
• Infertility may result from submucous myomas or with distortion of uterine cavity.
• Rapid growth, particularly in perimenopausal or postmenopausal patients, may indicate sarcoma.
Physical Exam
Presumptive diagnosis by abdominal and pelvic examination: Firm, smooth nodules or masses arising from uterus. Masses are mobile without pain.
TESTS
Lab
• Pregnancy test
• CBC with differential
Imaging
• Ultrasonography shows characteristic hypoechoic appearance.
• Saline-infusion hysterosonography may help to distinguish submucosal myomas.
• Hysterosalpingogram to evaluate contour of endometrial cavity
• CT scan, MRI may help to differentiate complex cases or used when uterine artery embolization is planned.
• IV pyelogram
• Barium enema
Diagnostic Procedures/Surgery
• Fractional dilation and curettage aids in ruling out cervical or uterine carcinomas.
• Hysteroscopy may help diagnose submucous myomas.
• Laparoscopy may be useful in complex cases and to rule out other pelvic disease or disorder.
Pathological Findings
• Myomas are usually multiple and vary in size and location; have been reported up to 100 lb.
• Gross pathology reveals firm tumors with characteristic whorl-like trabeculated appearance. A thin pseudo-capsular layer is present.
• Microscopic appearance reveals bundles of smooth muscle mixed with varying amounts of connective tissue elements running in different directions.
• Cellular variant has a preponderance of muscle cells. Mitoses are rare.
• May undergo various types of degeneration
- I. Hyaline degeneration: Very common
- II. Calcification: Late result of circulatory impairment to myomas
- III. Infection and suppuration: Most common with submucosal myomas
- IV. Necrosis: Most common with pedunculated myomas secondary to torsion
- V. Sarcomatous change: Incidence 1.0-0.1% of clinically apparent myomas
DIFFERENTIAL DIAGNOSIS
• Intrauterine pregnancy
• Ovarian tumor
• Cecal or sigmoid tumor
• Appendiceal abscess
• Diverticulitis
• Pelvic kidney
• Urachal cyst
TREATMENT
STABILIZATION
Outpatient usually; inpatient for some surgical procedures
GENERAL MEASURES
• Treatment must be individualized.
• Patients with minimal symptoms may be managed with iron preparations and analgesics.
• Conservative management: Asymptomatic myomas should be closely observed with pelvic examinations and ultrasonography at 3-6-month intervals, as long as size remains stable. Usually regression occurs after menopause.
• Patients that do not want surgery or pharmacologic therapy may consider uterine artery embolization (UAE).
• UAE averages 30-46% shrinkage of myomas (1); painful, may cause ovarian failure or amenorrhea
Diet
No restrictions
Activity
• After hysteroscopic or laparoscopic myomectomy, bed rest for 24 hours, no sexual intercourse for 2 weeks
• After laparotomy for myomectomy or hysterectomy, 3-5 days inpatient, followed by limited activity and no sexual intercourse for 1 month
MEDICATION (DRUGS)
Patients with minimal symptoms may be managed conservatively with iron preparations for anemia and analgesics.
First Line
• Progestins such as norethindrone, 10 mg/d, or medroxyprogesterone (Depo-Provera) 200 mg IM, once monthly, may reduce overall uterine size. (2)
- Contraindications: History of thromboembolic events; see the manufacturer's profile
- Adverse reactions: See the manufacturer's profile.
- Significant interactions: See the manufacturer's profile.
• Luteinizing hormone-releasing hormone (LHRH) agonists such as nafarelin (Synarel Nasal Spray), goserelin (Zoladex Depot), and leuprolide (Lupron Depot)
- Induce abrupt, artificial menopause and render patients asymptomatic.
- Induce atrophy of myomas by up to 40% within 2-3 months (2)
- May be valuable as a preoperative adjunct to myomectomy or hysterectomy by allowing recovery of anemia, donation of autologous blood, and possibly converting abdominal to vaginal hysterectomy, thereby decreasing postoperative pain, hospitalization, and morbidity (2)
- Not recommended for use >6 months because of osteoporosis risk
- Following discontinuation, myomas return within 60 days to pretherapy size
• Contraindications: Osteoporosis; refer to the manufacturer's profile
• Adverse reactions: Acute menopausal symptoms, decreased bone density; refer to manufacturer's profile
• Significant interactions: Refer to the manufacturer's profile.
SURGERY
• Surgical management is indicated in the following situations (2)[B]
- Excessive uterine size or excessive rate of growth (except during pregnancy)
- Submucosal location if associated with hypermenorrhea
- Pedunculated myomas may undergo torsion, pain, necrosis, and hemorrhage.
- Symptomatic from pressure on bladder or rectum
- If differentiation from ovarian mass is not possible
- If associated pelvic disease present (i.e., endometriosis, pelvic inflammatory disease)
- If infertility or habitual abortion is likely due to the anatomic location of the myoma
• Surgical procedures
- Hysteroscopic or laparoscopic cautery or laser myoma resection can be performed in selected cases.
- Endometrial ablation for small submucosal myomas
- Endometrial sampling should be performed prior to or in conjunction with procedure.
- Abdominal or laparoscopic myomectomies may be performed in younger women who want to maintain fertility. (2)[B]
- Hysterectomy, either vaginal or abdominal, is procedure of choice for symptomatic women who do not want to maintain fertility. (2)[B]
- Preliminary pap smear and endometrial biopsy should be performed to rule out malignant or premalignant conditions. (3)[B]
FOLLOW-UP
PROGNOSIS
• After abdominal myomectomy, 57% pregnancy rate in previously infertile patients (3)
• At least 10% of myomas recur after myomectomy.
COMPLICATIONS
• May mask other gynecologic malignancies (e.g., uterine sarcoma, ovarian cancer)
• Degenerating fibroid may cause pain.
- May rarely prolapse through the cervix
PATIENT MONITORING
• Newly diagnosed uterine myoma, if symptomatic or of excessive size: Every 2-3 months with pelvic exam and ultrasonography
• Monitor hemoglobin and hematocrit levels, if uterine bleeding is excessive.
• If uterine size and symptoms are stable, monitor only every 6-12 months.
REFERENCES
1. Gupta JK, Sinha AS, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2006;1.
2. Wallach EE, Vlahos NF. Uterine myomas: An overview of development, clinical features and management. Obstet Gynecol. 2004;104(2):393-406.
3. Lefebvre G, et al. The management of uterine leiomyomas. J Obstet Gynaecol Can. 2003;25(5):396-418.
BASICS
DESCRIPTION
• Uterine leiomyomas are well-circumscribed, pseudo-encapsulated benign tumors composed mainly of smooth muscle but with varying amounts of fibrous connective tissue.
• 3 major types
- Submucous: ~5% of all cases, evincing abnormal uterine bleeding and infection, and do occasionally protrude from cervix
- Subserous: Common; may become pedunculated and rarely parasitic
- Intramural: Common; may cause marked uterine enlargement
• System(s) Affected: Reproductive
• Synonym(s): Fibroids; Myoma; Fibromyoma; Myofibroma; Fibroleiomyoma
ALERT
Geriatric Considerations
In postmenopausal patients with newly diagnosed uterine myoma or enlarging uterine myomas, high suspicion of uterine sarcoma or other gynecologic malignancy
Pregnancy Considerations
• Pregnant women may need additional fetal testing if placenta is located over or near a fibroid.
• Complications during pregnancy include abortion, premature labor, 2nd-trimester rapid myoma growth leading to degeneration and pain, and 3rd-trimester fetal malpresentation and dystocia during labor and delivery.
• Previous myomectomy patients may develop uterine rupture during labor. Caesarean section is recommended if endometrial cavity has been entered during myomectomy.
GENERAL PREVENTION
Excessive growth may occur with estrogen stimulation (i.e., estrogen-containing birth control, HRT, and pregnancy).
EPIDEMIOLOGY
• Predominant age: 4th and 5th decades
• Predominant sex: Female only
Incidence
• Incidence increases with each decade during reproductive years and is highest in perimenopausal age group.
• Not seen in premenarchal females.
Prevalence
• 4-11% of all women
• 20% of all women 35 years of age
• 40% of women 50 years of age
RISK FACTORS
• Later reproductive and perimenopausal age groups
• 3-9 times higher among African Americans
ETIOLOGY
• May arise from totipotential cells that normally give rise to muscle and connective tissue cells
• May arise from small immature smooth muscle cell nests
• Positive correlation with estrogen stimulation (i.e., not seen before menarche), may grow rapidly during pregnancy, with use of oral estrogen, and with estrogen-producing tumors
• Myomas usually regress after pregnancy and menopause.
ASSOCIATED CONDITIONS
Endometrial carcinoma is also associated with high unopposed estrogen stimulation.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Most affected patients: Asymptomatic disease only becomes suspected based on results of pelvic examination.
• Most common symptom is abnormal uterine bleeding. Hypermenorrhea is most common. Symptoms of secondary anemia may result.
• Pressure on bladder may result in suprapubic discomfort, urinary frequency.
• Pressure on rectosigmoid may result in low back pain.
• Edema and varicosities of the lower extremities may result from large tumors.
• Pain may result from twisted, pedunculated myomas or degenerating, hemorrhagic, or infected myomas.
• Infertility may result from submucous myomas or with distortion of uterine cavity.
• Rapid growth, particularly in perimenopausal or postmenopausal patients, may indicate sarcoma.
Physical Exam
Presumptive diagnosis by abdominal and pelvic examination: Firm, smooth nodules or masses arising from uterus. Masses are mobile without pain.
TESTS
Lab
• Pregnancy test
• CBC with differential
Imaging
• Ultrasonography shows characteristic hypoechoic appearance.
• Saline-infusion hysterosonography may help to distinguish submucosal myomas.
• Hysterosalpingogram to evaluate contour of endometrial cavity
• CT scan, MRI may help to differentiate complex cases or used when uterine artery embolization is planned.
• IV pyelogram
• Barium enema
Diagnostic Procedures/Surgery
• Fractional dilation and curettage aids in ruling out cervical or uterine carcinomas.
• Hysteroscopy may help diagnose submucous myomas.
• Laparoscopy may be useful in complex cases and to rule out other pelvic disease or disorder.
Pathological Findings
• Myomas are usually multiple and vary in size and location; have been reported up to 100 lb.
• Gross pathology reveals firm tumors with characteristic whorl-like trabeculated appearance. A thin pseudo-capsular layer is present.
• Microscopic appearance reveals bundles of smooth muscle mixed with varying amounts of connective tissue elements running in different directions.
• Cellular variant has a preponderance of muscle cells. Mitoses are rare.
• May undergo various types of degeneration
- I. Hyaline degeneration: Very common
- II. Calcification: Late result of circulatory impairment to myomas
- III. Infection and suppuration: Most common with submucosal myomas
- IV. Necrosis: Most common with pedunculated myomas secondary to torsion
- V. Sarcomatous change: Incidence 1.0-0.1% of clinically apparent myomas
DIFFERENTIAL DIAGNOSIS
• Intrauterine pregnancy
• Ovarian tumor
• Cecal or sigmoid tumor
• Appendiceal abscess
• Diverticulitis
• Pelvic kidney
• Urachal cyst
TREATMENT
STABILIZATION
Outpatient usually; inpatient for some surgical procedures
GENERAL MEASURES
• Treatment must be individualized.
• Patients with minimal symptoms may be managed with iron preparations and analgesics.
• Conservative management: Asymptomatic myomas should be closely observed with pelvic examinations and ultrasonography at 3-6-month intervals, as long as size remains stable. Usually regression occurs after menopause.
• Patients that do not want surgery or pharmacologic therapy may consider uterine artery embolization (UAE).
• UAE averages 30-46% shrinkage of myomas (1); painful, may cause ovarian failure or amenorrhea
Diet
No restrictions
Activity
• After hysteroscopic or laparoscopic myomectomy, bed rest for 24 hours, no sexual intercourse for 2 weeks
• After laparotomy for myomectomy or hysterectomy, 3-5 days inpatient, followed by limited activity and no sexual intercourse for 1 month
MEDICATION (DRUGS)
Patients with minimal symptoms may be managed conservatively with iron preparations for anemia and analgesics.
First Line
• Progestins such as norethindrone, 10 mg/d, or medroxyprogesterone (Depo-Provera) 200 mg IM, once monthly, may reduce overall uterine size. (2)
- Contraindications: History of thromboembolic events; see the manufacturer's profile
- Adverse reactions: See the manufacturer's profile.
- Significant interactions: See the manufacturer's profile.
• Luteinizing hormone-releasing hormone (LHRH) agonists such as nafarelin (Synarel Nasal Spray), goserelin (Zoladex Depot), and leuprolide (Lupron Depot)
- Induce abrupt, artificial menopause and render patients asymptomatic.
- Induce atrophy of myomas by up to 40% within 2-3 months (2)
- May be valuable as a preoperative adjunct to myomectomy or hysterectomy by allowing recovery of anemia, donation of autologous blood, and possibly converting abdominal to vaginal hysterectomy, thereby decreasing postoperative pain, hospitalization, and morbidity (2)
- Not recommended for use >6 months because of osteoporosis risk
- Following discontinuation, myomas return within 60 days to pretherapy size
• Contraindications: Osteoporosis; refer to the manufacturer's profile
• Adverse reactions: Acute menopausal symptoms, decreased bone density; refer to manufacturer's profile
• Significant interactions: Refer to the manufacturer's profile.
SURGERY
• Surgical management is indicated in the following situations (2)[B]
- Excessive uterine size or excessive rate of growth (except during pregnancy)
- Submucosal location if associated with hypermenorrhea
- Pedunculated myomas may undergo torsion, pain, necrosis, and hemorrhage.
- Symptomatic from pressure on bladder or rectum
- If differentiation from ovarian mass is not possible
- If associated pelvic disease present (i.e., endometriosis, pelvic inflammatory disease)
- If infertility or habitual abortion is likely due to the anatomic location of the myoma
• Surgical procedures
- Hysteroscopic or laparoscopic cautery or laser myoma resection can be performed in selected cases.
- Endometrial ablation for small submucosal myomas
- Endometrial sampling should be performed prior to or in conjunction with procedure.
- Abdominal or laparoscopic myomectomies may be performed in younger women who want to maintain fertility. (2)[B]
- Hysterectomy, either vaginal or abdominal, is procedure of choice for symptomatic women who do not want to maintain fertility. (2)[B]
- Preliminary pap smear and endometrial biopsy should be performed to rule out malignant or premalignant conditions. (3)[B]
FOLLOW-UP
PROGNOSIS
• After abdominal myomectomy, 57% pregnancy rate in previously infertile patients (3)
• At least 10% of myomas recur after myomectomy.
COMPLICATIONS
• May mask other gynecologic malignancies (e.g., uterine sarcoma, ovarian cancer)
• Degenerating fibroid may cause pain.
- May rarely prolapse through the cervix
PATIENT MONITORING
• Newly diagnosed uterine myoma, if symptomatic or of excessive size: Every 2-3 months with pelvic exam and ultrasonography
• Monitor hemoglobin and hematocrit levels, if uterine bleeding is excessive.
• If uterine size and symptoms are stable, monitor only every 6-12 months.
REFERENCES
1. Gupta JK, Sinha AS, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2006;1.
2. Wallach EE, Vlahos NF. Uterine myomas: An overview of development, clinical features and management. Obstet Gynecol. 2004;104(2):393-406.
3. Lefebvre G, et al. The management of uterine leiomyomas. J Obstet Gynaecol Can. 2003;25(5):396-418.
UROLITHIASIS
UROLITHIASIS - Alison H. Blatt, MD
BASICS
DESCRIPTION
• Stone formation within the urinary tract: Urinary crystals bind to form a nidus, which grows to form a calculus (stone).
• Calculus may be asymptomatic or obstructive, or may be a source of chronic infection.
GENERAL PREVENTION
Increased water intake reduces the risk of recurrence and time to recurrence of urinary calculi.
ALERT
Pediatric Considerations
Rare; more common in males; low socioeconomic status
Pregnancy Considerations
• Pregnant women have the same incidence of renal colic as do nonpregnant women.
• Diagnosis is challenging: Most common differential is physiological hydronephrosis of pregnancy.
• Ultrasound; avoid irradiation
• Aim of treatment is pain control, renal function preservation and aseptic urine until birth or stone passage. Only 30% require some form of intervention.
• NSAIDs must be avoided; therefore, acetaminophen codeine is the mainstay.
EPIDEMIOLOGY
• Predominant age: Mean age is 40-50 years
• Predominant sex: Male > Female (~2:1)
• High frequency of urolithiasis worldwide although rare in a few parts of the world (e.g., in Greenland in the coastal areas of Japan)
• The worldwide epidemiology differs according to both geographical area and socioeconomic conditions (dietary intake and lifestyle).
- Radiolucent and infection stones are less influenced by environmental conditions.
• Vesical calculosis (bladder stones), due to malnutrition in early life, is frequent in Middle Eastern and Asian countries. The incidence is improving as social conditions gradually improve.
• Incidences in industrialized countries appear to be increasing, probably due to improved diagnostics, as well as increasingly rich diets and altered environmental conditions.
Incidence
In industrialized countries: 100-200 per 100,000
Prevalence
In industrialized countries: 5-10%
RISK FACTORS
• White > African American in regions with both populations
• Family history
• Diet rich in protein, refined carbohydrates, and sodium
• Occupations associated with a sedentary lifestyle or with a hot, dry workplace
• Incidence rates peak in summer.
Genetics
• Up to 20% of patients have a family history. However, spouse of stone formers have higher calcium excretion rates than controls, suggesting strong dietary-environmental factors.
• Autosomal dominant: Idiopathic hypercalciuria
• Autosomal recessive: Cystinuria, Lesch-Nyan syndrome, hyperoxaluria types I and II
• Ehler-Danlos syndrome, Marfan syndrome, Wilson disease, familial renal tubular acidosis
PATHOPHYSIOLOGY
• Supersaturation and dehydration
• Stasis of urine
- Renal malformation (e.g., horseshoe kidney)
- Incomplete bladder emptying (e.g., neuropathic bladder, prostate enlargement)
• Nucleation and epitaxy: Crystals may form in pure solutions or on existing surfaces (other crystals, cellular debris, etc.).
• Balance of promoters and inhibitors: Organic (Tamm-Horsfall protein, GAG, uropontin, nephrocalcin) and Inorganic (citrate, pyrophosphate)
ETIOLOGY
• Calcium oxalate and/or phosphate stones (80%)
- Idiopathic hypercalciuria
Autosomal dominant trait; present in 50% of calcium stone formers and 10% of the normal population
Absorptive hypercalciuria: Increased jejunal calcium absorption
Renal leak: Increased calcium excretion from renal proximal tubule
Resorptive hypercalciuria: Subtle hyperparathyroidism
- Hypercalcemia
Hyperparathyroidism
Sarcoidosis
Malignancy
Pagets disease
Multiple myeloma
- Hyperoxaluria
Enteric hyperoxaluria: Bowel disease, acidosis, or hypokalaemia; bile salt malbsorption leads to formation of calcium soaps, thus leaving increased oxalate available for colon absorption and subsequent increased renal excretion
Primary hyperoxaluria: Autosomal recessive, types I and II
Dietary hyperoxaluria
- Hyperuricemia
Seen in 10% of calcium stone formers
Acidosis, malbsorption, myeoloproliferative diseases, gout, chemotherapy, Lesch-Nyan syndrome (rare autosomal recessive disorder)
Thiazides, probenicid
- Hypocitraturia
Caused by acidosis: Infection, malabsorption, thiazides, hypokalaemia, dietary salt and protein
• Uric acid stones (10-15%): Hyperuricemia causes as above
• Struvite stones (5-10%): Infected urine with urease-producing organisms (most commonly proteus)
• Cystine stones (1%): Autosomal recessive disorder of renal tubular reabsorption of cystine
• Bladder stones
- Inadequate bladder emptying in adults
- In children, it is usually due to malnutrition.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Pain
- Renal colic: Acute onset of severe loin to groin pain; typically patient cannot lie still.
- Distal stones may present with referred pain in labia, penile meatus, or testis.
- Tender renal angle and/or iliac fossa
• Microscopic or gross hematuria occurs in 95% of patients.
• Nonspecific symptoms of nausea, vomiting, tachycardia, diaphoresis
• Low grade fever without infection
• High grade fever, cloudy urine. Infection requires urgent treatment (see below).
• Irritative lower urinary tract symptoms such as frequency and dysuria especially occur with stones at the vesico-ureteric junction.
• Asymptomatic. Particularly nonobstructing stones within the renal calyces
TESTS
Lab
• Urinalysis for red cells, leukocytes, nitrates, pH (acidic urine 5.5 is associated with uric acid stones, alkaline >7.0 with struvite stones)
• Midstream urine for microscopy, culture, and sensitivity.
• Bloods: FBC, urea, creatinine, electrolytes, calcium, and urate
• Blood culture if suspect sepsis
• Parathyroid hormone only if calcium elevated
• Stone analysis if/when stone passed
Imaging
• Noncontrast helical CT of the abdomen and pelvis is the investigation of choice where available.
- Stone is most commonly found at levels of ureteric luminal narrowing: The pelvi-ureteric junction, the pelvic brim, and the vesico-ureteric junction.
- If the obstruction is acute, proximal ureter and renal pelvis is dilated to the level of obstruction and perinephric "stranding" is seen.
- If chronic, renal atrophy may be noted.
• KUB is necessary when a stone is diagnosed to determine whether the stone is radio-opaque or lucent (determines treatment as well as type of follow-up imaging).
- Calcium oxalate/phosphate stones are radio-opaque.
- Uric acid stones are radiolucent.
- Staghorn calculi (that fill the shape of the renal calyces) are usually struvite and opaque.
- Cystine stones are faintly opaque ("ground-glass" appearance).
• IVP has been largely replaced by CT in the initial diagnostic workup.
• Ultrasound has no role in diagnosis due to its low sensitivity and specificity; exceptions are pregnancy and pediatrics.
DIFFERENTIAL DIAGNOSIS
• Appendicitis
• Ruptured aortic aneurysm
• Musculoskeletal strain
• Pyelonephritis (upper urinary tract infection)
• Pyonephrosis (obstructed upper urinary tract infection-emergency)
• Perinephric abscess
• Ectopic pregnancy
• Salpingitis
TREATMENT
PRE-HOSPITAL
• Analgesia
- Combination of NSAIDs (indomethacin suppository 100 mg) and acetaminophen-codeine orally
- Parenteral narcotic if above fails to control pain (morphine 5-10 mg IV or IM q4h)
- Antiemetic if required or prophylactically with parenteral narcotics
• Antibiotics only if patient septic and after urine and blood cultures taken
• Pushing fluids during an acute episode is not advised. It increases pain and probably does not improve stone passage rates.
STABILIZATION
Septic patients with pyonephrosis may require intravenous fluids, and in severe cases, cardiorespiratory support in intensive care even after relief of obstruction.
GENERAL MEASURES
• 75% of patients are successfully treated conservatively and pass the stone spontaneously
• Advise patient to strain urine and take regular analgesia. Present to hospital if pain is uncontrolled or fevers develop.
Diet
• Increased fluid intake for life cannot be overemphasized for decreasing recurrence.
- Encourage 2-3 L/d intake; advise patient to have "clear" urine rather than yellow.
• Diet modification has less effect than fluid intake on urine concentrations of stone substrates, and has low compliance rates.
• Calcium stone formers should minimize high oxalate foods such as spinach, rhubarb, peanuts, chocolates, and parsley.
• Decrease protein and salt intake.
• Lowering calcium intake is inadvisable and may even increase urine calcium excretion.
SPECIAL THERAPY
• Uric acid stone dissolution therapy
- Ural sachet 3x/d OR potassium citrate OR sodium bicarbonate to alkalinize the urine; keep pH >6.5
- Allopurinol 100-300 mg/d PO
• Cystine stone dissolution/prevention
- Captopril, D-penicillamine, alkalinizers
• Consider altering medications that increase risk of stone formation: Probenicid, loop diuretics, salicylic acid, salbutamol, indinavir, triamterine, acetazolamide
• Recurrent calcium stone formers may improve with thiazides; however, long-term use is limited by side effects such as hypotension, hypokalemia, weakness, and impotence.
• Orthophosphate is required in large daily doses to significantly reduce urine calcium excretion causing side effects of diarrhea, flatus, and bloating.
SURGERY
• Immediate relief of obstruction is imperative in 2 groups of patients
- Patients with signs of sepsis
- Renal failure (obstructed solitary kidney, bilateral obstruction)
• Uncontrolled pain despite adequate analgesia is the most common indication for semi-urgent endoscopic stenting.
• Emergency surgery to unobstruct kidney
- Placement of a retrograde stent (i.e., endoscopic surgery, usually requiring an anesthetic)
- Radiological placement of a percutaneous nephrostomy tube, usually performed in emergencies under local anesthetic
• Elective surgery for stone treatment
- Extracorporeal shock-wave lithotripsy (ESWL)
- Ureteroscopy with basket extraction orlithotripsy (laser or pneumatic)
- Percutaneous nephrolithotomy (PCNL)
- Open surgery uncommon
FOLLOW-UP
• Patients being treated conservatively with ureteric stones should be followed until imaging is clear (KUB 2nd weekly if stone is visible) or stone is visibly passed.
- These patients should be advised to strain their urine.
- If pain management is suboptimal or stone does not progress or pass within 2-4 weeks, patient should be referred to a urologist.
• Recurrent stone formers should have follow-up with a urologist for a full biochemical screen to identify reversible risk factors.
- 24 hour urine for volume, pH, creatinine, calcium, cystine, phosphate, oxalate, uric acid, magnesium
DISPOSITION
Issues for Referral
• Urgent referral of patients with urine infection/sepsis, or acute renal failure/solitary kidney
• Early referral of pregnant patients, large stones (>8 mm), chronic renal failure, children
• Referral if stone not passing at 2-4 weeks or pain is poorly controlled
• All patients with >1 stone or stone episode require referral for metabolic screening.
PROGNOSIS
• Spontaneous stone passage depends on stone location (proximal vs. distal) and stone size (5 mm 90% pass, >8 mm 10% pass)
• Stone recurrence: 50% of patients at 10 years
REFERENCES
1. Qiang W, Ke Z. Water for preventing urinary calculi. Cochrane Database of Systematic Reviews. 2004;3:CD004292.
2. Tiselius HG. Epidemiology and medical management of stone disease. BJU Int. 2003;91: 758-767.
3. Worster A, Preyra I, Weaver B, Haines T. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: A meta-analysis. Ann Emerg Med. 2002;40(3): 280-286.
BASICS
DESCRIPTION
• Stone formation within the urinary tract: Urinary crystals bind to form a nidus, which grows to form a calculus (stone).
• Calculus may be asymptomatic or obstructive, or may be a source of chronic infection.
GENERAL PREVENTION
Increased water intake reduces the risk of recurrence and time to recurrence of urinary calculi.
ALERT
Pediatric Considerations
Rare; more common in males; low socioeconomic status
Pregnancy Considerations
• Pregnant women have the same incidence of renal colic as do nonpregnant women.
• Diagnosis is challenging: Most common differential is physiological hydronephrosis of pregnancy.
• Ultrasound; avoid irradiation
• Aim of treatment is pain control, renal function preservation and aseptic urine until birth or stone passage. Only 30% require some form of intervention.
• NSAIDs must be avoided; therefore, acetaminophen codeine is the mainstay.
EPIDEMIOLOGY
• Predominant age: Mean age is 40-50 years
• Predominant sex: Male > Female (~2:1)
• High frequency of urolithiasis worldwide although rare in a few parts of the world (e.g., in Greenland in the coastal areas of Japan)
• The worldwide epidemiology differs according to both geographical area and socioeconomic conditions (dietary intake and lifestyle).
- Radiolucent and infection stones are less influenced by environmental conditions.
• Vesical calculosis (bladder stones), due to malnutrition in early life, is frequent in Middle Eastern and Asian countries. The incidence is improving as social conditions gradually improve.
• Incidences in industrialized countries appear to be increasing, probably due to improved diagnostics, as well as increasingly rich diets and altered environmental conditions.
Incidence
In industrialized countries: 100-200 per 100,000
Prevalence
In industrialized countries: 5-10%
RISK FACTORS
• White > African American in regions with both populations
• Family history
• Diet rich in protein, refined carbohydrates, and sodium
• Occupations associated with a sedentary lifestyle or with a hot, dry workplace
• Incidence rates peak in summer.
Genetics
• Up to 20% of patients have a family history. However, spouse of stone formers have higher calcium excretion rates than controls, suggesting strong dietary-environmental factors.
• Autosomal dominant: Idiopathic hypercalciuria
• Autosomal recessive: Cystinuria, Lesch-Nyan syndrome, hyperoxaluria types I and II
• Ehler-Danlos syndrome, Marfan syndrome, Wilson disease, familial renal tubular acidosis
PATHOPHYSIOLOGY
• Supersaturation and dehydration
• Stasis of urine
- Renal malformation (e.g., horseshoe kidney)
- Incomplete bladder emptying (e.g., neuropathic bladder, prostate enlargement)
• Nucleation and epitaxy: Crystals may form in pure solutions or on existing surfaces (other crystals, cellular debris, etc.).
• Balance of promoters and inhibitors: Organic (Tamm-Horsfall protein, GAG, uropontin, nephrocalcin) and Inorganic (citrate, pyrophosphate)
ETIOLOGY
• Calcium oxalate and/or phosphate stones (80%)
- Idiopathic hypercalciuria
Autosomal dominant trait; present in 50% of calcium stone formers and 10% of the normal population
Absorptive hypercalciuria: Increased jejunal calcium absorption
Renal leak: Increased calcium excretion from renal proximal tubule
Resorptive hypercalciuria: Subtle hyperparathyroidism
- Hypercalcemia
Hyperparathyroidism
Sarcoidosis
Malignancy
Pagets disease
Multiple myeloma
- Hyperoxaluria
Enteric hyperoxaluria: Bowel disease, acidosis, or hypokalaemia; bile salt malbsorption leads to formation of calcium soaps, thus leaving increased oxalate available for colon absorption and subsequent increased renal excretion
Primary hyperoxaluria: Autosomal recessive, types I and II
Dietary hyperoxaluria
- Hyperuricemia
Seen in 10% of calcium stone formers
Acidosis, malbsorption, myeoloproliferative diseases, gout, chemotherapy, Lesch-Nyan syndrome (rare autosomal recessive disorder)
Thiazides, probenicid
- Hypocitraturia
Caused by acidosis: Infection, malabsorption, thiazides, hypokalaemia, dietary salt and protein
• Uric acid stones (10-15%): Hyperuricemia causes as above
• Struvite stones (5-10%): Infected urine with urease-producing organisms (most commonly proteus)
• Cystine stones (1%): Autosomal recessive disorder of renal tubular reabsorption of cystine
• Bladder stones
- Inadequate bladder emptying in adults
- In children, it is usually due to malnutrition.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Pain
- Renal colic: Acute onset of severe loin to groin pain; typically patient cannot lie still.
- Distal stones may present with referred pain in labia, penile meatus, or testis.
- Tender renal angle and/or iliac fossa
• Microscopic or gross hematuria occurs in 95% of patients.
• Nonspecific symptoms of nausea, vomiting, tachycardia, diaphoresis
• Low grade fever without infection
• High grade fever, cloudy urine. Infection requires urgent treatment (see below).
• Irritative lower urinary tract symptoms such as frequency and dysuria especially occur with stones at the vesico-ureteric junction.
• Asymptomatic. Particularly nonobstructing stones within the renal calyces
TESTS
Lab
• Urinalysis for red cells, leukocytes, nitrates, pH (acidic urine 5.5 is associated with uric acid stones, alkaline >7.0 with struvite stones)
• Midstream urine for microscopy, culture, and sensitivity.
• Bloods: FBC, urea, creatinine, electrolytes, calcium, and urate
• Blood culture if suspect sepsis
• Parathyroid hormone only if calcium elevated
• Stone analysis if/when stone passed
Imaging
• Noncontrast helical CT of the abdomen and pelvis is the investigation of choice where available.
- Stone is most commonly found at levels of ureteric luminal narrowing: The pelvi-ureteric junction, the pelvic brim, and the vesico-ureteric junction.
- If the obstruction is acute, proximal ureter and renal pelvis is dilated to the level of obstruction and perinephric "stranding" is seen.
- If chronic, renal atrophy may be noted.
• KUB is necessary when a stone is diagnosed to determine whether the stone is radio-opaque or lucent (determines treatment as well as type of follow-up imaging).
- Calcium oxalate/phosphate stones are radio-opaque.
- Uric acid stones are radiolucent.
- Staghorn calculi (that fill the shape of the renal calyces) are usually struvite and opaque.
- Cystine stones are faintly opaque ("ground-glass" appearance).
• IVP has been largely replaced by CT in the initial diagnostic workup.
• Ultrasound has no role in diagnosis due to its low sensitivity and specificity; exceptions are pregnancy and pediatrics.
DIFFERENTIAL DIAGNOSIS
• Appendicitis
• Ruptured aortic aneurysm
• Musculoskeletal strain
• Pyelonephritis (upper urinary tract infection)
• Pyonephrosis (obstructed upper urinary tract infection-emergency)
• Perinephric abscess
• Ectopic pregnancy
• Salpingitis
TREATMENT
PRE-HOSPITAL
• Analgesia
- Combination of NSAIDs (indomethacin suppository 100 mg) and acetaminophen-codeine orally
- Parenteral narcotic if above fails to control pain (morphine 5-10 mg IV or IM q4h)
- Antiemetic if required or prophylactically with parenteral narcotics
• Antibiotics only if patient septic and after urine and blood cultures taken
• Pushing fluids during an acute episode is not advised. It increases pain and probably does not improve stone passage rates.
STABILIZATION
Septic patients with pyonephrosis may require intravenous fluids, and in severe cases, cardiorespiratory support in intensive care even after relief of obstruction.
GENERAL MEASURES
• 75% of patients are successfully treated conservatively and pass the stone spontaneously
• Advise patient to strain urine and take regular analgesia. Present to hospital if pain is uncontrolled or fevers develop.
Diet
• Increased fluid intake for life cannot be overemphasized for decreasing recurrence.
- Encourage 2-3 L/d intake; advise patient to have "clear" urine rather than yellow.
• Diet modification has less effect than fluid intake on urine concentrations of stone substrates, and has low compliance rates.
• Calcium stone formers should minimize high oxalate foods such as spinach, rhubarb, peanuts, chocolates, and parsley.
• Decrease protein and salt intake.
• Lowering calcium intake is inadvisable and may even increase urine calcium excretion.
SPECIAL THERAPY
• Uric acid stone dissolution therapy
- Ural sachet 3x/d OR potassium citrate OR sodium bicarbonate to alkalinize the urine; keep pH >6.5
- Allopurinol 100-300 mg/d PO
• Cystine stone dissolution/prevention
- Captopril, D-penicillamine, alkalinizers
• Consider altering medications that increase risk of stone formation: Probenicid, loop diuretics, salicylic acid, salbutamol, indinavir, triamterine, acetazolamide
• Recurrent calcium stone formers may improve with thiazides; however, long-term use is limited by side effects such as hypotension, hypokalemia, weakness, and impotence.
• Orthophosphate is required in large daily doses to significantly reduce urine calcium excretion causing side effects of diarrhea, flatus, and bloating.
SURGERY
• Immediate relief of obstruction is imperative in 2 groups of patients
- Patients with signs of sepsis
- Renal failure (obstructed solitary kidney, bilateral obstruction)
• Uncontrolled pain despite adequate analgesia is the most common indication for semi-urgent endoscopic stenting.
• Emergency surgery to unobstruct kidney
- Placement of a retrograde stent (i.e., endoscopic surgery, usually requiring an anesthetic)
- Radiological placement of a percutaneous nephrostomy tube, usually performed in emergencies under local anesthetic
• Elective surgery for stone treatment
- Extracorporeal shock-wave lithotripsy (ESWL)
- Ureteroscopy with basket extraction orlithotripsy (laser or pneumatic)
- Percutaneous nephrolithotomy (PCNL)
- Open surgery uncommon
FOLLOW-UP
• Patients being treated conservatively with ureteric stones should be followed until imaging is clear (KUB 2nd weekly if stone is visible) or stone is visibly passed.
- These patients should be advised to strain their urine.
- If pain management is suboptimal or stone does not progress or pass within 2-4 weeks, patient should be referred to a urologist.
• Recurrent stone formers should have follow-up with a urologist for a full biochemical screen to identify reversible risk factors.
- 24 hour urine for volume, pH, creatinine, calcium, cystine, phosphate, oxalate, uric acid, magnesium
DISPOSITION
Issues for Referral
• Urgent referral of patients with urine infection/sepsis, or acute renal failure/solitary kidney
• Early referral of pregnant patients, large stones (>8 mm), chronic renal failure, children
• Referral if stone not passing at 2-4 weeks or pain is poorly controlled
• All patients with >1 stone or stone episode require referral for metabolic screening.
PROGNOSIS
• Spontaneous stone passage depends on stone location (proximal vs. distal) and stone size (5 mm 90% pass, >8 mm 10% pass)
• Stone recurrence: 50% of patients at 10 years
REFERENCES
1. Qiang W, Ke Z. Water for preventing urinary calculi. Cochrane Database of Systematic Reviews. 2004;3:CD004292.
2. Tiselius HG. Epidemiology and medical management of stone disease. BJU Int. 2003;91: 758-767.
3. Worster A, Preyra I, Weaver B, Haines T. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: A meta-analysis. Ann Emerg Med. 2002;40(3): 280-286.
URINARY TRACT INFECTION IN MALES
URINARY TRACT INFECTION IN MALES - Scott A. Fields, MD
BASICS
DESCRIPTION
Cystitis is an infection of the lower urinary tract, usually resulting from a single gram-negative enteric bacteria. (See separate chapters for information on prostatitis, pyelonephritis, and nongonococcal urethritis.)
• System(s) Affected: Renal/Urologic
• Synonym(s): UTI; Cystitis
GENERAL PREVENTION
• Prompt treatment of predisposing factors
• Catheter use only when necessary; if needed, use aseptic technique and closed system, with removal as soon as possible
EPIDEMIOLOGY
• Predominant age: Increases with age. Uncommon in men 50 years old; 8 infections/10,000 men, ages 21-50 years
• Predominant sex: Male only (for this discussion)
Prevalence
Not common
RISK FACTORS
• Benign prostatic hypertrophy
• Cognitive impairment
• Fecal incontinence
• Urinary incontinence
• Anal intercourse
• Recent urologic surgery, catheterization
• Infection of the prostate or kidney
• Urinary tract instrumentation
• Immunocompromised host
• Outlet obstruction
Genetics
No specific genetic pattern
ETIOLOGY
• Escherichia coli (80% of infections)
• Klebsiella
• Enterobacter
• Proteus
• Pseudomonas
• Serratia
• Streptococcus faecalis and Staphylococcus
ASSOCIATED CONDITIONS
• Acute bacterial pyelonephritis
• Chronic bacterial pyelonephritis
• Urethritis
• Prostatitis
• Prostatic hypertrophy
• Prostate cancer
ALERT
Geriatric Considerations
Bacteriuria is common in the elderly, appears related to functional status, and is usually transient. If asymptomatic bacteriuria is noted, no treatment is needed.
Pediatric Considerations
Usually associated with obstruction to normal flow of urine, such as vesicoureteral reflux
DIAGNOSIS
SIGNS AND SYMPTOMS
• Urinary frequency
• Urinary urgency
• Dysuria
• Hesitancy
• Slow urinary stream
• Dribbling of urine
• Nocturia
• Suprapubic discomfort
• Low back pain
• Hematuria
• Systemic symptoms (chills, fever) present with concomitant pyelonephritis or prostatitis
History
Careful history and physical exam
TESTS
Urologic investigations are necessary to rule out other disorders.
Lab
• Pyuria
• Bacteriuria
• Urine dipstick leukocyte esterase (75-90% sensitivity, 95% specificity) and nitrate (35-85% sensitivity, 70% specificity)
• Urine culture: 10 high-power colonies of pathogens (or counts >100,000 bacteria/mL of urine) confirm diagnosis (E. coli, Klebsiella, Pseudomonas, other agents). Lower counts may also be indicative of infection, especially in presence of pyuria.
• Segmented bacteriologic localization cultures
- Variable block 1 (VB1): Collect 5-10 mL of urine from patient's initial voiding.
- VB2: Then a sample of sterile midstream urine is obtained.
- Expressed prostatic secretion (EPS): Prostatic massage is performed and EPS is collected from the meatus.
- VB3: Patient completes voiding, and fourth sample is collected.
- Cultures and sensitivity are collected from each specimen.
• Drugs that may alter lab results: Antibiotics prior to culture
Imaging
• IV pyelography
• Cystoscopy
• Ultrasound
Pathological Findings
Depends on site of infection
DIFFERENTIAL DIAGNOSIS
• Anatomic or functional pathology
• Urethritis
• Infections in other sites of the genitourinary tract (e.g., epididymis)
TREATMENT
STABILIZATION
Outpatient treatment, except for acute illness with toxicity or kidney failure
GENERAL MEASURES
• Hydration; analgesia if required
• Discontinue sexual activity until cured.
• Patient with indwelling catheters
- If asymptomatic bacterial colonization, no need to treat (sterilization of urine is not possible and resistant organisms may take up residence)
- If symptomatic of acute infection, institute treatment
Diet
No special diet
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Acute infection, 1st infection, no risk factors for treatment: Prescribe 7-10 days of oral antibiotics, either empirically or based on culture and sensitivity results. For empiric therapy, trimethoprim-sulfamethoxazole (SMX-TMP) b.i.d. will usually treat the most likely pathogens. (1-4,6-8)[C]
• Complicated or recurrent infection: Prescribe 14-21 days of antibiotics based on antimicrobial sensitivities with repeat urine check after the treatment. (1-4,6-8)[C]
• For contraindications, precautions, and possible significant interactions, refer to the manufacturer's information.
Second Line
According to culture and sensitivity results and patient's history
FOLLOW-UP
PROGNOSIS
Clearing of infections with appropriate antibiotic treatment
COMPLICATIONS
• Pyelonephritis
• Ascending infection
• Recurrent infection
PATIENT MONITORING
• Close follow-up until clinically well
• Repeat urinalysis after treatment.
REFERENCES
1. Finn SD. Urinary tract infectionsdiagnosis and treatment in women and men. Consultant. 1992;10:43-58.
2. Hooton TM, Stamm WE. Management of acute uncomplicated urinary tract infection in adults. Med Clin North Am. 1991;75:339-357.
3. Harrington RD, Hooton TM. Urinary tract infection risk factors and gender. J Gend Specif Med. 2000;3:27-34.
4. Hatton J, Hughes M, Raymond CH. Management of bacterial urinary tract infections in adults. Ann Pharmacother. 1994;28:1264-1272.
5. Khan AJ, Schaeffer HA, Evans H. Urinary tract infections in adolescent boys. J Natl Med Assoc. 1996;88:25-26.
6. Lipsky BA. Urinary tract infections in men. Epidemiology, pathophysiology, diagnosis, and treatment. Ann Intern Med. 1989;110:138-150.
7. Lipsky BA. Managing urinary tract infections in men. Hosp Pract (Off Ed). 2000;35:53-59, discussion 59-60.
8. Naber KG, et al. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). EAU guidelines for the management of urinary and male genital tract infections. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). Eur Urol. 2001;40:576-588.
MISCELLANEOUS
See also: Prostatic cancer; Prostatic hyperplasia, benign (BPH); Prostatitis; Pyelonephritis
BASICS
DESCRIPTION
Cystitis is an infection of the lower urinary tract, usually resulting from a single gram-negative enteric bacteria. (See separate chapters for information on prostatitis, pyelonephritis, and nongonococcal urethritis.)
• System(s) Affected: Renal/Urologic
• Synonym(s): UTI; Cystitis
GENERAL PREVENTION
• Prompt treatment of predisposing factors
• Catheter use only when necessary; if needed, use aseptic technique and closed system, with removal as soon as possible
EPIDEMIOLOGY
• Predominant age: Increases with age. Uncommon in men 50 years old; 8 infections/10,000 men, ages 21-50 years
• Predominant sex: Male only (for this discussion)
Prevalence
Not common
RISK FACTORS
• Benign prostatic hypertrophy
• Cognitive impairment
• Fecal incontinence
• Urinary incontinence
• Anal intercourse
• Recent urologic surgery, catheterization
• Infection of the prostate or kidney
• Urinary tract instrumentation
• Immunocompromised host
• Outlet obstruction
Genetics
No specific genetic pattern
ETIOLOGY
• Escherichia coli (80% of infections)
• Klebsiella
• Enterobacter
• Proteus
• Pseudomonas
• Serratia
• Streptococcus faecalis and Staphylococcus
ASSOCIATED CONDITIONS
• Acute bacterial pyelonephritis
• Chronic bacterial pyelonephritis
• Urethritis
• Prostatitis
• Prostatic hypertrophy
• Prostate cancer
ALERT
Geriatric Considerations
Bacteriuria is common in the elderly, appears related to functional status, and is usually transient. If asymptomatic bacteriuria is noted, no treatment is needed.
Pediatric Considerations
Usually associated with obstruction to normal flow of urine, such as vesicoureteral reflux
DIAGNOSIS
SIGNS AND SYMPTOMS
• Urinary frequency
• Urinary urgency
• Dysuria
• Hesitancy
• Slow urinary stream
• Dribbling of urine
• Nocturia
• Suprapubic discomfort
• Low back pain
• Hematuria
• Systemic symptoms (chills, fever) present with concomitant pyelonephritis or prostatitis
History
Careful history and physical exam
TESTS
Urologic investigations are necessary to rule out other disorders.
Lab
• Pyuria
• Bacteriuria
• Urine dipstick leukocyte esterase (75-90% sensitivity, 95% specificity) and nitrate (35-85% sensitivity, 70% specificity)
• Urine culture: 10 high-power colonies of pathogens (or counts >100,000 bacteria/mL of urine) confirm diagnosis (E. coli, Klebsiella, Pseudomonas, other agents). Lower counts may also be indicative of infection, especially in presence of pyuria.
• Segmented bacteriologic localization cultures
- Variable block 1 (VB1): Collect 5-10 mL of urine from patient's initial voiding.
- VB2: Then a sample of sterile midstream urine is obtained.
- Expressed prostatic secretion (EPS): Prostatic massage is performed and EPS is collected from the meatus.
- VB3: Patient completes voiding, and fourth sample is collected.
- Cultures and sensitivity are collected from each specimen.
• Drugs that may alter lab results: Antibiotics prior to culture
Imaging
• IV pyelography
• Cystoscopy
• Ultrasound
Pathological Findings
Depends on site of infection
DIFFERENTIAL DIAGNOSIS
• Anatomic or functional pathology
• Urethritis
• Infections in other sites of the genitourinary tract (e.g., epididymis)
TREATMENT
STABILIZATION
Outpatient treatment, except for acute illness with toxicity or kidney failure
GENERAL MEASURES
• Hydration; analgesia if required
• Discontinue sexual activity until cured.
• Patient with indwelling catheters
- If asymptomatic bacterial colonization, no need to treat (sterilization of urine is not possible and resistant organisms may take up residence)
- If symptomatic of acute infection, institute treatment
Diet
No special diet
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Acute infection, 1st infection, no risk factors for treatment: Prescribe 7-10 days of oral antibiotics, either empirically or based on culture and sensitivity results. For empiric therapy, trimethoprim-sulfamethoxazole (SMX-TMP) b.i.d. will usually treat the most likely pathogens. (1-4,6-8)[C]
• Complicated or recurrent infection: Prescribe 14-21 days of antibiotics based on antimicrobial sensitivities with repeat urine check after the treatment. (1-4,6-8)[C]
• For contraindications, precautions, and possible significant interactions, refer to the manufacturer's information.
Second Line
According to culture and sensitivity results and patient's history
FOLLOW-UP
PROGNOSIS
Clearing of infections with appropriate antibiotic treatment
COMPLICATIONS
• Pyelonephritis
• Ascending infection
• Recurrent infection
PATIENT MONITORING
• Close follow-up until clinically well
• Repeat urinalysis after treatment.
REFERENCES
1. Finn SD. Urinary tract infectionsdiagnosis and treatment in women and men. Consultant. 1992;10:43-58.
2. Hooton TM, Stamm WE. Management of acute uncomplicated urinary tract infection in adults. Med Clin North Am. 1991;75:339-357.
3. Harrington RD, Hooton TM. Urinary tract infection risk factors and gender. J Gend Specif Med. 2000;3:27-34.
4. Hatton J, Hughes M, Raymond CH. Management of bacterial urinary tract infections in adults. Ann Pharmacother. 1994;28:1264-1272.
5. Khan AJ, Schaeffer HA, Evans H. Urinary tract infections in adolescent boys. J Natl Med Assoc. 1996;88:25-26.
6. Lipsky BA. Urinary tract infections in men. Epidemiology, pathophysiology, diagnosis, and treatment. Ann Intern Med. 1989;110:138-150.
7. Lipsky BA. Managing urinary tract infections in men. Hosp Pract (Off Ed). 2000;35:53-59, discussion 59-60.
8. Naber KG, et al. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). EAU guidelines for the management of urinary and male genital tract infections. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). Eur Urol. 2001;40:576-588.
MISCELLANEOUS
See also: Prostatic cancer; Prostatic hyperplasia, benign (BPH); Prostatitis; Pyelonephritis
URTICARIA
URTICARIA - Weily Soong, MD
BASICS
DESCRIPTION
A rapid eruption of polymorphic-shaped cutaneous wheals with central swelling, erythema, and blanching; size ranges from a few millimeters to several centimeters; single or multiple superficial papules and plaques; associated with itching or burning; subsides within 24 hours with no scars or change in pigmentation; may be recurrent; often associated with angioedema (swelling of the lower dermis and subcutis); also known as hives.
• Spontaneous urticaria
- Acute: Persists 6 weeks
Vast number of possible triggers, e.g., foods, medications, insect stings/bites, infections, physical stimuli, and occupational exposures
Etiology is usually obvious to the patient and physician.
- Chronic: Persists >6 weeks
Can be either continuous (daily symptoms) or recurrent (periods with flares and periods with no symptoms)
The longer the urticaria persists, the more difficult to find the etiology
Usually not IgE mediated
Most likely idiopathic (~80% of cases), but reported associations with psychological stress, pseudoallergenic foods/additives, autoimmunity, chronic indolent infections, or malignancy
• Physical urticaria
- Dermatographism: Linear, itchy, red wheal and flare from scratching or rubbing the skin
- Cold urticaria: From exposure to cold; usually idiopathic but can be due to infections, neoplasia, or autoimmune diseases. The familial form, called Familial Cold Autoinflammatory Syndrome, is characterized by recurrent bouts of fever, urticaria, and joint pain triggered by cold, and is caused by mutations in the Cryopyrin gene resulting in the release of interleukin 1.
- Delayed pressure urticaria: Deeper and more painful urticaria; occurs 2-6 hours after pressure to skin (e.g., from elastic or shoes)
- Solar urticaria: From exposure to sunlight of different wavelengths, usually ultraviolet light; onset in minutes; subsides within 2 hours
- Heat urticaria: From direct contact with warm objects or air; rare
- Vibratory urticaria/angioedema: From strong vibrating mechanical forces; rare
• Special forms of urticaria
- Cholinergic urticaria: Due to brief increase of core body temperature; small pin-sized (5-10 mm) wheals surrounded by an erythema but can also have larger wheals; from physical exercise, stress, and hot showers
- Adrenergic urticaria: Caused by stress; extremely rare; has pinpoint-sized red wheals with a white halo
- Contact urticaria: Wheals at sites where chemical substances contact with the skin
- Aquagenic urticaria: Small wheals after contact with water at any temperature; rare
- Urticarial vasculitis: A leukocytoclastic vasculitis looking like urticaria and tending to last >24 hours; more painful than puritic; maybe palpable and purpuric
GENERAL PREVENTION
• Acute, physical, and special forms of urticaria: Avoidance of the potential trigger
• Chronic urticaria: Usually unable to prevent
EPIDEMIOLOGY
• Predominant in all ages: Acute form mainly in children; chronic form mainly in adults
• Predominant sex: Male = Female
• 50% of patients have urticaria with angioedema, 40% with urticaria only, 10% with angioedema only
• 20% of chronic urticaria have known causes.
Prevalence
• Affects 15-25% of population during lifetime
• In the US population: 1 in 1000
ALERT
Pediatric Considerations
• Acute isolated incidents are more frequent; affects 6-7% of preschool children; 17% of children have a history of atopic dermatitis
• In childhood acute urticaria, infection (especially respiratory and urinary tract) is the most frequently documented cause (49%), followed by drug (5%) and food allergies (3%)
RISK FACTORS
History of atopic diseases: Allergic rhinitis, asthma, atopic dermatitis, food and drug allergies
Genetics
No consistent pattern known
PATHOPHYSIOLOGY
• Caused by a degranulation of mast cells which triggers a release of inflammatory mediators (e.g., histamine and leukotrienes) to cause local vasodilatation, cellular infiltration (lymphocytes, eosinophils, mast cells, basophils, neutrophils), vascular permeability, and edema of the dermis of the skin (urticaria) or of subcutaneous skin tissue (angioedema)
• May be immune-mediated (IgE-mediated), complement-mediated, nonimmune-mediated (e.g., degranulation of mast cells by physical stimuli), autoimmune-mediated, or idiopathic
ETIOLOGY
• Spontaneous urticaria
- Acute
Viral infections: Upper respiratory tract (most common cause, especially in children), mononucleosis, viral hepatitis
Bacterial infections: Strep throat, sinusitis, dental caries, otitis, urinary tract
Foods, especially in children: Most common are peanut, tree nuts, seafood, milk, soy, fish, wheat, and eggs. Tend to be IgE mediated. Allergies to food preservatives and additives are possible but not common.
Drugs: Can be IgE-mediated (e.g., penicillin), nonIgE-mediated (e.g., aspirin and NSAIDs), or idiosyncratic
Inhalant, contact, ingestion, or occupational exposure
Insect bite or sting
Transfusion reaction
- Chronic: >80% of cases idiopathic; usually nonIgE-mediated
Chronic indolent infections: Helicobacter pylori, vaginitis, fungal or tinea, parasitic, chronic sinusitis, dental cavities, and chronic viral infections (hepatitis)
Collagen vascular disease (cutaneous vasculitis, serum sickness, lupus)
Thyroid autoimmunity
Autoimmune antibodies to the IgE receptor on mast cells and to the IgE antibody causing mast cell degranulation
Malignancy; rare
Emotional stress (little supporting evidence)
• Physical and special forms of urticaria: Nonimmune- mediated mast cell degranulation caused by a specific physical stimuli, body temperature changes, stress, chemical substances, and water
ASSOCIATED CONDITIONS
• Angioedema
• Anaphylaxis
DIAGNOSIS
SIGNS AND SYMPTOMS
• Seen alone or with angioedema
• Urticaria may be an initial symptom of a generalized anaphylactic reaction, potentially fatal.
• Single or multiple raised, blanched, central wheals surrounded by red flare anywhere on body
• Intensely pruritic
• Variably sized, 1-2 mm to 15-20 cm or larger; sometimes confluent
• Fast onset, resolves spontaneously in 48 hours
History
The most important: A detailed history and review of symptoms, including the timing/duration of the symptoms, potential triggers, and history of atopic diseases and autoimmune diseases
Physical Exam
A complete physical exam to detect any associated conditions (autoimmune; malignancy; and viral, bacterial, and fungal/tinea infections)
TESTS
Lab
• Acute urticaria: Testing depends on the history and the potential triggers.
- Allergy skin tests and radioallergosorbent test (RAST) for inhaled allergens, insects, drugs, or foods and for assessing other atopic conditions
- Infection: Pharyngeal culture, liver function tests, mononucleosis test, urine analysis
- Food and drug reactions: Elimination of or challenges with suspected agents
• Chronic urticaria: Depending on diagnostic suspicions
- CBC with differential
- Tests for H. pylori (e.g., antibodies)
- Thyroid function tests and anti-thyroid antibodies (anti-thyroperoxidase and anti-thyroglobulin)
- Autoimmune: ESR, antinuclear antibody (ANA), rheumatoid factor, complement (such as CH50), cryoglobulins
- Stool for ova and parasites
- Urine analysis
- Autologous serum skin testing
- Food and drug reactions: Elimination of or challenges with suspected agents
- Maligancy work-up, including serum protein electrophoresis and immunofixation assay
• Physical and special forms of urticaria
- Dermatographism: Scratch skin with a tongue blade, observe for surrounding uricaria.
- Cold urticaria: Ice cube testplace ice cube on skin 5 minutes, observe 10-15 minutes
- Cholinergic: Exercise challenge
- Solar: Expose skin to wavelengths of light.
- Delayed pressure: Apply 5-10-lb sandbag for 3 hours, observe
- Aquagenic: Apply water at various temperatures.
- Vibratory: Apply vibration 4-5 minutes with a lab mixing device, observe.
Imaging
Any imaging necessary to rule out chronic indolent infections (e.g., sinus CT) or malignancy
Diagnostic Procedures/Surgery
• Skin biopsy to rule out urticarial vasculitis
• Routine dental care to rule out dental caries
DIFFERENTIAL DIAGNOSIS
• Anaphylaxis (a potentially fatal generalized systemic allergic disorder with urticaria, angioedema, respiratory distress, abdominal pain, hypotension; may present initially with urticaria)
• Insect bites
• Morbilliform drug eruptions
• Erythema multiforme
• Systemic lupus erythematosus
• Vasculitis and polyarteritis
• Angioedema without urticaria (related to complement and bradykinin disorders, such as familial hereditary angioedema, angiotensin converting enzyme (ACE) inhbitor angioedema, complement deficiencies)
• Urticaria pigmentosa (mastocytosis). Pink lesions urticate when scratched (Darier sign).
• Bullous pemphigoid (urticarial stage)
TREATMENT
GENERAL MEASURES
Avoidance or elimination of the eliciting stimulus
Diet
If a particular food is implicated, avoidance of the food or a trial of avoiding the food for 2-3 weeks
Activity
Depends on the urticarial trigger
• Cold and heat urticaria: Avoid sudden changes in temperature (e.g., slowly getting into a cold swimming pool).
• Dermatographic and delayed-pressure urticaria: Spread out the amount of force per area applied to the skin.
• Solar urticaria: Avoid the sun; use sunscreen.
• Cholinergic urticaria: Avoid sudden changes in body temperature (e.g., slow warm-ups and cooldowns during exercise).
Complementary and Alternative Medicine
• Avoid use of alternative medicine drugs. Herbal and vitamin supplements may make the urticaria worse, because trace contaminants in the supplements might be allergenic.
• Beware of certain "experts" in alternative medicine who might place chronic urticarial patients on severe food and activity restrictions based on lab tests that have little scientific basis.
MEDICATION (DRUGS)
First Line
• 1st-generation antihistaminesmainly for short, intermittent attacks of urticaria; use is limited by its sedation and short half-life) (1,2)[A]
- Older children and adults: Hydroxyzine or diphenhydramine 25-50 mg q6h
- Children 6 years old: Diphenhydramine 12.5 mg (elixir) q6-8h (5 mg/kg/d) or hydroxyzine elixir (10 mg/5 mL) 2 mg/kg/d divided q6-8h
• 2nd-generation H1-blockersmore expensive; effectiveness like older antihistamines but less sedating; a longer half-life. (1,2)[A]
- Fexofenadine (Allegra): 180 mg/d
- Loratadine (Claritin): 10 mg/d
- Desloratadine (Clarinex): 5 mg/d
- Cetirizine (Zyrtec): 10 mg/d
• May need higher doses of antihistamines or a combination of multiple antihistamines for control
• Precautions
- Drowsiness and dry mouth and eyes
- Should be used with caution in the elderly and during pregnancy
Second Line
• Doxepin (Sinequan): Tricyclic antidepressant with strong H1- and H2-blocking properties; 10-25 mg at bedtime; sedation limits usefulness (2)[C]
• H2-blockers: mildly helpful (1,2)[C]
• Corticosteroids: For unresponsive cases, e.g., prednisone 40 mg/d for 5-7 days, taper as antihistamines are introduced; avoid chronic use due to the severe side effects which might be worse than the effects of the urticaria (2)[C]
• Cyproheptadine: Antihistamine and antiserotonergic agent (2)[C]
• Cyclosporine: Best-studied immunosuppressive therapy; effective (2.5-5 mg/kg/d) and steroid sparing (3)[C]
• Leukotriene antagonists: Safe and worth trying in chronic, unresponsive cases (2)[C]
• Intravenous immune globulin, plasmapheresis, sulfasalazine, dapsone, danazol, and hydroxychloroquine require further study. (3)
• Administering thyroid hormone may alleviate chronic urticaria in hypothyroid patients with autoantibodies. (3)[C]
FOLLOW-UP
DISPOSITION
Admission Criteria
If urticaria and angioedema progress into anaphylaxis or threaten the airway. Will need to be discharged with an EpiPen
Issues for Referral
• Referral to an allergist and immunologist for elucidating and testing of potential triggers, life-threatening reactions, and complex management
• Referral to a dermatologist for skin biopsy
• Referral to a rheumatologist for treatment of autoimmune causes of urticaria
PROGNOSIS
• 70% of acute symptoms are better in 72 hours.
• 30% of the patients are chronic.
• >50% of chronic idiopathic urticaria resolve in 3-5 years but are at risk for a reoccurrence many years later.
PATIENT MONITORING
If symptoms persist or recur, patient may need to keep a daily diary of potential triggers (foods, activities, etc.). Pictures of the urticarial lesions are helpful.
REFERENCES
1. Baxi S, Dinakar C. Urticaria and angioedema. Immunol Allergy Clin N Am. 2005;25:353-367.
2. Zuberbier T. Urticaria. Allergy. 2003;58:1224-1234.
3. Kaplan AP. Chronic urticaria: Pathogenesis and treatment. J Allergy Clin Immunol. 2004;114:465-474.
4. Joint Task Force on Practice Parameters. The diagnosis and management of urticaria: A practice parameter. Ann Allergy Asthma Immunol. 2000;85:521-544.
5. Wedi B, Raap U, Kapp A. Chronic urticaria and infections. Curr Opin Allergy Clin Immunol. 2004;4:387-396.
MISCELLANEOUS
See also: Anaphylaxis; Angioedema
BASICS
DESCRIPTION
A rapid eruption of polymorphic-shaped cutaneous wheals with central swelling, erythema, and blanching; size ranges from a few millimeters to several centimeters; single or multiple superficial papules and plaques; associated with itching or burning; subsides within 24 hours with no scars or change in pigmentation; may be recurrent; often associated with angioedema (swelling of the lower dermis and subcutis); also known as hives.
• Spontaneous urticaria
- Acute: Persists 6 weeks
Vast number of possible triggers, e.g., foods, medications, insect stings/bites, infections, physical stimuli, and occupational exposures
Etiology is usually obvious to the patient and physician.
- Chronic: Persists >6 weeks
Can be either continuous (daily symptoms) or recurrent (periods with flares and periods with no symptoms)
The longer the urticaria persists, the more difficult to find the etiology
Usually not IgE mediated
Most likely idiopathic (~80% of cases), but reported associations with psychological stress, pseudoallergenic foods/additives, autoimmunity, chronic indolent infections, or malignancy
• Physical urticaria
- Dermatographism: Linear, itchy, red wheal and flare from scratching or rubbing the skin
- Cold urticaria: From exposure to cold; usually idiopathic but can be due to infections, neoplasia, or autoimmune diseases. The familial form, called Familial Cold Autoinflammatory Syndrome, is characterized by recurrent bouts of fever, urticaria, and joint pain triggered by cold, and is caused by mutations in the Cryopyrin gene resulting in the release of interleukin 1.
- Delayed pressure urticaria: Deeper and more painful urticaria; occurs 2-6 hours after pressure to skin (e.g., from elastic or shoes)
- Solar urticaria: From exposure to sunlight of different wavelengths, usually ultraviolet light; onset in minutes; subsides within 2 hours
- Heat urticaria: From direct contact with warm objects or air; rare
- Vibratory urticaria/angioedema: From strong vibrating mechanical forces; rare
• Special forms of urticaria
- Cholinergic urticaria: Due to brief increase of core body temperature; small pin-sized (5-10 mm) wheals surrounded by an erythema but can also have larger wheals; from physical exercise, stress, and hot showers
- Adrenergic urticaria: Caused by stress; extremely rare; has pinpoint-sized red wheals with a white halo
- Contact urticaria: Wheals at sites where chemical substances contact with the skin
- Aquagenic urticaria: Small wheals after contact with water at any temperature; rare
- Urticarial vasculitis: A leukocytoclastic vasculitis looking like urticaria and tending to last >24 hours; more painful than puritic; maybe palpable and purpuric
GENERAL PREVENTION
• Acute, physical, and special forms of urticaria: Avoidance of the potential trigger
• Chronic urticaria: Usually unable to prevent
EPIDEMIOLOGY
• Predominant in all ages: Acute form mainly in children; chronic form mainly in adults
• Predominant sex: Male = Female
• 50% of patients have urticaria with angioedema, 40% with urticaria only, 10% with angioedema only
• 20% of chronic urticaria have known causes.
Prevalence
• Affects 15-25% of population during lifetime
• In the US population: 1 in 1000
ALERT
Pediatric Considerations
• Acute isolated incidents are more frequent; affects 6-7% of preschool children; 17% of children have a history of atopic dermatitis
• In childhood acute urticaria, infection (especially respiratory and urinary tract) is the most frequently documented cause (49%), followed by drug (5%) and food allergies (3%)
RISK FACTORS
History of atopic diseases: Allergic rhinitis, asthma, atopic dermatitis, food and drug allergies
Genetics
No consistent pattern known
PATHOPHYSIOLOGY
• Caused by a degranulation of mast cells which triggers a release of inflammatory mediators (e.g., histamine and leukotrienes) to cause local vasodilatation, cellular infiltration (lymphocytes, eosinophils, mast cells, basophils, neutrophils), vascular permeability, and edema of the dermis of the skin (urticaria) or of subcutaneous skin tissue (angioedema)
• May be immune-mediated (IgE-mediated), complement-mediated, nonimmune-mediated (e.g., degranulation of mast cells by physical stimuli), autoimmune-mediated, or idiopathic
ETIOLOGY
• Spontaneous urticaria
- Acute
Viral infections: Upper respiratory tract (most common cause, especially in children), mononucleosis, viral hepatitis
Bacterial infections: Strep throat, sinusitis, dental caries, otitis, urinary tract
Foods, especially in children: Most common are peanut, tree nuts, seafood, milk, soy, fish, wheat, and eggs. Tend to be IgE mediated. Allergies to food preservatives and additives are possible but not common.
Drugs: Can be IgE-mediated (e.g., penicillin), nonIgE-mediated (e.g., aspirin and NSAIDs), or idiosyncratic
Inhalant, contact, ingestion, or occupational exposure
Insect bite or sting
Transfusion reaction
- Chronic: >80% of cases idiopathic; usually nonIgE-mediated
Chronic indolent infections: Helicobacter pylori, vaginitis, fungal or tinea, parasitic, chronic sinusitis, dental cavities, and chronic viral infections (hepatitis)
Collagen vascular disease (cutaneous vasculitis, serum sickness, lupus)
Thyroid autoimmunity
Autoimmune antibodies to the IgE receptor on mast cells and to the IgE antibody causing mast cell degranulation
Malignancy; rare
Emotional stress (little supporting evidence)
• Physical and special forms of urticaria: Nonimmune- mediated mast cell degranulation caused by a specific physical stimuli, body temperature changes, stress, chemical substances, and water
ASSOCIATED CONDITIONS
• Angioedema
• Anaphylaxis
DIAGNOSIS
SIGNS AND SYMPTOMS
• Seen alone or with angioedema
• Urticaria may be an initial symptom of a generalized anaphylactic reaction, potentially fatal.
• Single or multiple raised, blanched, central wheals surrounded by red flare anywhere on body
• Intensely pruritic
• Variably sized, 1-2 mm to 15-20 cm or larger; sometimes confluent
• Fast onset, resolves spontaneously in 48 hours
History
The most important: A detailed history and review of symptoms, including the timing/duration of the symptoms, potential triggers, and history of atopic diseases and autoimmune diseases
Physical Exam
A complete physical exam to detect any associated conditions (autoimmune; malignancy; and viral, bacterial, and fungal/tinea infections)
TESTS
Lab
• Acute urticaria: Testing depends on the history and the potential triggers.
- Allergy skin tests and radioallergosorbent test (RAST) for inhaled allergens, insects, drugs, or foods and for assessing other atopic conditions
- Infection: Pharyngeal culture, liver function tests, mononucleosis test, urine analysis
- Food and drug reactions: Elimination of or challenges with suspected agents
• Chronic urticaria: Depending on diagnostic suspicions
- CBC with differential
- Tests for H. pylori (e.g., antibodies)
- Thyroid function tests and anti-thyroid antibodies (anti-thyroperoxidase and anti-thyroglobulin)
- Autoimmune: ESR, antinuclear antibody (ANA), rheumatoid factor, complement (such as CH50), cryoglobulins
- Stool for ova and parasites
- Urine analysis
- Autologous serum skin testing
- Food and drug reactions: Elimination of or challenges with suspected agents
- Maligancy work-up, including serum protein electrophoresis and immunofixation assay
• Physical and special forms of urticaria
- Dermatographism: Scratch skin with a tongue blade, observe for surrounding uricaria.
- Cold urticaria: Ice cube testplace ice cube on skin 5 minutes, observe 10-15 minutes
- Cholinergic: Exercise challenge
- Solar: Expose skin to wavelengths of light.
- Delayed pressure: Apply 5-10-lb sandbag for 3 hours, observe
- Aquagenic: Apply water at various temperatures.
- Vibratory: Apply vibration 4-5 minutes with a lab mixing device, observe.
Imaging
Any imaging necessary to rule out chronic indolent infections (e.g., sinus CT) or malignancy
Diagnostic Procedures/Surgery
• Skin biopsy to rule out urticarial vasculitis
• Routine dental care to rule out dental caries
DIFFERENTIAL DIAGNOSIS
• Anaphylaxis (a potentially fatal generalized systemic allergic disorder with urticaria, angioedema, respiratory distress, abdominal pain, hypotension; may present initially with urticaria)
• Insect bites
• Morbilliform drug eruptions
• Erythema multiforme
• Systemic lupus erythematosus
• Vasculitis and polyarteritis
• Angioedema without urticaria (related to complement and bradykinin disorders, such as familial hereditary angioedema, angiotensin converting enzyme (ACE) inhbitor angioedema, complement deficiencies)
• Urticaria pigmentosa (mastocytosis). Pink lesions urticate when scratched (Darier sign).
• Bullous pemphigoid (urticarial stage)
TREATMENT
GENERAL MEASURES
Avoidance or elimination of the eliciting stimulus
Diet
If a particular food is implicated, avoidance of the food or a trial of avoiding the food for 2-3 weeks
Activity
Depends on the urticarial trigger
• Cold and heat urticaria: Avoid sudden changes in temperature (e.g., slowly getting into a cold swimming pool).
• Dermatographic and delayed-pressure urticaria: Spread out the amount of force per area applied to the skin.
• Solar urticaria: Avoid the sun; use sunscreen.
• Cholinergic urticaria: Avoid sudden changes in body temperature (e.g., slow warm-ups and cooldowns during exercise).
Complementary and Alternative Medicine
• Avoid use of alternative medicine drugs. Herbal and vitamin supplements may make the urticaria worse, because trace contaminants in the supplements might be allergenic.
• Beware of certain "experts" in alternative medicine who might place chronic urticarial patients on severe food and activity restrictions based on lab tests that have little scientific basis.
MEDICATION (DRUGS)
First Line
• 1st-generation antihistaminesmainly for short, intermittent attacks of urticaria; use is limited by its sedation and short half-life) (1,2)[A]
- Older children and adults: Hydroxyzine or diphenhydramine 25-50 mg q6h
- Children 6 years old: Diphenhydramine 12.5 mg (elixir) q6-8h (5 mg/kg/d) or hydroxyzine elixir (10 mg/5 mL) 2 mg/kg/d divided q6-8h
• 2nd-generation H1-blockersmore expensive; effectiveness like older antihistamines but less sedating; a longer half-life. (1,2)[A]
- Fexofenadine (Allegra): 180 mg/d
- Loratadine (Claritin): 10 mg/d
- Desloratadine (Clarinex): 5 mg/d
- Cetirizine (Zyrtec): 10 mg/d
• May need higher doses of antihistamines or a combination of multiple antihistamines for control
• Precautions
- Drowsiness and dry mouth and eyes
- Should be used with caution in the elderly and during pregnancy
Second Line
• Doxepin (Sinequan): Tricyclic antidepressant with strong H1- and H2-blocking properties; 10-25 mg at bedtime; sedation limits usefulness (2)[C]
• H2-blockers: mildly helpful (1,2)[C]
• Corticosteroids: For unresponsive cases, e.g., prednisone 40 mg/d for 5-7 days, taper as antihistamines are introduced; avoid chronic use due to the severe side effects which might be worse than the effects of the urticaria (2)[C]
• Cyproheptadine: Antihistamine and antiserotonergic agent (2)[C]
• Cyclosporine: Best-studied immunosuppressive therapy; effective (2.5-5 mg/kg/d) and steroid sparing (3)[C]
• Leukotriene antagonists: Safe and worth trying in chronic, unresponsive cases (2)[C]
• Intravenous immune globulin, plasmapheresis, sulfasalazine, dapsone, danazol, and hydroxychloroquine require further study. (3)
• Administering thyroid hormone may alleviate chronic urticaria in hypothyroid patients with autoantibodies. (3)[C]
FOLLOW-UP
DISPOSITION
Admission Criteria
If urticaria and angioedema progress into anaphylaxis or threaten the airway. Will need to be discharged with an EpiPen
Issues for Referral
• Referral to an allergist and immunologist for elucidating and testing of potential triggers, life-threatening reactions, and complex management
• Referral to a dermatologist for skin biopsy
• Referral to a rheumatologist for treatment of autoimmune causes of urticaria
PROGNOSIS
• 70% of acute symptoms are better in 72 hours.
• 30% of the patients are chronic.
• >50% of chronic idiopathic urticaria resolve in 3-5 years but are at risk for a reoccurrence many years later.
PATIENT MONITORING
If symptoms persist or recur, patient may need to keep a daily diary of potential triggers (foods, activities, etc.). Pictures of the urticarial lesions are helpful.
REFERENCES
1. Baxi S, Dinakar C. Urticaria and angioedema. Immunol Allergy Clin N Am. 2005;25:353-367.
2. Zuberbier T. Urticaria. Allergy. 2003;58:1224-1234.
3. Kaplan AP. Chronic urticaria: Pathogenesis and treatment. J Allergy Clin Immunol. 2004;114:465-474.
4. Joint Task Force on Practice Parameters. The diagnosis and management of urticaria: A practice parameter. Ann Allergy Asthma Immunol. 2000;85:521-544.
5. Wedi B, Raap U, Kapp A. Chronic urticaria and infections. Curr Opin Allergy Clin Immunol. 2004;4:387-396.
MISCELLANEOUS
See also: Anaphylaxis; Angioedema
URINARY INCONTINENCE
URINARY INCONTINENCE - Pamela I. Ellsworth, MD
BASICS
DESCRIPTION
Involuntary loss of urine from the bladder
• May occur while asleep or awake
• Amount of urine lost may vary greatly.
• Condition comes to medical attention when it is perceived to be a social and/or hygiene problem by the patient or caregiver
• System(s) Affected: Renal/Urologic; Skin/Exocrine
• Synonym(s): Transient incontinence; Urge incontinence; Overflow incontinence; Stress incontinence; Overactive bladder
GENERAL PREVENTION
• Routine Kegel exercises after childbirth
• Regular pelvic examination of female patients to detect pelvic pathology
EPIDEMIOLOGY
• Predominant age: Elderly
• Predominant sex: Female > Male
Prevalence
• 1 in 20 people in the US
• Women (community dwelling)
- Aged 65 years: 10%
- Aged >65 years: 35%
• Men (community-dwelling)
- Aged 65 years: 1.5%
- Aged 65: 1.5%
• Institutionalized men and women aged >65 years: 30-50%
ALERT
Geriatric Considerations
This problem is most commonly seen in older patients.
Pediatric Considerations
Neurogenic, congenital, and idiopathic overactive bladder also occurs in children.
RISK FACTORS
• Increasing age
• Female sex/estrogen deficiency
• Prostatic hypertrophy (males)
• Multiparity (females)
• Dementia
• Stroke
• Diabetes
• Spinal cord injury
• Multiple sclerosis
• Obesity
• Hysterectomy
• Vaginal childbirth
• Functional impairment
Genetics
Unknown
ETIOLOGY
• Urgency urinary incontinence (UUI)
- Idiopathic
- Neurogenic (stroke, dementia, Parkinson disease, multiple sclerosis)
- Inflammatory (infection, tumors, stones, diverticula)
• Stress urinary incontinence (SUI)
- Genuine (types 0, 1, 2): pelvic floor muscle weakness, urethral hypermobility
- Intrinsic sphincteric deficiency (type 3): Post transurethral resection of the prostate (TURP), post radical prostatectomy, prior urethral/pelvic surgery
- May occur during pregnancy
• Mixed (MUI): Stress plus urge incontinence
• Overflow incontinence
- Bladder outlet obstruction (benign prostatic hyperplasia, urethral stricture, pelvic prolapse)
- Neurogenic bladder (diabetes, spinal cord injury, multiple sclerosis)
• Transient/reversible: Delirium, infection, atrophic urethritis/vaginitis, excessive urine output, restricted mobility, stool impaction (DIAPPERS)
DIAGNOSIS
SIGNS AND SYMPTOMS
• Involuntary loss of urine
• May be associated with urinary urgency, or exertion
History
The diagnosis is often made by history.
Physical Exam
• Men: Palpate abdomen (for distended bladder), digital rectal exam (for prostatic hypertrophy/cancer/fecal impaction), and neurologic exam
• Women: Palpate abdomen (for distended bladder), pelvic exam (for gynecologic pathology), rectal exam (for fecal impaction), and neurologic exam
• Assess lower extremities for edema.
• Helpful to ask the patient to reproduce the activities (e.g., coughing, sneezing, laughing) that result in loss of urine
• Urinary diaries over 2-3 days
TESTS
Urodynamic evaluation may be indicated in select patients.
• Uroflowmetry: Poor flow rate may be indicative of obstruction or poor detrusor contractility.
• Cystometrogram: May show abnormal sphincter pressure or bladder function
• Pressure flow: High pressure with low flow may indicate obstruction.
• Video: Visualization to rule out diverticulum, reflux
• Electromyogram: Assesses sphincteric activity
Lab
• Urinalysis: R/0 glycosuria (diabetes), proteinuria (glomerular disease), white blood cells (infection), red blood cells (tumor), or bacteria (infection)
• Urine culture: Positive if urinary tract infection
• Drugs that may alter lab results
- Diuretics (low urine specific gravity)
- Antibiotics (negative urine culture)
• Disorders producing abnormal lab results generally contribute to the problem of incontinence.
Imaging
May be indicated in some patients
• Renal ultrasound to rule out hydronephrosis
• Bladder scan or ultrasound postvoid residual: May show increased residual urine (normally 50 mL); ultrasound can assess bladder wall thickness and rule out bladder stones
• Voiding cystourethrogram: May show bladder and/or urethral pathology
Pathological Findings
• Relate to the primary cause of incontinence
• Intrinsic urinary sphincter disorder
• Prostatic hypertrophy
• Neurogenic bladder
• Bladder tumors
DIFFERENTIAL DIAGNOSIS
• Urinary tract infection
• Vaginal discharge (women)
• Urethral discharge (men)
• Medication effect (diuretics, alcohol, caffeine, anticholinergics, -agonists, calcium channel blockers, -adrenergic blockers, antiparkinson drugs, angiotensin-converting enzyme inhibitors)
• Polyuria (diabetes, excessive water intake)
• Bladder tumor
TREATMENT
STABILIZATION
Outpatient evaluation and management
GENERAL MEASURES
Identification and specific treatment of all primary conditions relating to urinary incontinence (e.g., urinary tract infection, bladder tumors, prostatic hypertrophy, diabetes)
• Pelvic floor muscle therapy (PFMT) should be offered as 1st line therapy to all women with SUI, UUI, or MUI.
• Females with SUI or MUI combination of PFMT/bladder training may be more effective than PFMT alone in the short term.
• PFMT in men with post RRPX incontinence
• Biofeedback/behavioral training
• Behavioral therapy in men with incontinence
• Intermittent catherization if overflow incontinence
• Incontinence pads
• Indwelling catheterization (selected patients); rarely
• Condom catheters (male patients)
• Treatment for fecal impaction
• Weighted vaginal cones and electrical stimulation appear to be equally effective for women with SUI, but these may have side effects.
Diet
• In situations in which access to bathroom facilities is limited, patients should avoid high-volume fluid intake.
• Caffeine may aggravate overactive bladder symptoms by increasing urine volume and by having an irritant effect on the bladder.
• Weight loss: Obesity is an independent risk factor for urinary incontinence.
Activity
Encourage full activity.
MEDICATION (DRUGS)
First Line
• UUI (A, level of evidence 1)
- Oxybutynin (Ditropan XL): 5-30 mg/d
- Oxybutynin (Ditropan): 2.5-5 mg q.i.d.
- Tolterodine (Detrol IR): 1-2 mg b.i.d.
- Tolterodine (Detrol LA): 2-4 mg/d
- Trospium chloride (Sanctura): 20 mg b.i.d
- Topical estrogen
- Flavoxate (Urispas): 100-200 mg t.i.d.
- Imipramine (Tofranil): 25-50 mg t.i.d.
• SUI
- Pseudoephedrine (Sudafed): 30-60 mg t.i.d.): Weak evidence to suggest alpha-adrenergic agent is better than PBO
- Imipramine (Tofranil): 25-50 mg t.i.d.
- Topical estrogen
• Overflow incontinence secondary to BPH
- Doxazosin (Cardura): 1-8 mg/d
- Terazosin (Hytrin): 1-10 mg/d
- Tamsulosin (Flomax): 0.4-0.8 mg/d
- 5-alpha reductase inhibitors
- Finasteride (Proscar): 5 mg/d
- Dutasteride (Avodart): 0.5 mg/d
• Contraindications
- Review each medication before initiation.
- Anticholinergic agents are contraindicated in patients with glaucoma, decreased gastrointestinal motility, or bladder outlet obstruction (e.g., prostatic hypertrophy).
• Precautions
- Use the smallest dose possible in elderly
- Common side effects include dry mouth, blurred vision, constipation, postural hypotension (alpha-blockers), and cognitive dysfunction.
• Significant possible interactions: These vary for each of the drugs listed.
Second Line
Desmopressin (DDAVP) nasal spray (nocturnal enuresis)
SURGERY
• Male patients with overflow incontinence secondary to prostatic hypertrophy benefit from prostatic reduction (e.g., TURP). Men with post-radical prostatectomy incontinence and post-TURP incontinence may benefit from bulking agents (4-20% report being dry), artificial sphincter (success rates range from 59-85%), or male sling (cure rate ranging from 76-86%).
• Female patients with stress incontinence may benefit from open colposuspension (cure rate 85%, A), autologous sling, transvaginal tape procedure (cure rate 81%, level of evidence 2)
• Female patients with poor urethral tone may benefit from periurethral bulking agents (low morbidity but low long-term success rate), or sling procedures.
• Neuromodulation for women with refractory UUI.
• Rarely with refractory UUI augmentation cystoplasty
FOLLOW-UP
DISPOSITION
Discharge Criteria
Most surgical procedures are outpatient procedures or overnite stay. Most patients are taught clean intermittent catheterization prior to surgical intervention.
Issues for Referral
• Recurrent UTIs
• Microscopic hematuria
PROGNOSIS
• Generally good; most patients can achieve an increase in bladder control with appropriate medical/behavioral management
• Some experts feel sphincter incompetence is best treated surgically.
COMPLICATIONS
• Urinary tract infections
• Hydronephrosis (with atonic bladder or outlet obstruction)
• Renal failure (with obstructive hydronephrosis)
• Bladder calculi
• Skin irritation or infection
• Increased incidence of falls and fractures in elderly with overactive bladder
• Adverse drug events
PATIENT MONITORING
• With medical, behavioral, and PFMT regular follow-up is indicated to ensure proper technique and compliance and to assess response.
• Ask about side effects of medication.
• Check for orthostatic hypotension (in patients using alpha-blockers).
REFERENCES
1. Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 3rd ed. Plymouth, UK: Health Publication Ltd; 2005.
2. Alhasso A, Glazener CMA, Pickard R. N'Dow Adrenergic drugs for urinary incontinence in adults. Cochrane Database of Systematic Reviews. 2005;(4).
3. Hay-Smith J, Herbison P, Ellis G, Moore K. Anticholinergic drugs versus placebo for OAB syndrome in adults. Cochrane Database of Systematic Reviews. 2002;(3):CD003781.
4. Herbison P, Plevnik S, Mantle J. Weighted vaginal cones for urinary incontinence. Cochrane Database of Systematic Reviews. 2002;(1):CD002114.
5. Borello-France D, Burgio KL. Nonsurgical treatment of urinary incontinence. Clin Obstet Gynecol. 2004;47:70-82.
6. Fine P, Antonini TG, Appell R. Clinical evaluation of women with lower urinary tract dysfunction. Clin Obstet Gynecol. 2004;47:44-52.
MISCELLANEOUS
See also: Prostatic hyperplasia, benign (BPH); Urethritis; Urinary tract infection in females; Urinary tract infection in males;
BASICS
DESCRIPTION
Involuntary loss of urine from the bladder
• May occur while asleep or awake
• Amount of urine lost may vary greatly.
• Condition comes to medical attention when it is perceived to be a social and/or hygiene problem by the patient or caregiver
• System(s) Affected: Renal/Urologic; Skin/Exocrine
• Synonym(s): Transient incontinence; Urge incontinence; Overflow incontinence; Stress incontinence; Overactive bladder
GENERAL PREVENTION
• Routine Kegel exercises after childbirth
• Regular pelvic examination of female patients to detect pelvic pathology
EPIDEMIOLOGY
• Predominant age: Elderly
• Predominant sex: Female > Male
Prevalence
• 1 in 20 people in the US
• Women (community dwelling)
- Aged 65 years: 10%
- Aged >65 years: 35%
• Men (community-dwelling)
- Aged 65 years: 1.5%
- Aged 65: 1.5%
• Institutionalized men and women aged >65 years: 30-50%
ALERT
Geriatric Considerations
This problem is most commonly seen in older patients.
Pediatric Considerations
Neurogenic, congenital, and idiopathic overactive bladder also occurs in children.
RISK FACTORS
• Increasing age
• Female sex/estrogen deficiency
• Prostatic hypertrophy (males)
• Multiparity (females)
• Dementia
• Stroke
• Diabetes
• Spinal cord injury
• Multiple sclerosis
• Obesity
• Hysterectomy
• Vaginal childbirth
• Functional impairment
Genetics
Unknown
ETIOLOGY
• Urgency urinary incontinence (UUI)
- Idiopathic
- Neurogenic (stroke, dementia, Parkinson disease, multiple sclerosis)
- Inflammatory (infection, tumors, stones, diverticula)
• Stress urinary incontinence (SUI)
- Genuine (types 0, 1, 2): pelvic floor muscle weakness, urethral hypermobility
- Intrinsic sphincteric deficiency (type 3): Post transurethral resection of the prostate (TURP), post radical prostatectomy, prior urethral/pelvic surgery
- May occur during pregnancy
• Mixed (MUI): Stress plus urge incontinence
• Overflow incontinence
- Bladder outlet obstruction (benign prostatic hyperplasia, urethral stricture, pelvic prolapse)
- Neurogenic bladder (diabetes, spinal cord injury, multiple sclerosis)
• Transient/reversible: Delirium, infection, atrophic urethritis/vaginitis, excessive urine output, restricted mobility, stool impaction (DIAPPERS)
DIAGNOSIS
SIGNS AND SYMPTOMS
• Involuntary loss of urine
• May be associated with urinary urgency, or exertion
History
The diagnosis is often made by history.
Physical Exam
• Men: Palpate abdomen (for distended bladder), digital rectal exam (for prostatic hypertrophy/cancer/fecal impaction), and neurologic exam
• Women: Palpate abdomen (for distended bladder), pelvic exam (for gynecologic pathology), rectal exam (for fecal impaction), and neurologic exam
• Assess lower extremities for edema.
• Helpful to ask the patient to reproduce the activities (e.g., coughing, sneezing, laughing) that result in loss of urine
• Urinary diaries over 2-3 days
TESTS
Urodynamic evaluation may be indicated in select patients.
• Uroflowmetry: Poor flow rate may be indicative of obstruction or poor detrusor contractility.
• Cystometrogram: May show abnormal sphincter pressure or bladder function
• Pressure flow: High pressure with low flow may indicate obstruction.
• Video: Visualization to rule out diverticulum, reflux
• Electromyogram: Assesses sphincteric activity
Lab
• Urinalysis: R/0 glycosuria (diabetes), proteinuria (glomerular disease), white blood cells (infection), red blood cells (tumor), or bacteria (infection)
• Urine culture: Positive if urinary tract infection
• Drugs that may alter lab results
- Diuretics (low urine specific gravity)
- Antibiotics (negative urine culture)
• Disorders producing abnormal lab results generally contribute to the problem of incontinence.
Imaging
May be indicated in some patients
• Renal ultrasound to rule out hydronephrosis
• Bladder scan or ultrasound postvoid residual: May show increased residual urine (normally 50 mL); ultrasound can assess bladder wall thickness and rule out bladder stones
• Voiding cystourethrogram: May show bladder and/or urethral pathology
Pathological Findings
• Relate to the primary cause of incontinence
• Intrinsic urinary sphincter disorder
• Prostatic hypertrophy
• Neurogenic bladder
• Bladder tumors
DIFFERENTIAL DIAGNOSIS
• Urinary tract infection
• Vaginal discharge (women)
• Urethral discharge (men)
• Medication effect (diuretics, alcohol, caffeine, anticholinergics, -agonists, calcium channel blockers, -adrenergic blockers, antiparkinson drugs, angiotensin-converting enzyme inhibitors)
• Polyuria (diabetes, excessive water intake)
• Bladder tumor
TREATMENT
STABILIZATION
Outpatient evaluation and management
GENERAL MEASURES
Identification and specific treatment of all primary conditions relating to urinary incontinence (e.g., urinary tract infection, bladder tumors, prostatic hypertrophy, diabetes)
• Pelvic floor muscle therapy (PFMT) should be offered as 1st line therapy to all women with SUI, UUI, or MUI.
• Females with SUI or MUI combination of PFMT/bladder training may be more effective than PFMT alone in the short term.
• PFMT in men with post RRPX incontinence
• Biofeedback/behavioral training
• Behavioral therapy in men with incontinence
• Intermittent catherization if overflow incontinence
• Incontinence pads
• Indwelling catheterization (selected patients); rarely
• Condom catheters (male patients)
• Treatment for fecal impaction
• Weighted vaginal cones and electrical stimulation appear to be equally effective for women with SUI, but these may have side effects.
Diet
• In situations in which access to bathroom facilities is limited, patients should avoid high-volume fluid intake.
• Caffeine may aggravate overactive bladder symptoms by increasing urine volume and by having an irritant effect on the bladder.
• Weight loss: Obesity is an independent risk factor for urinary incontinence.
Activity
Encourage full activity.
MEDICATION (DRUGS)
First Line
• UUI (A, level of evidence 1)
- Oxybutynin (Ditropan XL): 5-30 mg/d
- Oxybutynin (Ditropan): 2.5-5 mg q.i.d.
- Tolterodine (Detrol IR): 1-2 mg b.i.d.
- Tolterodine (Detrol LA): 2-4 mg/d
- Trospium chloride (Sanctura): 20 mg b.i.d
- Topical estrogen
- Flavoxate (Urispas): 100-200 mg t.i.d.
- Imipramine (Tofranil): 25-50 mg t.i.d.
• SUI
- Pseudoephedrine (Sudafed): 30-60 mg t.i.d.): Weak evidence to suggest alpha-adrenergic agent is better than PBO
- Imipramine (Tofranil): 25-50 mg t.i.d.
- Topical estrogen
• Overflow incontinence secondary to BPH
- Doxazosin (Cardura): 1-8 mg/d
- Terazosin (Hytrin): 1-10 mg/d
- Tamsulosin (Flomax): 0.4-0.8 mg/d
- 5-alpha reductase inhibitors
- Finasteride (Proscar): 5 mg/d
- Dutasteride (Avodart): 0.5 mg/d
• Contraindications
- Review each medication before initiation.
- Anticholinergic agents are contraindicated in patients with glaucoma, decreased gastrointestinal motility, or bladder outlet obstruction (e.g., prostatic hypertrophy).
• Precautions
- Use the smallest dose possible in elderly
- Common side effects include dry mouth, blurred vision, constipation, postural hypotension (alpha-blockers), and cognitive dysfunction.
• Significant possible interactions: These vary for each of the drugs listed.
Second Line
Desmopressin (DDAVP) nasal spray (nocturnal enuresis)
SURGERY
• Male patients with overflow incontinence secondary to prostatic hypertrophy benefit from prostatic reduction (e.g., TURP). Men with post-radical prostatectomy incontinence and post-TURP incontinence may benefit from bulking agents (4-20% report being dry), artificial sphincter (success rates range from 59-85%), or male sling (cure rate ranging from 76-86%).
• Female patients with stress incontinence may benefit from open colposuspension (cure rate 85%, A), autologous sling, transvaginal tape procedure (cure rate 81%, level of evidence 2)
• Female patients with poor urethral tone may benefit from periurethral bulking agents (low morbidity but low long-term success rate), or sling procedures.
• Neuromodulation for women with refractory UUI.
• Rarely with refractory UUI augmentation cystoplasty
FOLLOW-UP
DISPOSITION
Discharge Criteria
Most surgical procedures are outpatient procedures or overnite stay. Most patients are taught clean intermittent catheterization prior to surgical intervention.
Issues for Referral
• Recurrent UTIs
• Microscopic hematuria
PROGNOSIS
• Generally good; most patients can achieve an increase in bladder control with appropriate medical/behavioral management
• Some experts feel sphincter incompetence is best treated surgically.
COMPLICATIONS
• Urinary tract infections
• Hydronephrosis (with atonic bladder or outlet obstruction)
• Renal failure (with obstructive hydronephrosis)
• Bladder calculi
• Skin irritation or infection
• Increased incidence of falls and fractures in elderly with overactive bladder
• Adverse drug events
PATIENT MONITORING
• With medical, behavioral, and PFMT regular follow-up is indicated to ensure proper technique and compliance and to assess response.
• Ask about side effects of medication.
• Check for orthostatic hypotension (in patients using alpha-blockers).
REFERENCES
1. Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 3rd ed. Plymouth, UK: Health Publication Ltd; 2005.
2. Alhasso A, Glazener CMA, Pickard R. N'Dow Adrenergic drugs for urinary incontinence in adults. Cochrane Database of Systematic Reviews. 2005;(4).
3. Hay-Smith J, Herbison P, Ellis G, Moore K. Anticholinergic drugs versus placebo for OAB syndrome in adults. Cochrane Database of Systematic Reviews. 2002;(3):CD003781.
4. Herbison P, Plevnik S, Mantle J. Weighted vaginal cones for urinary incontinence. Cochrane Database of Systematic Reviews. 2002;(1):CD002114.
5. Borello-France D, Burgio KL. Nonsurgical treatment of urinary incontinence. Clin Obstet Gynecol. 2004;47:70-82.
6. Fine P, Antonini TG, Appell R. Clinical evaluation of women with lower urinary tract dysfunction. Clin Obstet Gynecol. 2004;47:44-52.
MISCELLANEOUS
See also: Prostatic hyperplasia, benign (BPH); Urethritis; Urinary tract infection in females; Urinary tract infection in males;
URETHRITIS
URETHRITIS - Chad M.Braun, MD
BASICS
DESCRIPTION
Syndrome of urethral inflammation marked by painful urination, urethral pruritis, and discharge
• Usually a sexually transmitted infection (STI); other causes not uncommon
• Untreated cases may gradually resolve, but complications, such as urethral stricture in males or pelvic inflammatory disease (PID) in women, may ensue.
• System(s) Affected: Renal/Urologic
GENERAL PREVENTION
• Safer sex protection techniques
• Sexual abstinence only sure way for complete prevention of STI-related causes
• Treatment of all sexual partners
EPIDEMIOLOGY
• Predominant age: 15-24 years, sexually active
• Predominant sex: Classic symptoms more commonly reported by males; incidence in females probably equal
Incidence
Very common: >830,000 cases of chlamydia and 350,000 cases of gonorrhea reported in 2002 in the US
RISK FACTORS
• Multiple sexual partners
• History of other STI
• Unprotected sexual activity
ETIOLOGY
• Predominantly Neisseria gonorrhoeae and Chlamydia trachomatis infection, often together
• Less common infectious agents, including
- Ureaplasma urealyticum
- Trichomonas vaginalis
- Herpesvirus
- Mycoplasma genitalium
• Noninfectious causes (generally rare)
- Foreign bodies, soaps, shampoos, douches, spermicides, urethral instrumentation
ASSOCIATED CONDITIONS
Other STIs: Patients should be strongly urged to undergo testing for syphilis, hepatitis B, and HIV.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Both sexes may be asymptomatic carriers of the causative organisms.
• In males: Abrupt onset of symptoms 3-5 days after exposure to an infected sexual partner
• In females: Classic urethral syndrome often is not present. Infections that cause simple urethritis in males will often have symptoms other than dysuria, including vaginal discharge and cervicitis.
• Dysuria: Pain throughout urination
• Urethral discharge; may be profuse and purulent in acute gonorrhea, or scanty, evident only with milking of the urethra, with other causes
• Urethral itching or tenderness
• Tenderness, edema, and inflammation of the urethral meatus, especially in women
• Dyspareunia
• Vaginitis, cystitis, cervicitis in women
• Proctitis, pharyngitis, conjunctivitis may also be present (sexual history is important)
• Fever is not part of the syndrome and suggests another diagnosis.
• Bloody discharge: Rarely seen and suggests another diagnosis
• Suprapubic or abdominal pain suggests another diagnosis or presence of complications, e.g., PID, prostatitis, or cystitis.
ALERT
Pediatric Considerations
Proven cases of gonorrhea, chlamydia, and trichomoniasis should raise the question of sexual abuse.
TESTS
For patients who present without symptoms stating that a sexual partner was treated for this problem: Obtain specimens for lab tests, but immediate treatment is recommended.
Screening
• The US Preventative Services Task Force (USPSTF) recommends routine screening in all sexually active women 25 years old and younger and all other women at increased risk of infection. (4)[A]
• The optimal screening interval is uncertain.
• They make no recommendation for or against the screening of low-risk women. (4)[A]
• The USPSTF states that the evidence is insufficient to recommend for or against screening in asymptomatic men at increased risk. (4)[I]
Lab (1)[C]
• Gram stain of discharge: Intracellular gram-negative diplococci strongly indicate gonorrhea; 5 or more white blood cells (WBC) per high-power field (HPF) indicate urethritis.
• Cultures or reagin detection: DNA probe is probably the best screening test.
- Cultures may be difficult to obtain correctly but allow for antimicrobial sensitivity testing.
- Polymerase chain reaction (PCR) assay on urine is more sensitive and specific, but costly. Can get PCR on sample from ThinPrep test. Negatives may be false results or may indicate another infecting organism.
• Urinalysis: If indicated, sample discharge before patient voids; usually normal in cases of simple urethritis.
- 1st-void urine is often positive for leukocyte esterase and should have 10 or more WBC per HPF in urethritis.
- Ideally, men should not have urinated for at least 4 hours prior.
- Symptomatic patients in whom no urethritis is detected initially should be retested having held their urine overnight.
• Urine culture: Performed only if gram stain of discharge is unremarkable or unobtainable
• Wet prep of discharge: May reveal Trichomonas; usually reserved in males who fail adequate treatment for gonorrhea and chlamydia
• Syphilis, HIV, and hepatitis B serology as indicated to rule out concomitant STIs
• Recent treatment with antibiotics may lead to false-negative results.
Diagnostic Procedures/Surgery
Urethrocystoscopy for cases with suspected foreign body, intraurethral warts, urethral stricture
Pathological Findings
Urethral strictures (untreated gonorrhea), intraurethral lesions (venereal warts, congenital anomalies)
DIFFERENTIAL DIAGNOSIS
• Other urinary tract infections
- Cystitis
- Epididymitis
- Prostatitis
- PID
- Pyelonephritis
• Atrophy, especially in postmenopausal women
• Stevens-Johnson syndrome
• Reiter syndrome: Arthritis, uveitis, and urethritis
• Wegener granulomatosis may have urethritis as one of its manifestations.
TREATMENT
STABILIZATION
• Most cases can be treated in the outpatient setting.
• Single-dose regimens can be directly observed in the office for noncompliant or high-risk patients.
• Antibiotics should not be withheld from symptomatic patients until culture (test) results are known, rather they should be initiated as soon as cultures (samples) have been collected.
• Treatment should cover both gonorrhea and chlamydia because they cause the majority of cases and often coexist.
• Patients with persistent symptoms and signs after adequate treatment should be
- Evaluated and/or treated for trichomoniasis
- Retreated with the original regimen if not compliant or re-exposed
- Retreated with an alternative regimen for 14 days if U. urealyticum is suspected (tetracycline resistance in 10% of isolates)
- Evaluated for HSV
GENERAL MEASURES
Identification and treatment of sexual partners
All sexual partners within the previous 60 days should be investigated and treated.
Diet
Avoid alcohol with metronidazole.
Activity
• Full activity
• No sexual intercourse until 7 days after single dose therapy or completion of 7-day therapy
MEDICATION (DRUGS)
First Line
• Gonorrhea: (1)[C]
- Cefixime: 400 mg PO single dose
- Ceftriaxone: 125 mg IM single dose (superior for gonococcal pharynigitis)
• Chlamydia: (5)[A]
- Azithromycin: 1 g PO single dose
- Doxycycline: 100 mg PO b.i.d. for 7 days
• Trichomoniasis: Metronidazole 2 g PO single dose or 250 mg t.i.d. for 7 days
• Recurrent and resistant urethritis: (5)[C] Metronidazole 2 mg PO single dose PLUS erythromycin base 500 mg PO q.i.d. for 7 days or erythromycin ethylsuccinate 800 mg PO q.i.d. for 7 days
• Contraindications: Sensitivity to any of the indicated medications. Pregnant patients should not receive tetracyclines, and metronidazole should be avoided in the 1st trimester.
• Precautions: Patients taking tetracyclines need to be told of the possibility of increased sensitivity to sunlight.
• Significant possible interactions
- Tetracyclines should not be taken with milk products or antacids.
- Oral contraceptives may be rendered ineffective by oral antibiotics. Patients and partners should use a backup method of birth control for remainder of the cycle.
ALERT
Pregnancy Considerations
• Tetracyclines and quinolones are contraindicated.
• Avoid erythromycin estolate because of an increased risk of cholestatic jaundice; otherwise use the standard treatment recommendations.
• 7-day therapy for chlamydia is favored in pregnancy, but single dose is still recommended.
Second Line
• Gonorrhea
- Because of the spread of quinolone-resistant N. gonorrhoeae from the Pacific and Asia, quinolones are no longer recommended treatment in individuals who have acquired gonorrhea from that area. (2)[C]
- Fluoroquinolones are also not recommended as 1st-line therapy for people in Hawaii and California and men who have sex with men, because of endemic spread of quinolone-resistant gonorrhea. (2)[C]
- Resistance to penicillin and tetracycline has been reported in up to 1/3 of isolates of N. gonorrhoeae.
- Ciprofloxacin: 500 mg PO single dose (1)[C]
- Ofloxacin: 400 mg PO single dose (1)[C]
- Levofloxacin: 250 mg PO single dose (1)[C]
- Others drugs are available, but offer no particular advantage over the drugs of choice.
• Chlamydia
- Erythromycin base: 500 mg PO q.i.d. for 7 days (5)[A]
- Erythromycin ethylsuccinate: 800 mg PO q.i.d. for 7 days. If intolerant of high-dose erythromycin: Erythromycin base 250 mg PO q.i.d. for 14 days or erythromycin ethylsuccinate 400 mg PO q.i.d. for 14 days
- Ofloxacin: 300 mg PO b.i.d. for 7 days (5)[A]
- Levofloxacin: 500 mg PO daily for 7 days
FOLLOW-UP
DISPOSITION
Outpatient management
PROGNOSIS
If the diagnosis is firmly established, appropriate medications are prescribed, and the patient is compliant with treatment, there will be relief of symptoms within days and the problem will resolve without sequelae.
COMPLICATIONS
• Stricture formation
• Epididymitis
• PID in women
• Disseminated gonococcal infection
• Gonococcal meningitis
• Gonococcal endocarditis
• Perinatal transmission (chlamydial conjunctivitis, chlamydial pneumonia, ophthalmia neonatorum)
• Reiter syndrome
PATIENT MONITORING
Instruct patients to return if symptoms persist or recur after completing treatment. Test of cure cultures is not usually required unless patient is pregnant.
REFERENCES
1. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines for 2002. MMWR Recomm Rep. 2002;51(RR-06):1-80.
2. Centers for Disease Control and Prevention. Increases in fluoroquinolone-resistant Neisseria gonorrhoeae among men who have sex with menUnited States, 2003, and revised recommendations for gonorrhea treatment, 2004. MMWR Morb Mortal Wkly Rep. 2004;53:335-338.
3. Groseclose SL et al. Centers for Disease Control and Prevention. Summary of notifiable diseasesUnited States, 2002. MMWR Morb Mortal Wkly Rep. 2004;51:1-84.
4. Berg AO. Screening for chlamydia infections: Recommendations and rationale. Am J Prev Med. 2001;20:90-4.
5. 2002 National Guideline on the Management of Non-gonoccal urethritis, Association for Genitourinary Medicine.
MISCELLANEOUS
See also: Chlamydial sexually transmitted diseases; Epididymitis; Gonococcal infections; Pelvic inflammatory disease (PID); Prostatitis; Urinary tract infection in females; Urinary tract infection in males; Vulvovaginitis, bacterial; Vulvovaginitis, candidal
BASICS
DESCRIPTION
Syndrome of urethral inflammation marked by painful urination, urethral pruritis, and discharge
• Usually a sexually transmitted infection (STI); other causes not uncommon
• Untreated cases may gradually resolve, but complications, such as urethral stricture in males or pelvic inflammatory disease (PID) in women, may ensue.
• System(s) Affected: Renal/Urologic
GENERAL PREVENTION
• Safer sex protection techniques
• Sexual abstinence only sure way for complete prevention of STI-related causes
• Treatment of all sexual partners
EPIDEMIOLOGY
• Predominant age: 15-24 years, sexually active
• Predominant sex: Classic symptoms more commonly reported by males; incidence in females probably equal
Incidence
Very common: >830,000 cases of chlamydia and 350,000 cases of gonorrhea reported in 2002 in the US
RISK FACTORS
• Multiple sexual partners
• History of other STI
• Unprotected sexual activity
ETIOLOGY
• Predominantly Neisseria gonorrhoeae and Chlamydia trachomatis infection, often together
• Less common infectious agents, including
- Ureaplasma urealyticum
- Trichomonas vaginalis
- Herpesvirus
- Mycoplasma genitalium
• Noninfectious causes (generally rare)
- Foreign bodies, soaps, shampoos, douches, spermicides, urethral instrumentation
ASSOCIATED CONDITIONS
Other STIs: Patients should be strongly urged to undergo testing for syphilis, hepatitis B, and HIV.
DIAGNOSIS
SIGNS AND SYMPTOMS
• Both sexes may be asymptomatic carriers of the causative organisms.
• In males: Abrupt onset of symptoms 3-5 days after exposure to an infected sexual partner
• In females: Classic urethral syndrome often is not present. Infections that cause simple urethritis in males will often have symptoms other than dysuria, including vaginal discharge and cervicitis.
• Dysuria: Pain throughout urination
• Urethral discharge; may be profuse and purulent in acute gonorrhea, or scanty, evident only with milking of the urethra, with other causes
• Urethral itching or tenderness
• Tenderness, edema, and inflammation of the urethral meatus, especially in women
• Dyspareunia
• Vaginitis, cystitis, cervicitis in women
• Proctitis, pharyngitis, conjunctivitis may also be present (sexual history is important)
• Fever is not part of the syndrome and suggests another diagnosis.
• Bloody discharge: Rarely seen and suggests another diagnosis
• Suprapubic or abdominal pain suggests another diagnosis or presence of complications, e.g., PID, prostatitis, or cystitis.
ALERT
Pediatric Considerations
Proven cases of gonorrhea, chlamydia, and trichomoniasis should raise the question of sexual abuse.
TESTS
For patients who present without symptoms stating that a sexual partner was treated for this problem: Obtain specimens for lab tests, but immediate treatment is recommended.
Screening
• The US Preventative Services Task Force (USPSTF) recommends routine screening in all sexually active women 25 years old and younger and all other women at increased risk of infection. (4)[A]
• The optimal screening interval is uncertain.
• They make no recommendation for or against the screening of low-risk women. (4)[A]
• The USPSTF states that the evidence is insufficient to recommend for or against screening in asymptomatic men at increased risk. (4)[I]
Lab (1)[C]
• Gram stain of discharge: Intracellular gram-negative diplococci strongly indicate gonorrhea; 5 or more white blood cells (WBC) per high-power field (HPF) indicate urethritis.
• Cultures or reagin detection: DNA probe is probably the best screening test.
- Cultures may be difficult to obtain correctly but allow for antimicrobial sensitivity testing.
- Polymerase chain reaction (PCR) assay on urine is more sensitive and specific, but costly. Can get PCR on sample from ThinPrep test. Negatives may be false results or may indicate another infecting organism.
• Urinalysis: If indicated, sample discharge before patient voids; usually normal in cases of simple urethritis.
- 1st-void urine is often positive for leukocyte esterase and should have 10 or more WBC per HPF in urethritis.
- Ideally, men should not have urinated for at least 4 hours prior.
- Symptomatic patients in whom no urethritis is detected initially should be retested having held their urine overnight.
• Urine culture: Performed only if gram stain of discharge is unremarkable or unobtainable
• Wet prep of discharge: May reveal Trichomonas; usually reserved in males who fail adequate treatment for gonorrhea and chlamydia
• Syphilis, HIV, and hepatitis B serology as indicated to rule out concomitant STIs
• Recent treatment with antibiotics may lead to false-negative results.
Diagnostic Procedures/Surgery
Urethrocystoscopy for cases with suspected foreign body, intraurethral warts, urethral stricture
Pathological Findings
Urethral strictures (untreated gonorrhea), intraurethral lesions (venereal warts, congenital anomalies)
DIFFERENTIAL DIAGNOSIS
• Other urinary tract infections
- Cystitis
- Epididymitis
- Prostatitis
- PID
- Pyelonephritis
• Atrophy, especially in postmenopausal women
• Stevens-Johnson syndrome
• Reiter syndrome: Arthritis, uveitis, and urethritis
• Wegener granulomatosis may have urethritis as one of its manifestations.
TREATMENT
STABILIZATION
• Most cases can be treated in the outpatient setting.
• Single-dose regimens can be directly observed in the office for noncompliant or high-risk patients.
• Antibiotics should not be withheld from symptomatic patients until culture (test) results are known, rather they should be initiated as soon as cultures (samples) have been collected.
• Treatment should cover both gonorrhea and chlamydia because they cause the majority of cases and often coexist.
• Patients with persistent symptoms and signs after adequate treatment should be
- Evaluated and/or treated for trichomoniasis
- Retreated with the original regimen if not compliant or re-exposed
- Retreated with an alternative regimen for 14 days if U. urealyticum is suspected (tetracycline resistance in 10% of isolates)
- Evaluated for HSV
GENERAL MEASURES
Identification and treatment of sexual partners
All sexual partners within the previous 60 days should be investigated and treated.
Diet
Avoid alcohol with metronidazole.
Activity
• Full activity
• No sexual intercourse until 7 days after single dose therapy or completion of 7-day therapy
MEDICATION (DRUGS)
First Line
• Gonorrhea: (1)[C]
- Cefixime: 400 mg PO single dose
- Ceftriaxone: 125 mg IM single dose (superior for gonococcal pharynigitis)
• Chlamydia: (5)[A]
- Azithromycin: 1 g PO single dose
- Doxycycline: 100 mg PO b.i.d. for 7 days
• Trichomoniasis: Metronidazole 2 g PO single dose or 250 mg t.i.d. for 7 days
• Recurrent and resistant urethritis: (5)[C] Metronidazole 2 mg PO single dose PLUS erythromycin base 500 mg PO q.i.d. for 7 days or erythromycin ethylsuccinate 800 mg PO q.i.d. for 7 days
• Contraindications: Sensitivity to any of the indicated medications. Pregnant patients should not receive tetracyclines, and metronidazole should be avoided in the 1st trimester.
• Precautions: Patients taking tetracyclines need to be told of the possibility of increased sensitivity to sunlight.
• Significant possible interactions
- Tetracyclines should not be taken with milk products or antacids.
- Oral contraceptives may be rendered ineffective by oral antibiotics. Patients and partners should use a backup method of birth control for remainder of the cycle.
ALERT
Pregnancy Considerations
• Tetracyclines and quinolones are contraindicated.
• Avoid erythromycin estolate because of an increased risk of cholestatic jaundice; otherwise use the standard treatment recommendations.
• 7-day therapy for chlamydia is favored in pregnancy, but single dose is still recommended.
Second Line
• Gonorrhea
- Because of the spread of quinolone-resistant N. gonorrhoeae from the Pacific and Asia, quinolones are no longer recommended treatment in individuals who have acquired gonorrhea from that area. (2)[C]
- Fluoroquinolones are also not recommended as 1st-line therapy for people in Hawaii and California and men who have sex with men, because of endemic spread of quinolone-resistant gonorrhea. (2)[C]
- Resistance to penicillin and tetracycline has been reported in up to 1/3 of isolates of N. gonorrhoeae.
- Ciprofloxacin: 500 mg PO single dose (1)[C]
- Ofloxacin: 400 mg PO single dose (1)[C]
- Levofloxacin: 250 mg PO single dose (1)[C]
- Others drugs are available, but offer no particular advantage over the drugs of choice.
• Chlamydia
- Erythromycin base: 500 mg PO q.i.d. for 7 days (5)[A]
- Erythromycin ethylsuccinate: 800 mg PO q.i.d. for 7 days. If intolerant of high-dose erythromycin: Erythromycin base 250 mg PO q.i.d. for 14 days or erythromycin ethylsuccinate 400 mg PO q.i.d. for 14 days
- Ofloxacin: 300 mg PO b.i.d. for 7 days (5)[A]
- Levofloxacin: 500 mg PO daily for 7 days
FOLLOW-UP
DISPOSITION
Outpatient management
PROGNOSIS
If the diagnosis is firmly established, appropriate medications are prescribed, and the patient is compliant with treatment, there will be relief of symptoms within days and the problem will resolve without sequelae.
COMPLICATIONS
• Stricture formation
• Epididymitis
• PID in women
• Disseminated gonococcal infection
• Gonococcal meningitis
• Gonococcal endocarditis
• Perinatal transmission (chlamydial conjunctivitis, chlamydial pneumonia, ophthalmia neonatorum)
• Reiter syndrome
PATIENT MONITORING
Instruct patients to return if symptoms persist or recur after completing treatment. Test of cure cultures is not usually required unless patient is pregnant.
REFERENCES
1. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines for 2002. MMWR Recomm Rep. 2002;51(RR-06):1-80.
2. Centers for Disease Control and Prevention. Increases in fluoroquinolone-resistant Neisseria gonorrhoeae among men who have sex with menUnited States, 2003, and revised recommendations for gonorrhea treatment, 2004. MMWR Morb Mortal Wkly Rep. 2004;53:335-338.
3. Groseclose SL et al. Centers for Disease Control and Prevention. Summary of notifiable diseasesUnited States, 2002. MMWR Morb Mortal Wkly Rep. 2004;51:1-84.
4. Berg AO. Screening for chlamydia infections: Recommendations and rationale. Am J Prev Med. 2001;20:90-4.
5. 2002 National Guideline on the Management of Non-gonoccal urethritis, Association for Genitourinary Medicine.
MISCELLANEOUS
See also: Chlamydial sexually transmitted diseases; Epididymitis; Gonococcal infections; Pelvic inflammatory disease (PID); Prostatitis; Urinary tract infection in females; Urinary tract infection in males; Vulvovaginitis, bacterial; Vulvovaginitis, candidal
URINARY TRACT INFECTION IN FEMALES
URINARY TRACT INFECTION IN FEMALES - Barry D.Weiss, MD
BASICS
DESCRIPTION
• Inflammation of the bladder mucosa
• This topic refers primarily to infectious cystitis; other urinary tract infections (UTIs) are discussed elsewhere.
• System(s) Affected: Renal/Urologic
• Synonym(s): Cystitis
GENERAL PREVENTION
• Maintain good hydration.
• Women with frequent or intercourse-related UTI should empty bladder immediately before and following intercourse and consider postcoital antibiotic treatment.
• Avoid feminine hygiene sprays and scented douches.
• Wipe urethra from front to back.
EPIDEMIOLOGY
• Predominant age: Young adults and older
• Predominant sex: Female only (for this discussion)
Incidence
Accounts for 7 million doctor visits a year
Prevalence
• ~3-8% of women have bacteriuria at any given time.
• ~30% of females have at least one UTI.
RISK FACTORS
• Previous UTI
• Diabetes mellitus
• Pregnancy
• More frequent or vigorous sexual activity than usual
• Use of spermicides or diaphragm
• Underlying abnormalities of the urinary tract, such as tumors, calculi, strictures, incomplete bladder emptying
ETIOLOGY
Acute infection, usually with Gram-negative bacteria (Escherichia coli in >90% of uncomplicated cystitis)
ASSOCIATED CONDITIONS
Described under "Risk Factors"
ALERT
Geriatric Considerations
• Elderly are more apt to have underlying urinary tract abnormality.
• Acute UTI is sometimes associated with incontinence or mental status changes in the elderly.
Pediatric Considerations
UTI in children, especially in those 1 year of age should prompt workup for urinary tract anomalies.
DIAGNOSIS
SIGNS AND SYMPTOMS
Note: Any or all may be present.
• Burning during urination
• Pain during urination
• Urgency (sensation of need to urinate frequently)
• Frequency
• Sensation of incomplete bladder emptying
• Blood in urine
• Lower abdominal pain or cramping
• Offensive odor of urine
• Nocturia
TESTS
Some recent research suggests the most cost-effective approach is empiric treatment without lab tests in nonpregnant premenopausal women with symptoms of UTI and no risks for complicated infection.
Lab
• Urinalysis demonstrating pyuria (>10 neutrophils/high power field [HPF] on microscopic exam). Leukocyte esterase dipsticks are also useful for detecting pyuria, but fail to detect pyuria in up to 20% of patients, and false positives occur from vaginal leukocytes.
• Urinalysis demonstrating bacteriuria (any amount on unspun urine, or 10 rod-shaped bacteria/HPF on centrifuged urine). Nitrite dipsticks are also useful (and 94% specific), but fail to detect bacteriuria in 30-50% of patients. Nitrite dipsticks may be negative in patients who do not eat meat.
• Urine culture demonstrating growth of single species of bacteria. Suspect contaminated specimen when culture shows multiple types of bacteria.
• Classic symptoms in nonpregnant young adult female with first episode of UTI require no urine culture for diagnosis. Obtain urinalysis and culture in other age groups, if it is a repeat episode, if the patient is pregnant, or if the symptoms are not classic.
Imaging
For all infants; may be indicated for older patients with recurrent infections
• Ultrasound imaging is the 1st-choice test.
• For infants and children, obtain ultrasound; if ureteral dilation is detected, obtain either voiding cystourethrogram or isotope cystogram to detect reflux.
Diagnostic Procedures/Surgery
• Suprapubic bladder aspiration or urethral catheterization to obtain urine specimen from infants
• Urethral catheterization to obtain urine specimen from children and adults if voided urine is suspected of being contaminated
DIFFERENTIAL DIAGNOSIS
• Vaginitis
• Sexually transmitted diseases causing urethritis or pyuria
• Hematuria from causes other than infection (e.g., neoplasia, calculi)
• Interstitial cystitis
• Psychologic dysfunction
TREATMENT
STABILIZATION
Outpatient treatment, except for complicated or upper tract infections
GENERAL MEASURES
• Maintain good hydration.
• 1/4 of women with simple UTI experience a second UTI within 6 months, and 1/2 at some time during their lifetime. Patients with multiple recurrent UTI and no underlying urinary tract abnormality may receive long-term prophylactic antibiotic treatment. Trimethoprim-sulfamethoxazole (TMP-SMX) and nitrofurantoin are commonly used.
• Patients with chronic indwelling urinary catheters always have colonization of urine, usually with multiple bacterial species. This should not be treated unless symptomatic with fever, sepsis, or other systemic symptoms.
• Preliminary studies indicate that Vaccinium macrocarpon (cranberry juice) may help prevent and treat UTIs by inhibiting bacterial adherence to the bladder epithelium.
• UTI during pregnancy always requires culture/sensitivity and usually requires a 10-14-day treatment. Following the treatment of acute infection, pregnant women often receive prophylactic antibiotics for the remainder of pregnancy.
Diet
No special diet
Activity
Avoid sexual intercourse when symptoms are present.
ALERT
Elderly may have bacteriuria without symptoms; generally this does not require treatment, if the urinary tract is otherwise normal.
MEDICATION (DRUGS)
• 1st, rare, or infrequent UTIs in older children, adolescents, and adults who are nonpregnant, nondiabetic, afebrile, nonimmunocompromised, and have no abnormality of the urinary tract (i.e., uncomplicated)
- 3-day treatment with fluoroquinolone or TMP-SMX. Increasing resistance being reported to TMP-SMX. It is the preferred treatment if local sensitivity patterns indicate low resistance rates.
- New studies show 3-day therapy may be used in children.
• Postcoital: Single-dose TMP-SMX or cephalexin may reduce frequency of UTI in sexually active women.
• Pregnant patients: 10-14-day or longer treatment with pregnancy-safe antibiotic chosen based on culture/sensitivity results. May begin with cephalosporin, amoxicillin, or other antibiotic while awaiting culture/sensitivity results.
• All other patients: 10-14-day treatment with antibiotic chosen based on culture/sensitivity results. May begin with fluoroquinolone, TMP-SMX, cephalosporin, or other antibiotic while awaiting culture/sensitivity results.
• Contraindications
- Refer to the manufacturer's literature.
- Fluoroquinolones are not safe during pregnancy or for treatment of children.
- TMP-SMX use in pregnancy is not desirable (especially in the 3rd trimester), but is appropriate in some circumstances.
• Precautions: Refer to the manufacturer's literature.
• Significant possible interactions: Refer to the manufacturer's literature.
• Change the antibiotic if it is indicated by the culture/sensitivity results.
FOLLOW-UP
PROGNOSIS
Symptoms resolve within 2-3 days after starting a treatment in almost all patients.
COMPLICATIONS
• Pyelonephritis or sepsis
• Renal abscess
• Acute urinary outlet obstruction
ALERT
Infants and young children with cystitis are at higher risk of pyelonephritis.
PATIENT MONITORING
• 1st or rare UTI: In young or middle age, nonpregnant adult females require no follow-up if cured after 3-day therapy. If not resolved within 2-3 days, obtain culture/sensitivity and change antibiotic accordingly.
• All other patients should have post-treatment urine culture to document eradication of infection.
REFERENCES
1. Barry HG, Ebell MH, Hickner J. Evaluation of suspected urinary tract infection in ambulatory women: A cost-utility analysis of office-based strategies. J Fam Pract. 1997;44:49-60.
2. Bent S, et al. Does this woman have an acute uncomplicated urinary tract infection. JAMA. 2002;287:2701-2710.
3. Ebell MH, Barry NC. Urinary tract infection. In: Weiss BD, ed. 20 Common Problems in Primary Care. New York, NY: McGraw-Hill; 1999.
4. Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA. 1999;281:736-738.
5. Huang ES, Stafford RS. National patterns in the treatment of urinary tract infections in women by ambulatory care physicians. Arch Intern Med. 2002;162:41-47.
6. Stamm WE, Hooton T. Management of urinary tract infections in adults. N Engl J Med. 1993;329:1328-1334.
MISCELLANEOUS
See also: Pyelonephritis
BASICS
DESCRIPTION
• Inflammation of the bladder mucosa
• This topic refers primarily to infectious cystitis; other urinary tract infections (UTIs) are discussed elsewhere.
• System(s) Affected: Renal/Urologic
• Synonym(s): Cystitis
GENERAL PREVENTION
• Maintain good hydration.
• Women with frequent or intercourse-related UTI should empty bladder immediately before and following intercourse and consider postcoital antibiotic treatment.
• Avoid feminine hygiene sprays and scented douches.
• Wipe urethra from front to back.
EPIDEMIOLOGY
• Predominant age: Young adults and older
• Predominant sex: Female only (for this discussion)
Incidence
Accounts for 7 million doctor visits a year
Prevalence
• ~3-8% of women have bacteriuria at any given time.
• ~30% of females have at least one UTI.
RISK FACTORS
• Previous UTI
• Diabetes mellitus
• Pregnancy
• More frequent or vigorous sexual activity than usual
• Use of spermicides or diaphragm
• Underlying abnormalities of the urinary tract, such as tumors, calculi, strictures, incomplete bladder emptying
ETIOLOGY
Acute infection, usually with Gram-negative bacteria (Escherichia coli in >90% of uncomplicated cystitis)
ASSOCIATED CONDITIONS
Described under "Risk Factors"
ALERT
Geriatric Considerations
• Elderly are more apt to have underlying urinary tract abnormality.
• Acute UTI is sometimes associated with incontinence or mental status changes in the elderly.
Pediatric Considerations
UTI in children, especially in those 1 year of age should prompt workup for urinary tract anomalies.
DIAGNOSIS
SIGNS AND SYMPTOMS
Note: Any or all may be present.
• Burning during urination
• Pain during urination
• Urgency (sensation of need to urinate frequently)
• Frequency
• Sensation of incomplete bladder emptying
• Blood in urine
• Lower abdominal pain or cramping
• Offensive odor of urine
• Nocturia
TESTS
Some recent research suggests the most cost-effective approach is empiric treatment without lab tests in nonpregnant premenopausal women with symptoms of UTI and no risks for complicated infection.
Lab
• Urinalysis demonstrating pyuria (>10 neutrophils/high power field [HPF] on microscopic exam). Leukocyte esterase dipsticks are also useful for detecting pyuria, but fail to detect pyuria in up to 20% of patients, and false positives occur from vaginal leukocytes.
• Urinalysis demonstrating bacteriuria (any amount on unspun urine, or 10 rod-shaped bacteria/HPF on centrifuged urine). Nitrite dipsticks are also useful (and 94% specific), but fail to detect bacteriuria in 30-50% of patients. Nitrite dipsticks may be negative in patients who do not eat meat.
• Urine culture demonstrating growth of single species of bacteria. Suspect contaminated specimen when culture shows multiple types of bacteria.
• Classic symptoms in nonpregnant young adult female with first episode of UTI require no urine culture for diagnosis. Obtain urinalysis and culture in other age groups, if it is a repeat episode, if the patient is pregnant, or if the symptoms are not classic.
Imaging
For all infants; may be indicated for older patients with recurrent infections
• Ultrasound imaging is the 1st-choice test.
• For infants and children, obtain ultrasound; if ureteral dilation is detected, obtain either voiding cystourethrogram or isotope cystogram to detect reflux.
Diagnostic Procedures/Surgery
• Suprapubic bladder aspiration or urethral catheterization to obtain urine specimen from infants
• Urethral catheterization to obtain urine specimen from children and adults if voided urine is suspected of being contaminated
DIFFERENTIAL DIAGNOSIS
• Vaginitis
• Sexually transmitted diseases causing urethritis or pyuria
• Hematuria from causes other than infection (e.g., neoplasia, calculi)
• Interstitial cystitis
• Psychologic dysfunction
TREATMENT
STABILIZATION
Outpatient treatment, except for complicated or upper tract infections
GENERAL MEASURES
• Maintain good hydration.
• 1/4 of women with simple UTI experience a second UTI within 6 months, and 1/2 at some time during their lifetime. Patients with multiple recurrent UTI and no underlying urinary tract abnormality may receive long-term prophylactic antibiotic treatment. Trimethoprim-sulfamethoxazole (TMP-SMX) and nitrofurantoin are commonly used.
• Patients with chronic indwelling urinary catheters always have colonization of urine, usually with multiple bacterial species. This should not be treated unless symptomatic with fever, sepsis, or other systemic symptoms.
• Preliminary studies indicate that Vaccinium macrocarpon (cranberry juice) may help prevent and treat UTIs by inhibiting bacterial adherence to the bladder epithelium.
• UTI during pregnancy always requires culture/sensitivity and usually requires a 10-14-day treatment. Following the treatment of acute infection, pregnant women often receive prophylactic antibiotics for the remainder of pregnancy.
Diet
No special diet
Activity
Avoid sexual intercourse when symptoms are present.
ALERT
Elderly may have bacteriuria without symptoms; generally this does not require treatment, if the urinary tract is otherwise normal.
MEDICATION (DRUGS)
• 1st, rare, or infrequent UTIs in older children, adolescents, and adults who are nonpregnant, nondiabetic, afebrile, nonimmunocompromised, and have no abnormality of the urinary tract (i.e., uncomplicated)
- 3-day treatment with fluoroquinolone or TMP-SMX. Increasing resistance being reported to TMP-SMX. It is the preferred treatment if local sensitivity patterns indicate low resistance rates.
- New studies show 3-day therapy may be used in children.
• Postcoital: Single-dose TMP-SMX or cephalexin may reduce frequency of UTI in sexually active women.
• Pregnant patients: 10-14-day or longer treatment with pregnancy-safe antibiotic chosen based on culture/sensitivity results. May begin with cephalosporin, amoxicillin, or other antibiotic while awaiting culture/sensitivity results.
• All other patients: 10-14-day treatment with antibiotic chosen based on culture/sensitivity results. May begin with fluoroquinolone, TMP-SMX, cephalosporin, or other antibiotic while awaiting culture/sensitivity results.
• Contraindications
- Refer to the manufacturer's literature.
- Fluoroquinolones are not safe during pregnancy or for treatment of children.
- TMP-SMX use in pregnancy is not desirable (especially in the 3rd trimester), but is appropriate in some circumstances.
• Precautions: Refer to the manufacturer's literature.
• Significant possible interactions: Refer to the manufacturer's literature.
• Change the antibiotic if it is indicated by the culture/sensitivity results.
FOLLOW-UP
PROGNOSIS
Symptoms resolve within 2-3 days after starting a treatment in almost all patients.
COMPLICATIONS
• Pyelonephritis or sepsis
• Renal abscess
• Acute urinary outlet obstruction
ALERT
Infants and young children with cystitis are at higher risk of pyelonephritis.
PATIENT MONITORING
• 1st or rare UTI: In young or middle age, nonpregnant adult females require no follow-up if cured after 3-day therapy. If not resolved within 2-3 days, obtain culture/sensitivity and change antibiotic accordingly.
• All other patients should have post-treatment urine culture to document eradication of infection.
REFERENCES
1. Barry HG, Ebell MH, Hickner J. Evaluation of suspected urinary tract infection in ambulatory women: A cost-utility analysis of office-based strategies. J Fam Pract. 1997;44:49-60.
2. Bent S, et al. Does this woman have an acute uncomplicated urinary tract infection. JAMA. 2002;287:2701-2710.
3. Ebell MH, Barry NC. Urinary tract infection. In: Weiss BD, ed. 20 Common Problems in Primary Care. New York, NY: McGraw-Hill; 1999.
4. Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA. 1999;281:736-738.
5. Huang ES, Stafford RS. National patterns in the treatment of urinary tract infections in women by ambulatory care physicians. Arch Intern Med. 2002;162:41-47.
6. Stamm WE, Hooton T. Management of urinary tract infections in adults. N Engl J Med. 1993;329:1328-1334.
MISCELLANEOUS
See also: Pyelonephritis
ULCERATIVE COLITIS
ULCERATIVE COLITIS - Venu G. Pillarisetty, MD; Ruben Peralta, MD, FACS
BASICS
DESCRIPTION
An idiopathic inflammatory disease of the colon mucosa, affecting the rectum and usually extending proximally to involve the entire colon in a continuous manner.
• At least 95% have rectal involvement
• 50% limited to rectum and sigmoid.
• 30-40% of patients have disease beyond the sigmoid, but not of the entire colon.
• 20% have pancolitis.
EPIDEMIOLOGY
• Predominant age: 15-35. 2nd and smaller peak in the 7th decade.
• Predominant sex: Female slightly > Male
Incidence
US population: 5-12 new cases per 100,000
Prevalence
70-150/100,000
ALERT
Pediatric Considerations
Twenty percent of patients are 21 years
Pregnancy Considerations
• Outcome of pregnancy similar to general population. 1 study showed 30% of those with inactive disease at onset of pregnancy relapsed and 14% did so in 1st trimester.
• Treatment with sulfasalazine does not seem to affect outcome of pregnancy.
• Recommend that patient delays pregnancy until time when disease is inactive.
RISK FACTORS
• Better sanitation, artificial work environments (e.g., indoors), and fatty food increase risk
• NSAIDs can activate disease
• Appendectomy is protective against later development of disease
• Negative association with smoking (relative risk of smokers is 40% of nonsmokers)
Genetics
Family history in 5-10% in population surveys and 20-30% in referral-based studies. More common in the Jewish population.
ETIOLOGY
Unknown; major hypotheses include allergy to dietary components and abnormal immune responses to bacterial or self-antigens; final outcome is mucosal inflammation secondary to immune cell infiltration (1)[B]).
ASSOCIATED CONDITIONS
• Extracolonic manifestations in 10-15%
• Arthritic conditions including large joint arthritis, sacroiliitis, and ankylosing spondylitis. Infliximab has had a favorable response in treating these conditions.
• Pyoderma gangrenosum and other skin conditions; infliximab has helped.
• Episcleritis and uveal tract disease
• Sclerosing cholangitis; ursodeoxycholic acid is helpful
DIAGNOSIS
SIGNS AND SYMPTOMS
• Bloody diarrhea (watery stool accompanied by blood, pus, and mucus)
• Tenesmus
• Abdominal pain; tenderness in severe disease
• Rectal urgency, occasional fecal incontinence
• Fever
• Weight loss
• Arthralgias and arthritis: 15-20%
• Spondylitis: 3-6%
• Ocular: 4-10% include episcleritis, uveitis, cataracts, keratopathy, marginal corneal ulceration, and central serous retinopathy
• Erythema nodosum
• Pyoderma gangrenosum
• Aphthous ulcers of mouth: 5-10%
• Asymptomatic fatty liver (common); occasional hepatomegaly
• Pericholangitis (uncommon)
• Primary sclerosing cholangitis: 1-4%
• Cirrhosis of liver: 1-5%
• Bile duct carcinoma
• Thromboembolic disease: 1-6%
• Pericarditis (rare)
• Amyloidosis (rare)
TESTS
Lab
• Anemia may reflect chronic disease as well as iron deficiency from blood loss.
• Leukocytosis during exacerbation
• Elevated ESR and C-reactive protein
• Electrolyte abnormalities, especially hypokalemia
• Hypoalbuminemia
• Elevated liver function tests
• Perinuclear antineutrophil cytoplasmic antibody is elevated in 85% of cases of ulcerative colitis and 15% of Crohn disease.
• Antiglycan antibody is elevated in 75% of Crohn disease and 5% of ulcerative colitis cases.
Imaging
• Plain abdominal films
- Invaluable in management of acute complications of ulcerative colitis and should be immediately available in all patients who show tenderness of the colon, fever, and leukocytosis
- Permit the early diagnosis of toxic megacolon and perforation and treatment planning; toxic megacolon is most severe near the cecum and is present when diameter >12 cm.
• Barium enema
- Mucosal irregularities, effacement of haustra, pseudopolyposis
• Upper gastrointestinal series with small bowel follow-through to rule out Crohn disease
Diagnostic Procedures/Surgery
• Sigmoidoscopy; may include biopsy
- Should be sufficient to make initial diagnosis
• Colonoscopy; may include biopsy for evaluation for premalignant features
- To differentiate from Crohn disease
- To investigate suspected stricture or mass
- To define the extent and location of involvement and specific segments
- Full colonoscopy contraindicated in active disease or colonic dilatation because of risk of perforation
Pathological Findings
Inflammation of the colonic mucosa with ulcerations
• Ulcerations are hyperemic and hemorrhagic.
• Rectum is involved 95% of the time.
• The inflammation extends proximally in a continuous fashion but for a variable distance.
• May affect terminal ileum, so-called backwash ileitis.
DIFFERENTIAL DIAGNOSIS
• Other sources of rectal bleeding, including hemorrhoids, neoplasms, colonic diverticula, arteriovenous malformation, Crohn disease
• Infectious diarrhea including bacterial (enterotoxigenic Escherichia coli, E. coli 0157:H7, Salmonella, Shigella, Aeromonas, Plesiomonas) and parasitic (Entamoeba histolytica)
• Herpes simplex, Chlamydia trachomatis, Cryptosporidium, Isospora belli, cytomegalovirus
• Antibiotic-associated diarrhea
• Radiation proctitis
• Ischemic proctitis and colitis
TREATMENT
STABILIZATION
Hospitalization for severe exacerbations
GENERAL MEASURES
Control inflammation, prevent complications, and replace nutritional losses and blood volume.
Diet
No specific diet; milk products not withheld unless an associated lactase deficiency exists
Activity
Full activity as tolerated
MEDICATION (DRUGS)
First Line
• Sulfasalazine is treatment of choice both for mild exacerbations and for chronic treatment. Used to decrease the frequency of relapses (dosage range 2-6 g/d).
• Proctitis or proctosigmoiditis may be treated topically with steroid enemas or mesalamine (5-aminosalicylic acid [5-ASA]) enemas and suppositories.
• Oral or parenteral corticosteroids are used for more severe exacerbations (e.g., prednisone 40-60 mg/d, gradual taper over 2 months).
• 10% of patients have chronic disease and require continuous low to moderate steroid doses.
• Newer agents include oral 5-ASA derivatives.
• Immunomodulators, such as azathioprine, mercaptopurine (6-mercaptopurine), methotrexate, and cyclosporine, used in patients unresponsive to steroids and 5-ASA drugs or who cannot be weaned from high-dose steroids.
- Most experience is with azathioprine and mercaptopurine.
- Daily plain films of the abdomen are obtained until improvement occurs.
- If dilatation of colon increases or treatment has failed to attain reversal in 72 hours, emergency colectomy is indicated.
• Antimicrobial agents (antimycobacterials and metronidazole) are sometimes useful in Crohn disease, but not in ulcerative colitis.
• Antidiarrheal agents such as diphenoxylate-atropine and loperamide may be used to help control diarrhea, but require careful monitoring because they may precipitate toxic megacolon.
• Precautions: Use of antidiarrheal agents in severe disease could precipitate toxic megacolon.
Second Line
• Budesonide is a less toxic steroid almost totally cleared by the liver; it may help avoid steroid risks.
• Several preparations of 5-ASA exist, but results seem best with sulfasalazine in full dose.
• Infliximab recently was found to improve long-term outcomes in patients with moderate to severe disease despite treatment with other medications. (2)[B]
SURGERY
• Emergency surgery for massive hemorrhage, perforation, and toxic dilatation of the colon
• Surgery indicated for cancer, persistent multisite mucosal dysplasia, and patients refractory to all other forms of therapy.
• Total colectomy with ileostomy pouch is curative.
• Many patients prefer a continent ileostomy (J-pouch) emptying through the rectum.
• With the continent ileostomy operations, "pouchitis" occurs in ~10% with erratic partial response to antibiotics.
• Subtotal colectomy with the ileum connected to the rectal stump also may be performed.
• Regular proctoscopic surveillance is required because colonic mucosa is retained, thereby leaving a risk of future cancer development.
FOLLOW-UP
PROGNOSIS
• Variable course; mortality for initial attack is ~5%. 75-85% experience relapse, and up to 20% eventually require colectomy.
• Colon cancer risk is the single most important risk factor affecting long-term prognosis.
• Left-sided colitis and ulcerative proctitis have favorable prognosis with probable normal lifespan.
ALERT
Geriatric Considerations
Increased mortality if 1st presentation after 60 years of age
COMPLICATIONS
• Perforation
• Toxic megacolon
• Liver disease
• Stricture formation (less than Crohn disease)
• Colon cancer (may occur in as many as 30% of those with pancolitis for 25 years). Incidence of cancer is cumulative over time and begins after 7-8 years of the disease; risk may be considerably less in left-sided disease.
PATIENT MONITORING
• Colonoscopy for cancer surveillance with biopsy of the mucosa for evidence of dysplasia every 1-2 years after the disease has been present for 7-8 years. This is particularly important in pancolitis. Low-grade dysplasia warrants more frequent evaluation (e.g., every 3-6 months), and high-grade dysplasia (or low-grade dysplasia within a mass) warrants consideration of colectomy.
• Magnification chromoendoscopy has been shown to be capable of detecting significantly more intraepithelial neoplasias than conventional colonoscopy. (3)[B]
• Annual liver tests
• Cholangiography for cholestasis
Pediatric Considerations
Cancer surveillance is important because occurrence of cancer relates to the duration and extent of disease, whether frequently symptomatic or not.
REFERENCES
1. Hanauer SB. Inflammatory bowel disease: Epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 2006;12:S3-S9.
2. Rutgeerts R, Sandborn WJ, Feagan BG. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462-2476.
3. Kiesslich R, Hoffman A, Neurath MF. Colonoscopy, tumors, and inflammatory bowel diseasenew diagnostic methods. Endoscopy 2006;38(1):5-10.
BASICS
DESCRIPTION
An idiopathic inflammatory disease of the colon mucosa, affecting the rectum and usually extending proximally to involve the entire colon in a continuous manner.
• At least 95% have rectal involvement
• 50% limited to rectum and sigmoid.
• 30-40% of patients have disease beyond the sigmoid, but not of the entire colon.
• 20% have pancolitis.
EPIDEMIOLOGY
• Predominant age: 15-35. 2nd and smaller peak in the 7th decade.
• Predominant sex: Female slightly > Male
Incidence
US population: 5-12 new cases per 100,000
Prevalence
70-150/100,000
ALERT
Pediatric Considerations
Twenty percent of patients are 21 years
Pregnancy Considerations
• Outcome of pregnancy similar to general population. 1 study showed 30% of those with inactive disease at onset of pregnancy relapsed and 14% did so in 1st trimester.
• Treatment with sulfasalazine does not seem to affect outcome of pregnancy.
• Recommend that patient delays pregnancy until time when disease is inactive.
RISK FACTORS
• Better sanitation, artificial work environments (e.g., indoors), and fatty food increase risk
• NSAIDs can activate disease
• Appendectomy is protective against later development of disease
• Negative association with smoking (relative risk of smokers is 40% of nonsmokers)
Genetics
Family history in 5-10% in population surveys and 20-30% in referral-based studies. More common in the Jewish population.
ETIOLOGY
Unknown; major hypotheses include allergy to dietary components and abnormal immune responses to bacterial or self-antigens; final outcome is mucosal inflammation secondary to immune cell infiltration (1)[B]).
ASSOCIATED CONDITIONS
• Extracolonic manifestations in 10-15%
• Arthritic conditions including large joint arthritis, sacroiliitis, and ankylosing spondylitis. Infliximab has had a favorable response in treating these conditions.
• Pyoderma gangrenosum and other skin conditions; infliximab has helped.
• Episcleritis and uveal tract disease
• Sclerosing cholangitis; ursodeoxycholic acid is helpful
DIAGNOSIS
SIGNS AND SYMPTOMS
• Bloody diarrhea (watery stool accompanied by blood, pus, and mucus)
• Tenesmus
• Abdominal pain; tenderness in severe disease
• Rectal urgency, occasional fecal incontinence
• Fever
• Weight loss
• Arthralgias and arthritis: 15-20%
• Spondylitis: 3-6%
• Ocular: 4-10% include episcleritis, uveitis, cataracts, keratopathy, marginal corneal ulceration, and central serous retinopathy
• Erythema nodosum
• Pyoderma gangrenosum
• Aphthous ulcers of mouth: 5-10%
• Asymptomatic fatty liver (common); occasional hepatomegaly
• Pericholangitis (uncommon)
• Primary sclerosing cholangitis: 1-4%
• Cirrhosis of liver: 1-5%
• Bile duct carcinoma
• Thromboembolic disease: 1-6%
• Pericarditis (rare)
• Amyloidosis (rare)
TESTS
Lab
• Anemia may reflect chronic disease as well as iron deficiency from blood loss.
• Leukocytosis during exacerbation
• Elevated ESR and C-reactive protein
• Electrolyte abnormalities, especially hypokalemia
• Hypoalbuminemia
• Elevated liver function tests
• Perinuclear antineutrophil cytoplasmic antibody is elevated in 85% of cases of ulcerative colitis and 15% of Crohn disease.
• Antiglycan antibody is elevated in 75% of Crohn disease and 5% of ulcerative colitis cases.
Imaging
• Plain abdominal films
- Invaluable in management of acute complications of ulcerative colitis and should be immediately available in all patients who show tenderness of the colon, fever, and leukocytosis
- Permit the early diagnosis of toxic megacolon and perforation and treatment planning; toxic megacolon is most severe near the cecum and is present when diameter >12 cm.
• Barium enema
- Mucosal irregularities, effacement of haustra, pseudopolyposis
• Upper gastrointestinal series with small bowel follow-through to rule out Crohn disease
Diagnostic Procedures/Surgery
• Sigmoidoscopy; may include biopsy
- Should be sufficient to make initial diagnosis
• Colonoscopy; may include biopsy for evaluation for premalignant features
- To differentiate from Crohn disease
- To investigate suspected stricture or mass
- To define the extent and location of involvement and specific segments
- Full colonoscopy contraindicated in active disease or colonic dilatation because of risk of perforation
Pathological Findings
Inflammation of the colonic mucosa with ulcerations
• Ulcerations are hyperemic and hemorrhagic.
• Rectum is involved 95% of the time.
• The inflammation extends proximally in a continuous fashion but for a variable distance.
• May affect terminal ileum, so-called backwash ileitis.
DIFFERENTIAL DIAGNOSIS
• Other sources of rectal bleeding, including hemorrhoids, neoplasms, colonic diverticula, arteriovenous malformation, Crohn disease
• Infectious diarrhea including bacterial (enterotoxigenic Escherichia coli, E. coli 0157:H7, Salmonella, Shigella, Aeromonas, Plesiomonas) and parasitic (Entamoeba histolytica)
• Herpes simplex, Chlamydia trachomatis, Cryptosporidium, Isospora belli, cytomegalovirus
• Antibiotic-associated diarrhea
• Radiation proctitis
• Ischemic proctitis and colitis
TREATMENT
STABILIZATION
Hospitalization for severe exacerbations
GENERAL MEASURES
Control inflammation, prevent complications, and replace nutritional losses and blood volume.
Diet
No specific diet; milk products not withheld unless an associated lactase deficiency exists
Activity
Full activity as tolerated
MEDICATION (DRUGS)
First Line
• Sulfasalazine is treatment of choice both for mild exacerbations and for chronic treatment. Used to decrease the frequency of relapses (dosage range 2-6 g/d).
• Proctitis or proctosigmoiditis may be treated topically with steroid enemas or mesalamine (5-aminosalicylic acid [5-ASA]) enemas and suppositories.
• Oral or parenteral corticosteroids are used for more severe exacerbations (e.g., prednisone 40-60 mg/d, gradual taper over 2 months).
• 10% of patients have chronic disease and require continuous low to moderate steroid doses.
• Newer agents include oral 5-ASA derivatives.
• Immunomodulators, such as azathioprine, mercaptopurine (6-mercaptopurine), methotrexate, and cyclosporine, used in patients unresponsive to steroids and 5-ASA drugs or who cannot be weaned from high-dose steroids.
- Most experience is with azathioprine and mercaptopurine.
- Daily plain films of the abdomen are obtained until improvement occurs.
- If dilatation of colon increases or treatment has failed to attain reversal in 72 hours, emergency colectomy is indicated.
• Antimicrobial agents (antimycobacterials and metronidazole) are sometimes useful in Crohn disease, but not in ulcerative colitis.
• Antidiarrheal agents such as diphenoxylate-atropine and loperamide may be used to help control diarrhea, but require careful monitoring because they may precipitate toxic megacolon.
• Precautions: Use of antidiarrheal agents in severe disease could precipitate toxic megacolon.
Second Line
• Budesonide is a less toxic steroid almost totally cleared by the liver; it may help avoid steroid risks.
• Several preparations of 5-ASA exist, but results seem best with sulfasalazine in full dose.
• Infliximab recently was found to improve long-term outcomes in patients with moderate to severe disease despite treatment with other medications. (2)[B]
SURGERY
• Emergency surgery for massive hemorrhage, perforation, and toxic dilatation of the colon
• Surgery indicated for cancer, persistent multisite mucosal dysplasia, and patients refractory to all other forms of therapy.
• Total colectomy with ileostomy pouch is curative.
• Many patients prefer a continent ileostomy (J-pouch) emptying through the rectum.
• With the continent ileostomy operations, "pouchitis" occurs in ~10% with erratic partial response to antibiotics.
• Subtotal colectomy with the ileum connected to the rectal stump also may be performed.
• Regular proctoscopic surveillance is required because colonic mucosa is retained, thereby leaving a risk of future cancer development.
FOLLOW-UP
PROGNOSIS
• Variable course; mortality for initial attack is ~5%. 75-85% experience relapse, and up to 20% eventually require colectomy.
• Colon cancer risk is the single most important risk factor affecting long-term prognosis.
• Left-sided colitis and ulcerative proctitis have favorable prognosis with probable normal lifespan.
ALERT
Geriatric Considerations
Increased mortality if 1st presentation after 60 years of age
COMPLICATIONS
• Perforation
• Toxic megacolon
• Liver disease
• Stricture formation (less than Crohn disease)
• Colon cancer (may occur in as many as 30% of those with pancolitis for 25 years). Incidence of cancer is cumulative over time and begins after 7-8 years of the disease; risk may be considerably less in left-sided disease.
PATIENT MONITORING
• Colonoscopy for cancer surveillance with biopsy of the mucosa for evidence of dysplasia every 1-2 years after the disease has been present for 7-8 years. This is particularly important in pancolitis. Low-grade dysplasia warrants more frequent evaluation (e.g., every 3-6 months), and high-grade dysplasia (or low-grade dysplasia within a mass) warrants consideration of colectomy.
• Magnification chromoendoscopy has been shown to be capable of detecting significantly more intraepithelial neoplasias than conventional colonoscopy. (3)[B]
• Annual liver tests
• Cholangiography for cholestasis
Pediatric Considerations
Cancer surveillance is important because occurrence of cancer relates to the duration and extent of disease, whether frequently symptomatic or not.
REFERENCES
1. Hanauer SB. Inflammatory bowel disease: Epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 2006;12:S3-S9.
2. Rutgeerts R, Sandborn WJ, Feagan BG. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462-2476.
3. Kiesslich R, Hoffman A, Neurath MF. Colonoscopy, tumors, and inflammatory bowel diseasenew diagnostic methods. Endoscopy 2006;38(1):5-10.
TYPHUS FEVERS
TYPHUS FEVERS - Jeremy Golding, MD
BASICS
DESCRIPTION
• Acute infectious diseases caused by 3 species of rickettsiae
- Epidemic typhus: Human-to-human transmission by body louse vector. Primarily in circumstances such as refugee camps, war, famine, and disaster. Recrudescent disease (Brill-Zinsser Disease), occurring years after initial infection, can be source of human outbreak. Flying squirrels are also a reservoir.
- Endemic (murine) typhus: Infection by rodents. To humans by rat flea bite.
- Scrub typhus: Infection and infestation of chiggers and of rodents. To humans by the chigger. Primarily in Asia and Western Pacific areas.
• System(s) Affected: Endocrine/Metabolic; Hemic/Lymphatic/Immunologic; Pulmonary; Skin/Exocrine
• Synonym(s): Louse-borne typhus; Brill-Zinsser disease; Murine typhus
GENERAL PREVENTION
Avoid vectors for each disease
• Scrub typhus: Wear protective clothing and use insect repellents.
• Endemic typhus: Practice ectoparasite and rodent control.
• Epidemic typhus: Delousing and cleaning of clothing; vaccine may be considered for those at high risk of exposure (typhus vaccine production has been discontinued in the US).
EPIDEMIOLOGY
• Epidemic and endemic typhus: Rare in US
• Scrub typhus: Travelers returning from endemic areas only (rare)
Incidence
Endemic typhus: 100 cases annually, primarily in states around Gulf of Mexico, especially south Texas, under-reporting suspected
RISK FACTORS
• Exposure to vectors (e.g., during travel to countries where endemic)
• Elderly may have more severe disease
ETIOLOGY
• Epidemic typhus by Rickettsia prowazekii
• Endemic typhus by R. typhi
• Scrub typhus by R. tsutsugamushi
DIAGNOSIS
SIGNS AND SYMPTOMS
• General
- Acute onset
- Fever
- Chills
- Headache
- Myalgia
- Malaise
- Diffuse organ involvement (e.g., intestine, liver, heart, kidneys, brain)
• Epidemic typhus
- Incubation period ~1 week
- Macular or maculopapular rash, begins on trunk spreads to extremities about 5th day of illness
- Nonproductive cough
- Pulmonary infiltrates
- Conjunctivitis
- Neurologic involvement
• Endemic typhus
- Incubation period 1-2 weeks
- Macular or maculopapular rash beginning on trunk 3rd-5th day of illness, spreads to trunk ~5th day
- Duration 12 days untreated
- Usually milder illness
• Scrub typhus
- Incubation period 1-3 weeks
- Eschar at bite site
- Regional lymphadenopathy
- Generalized lymphadenopathy
- Splenomegaly
- Macular or maculopapular rash beginning on trunk about the 5th day of illness
- Relative bradycardia early in disease
- Ocular pain
- Conjunctival injection
History
Travel or other risk exposure
Physical Exam
As above
TESTS
Specific serologic test showing a rising antibody titer. Isolation of Rickettsia should be undertaken only in special laboratories, to minimize risk of laboratory-acquired infection.
Lab
• Leukocyte findings usually normal
• Abnormalities reflecting the particular organs affected
• Weil-Felix serologic reaction may be positive; test value limited to mid-illness or after, and by low sensitivity and specificity. Epidemic and endemic typhus, 4-fold titer rise or titer >1/320 to OX-19. Scrub typhus, 4-fold rise in titer to OX-K.
• Hyponatremia in severe cases
• Hypoalbuminemia in severe cases
• Drugs that may alter lab results: Prior antibiotic use
Pathological Findings
Diffuse vasculitis
DIFFERENTIAL DIAGNOSIS
• Any acute febrile disease
• Rocky Mountain spotted fever
• Meningococcemia
• Bacterial meningitis
• Mediterranean spotted fever (boutonneuse fever) (R. conorii)
• Measles
• Rubella
• Toxoplasmosis
• Leptospirosis
• Typhoid fever
• Dengue
• Relapsing fever
• Secondary syphilis
• Viral syndromes: Mononucleosis, acute retroviral syndrome
TREATMENT
STABILIZATION
Outpatient care unless severely ill
GENERAL MEASURES
• Protect agitated patient from injury
• Skin and mouth care
• Supportive care for the severely ill, directed at the complications
Diet
As tolerated
Activity
Bed rest during acute stages, otherwise as tolerated
MEDICATION (DRUGS)
First Line
• Treatment should begin when diagnosis is reasonably likely and continue until the patient's state is improved and the patient is afebrile for a minimum of 48 hours. Usual treatment course: 5-7 days.
• Children 8 years of age and adults
- Tetracycline, or a congener: 25 mg/kg PO initially, and then 25 mg/kg/d in equally divided doses q6h
- If severely ill, may use doxycycline IV: Adults 100 mg q12h, children 8 years of age 5 mg/kg/d (maximum of 200 mg/d)
• Children 8 years of age, pregnant women, or if typhoid fever is possible cause of illness
- Chloramphenicol: 50 mg/kg PO initially, and then 50 mg/kg daily in equally divided doses q6h
- If severely ill, chloramphenicol sodium succinate: 20 mg/kg IV initially, infused over 30-45 minutes, and then 50 mg/kg/d infused in equally divided doses q6h until orally tolerable
• Precautions: Refer to the manufacturer's profile for each drug.
• Significant possible interactions: Refer to the manufacturer's profile for each drug.
Second Line
• Doxycycline: Single oral dose of 100 or 200 mg for those in refugee camps, victims of disasters, or in presence of limited medical services
• Isolated reports indicate that erythromycin and ciprofloxacin are effective.
FOLLOW-UP
DISPOSITION
Admission Criteria
Severely ill or constitutionally unstable (e.g., shock)
PROGNOSIS
• Recovery is expected if treatment is instituted before onset of complications.
• Relapses may follow treatment, especially if initiated within 48 hours of onset (this is not an indication to delay treatment). Relapses are treated same as primary disease.
• Without treatment, mortality rate of typhus is 40-60% for epidemic, 1-2% for endemic, and up to 30% for scrub. Mortality is higher among the elderly.
COMPLICATIONS
• Consequences of specific organ system involvement in the 2nd week (e.g., azotemia, meningoencephalitis, seizures, delirium, coma, myocardial failure, hyponatremia, hypoalbuminemia, hypovolemia, and shock)
• Death
PATIENT MONITORING
Severely ill patients should be observed regularly in the hospital. Outpatients should be checked periodically as improvement is evident.
REFERENCES
1. Azad AF, Beard CB. Rickettsial pathogens and their arthropod vectors. Emerg Infect Dis. 1998;4:179-186.
2. Azad AF, et al. Flea-borne rickettsioses: Ecologic considerations. Emerg Infect Dis. 1997;3:319-327.
3. Dumlev JS, Taylor JP, Walker DH. Clinical and laboratory features of murine typhus in south Texas, 1980 through 1987. JAMA. 1991;266:1365-1370.
4. Jensenius M, Forunier PE, Raoult D. Rickettsioses and the international traveler. Clin Infect Dis. 2004;39:1493-1499.
5. Mandell GL, Bennett JF, Dolin R, eds. Principles and Practice of Infectious Diseases, 6th ed. New York: Churchill Livingstone, 2004.
6. Raoult D, Roux V. The body louse as a vector of reemerging human diseases. Clin Infect Dis. 1999;29:888-911.
7. Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. 2003;16:429-436.
MISCELLANEOUS
• Severe headache is often intractable and not eased by the standard drugs.
• Report case to appropriate health department or other agency.
BASICS
DESCRIPTION
• Acute infectious diseases caused by 3 species of rickettsiae
- Epidemic typhus: Human-to-human transmission by body louse vector. Primarily in circumstances such as refugee camps, war, famine, and disaster. Recrudescent disease (Brill-Zinsser Disease), occurring years after initial infection, can be source of human outbreak. Flying squirrels are also a reservoir.
- Endemic (murine) typhus: Infection by rodents. To humans by rat flea bite.
- Scrub typhus: Infection and infestation of chiggers and of rodents. To humans by the chigger. Primarily in Asia and Western Pacific areas.
• System(s) Affected: Endocrine/Metabolic; Hemic/Lymphatic/Immunologic; Pulmonary; Skin/Exocrine
• Synonym(s): Louse-borne typhus; Brill-Zinsser disease; Murine typhus
GENERAL PREVENTION
Avoid vectors for each disease
• Scrub typhus: Wear protective clothing and use insect repellents.
• Endemic typhus: Practice ectoparasite and rodent control.
• Epidemic typhus: Delousing and cleaning of clothing; vaccine may be considered for those at high risk of exposure (typhus vaccine production has been discontinued in the US).
EPIDEMIOLOGY
• Epidemic and endemic typhus: Rare in US
• Scrub typhus: Travelers returning from endemic areas only (rare)
Incidence
Endemic typhus: 100 cases annually, primarily in states around Gulf of Mexico, especially south Texas, under-reporting suspected
RISK FACTORS
• Exposure to vectors (e.g., during travel to countries where endemic)
• Elderly may have more severe disease
ETIOLOGY
• Epidemic typhus by Rickettsia prowazekii
• Endemic typhus by R. typhi
• Scrub typhus by R. tsutsugamushi
DIAGNOSIS
SIGNS AND SYMPTOMS
• General
- Acute onset
- Fever
- Chills
- Headache
- Myalgia
- Malaise
- Diffuse organ involvement (e.g., intestine, liver, heart, kidneys, brain)
• Epidemic typhus
- Incubation period ~1 week
- Macular or maculopapular rash, begins on trunk spreads to extremities about 5th day of illness
- Nonproductive cough
- Pulmonary infiltrates
- Conjunctivitis
- Neurologic involvement
• Endemic typhus
- Incubation period 1-2 weeks
- Macular or maculopapular rash beginning on trunk 3rd-5th day of illness, spreads to trunk ~5th day
- Duration 12 days untreated
- Usually milder illness
• Scrub typhus
- Incubation period 1-3 weeks
- Eschar at bite site
- Regional lymphadenopathy
- Generalized lymphadenopathy
- Splenomegaly
- Macular or maculopapular rash beginning on trunk about the 5th day of illness
- Relative bradycardia early in disease
- Ocular pain
- Conjunctival injection
History
Travel or other risk exposure
Physical Exam
As above
TESTS
Specific serologic test showing a rising antibody titer. Isolation of Rickettsia should be undertaken only in special laboratories, to minimize risk of laboratory-acquired infection.
Lab
• Leukocyte findings usually normal
• Abnormalities reflecting the particular organs affected
• Weil-Felix serologic reaction may be positive; test value limited to mid-illness or after, and by low sensitivity and specificity. Epidemic and endemic typhus, 4-fold titer rise or titer >1/320 to OX-19. Scrub typhus, 4-fold rise in titer to OX-K.
• Hyponatremia in severe cases
• Hypoalbuminemia in severe cases
• Drugs that may alter lab results: Prior antibiotic use
Pathological Findings
Diffuse vasculitis
DIFFERENTIAL DIAGNOSIS
• Any acute febrile disease
• Rocky Mountain spotted fever
• Meningococcemia
• Bacterial meningitis
• Mediterranean spotted fever (boutonneuse fever) (R. conorii)
• Measles
• Rubella
• Toxoplasmosis
• Leptospirosis
• Typhoid fever
• Dengue
• Relapsing fever
• Secondary syphilis
• Viral syndromes: Mononucleosis, acute retroviral syndrome
TREATMENT
STABILIZATION
Outpatient care unless severely ill
GENERAL MEASURES
• Protect agitated patient from injury
• Skin and mouth care
• Supportive care for the severely ill, directed at the complications
Diet
As tolerated
Activity
Bed rest during acute stages, otherwise as tolerated
MEDICATION (DRUGS)
First Line
• Treatment should begin when diagnosis is reasonably likely and continue until the patient's state is improved and the patient is afebrile for a minimum of 48 hours. Usual treatment course: 5-7 days.
• Children 8 years of age and adults
- Tetracycline, or a congener: 25 mg/kg PO initially, and then 25 mg/kg/d in equally divided doses q6h
- If severely ill, may use doxycycline IV: Adults 100 mg q12h, children 8 years of age 5 mg/kg/d (maximum of 200 mg/d)
• Children 8 years of age, pregnant women, or if typhoid fever is possible cause of illness
- Chloramphenicol: 50 mg/kg PO initially, and then 50 mg/kg daily in equally divided doses q6h
- If severely ill, chloramphenicol sodium succinate: 20 mg/kg IV initially, infused over 30-45 minutes, and then 50 mg/kg/d infused in equally divided doses q6h until orally tolerable
• Precautions: Refer to the manufacturer's profile for each drug.
• Significant possible interactions: Refer to the manufacturer's profile for each drug.
Second Line
• Doxycycline: Single oral dose of 100 or 200 mg for those in refugee camps, victims of disasters, or in presence of limited medical services
• Isolated reports indicate that erythromycin and ciprofloxacin are effective.
FOLLOW-UP
DISPOSITION
Admission Criteria
Severely ill or constitutionally unstable (e.g., shock)
PROGNOSIS
• Recovery is expected if treatment is instituted before onset of complications.
• Relapses may follow treatment, especially if initiated within 48 hours of onset (this is not an indication to delay treatment). Relapses are treated same as primary disease.
• Without treatment, mortality rate of typhus is 40-60% for epidemic, 1-2% for endemic, and up to 30% for scrub. Mortality is higher among the elderly.
COMPLICATIONS
• Consequences of specific organ system involvement in the 2nd week (e.g., azotemia, meningoencephalitis, seizures, delirium, coma, myocardial failure, hyponatremia, hypoalbuminemia, hypovolemia, and shock)
• Death
PATIENT MONITORING
Severely ill patients should be observed regularly in the hospital. Outpatients should be checked periodically as improvement is evident.
REFERENCES
1. Azad AF, Beard CB. Rickettsial pathogens and their arthropod vectors. Emerg Infect Dis. 1998;4:179-186.
2. Azad AF, et al. Flea-borne rickettsioses: Ecologic considerations. Emerg Infect Dis. 1997;3:319-327.
3. Dumlev JS, Taylor JP, Walker DH. Clinical and laboratory features of murine typhus in south Texas, 1980 through 1987. JAMA. 1991;266:1365-1370.
4. Jensenius M, Forunier PE, Raoult D. Rickettsioses and the international traveler. Clin Infect Dis. 2004;39:1493-1499.
5. Mandell GL, Bennett JF, Dolin R, eds. Principles and Practice of Infectious Diseases, 6th ed. New York: Churchill Livingstone, 2004.
6. Raoult D, Roux V. The body louse as a vector of reemerging human diseases. Clin Infect Dis. 1999;29:888-911.
7. Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. 2003;16:429-436.
MISCELLANEOUS
• Severe headache is often intractable and not eased by the standard drugs.
• Report case to appropriate health department or other agency.
TYPHOID FEVER
TYPHOID FEVER - D. W. MacPherson, MD, MSc (CTM), FRCPC
BASICS
DESCRIPTION
• Typhoid fever is an acute systemic illness in humans caused by Salmonella typhi. It is a classic example of enteric fever caused by the Salmonella bacterium.
• It is endemic in some developing nations where sanitation is poor. Most cases in North America and other developed nations are acquired after travel to disease-endemic areas.
• Mode of transmission is fecal-oral through ingestion of contaminated food (commonly poultry), water, and milk. Incubation period varies from 7-21 days.
• System(s) Affected: Gastrointestinal; Pulmonary; Skin/Exocrine
• Synonym(s): Typhoid; Typhus abdominalis; Enteric fever
ALERT
Geriatric Considerations
Disease more serious in elderly
Pediatric Considerations
Disease more serious in infants but may be milder in children
GENERAL PREVENTION
• For high-risk travel to an endemic area, consider vaccination for typhoid
- Parenteral ViCPS or capsular polysaccharide typhoid vaccine (Typhim Vi) or
- Ty21a or live oral typhoid vaccine (Vivotif Berna), particularly if traveler will be at prolonged risk (>4 weeks)
• Avoid tap water, salad/raw vegetables, unpeeled fruits, and dairy products during tropical travel.
• Avoid poultry or poultry products left unrefrigerated for prolonged periods.
• Consider vaccination for workers exposed to S. typhi, or those with household or intimate exposure to a carrier of S. typhi
• The parenteral heat-phenol-inactivated vaccine (manufactured by Wyeth-Ayerst) has been discontinued.
Typhoid Fever Vaccinations
Number Time Total time needed Minimum age Booster of doses between to set aside for vaccination needed Vaccine name How given necessary doses for vaccination every... Ty21a (Vivotif 1 capsule 4 2 days 2 weeks 6 years 5 years Berna, Swiss by mouth Serum and Vaccine Institute) ViCPS (Typhim Vi, Pasteur Injection 1 N/A 2 weeks 2 years 2 years Merieux)
EPIDEMIOLOGY
• Predominant age: All ages
• Predominant sex: Male = Female
Incidence
Per year 300-500 new cases
RISK FACTORS
Must be considered in any patient presenting with fever after tropical travel or exposure to chronic carrier
ETIOLOGY
S. typhi
DIAGNOSIS
SIGNS AND SYMPTOMS
• Fever
• Headache
• Malaise
• Abdominal discomfort/bloating/constipation
• Diarrhea (less common)
• Dry cough
• Confusion/lethargy
• Rose spot (transient erythematous maculopapular rash in anterior thorax or upper abdomen)
• Splenomegaly
• Hepatomegaly
• Cervical adenopathy
• Relative bradycardia
• Conjunctivitis
History
Travel and exposure
Physical Exam
Constitutionally unwell, fever, relative bradycardia, Rose spots, abdominal pain, hepato-splenmegaly
TESTS
Lab
• Definitive diagnosis by isolation of S. typhi from blood. Isolation of S. typhi in sputum, urine, or stool is presumptive diagnosis in typical clinical presentation.
• Serology is nonspecific and usually not useful.
• If multiple blood cultures have negative result or in patients with prior antibiotic therapy, diagnostic yield is better with bone marrow culture.
• Anemia, leukopenia (neutropenia), thrombocytopenia, or evidence of disseminated intravascular coagulopathy are supportive evidence. Elevated liver enzyme levels are commonly found.
• Drugs that may alter lab results
- Prior antibiotic therapy
- Vaccination
Imaging
Consider serial plain abdominal films for evidence of intestinal perforation.
Diagnostic Procedures/Surgery
Bone marrow for culture is rarely indicated
Pathological Findings
Classically, mononuclear proliferation involving lymphoid tissue of intestinal tract, especially Peyer patch in terminal ileum
DIFFERENTIAL DIAGNOSIS
• Malaria
• "Enteric fever-like" syndrome caused by Yersinia enterocolitica, pseudotuberculosis, and Campylobacter spp.
• Enteric fever caused by nontyphoid Salmonella spp.
• Infectious hepatitis
• Atypical pneumonia
• Infectious mononucleosis
• Subacute bacterial endocarditis
• Tuberculosis
• Brucellosis
• Q fever
• toxoplasmosis
• Viral infections: Epstein-Barr virus, cytomegalovirus, viral hemorrhagic agents
TREATMENT
STABILIZATION
• Inpatient if acutely ill
• Outpatient for less-ill patient or for carrier
GENERAL MEASURES
• Fluid and electrolyte support
• Strict isolation of patient's linen, stool, and urine
• Monitor clinically and consider serial plain abdominal films for evidence of perforation, usually in the 3rd-4th week of illness.
• Indication for treatment must be determined on an individual basis. Factors to be considered are age, public health risk (e.g., food handler, chronic care facilities, medical personnel), intolerance to antibiotics, and evidence of biliary tract disease.
• For hemorrhage: Blood transfusion and management of shock
Diet
If abdominal symptoms severe, nothing by mouth. With improvement, normal low-residue diet, possibly high calorie
Activity
Bed rest initially, then as tolerated
Nursing
Observe enteric precautions.
MEDICATION (DRUGS)
First Line
• Chloramphenicol: Pediatric 50 mg/kg/d PO q.i.d. 2 weeks; adult dose 50 mg/kg/d, divided q6h 2 weeks; or
• Ampicillin: Pediatric 100 mg/kg/d q.i.d. PO 2 weeks; adults 500 mg q6h 2 weeks; or
• Ciprofloxacin: 500 mg PO b.i.d. 2 weeks, indicated in multiple drug-resistant typhoid, has been successfully and safely used in children; or
• Ceftriaxone: 1-2 g IV once daily 2 weeks; or
• Furazolidone: 7.5 mg/kg/d PO 10 days; in uncomplicated multiple drug-resistant typhoid; safe in children; efficacy >85% cure
• Chronic carrier state:
- Ampicillin: 4-5 g/d + probenecid 2 g/d q.i.d. 6 weeks (for patients with normally functioning gallbladder without evidence of cholelithiasis)
- Ciprofloxacin: 500 mg PO b.i.d. 4-6 weeks is also efficacious. NOTE: Chloramphenicol resistance has been reported in Mexico, South America, Central America, Southeast Asia, India, Pakistan, Middle East, and Africa.
• Contraindications: Refer to the manufacturer's profile for each drug.
• Precautions: Rarely, Jarisch-Herxheimer reaction appears after antimicrobial therapy.
• Significant possible interactions: Refer to the manufacturer's profile for each drug.
Second Line
Trimethoprim-sulfamethoxazole
ALERT
Pregnancy Considerations
Ciprofloxacin therapy is relatively contraindicated in pregnant patients.
SURGERY
• Complications: Bowel perforation
• Cholecystectomy may be warranted in carriers with cholelithiasis, relapse after therapy, or intolerance to antimicrobial therapy.
FOLLOW-UP
DISPOSITION
Admission Criteria
Clinical severity
Issues for Referral
Complications of sepsis, bowel perforation
PROGNOSIS
Overall prognosis good with therapy; 2% mortality rate; 15% relapse rate with some antibiotic treatments; 3% bowel perforation
COMPLICATIONS
• Intestinal hemorrhage and perforation in distal ileum
• Patients may become chronic carriers (up to 3%), defined as persistent stool excretor for longer than 1 year
• Predilection for seeding in the biliary tract exists and may become a focus for relapse of typhoid fever. Most common in females and the elderly (>50 years old).
• Osteomyelitis found especially in patients with sickle cell anemia, systemic lupus erythematosus, hematologic neoplasms, and in immunosuppressed hosts
• Endovascular infection in the elderly and in patients with history of bypass operation or aneurysm
• Rarely, endocarditis or meningitis
PATIENT MONITORING
See "General Measures."
REFERENCES
1. Crump JA, et al. Estimating the incidence of typhoid fever and other febrile illnesses in developing countries. Emerg Infect Dis. 2003; Available at: http://www.cdc.gov/ncidod/EID/vol9no5/02-0428.htm. Accessed June 18, 2006.
2. Dick L. Travel medicine: helping patients prepare for trips abroad. Am Fam Physician. 1998;58:383-398, 401-402.
3. Mandell GL. Principles and Practice of Infectious Diseases. 6th ed. New York, NY: Churchill Livingstone; 2004.
4. Peter G, et al. Lessons learned from a review of the development of selected vaccines. Pediatrics. 1999;104:942-950.
5. Rowe B, Ward LR, Threlfall EJ. Multidrug-resistant Salmonella typhi: A worldwide epidemic. Clin Infect Dis. 1997;24(suppl 1):S106-S109.
6. Thompson RF, Bass DM, Hoffman SL. Travel vaccines. Infect Dis Clin North Amer. 1999;13:49-67.
7. Yoon J, Segal-Maurer S, Rahal JJ. An outbreak of domestically acquired typhoid fever in Queens, NY. Arch Intern Med. 2004;164:565-567.
8. Centers for Disease Control and Prevention. Typhoid Fever. (dated January 10, 2005). Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/files/typhoid_fever_FAQ.pdf
BASICS
DESCRIPTION
• Typhoid fever is an acute systemic illness in humans caused by Salmonella typhi. It is a classic example of enteric fever caused by the Salmonella bacterium.
• It is endemic in some developing nations where sanitation is poor. Most cases in North America and other developed nations are acquired after travel to disease-endemic areas.
• Mode of transmission is fecal-oral through ingestion of contaminated food (commonly poultry), water, and milk. Incubation period varies from 7-21 days.
• System(s) Affected: Gastrointestinal; Pulmonary; Skin/Exocrine
• Synonym(s): Typhoid; Typhus abdominalis; Enteric fever
ALERT
Geriatric Considerations
Disease more serious in elderly
Pediatric Considerations
Disease more serious in infants but may be milder in children
GENERAL PREVENTION
• For high-risk travel to an endemic area, consider vaccination for typhoid
- Parenteral ViCPS or capsular polysaccharide typhoid vaccine (Typhim Vi) or
- Ty21a or live oral typhoid vaccine (Vivotif Berna), particularly if traveler will be at prolonged risk (>4 weeks)
• Avoid tap water, salad/raw vegetables, unpeeled fruits, and dairy products during tropical travel.
• Avoid poultry or poultry products left unrefrigerated for prolonged periods.
• Consider vaccination for workers exposed to S. typhi, or those with household or intimate exposure to a carrier of S. typhi
• The parenteral heat-phenol-inactivated vaccine (manufactured by Wyeth-Ayerst) has been discontinued.
Typhoid Fever Vaccinations
Number Time Total time needed Minimum age Booster of doses between to set aside for vaccination needed Vaccine name How given necessary doses for vaccination every... Ty21a (Vivotif 1 capsule 4 2 days 2 weeks 6 years 5 years Berna, Swiss by mouth Serum and Vaccine Institute) ViCPS (Typhim Vi, Pasteur Injection 1 N/A 2 weeks 2 years 2 years Merieux)
EPIDEMIOLOGY
• Predominant age: All ages
• Predominant sex: Male = Female
Incidence
Per year 300-500 new cases
RISK FACTORS
Must be considered in any patient presenting with fever after tropical travel or exposure to chronic carrier
ETIOLOGY
S. typhi
DIAGNOSIS
SIGNS AND SYMPTOMS
• Fever
• Headache
• Malaise
• Abdominal discomfort/bloating/constipation
• Diarrhea (less common)
• Dry cough
• Confusion/lethargy
• Rose spot (transient erythematous maculopapular rash in anterior thorax or upper abdomen)
• Splenomegaly
• Hepatomegaly
• Cervical adenopathy
• Relative bradycardia
• Conjunctivitis
History
Travel and exposure
Physical Exam
Constitutionally unwell, fever, relative bradycardia, Rose spots, abdominal pain, hepato-splenmegaly
TESTS
Lab
• Definitive diagnosis by isolation of S. typhi from blood. Isolation of S. typhi in sputum, urine, or stool is presumptive diagnosis in typical clinical presentation.
• Serology is nonspecific and usually not useful.
• If multiple blood cultures have negative result or in patients with prior antibiotic therapy, diagnostic yield is better with bone marrow culture.
• Anemia, leukopenia (neutropenia), thrombocytopenia, or evidence of disseminated intravascular coagulopathy are supportive evidence. Elevated liver enzyme levels are commonly found.
• Drugs that may alter lab results
- Prior antibiotic therapy
- Vaccination
Imaging
Consider serial plain abdominal films for evidence of intestinal perforation.
Diagnostic Procedures/Surgery
Bone marrow for culture is rarely indicated
Pathological Findings
Classically, mononuclear proliferation involving lymphoid tissue of intestinal tract, especially Peyer patch in terminal ileum
DIFFERENTIAL DIAGNOSIS
• Malaria
• "Enteric fever-like" syndrome caused by Yersinia enterocolitica, pseudotuberculosis, and Campylobacter spp.
• Enteric fever caused by nontyphoid Salmonella spp.
• Infectious hepatitis
• Atypical pneumonia
• Infectious mononucleosis
• Subacute bacterial endocarditis
• Tuberculosis
• Brucellosis
• Q fever
• toxoplasmosis
• Viral infections: Epstein-Barr virus, cytomegalovirus, viral hemorrhagic agents
TREATMENT
STABILIZATION
• Inpatient if acutely ill
• Outpatient for less-ill patient or for carrier
GENERAL MEASURES
• Fluid and electrolyte support
• Strict isolation of patient's linen, stool, and urine
• Monitor clinically and consider serial plain abdominal films for evidence of perforation, usually in the 3rd-4th week of illness.
• Indication for treatment must be determined on an individual basis. Factors to be considered are age, public health risk (e.g., food handler, chronic care facilities, medical personnel), intolerance to antibiotics, and evidence of biliary tract disease.
• For hemorrhage: Blood transfusion and management of shock
Diet
If abdominal symptoms severe, nothing by mouth. With improvement, normal low-residue diet, possibly high calorie
Activity
Bed rest initially, then as tolerated
Nursing
Observe enteric precautions.
MEDICATION (DRUGS)
First Line
• Chloramphenicol: Pediatric 50 mg/kg/d PO q.i.d. 2 weeks; adult dose 50 mg/kg/d, divided q6h 2 weeks; or
• Ampicillin: Pediatric 100 mg/kg/d q.i.d. PO 2 weeks; adults 500 mg q6h 2 weeks; or
• Ciprofloxacin: 500 mg PO b.i.d. 2 weeks, indicated in multiple drug-resistant typhoid, has been successfully and safely used in children; or
• Ceftriaxone: 1-2 g IV once daily 2 weeks; or
• Furazolidone: 7.5 mg/kg/d PO 10 days; in uncomplicated multiple drug-resistant typhoid; safe in children; efficacy >85% cure
• Chronic carrier state:
- Ampicillin: 4-5 g/d + probenecid 2 g/d q.i.d. 6 weeks (for patients with normally functioning gallbladder without evidence of cholelithiasis)
- Ciprofloxacin: 500 mg PO b.i.d. 4-6 weeks is also efficacious. NOTE: Chloramphenicol resistance has been reported in Mexico, South America, Central America, Southeast Asia, India, Pakistan, Middle East, and Africa.
• Contraindications: Refer to the manufacturer's profile for each drug.
• Precautions: Rarely, Jarisch-Herxheimer reaction appears after antimicrobial therapy.
• Significant possible interactions: Refer to the manufacturer's profile for each drug.
Second Line
Trimethoprim-sulfamethoxazole
ALERT
Pregnancy Considerations
Ciprofloxacin therapy is relatively contraindicated in pregnant patients.
SURGERY
• Complications: Bowel perforation
• Cholecystectomy may be warranted in carriers with cholelithiasis, relapse after therapy, or intolerance to antimicrobial therapy.
FOLLOW-UP
DISPOSITION
Admission Criteria
Clinical severity
Issues for Referral
Complications of sepsis, bowel perforation
PROGNOSIS
Overall prognosis good with therapy; 2% mortality rate; 15% relapse rate with some antibiotic treatments; 3% bowel perforation
COMPLICATIONS
• Intestinal hemorrhage and perforation in distal ileum
• Patients may become chronic carriers (up to 3%), defined as persistent stool excretor for longer than 1 year
• Predilection for seeding in the biliary tract exists and may become a focus for relapse of typhoid fever. Most common in females and the elderly (>50 years old).
• Osteomyelitis found especially in patients with sickle cell anemia, systemic lupus erythematosus, hematologic neoplasms, and in immunosuppressed hosts
• Endovascular infection in the elderly and in patients with history of bypass operation or aneurysm
• Rarely, endocarditis or meningitis
PATIENT MONITORING
See "General Measures."
REFERENCES
1. Crump JA, et al. Estimating the incidence of typhoid fever and other febrile illnesses in developing countries. Emerg Infect Dis. 2003; Available at: http://www.cdc.gov/ncidod/EID/vol9no5/02-0428.htm. Accessed June 18, 2006.
2. Dick L. Travel medicine: helping patients prepare for trips abroad. Am Fam Physician. 1998;58:383-398, 401-402.
3. Mandell GL. Principles and Practice of Infectious Diseases. 6th ed. New York, NY: Churchill Livingstone; 2004.
4. Peter G, et al. Lessons learned from a review of the development of selected vaccines. Pediatrics. 1999;104:942-950.
5. Rowe B, Ward LR, Threlfall EJ. Multidrug-resistant Salmonella typhi: A worldwide epidemic. Clin Infect Dis. 1997;24(suppl 1):S106-S109.
6. Thompson RF, Bass DM, Hoffman SL. Travel vaccines. Infect Dis Clin North Amer. 1999;13:49-67.
7. Yoon J, Segal-Maurer S, Rahal JJ. An outbreak of domestically acquired typhoid fever in Queens, NY. Arch Intern Med. 2004;164:565-567.
8. Centers for Disease Control and Prevention. Typhoid Fever. (dated January 10, 2005). Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/files/typhoid_fever_FAQ.pdf
TURNER SYNDROME
TURNER SYNDROME - Katrina Carter, MD
BASICS
DESCRIPTION
• Most common sex chromosome abnormality in females
• Usually absence of one X chromosome, resulting in an XO genotype
• Edema of hands, feet, and excess skin of the neck (e.g., webbing) are presenting features during infancy.
• As children, girls are short and may have left-sided heart or aortic abnormalities.
• Primary amenorrhea and delayed onset of puberty with short stature are important clues during adolescence.
• System(s) Affected: Cardiovascular; Endocrine/Metabolic; Musculoskeletal; Nervous; Renal/Urologic; Reproductive
• Synonym(s): Ullrich-Turner syndrome; Bonnevie-Ullrich syndrome, XO syndrome, Monosomy X; Short stature; Sexual infantilism; Gonadal dysgenesis
GENERAL PREVENTION
Prenatal detection is available for high-risk couples (who carry chromosomal translocations or who have had an affected child). No in utero treatment exists, but pregnancy termination is an option if a fetus with Turner syndrome is identified.
EPIDEMIOLOGY
• Predominant age: All ages
• Predominant sex: Female only
Incidence
• 1/1,900 live female births
• 3% of all females conceived
• Accounts for 15% of all spontaneously aborted fetuses (1)
RISK FACTORS
Familial chromosome translocations involving the X chromosome increase the risk of conceiving a child with Turner syndrome.
Genetics
• Usually sporadic deletion
• Usually a deletion of one X chromosome in a female, but may be a deletion of the SRY portion of a Y chromosome in a male. With the SRY portion of the Y gene missing, these individuals develop as females. (1)
ETIOLOGY
Monosomy for all or part of the X chromosome can result in symptoms consistent with Turner syndrome.
ASSOCIATED CONDITIONS
• Hashimoto thyroiditis
• Hypothyroidism
• Alopecia
• Vitiligo
• Gastrointestinal vascular malformations
• Gastrointestinal disorders
• Carbohydrate intolerance
• Aortic dissection in adults
• Deafness
DIAGNOSIS
SIGNS AND SYMPTOMS
Frequencies are for classic 45, X and vary with other chromosomal abnormalities associated with Turner syndrome:
• Short stature (98%)
• Gonadal dysgenesis (95%)
• Lymphedema of hands and feet present at birth (70%)
• Broad chest (75%)
• Hypoplastic, widely spaced nipples (78%)
• Prominent, anomalous ears with hearing impairment (70%)
• High palate (82%)
• Short neck (80%)
• Webbing of neck (65%)
• Low hairline (80%)
• Cubitus valgus (75%)
• Short 4th metacarpal (65%)
• Nail hypoplasia (75%)
• Excess nevi (70%)
• Renal anomalies (60%)
• Cardiovascular abnormalities (30%)
• Ocular abnormalities
• CNS abnormalities
TESTS
Upper-/lower-extremity BP
Lab
• Chromosome analysis: A buccal smear is not adequate to rule out diagnosis of Turner syndrome, An analysis of at least 20 cells is required, if history and physical exam is highly suspicious, an analysys from 2 cell types should be done, such as from blood and skin.
• At puberty, follicle-stimulating hormone (FSH) and luteinizing hormone levels may approach levels consistent with absence of ovaries. FSH may be transiently high in infancy.
• High incidence of thyroid problems should prompt evaluation of thyroid function annually
Imaging
• Renal ultrasound
• Cardiac ultrasound
• ECG
Pathological Findings
• Ovarian dysgenesis (>90%): Streak gonads, atretic follicles, or no follicles present
• Renal: Horseshoe kidney, double collecting system (60%)
• Cardiac: Bicuspid aortic valve, coarctation of aorta, valvular aortic stenosis (70% of patients with heart defects also have coarctation), hypertension
• Bone dysplasia (>50%), osteoporosis
• Gonadoblastomas in patients with X/XY mosaicism
• Ocular abnormalities: Amblyopia, ptosis, strabismus, red/green color blindness
• Gastrointestinal: Increased incidence of Celiac Disease
• CNS abnormalities: Attention deficit hyperactivity disorder (ADHD), decreased visuospatial organization
DIFFERENTIAL DIAGNOSIS
• Short stature
- Noonan syndrome
- Hypothyroidism
- Familial short stature
- Dyschondrosteosis (Leri-Weill syndrome)
- Brachydactyly E
- Growth hormone deficiency
- Glucocorticoid excess
- Klippel-Feil anomaly
- Short stature due to chronic disease
• Amenorrhea or delayed puberty
- Pure gonadal dysgenesis
- Polycystic ovary syndrome (Stein-Leventhal syndrome)
- Primary/secondary amenorrhea
• Lymphedema
- Hereditary congenital lymphedema
- Milroy disease
- Lymphedema with recurrent cholestasis
- Lymphedema with intestinal lymphangiectasia
• Other
- Multiple pterygium syndrome
- Pseudohypoparathyroid
TREATMENT
STABILIZATION
Outpatient
GENERAL MEASURES
After diagnosis has been confirmed by karyotype, the following measures are appropriate
• Cardiology evaluation to include upper- and lower-extremity BPs, and ECG. If an abnormality exists, prophylactic antibiotics may be indicated (e.g., in cases of dental procedures).
• Renal ultrasound or IV pyelography
• Thyroid function test and antithyroid antibodies
• Routine hearing examination
• Treat gonadal failure in girls who do not enter puberty spontaneously
- Replacement therapy: Begin with 1-2 years of low-dose estrogen, followed by larger-dose estrogens cycled with progesterone.
- Maintenance therapy: Birth control pills, after menses onset and secondary sexual characteristics are established. Continue into patient's 5th decade.
- Routine gynecologic evaluation is indicated.
- Infertility is the general rule, 2% are able to conceive spontaneously (1), but alternatives such as in vitro fertilization and embryo transfer may be options.
- High risk of maternal mortality secondary to cardiac complications during pregnancy. Aortic root dimensions must be monitored throughout pregnancy by ECG.
• Growth retardation has been managed with sex hormone replacement, anabolic agents, and human recombinant growth hormone (hrGH). Some patients increase final height attainment with hrGH treatment. Start hrGH therapy (0.05 mg/kg SC once daily) before significant growth deceleration occurs (between 3 and 10 years of age).
• Intelligence is usually normal. Problems may exist in nonverbal areas such as evaluating objects in relationship to one another. If concerns about school performance arise, patients should be evaluated and treated. May be at increased incidence for ADHD. (1)
• Regular visits to primary care physician are recommended. Be aware of the social and emotional problems associated with issues such as short stature and infertility.
Diet
Normal, but tendency toward obesity ought to be considered
Activity
Usually normal with no restrictions except specific limitations that may be placed if associated with certain cardiac or renal abnormalities
SURGERY
• Removal of gonads is needed in patients with X/XY syndrome/mosaicism.
• Physical appearance may be enhanced by reconstructive surgery for inner canthal folds, protruding auricles, and webbed neck
FOLLOW-UP
PROGNOSIS
Most girls with Turner syndrome can be expected to lead reasonably normal lives with appropriate medical management.
COMPLICATIONS
Complications are related to associated abnormalities.
PATIENT MONITORING
• Regularly measure growth parameters.
• Check BP regularly.
• Get annual urinalysis if renal abnormality is present.
• Monitor for signs of hypothyroidism, annual thyroid-stimulating hormone
• Regular hearing testing
• Regular eye exams
• Consider screening for occult blood loss.
• Regular cardiac exams with sonography of the aortic root in adult women
REFERENCES
1. Tyler C. Down syndrome, Turner's syndrome, and Klinefelter's syndrome: Primary care throughout the life span. Primary Care Clinics in Office Practice. 2004;31:627-648.
2. Frias JL, Davenport ML. The Committee on Genetics and the Section on Endocrinology. Health supervision for children with Turner syndrome. Pediatrics. 2003;111:692-702.
3. Hall JG, Gilchrist DM. Turner's syndrome and its variants. Pediatr Clin North Amer. 1990;37:1421-1440.
4. Jones KL. Smith's Recognizable Patterns of Human Malformation. Philadelphia, PA: WB Saunders; 1997.
5. Ranke MB, Saenger P. Turner's syndrome. Lancet. 2001;358:309-314.
6. Sanger P. Turner syndrome. N Engl J Med. 1996;335:1749-1754.
MISCELLANEOUS
See also: Amenorrhea; Coarctation of the aorta; Hypothyroidism, adult; Thyroiditis
BASICS
DESCRIPTION
• Most common sex chromosome abnormality in females
• Usually absence of one X chromosome, resulting in an XO genotype
• Edema of hands, feet, and excess skin of the neck (e.g., webbing) are presenting features during infancy.
• As children, girls are short and may have left-sided heart or aortic abnormalities.
• Primary amenorrhea and delayed onset of puberty with short stature are important clues during adolescence.
• System(s) Affected: Cardiovascular; Endocrine/Metabolic; Musculoskeletal; Nervous; Renal/Urologic; Reproductive
• Synonym(s): Ullrich-Turner syndrome; Bonnevie-Ullrich syndrome, XO syndrome, Monosomy X; Short stature; Sexual infantilism; Gonadal dysgenesis
GENERAL PREVENTION
Prenatal detection is available for high-risk couples (who carry chromosomal translocations or who have had an affected child). No in utero treatment exists, but pregnancy termination is an option if a fetus with Turner syndrome is identified.
EPIDEMIOLOGY
• Predominant age: All ages
• Predominant sex: Female only
Incidence
• 1/1,900 live female births
• 3% of all females conceived
• Accounts for 15% of all spontaneously aborted fetuses (1)
RISK FACTORS
Familial chromosome translocations involving the X chromosome increase the risk of conceiving a child with Turner syndrome.
Genetics
• Usually sporadic deletion
• Usually a deletion of one X chromosome in a female, but may be a deletion of the SRY portion of a Y chromosome in a male. With the SRY portion of the Y gene missing, these individuals develop as females. (1)
ETIOLOGY
Monosomy for all or part of the X chromosome can result in symptoms consistent with Turner syndrome.
ASSOCIATED CONDITIONS
• Hashimoto thyroiditis
• Hypothyroidism
• Alopecia
• Vitiligo
• Gastrointestinal vascular malformations
• Gastrointestinal disorders
• Carbohydrate intolerance
• Aortic dissection in adults
• Deafness
DIAGNOSIS
SIGNS AND SYMPTOMS
Frequencies are for classic 45, X and vary with other chromosomal abnormalities associated with Turner syndrome:
• Short stature (98%)
• Gonadal dysgenesis (95%)
• Lymphedema of hands and feet present at birth (70%)
• Broad chest (75%)
• Hypoplastic, widely spaced nipples (78%)
• Prominent, anomalous ears with hearing impairment (70%)
• High palate (82%)
• Short neck (80%)
• Webbing of neck (65%)
• Low hairline (80%)
• Cubitus valgus (75%)
• Short 4th metacarpal (65%)
• Nail hypoplasia (75%)
• Excess nevi (70%)
• Renal anomalies (60%)
• Cardiovascular abnormalities (30%)
• Ocular abnormalities
• CNS abnormalities
TESTS
Upper-/lower-extremity BP
Lab
• Chromosome analysis: A buccal smear is not adequate to rule out diagnosis of Turner syndrome, An analysis of at least 20 cells is required, if history and physical exam is highly suspicious, an analysys from 2 cell types should be done, such as from blood and skin.
• At puberty, follicle-stimulating hormone (FSH) and luteinizing hormone levels may approach levels consistent with absence of ovaries. FSH may be transiently high in infancy.
• High incidence of thyroid problems should prompt evaluation of thyroid function annually
Imaging
• Renal ultrasound
• Cardiac ultrasound
• ECG
Pathological Findings
• Ovarian dysgenesis (>90%): Streak gonads, atretic follicles, or no follicles present
• Renal: Horseshoe kidney, double collecting system (60%)
• Cardiac: Bicuspid aortic valve, coarctation of aorta, valvular aortic stenosis (70% of patients with heart defects also have coarctation), hypertension
• Bone dysplasia (>50%), osteoporosis
• Gonadoblastomas in patients with X/XY mosaicism
• Ocular abnormalities: Amblyopia, ptosis, strabismus, red/green color blindness
• Gastrointestinal: Increased incidence of Celiac Disease
• CNS abnormalities: Attention deficit hyperactivity disorder (ADHD), decreased visuospatial organization
DIFFERENTIAL DIAGNOSIS
• Short stature
- Noonan syndrome
- Hypothyroidism
- Familial short stature
- Dyschondrosteosis (Leri-Weill syndrome)
- Brachydactyly E
- Growth hormone deficiency
- Glucocorticoid excess
- Klippel-Feil anomaly
- Short stature due to chronic disease
• Amenorrhea or delayed puberty
- Pure gonadal dysgenesis
- Polycystic ovary syndrome (Stein-Leventhal syndrome)
- Primary/secondary amenorrhea
• Lymphedema
- Hereditary congenital lymphedema
- Milroy disease
- Lymphedema with recurrent cholestasis
- Lymphedema with intestinal lymphangiectasia
• Other
- Multiple pterygium syndrome
- Pseudohypoparathyroid
TREATMENT
STABILIZATION
Outpatient
GENERAL MEASURES
After diagnosis has been confirmed by karyotype, the following measures are appropriate
• Cardiology evaluation to include upper- and lower-extremity BPs, and ECG. If an abnormality exists, prophylactic antibiotics may be indicated (e.g., in cases of dental procedures).
• Renal ultrasound or IV pyelography
• Thyroid function test and antithyroid antibodies
• Routine hearing examination
• Treat gonadal failure in girls who do not enter puberty spontaneously
- Replacement therapy: Begin with 1-2 years of low-dose estrogen, followed by larger-dose estrogens cycled with progesterone.
- Maintenance therapy: Birth control pills, after menses onset and secondary sexual characteristics are established. Continue into patient's 5th decade.
- Routine gynecologic evaluation is indicated.
- Infertility is the general rule, 2% are able to conceive spontaneously (1), but alternatives such as in vitro fertilization and embryo transfer may be options.
- High risk of maternal mortality secondary to cardiac complications during pregnancy. Aortic root dimensions must be monitored throughout pregnancy by ECG.
• Growth retardation has been managed with sex hormone replacement, anabolic agents, and human recombinant growth hormone (hrGH). Some patients increase final height attainment with hrGH treatment. Start hrGH therapy (0.05 mg/kg SC once daily) before significant growth deceleration occurs (between 3 and 10 years of age).
• Intelligence is usually normal. Problems may exist in nonverbal areas such as evaluating objects in relationship to one another. If concerns about school performance arise, patients should be evaluated and treated. May be at increased incidence for ADHD. (1)
• Regular visits to primary care physician are recommended. Be aware of the social and emotional problems associated with issues such as short stature and infertility.
Diet
Normal, but tendency toward obesity ought to be considered
Activity
Usually normal with no restrictions except specific limitations that may be placed if associated with certain cardiac or renal abnormalities
SURGERY
• Removal of gonads is needed in patients with X/XY syndrome/mosaicism.
• Physical appearance may be enhanced by reconstructive surgery for inner canthal folds, protruding auricles, and webbed neck
FOLLOW-UP
PROGNOSIS
Most girls with Turner syndrome can be expected to lead reasonably normal lives with appropriate medical management.
COMPLICATIONS
Complications are related to associated abnormalities.
PATIENT MONITORING
• Regularly measure growth parameters.
• Check BP regularly.
• Get annual urinalysis if renal abnormality is present.
• Monitor for signs of hypothyroidism, annual thyroid-stimulating hormone
• Regular hearing testing
• Regular eye exams
• Consider screening for occult blood loss.
• Regular cardiac exams with sonography of the aortic root in adult women
REFERENCES
1. Tyler C. Down syndrome, Turner's syndrome, and Klinefelter's syndrome: Primary care throughout the life span. Primary Care Clinics in Office Practice. 2004;31:627-648.
2. Frias JL, Davenport ML. The Committee on Genetics and the Section on Endocrinology. Health supervision for children with Turner syndrome. Pediatrics. 2003;111:692-702.
3. Hall JG, Gilchrist DM. Turner's syndrome and its variants. Pediatr Clin North Amer. 1990;37:1421-1440.
4. Jones KL. Smith's Recognizable Patterns of Human Malformation. Philadelphia, PA: WB Saunders; 1997.
5. Ranke MB, Saenger P. Turner's syndrome. Lancet. 2001;358:309-314.
6. Sanger P. Turner syndrome. N Engl J Med. 1996;335:1749-1754.
MISCELLANEOUS
See also: Amenorrhea; Coarctation of the aorta; Hypothyroidism, adult; Thyroiditis
TULAREMIA
TULAREMIA - Omar A. Khan, MD, MHS
BASICS
DESCRIPTION
• Zoonotic infection caused by 2 subspecies of Francisella tularensis(subsp. tularensis and holarctica).
• Incubation averages 3-4 days; range, 1-21 days. May be ulceroglandular, glandular, typhoidal, oculoglandular, or oropharyngeal in manifestation
• System(s) Affected: Cardiovascular; Hemic/Lymphatic/Immunologic; Pulmonary; Skin/Exocrine
• Synonym(s): Rabbit fever; Deer-fly fever; Pasteurella tularensis; Bacterium tularense; Tick fever; Ohara disease; Francis disease
GENERAL PREVENTION
• Wear tick repellents.
• Avoid contact with material (e.g., water) that may have been in contact with infected animals.
• Remove tick by grasping near its mouth parts.
• Avoid squeezing body of engorged tick.
• Wear gloves while handling game and other animals, especially rabbits and rodents.
• Cook wild game thoroughly.
• Lab workers. Wear protective hoods and use negative-pressure cabinets when working with F. tularensis. Follow Biosafety Level 3 precautions
• A live attenuated vaccine applied intradermally to high-risk individuals (e.g., military personnel) is not available for general use.
EPIDEMIOLOGY
• Predominant age: All ages; more likely to occur in young adults with outdoor interests
• Predominant sex: Male Female
Incidence
0.1/100,000; high rate of asymptomatic infection in endemic areas
Prevalence
~200 cases reported annually in US; likely an under-reported disease.
RISK FACTORS
• Location in endemic area; 50% of US cases in Arkansas, Missouri, Oklahoma, Tennessee, and Texas; also in South Dakota, Montana, Kansas, Colorado, and Illinois
• Non-US cases occur in Eastern Europe, China, Japan, and northern Europe, with predilection for rural areas.
• Outdoor work
• Rural residence
• Handling wild game or infected hay
• Laboratory work with the causative organism
PATHOPHYSIOLOGY
• Acquired through arthropod, fly, or mosquito vector (see "Etiology").
• Depending on route of infection, may cause a respiratory illness septicemia, or local ulceration and lymphadenopathy.
• Of the 2 subspecies, tularensis is more virulent than holarctica.
ETIOLOGY
Inoculation of F. tularensis via
• Tick bite (most common)
• Deer fly (Chrysops) bite (less common than via tick bites)
• Mosquitoes, especially in Eastern Europe
• Aerosol inhalation, from contaminated dust, hay, or pelts
• Contact of skin or mucous membranes with blood or tissue of infected carcass (e.g., pathogen can penetrate unbroken skin)
• Ingestion of undercooked meat of infected animals
• Ingestion of contaminated water
• Laboratory-acquired infections (usually respiratory)
ASSOCIATED CONDITIONS
• Other arthropod-borne diseases
• Tularemic conjunctivitis
• Bacteremia/septicemia
• Lymphadenopathy
• Pneumonia
DIAGNOSIS
SIGNS AND SYMPTOMS
• Nearly all patients suffer fever, chills, fatigue, and malaise; rash/ulcer may be present.
• Ulceroglandular at bite site (75% of cases)
- Nonhealing ulcer
- Regional adenopathy
• Glandular
- Localized adenopathy, sometimes suppurative
- Usually no ulcer
• Typhoidal
- Systemic febrile illness
- Fulminating sepsis
- Pleuropulmonary disease
- Usually no ulcer
• Oropharyngeal
- Exudative pharyngitis
- Gastrointestinal symptoms
- Cervical adenopathy
• Oculoglandular
- Purulent conjunctivitis
- Regional adenopathy
History
• Thorough history of patient's contact with known vectors, reservoirs (e.g., game animals, wild rodents), lab exposure, or exposure to infected materials such as water or hay Social history including place of residence and leisure activities
• Travel history focusing on known risk factors and countries/states of high prevalence
Physical Exam
Focused exam based on symptoms
• Presence of fever
• Skin: Look for nonhealing ulcer
• Eyes: Conjunctivitis
• Throat: Pharyngitis
• Gastrointestinal: If nausea, vomiting, diarrhea
• Lymphatic system: Lymphadenopathy
• Pulmonary: Findings suggestive of pneumonia
TESTS
• Referral to specialized lab for ELISA-based serological testing or polymerase chain reaction (PCR)
• Pleomorphic Gram-negative coccobacilli
• Culture of ulcer exudate (2 distinct varieties of the organism exist)
- Jellison Type A biovar tularensis is more virulent and is prevalent in North America.
- Jellison Type B biovar holarctica is less virulent and is prevalent in Europe and Asia.
Lab
• 4-fold rise in antibody titer (peak, 4-8 weeks)
• Convalescent titer of 160
• Elevated ESR
• Normal leukocyte count, left shift
• PCR, if available
• Disorders that may alter lab results: Brucella antibodies may cross-react
• ELISA-based serologic testing is more specific.
Imaging
Chest radiograph may show ill-defined infiltrates, lobar consolidation, or pleural effusion.
Diagnostic Procedures/Surgery
• Lymph node aspiration done once antibiotic therapy has been started to avoid bacteremia
• Thoracentesis
• Extreme care should be taken when handling infected material due to concern for aerosolization.
Pathological Findings
• Necrotic areas in liver, spleen, and other organs
• Caseating granulomata
• Microscopic foci with polymorphonuclear leukocytes, macrophages, giant cells
DIFFERENTIAL DIAGNOSIS
• Ulceroglandular/glandular
- Staphylococcal infections
- Streptococcal infections
- Cat-scratch disease
- Lymphoma
- Pasteurella infections
- Lymphogranuloma venereum
- Sporotrichosis
- Anthrax
- Plague
- Toxoplasmosis
• Typhoidal
- Legionellosis
- Rocky Mountain spotted fever
- Ehrlichiosis
- Borreliosis (including Lyme disease)
- Infectious mononucleosis
- Nontyphoid salmonellosis
- Typhoid fever
- Brucellosis
- Q fever
- Psittacosis
- Tick-borne typhus
- Viral pneumonia
- Tuberculosis
• Oropharyngeal
- Streptococcal pharyngitis
- Viral pharyngitis
- Diphtheric pharyngitis
- Infectious mononucleosis
• Oculoglandular
- Bacterial (e.g., gonorrheal) or viral (e.g., HSV) conjunctivitis
TREATMENT
STABILIZATION
Inpatient or outpatient, depending on severity
GENERAL MEASURES
• Isolation not needed for patient, but handle secretions carefully
• Hydration, fever control, antibiotics
• Wet saline dressings for skin lesions
• Recovery requires intact cell-mediated immunity
• Bacterium is readily killed off by heat (56C for 10 minutes). May remain viable frozen 3 years
Diet
As tolerated, high calorie, easily digestible
Nursing
Monitor for fever or shortness of breath (pneumonia risk) or septicemia
MEDICATION (DRUGS)
First Line
• Aminoglycosides (streptomycin or gentamicin) are the antimicrobials of choice
- Streptomycin: 15-20 mg/kg/d IM, divided b.i.d., for 7-14 days, not to exceed 2 g/d
- Gentamicin: 3-5 mg/kg/d; divided b.i.d. dosing may be possible.
- Fluoroquinolones are gaining acceptance, and may be used as alternative therapy.
• Contraindications
- Known hypersensitivity, pregnancy
- Doxycycline or ciprofloxacin are considered drugs of choice in mass-casualty situation (e.g., biowarfare). Prophylactic use in postexposure period is suggested
• Precautions
- Long-term therapy may damage the 8th cranial nerve.
- Reduce dosage in patients with known renal dysfunction.
- Long-term therapy may induce renal dysfunction.
- Use cautiously, with care postanesthesia (respiratory paralysis), and in patients with myasthenia gravis.
• Significant possible interactions
- Other aminoglycosides, cephaloridine, polymyxin B, amphotericin B, colistin, muscle relaxants, paralyzing anesthetic agents
• -Lactams (e.g., penicillin derivatives), most cephalosporins, and many macrolides are ineffective or have resistance.
Second Line
• Chloramphenicol: May be difficult to obtain
• Tetracyclines: Higher relapse rate
• Postexposure prophylaxis (effective if administered within 24 hours of an aerosol exposure in a mass-casualty situation)
- Ciprofloxacin: 500 mg PO b.i.d. for 10 days
- Doxycycline (Doryx, Vibra-Tabs, Vibramycin): 100 mg PO b.i.d. for 14-21 days
ALERT
Pregnancy Considerations
Aminoglycosides and quinolones all carry cautions for use in pregnant or pediatric patients
SURGERY
Incision and drainage of abscesses if needed
FOLLOW-UP
DISPOSITION
Admission Criteria
• Fever with shortness of breath
• Concern for septicemia
• Need for surgery
• Risk of biowarfare
Discharge Criteria
• Improvement in symptoms
• Ability to tolerate oral antibiotics
• Compliance
Issues for Referral
• Considered infectious disease referral
• Appropriate public health authority (e.g., state, CDC, WHO) notified of suspected cases
PROGNOSIS
• Cure, if disorder is treated early and vigorously
• Immunity is life-long
• Mortality: 1-3%, higher in typhoidal disease
COMPLICATIONS
• Lung abscess
• Adult respiratory distress syndrome
• Hepatic dysfunction
• Rhabdomyolysis
• Renal failure
• Osteomyelitis, meningitis, endocarditis, pericarditis, peritonitis, conjunctivitis
• Mediastinitis
• Drug-induced side effects (e.g., diarrhea, renal failure)
PATIENT MONITORING
• Monitor function of 8th cranial nerve during long-term therapy with aminoglycosides.
• Monitor renal function during long-term therapy with aminoglycosides or quinolones.
REFERENCES
1. Eliasson H, Broman T, Forsman M, Back E. Tularemia: Current epidemiology and disease management. Infect Dis Clin North Am. 2006;20(2).
2. Tularemia. In: Darling RG, Woods JB, eds. USAMRIID Medical Management of Biological Casualties Handbook, 5th ed. Fort Detrick, Maryland:, 2004.
3. Sjostedt A. Tularemia. In: Heymann DL, ed. Control of Communicable Diseases Manual. Washington, DC: APHA Press, 2004.
4. Cronquist SD. Tularemia: The disease and the weapon. Dermatol Clin. 2004;22(3):313-320.
5. Farlow J, Wagner DM, Dukerich M, et al. Francisella tularensis in the United States. Emerg Infect Dis. 2005;11(12):1835-1841.
ADDITIONAL READING
Public health response to biological and chemical weapons: WHO guidance. World Health Organization, Geneva, Switzerland, 2004.
MISCELLANEOUS
• See also: Bartonella infections; Diphtheria; Ehrlichiosis; Lymphogranuloma venereum; Plague; Psittacosis; Rocky Mountain spotted fever; Toxoplasmosis; Typhus fevers
• Other notes: Incidence is higher in summer and fall; discussed as a possible bioweapon.
BASICS
DESCRIPTION
• Zoonotic infection caused by 2 subspecies of Francisella tularensis(subsp. tularensis and holarctica).
• Incubation averages 3-4 days; range, 1-21 days. May be ulceroglandular, glandular, typhoidal, oculoglandular, or oropharyngeal in manifestation
• System(s) Affected: Cardiovascular; Hemic/Lymphatic/Immunologic; Pulmonary; Skin/Exocrine
• Synonym(s): Rabbit fever; Deer-fly fever; Pasteurella tularensis; Bacterium tularense; Tick fever; Ohara disease; Francis disease
GENERAL PREVENTION
• Wear tick repellents.
• Avoid contact with material (e.g., water) that may have been in contact with infected animals.
• Remove tick by grasping near its mouth parts.
• Avoid squeezing body of engorged tick.
• Wear gloves while handling game and other animals, especially rabbits and rodents.
• Cook wild game thoroughly.
• Lab workers. Wear protective hoods and use negative-pressure cabinets when working with F. tularensis. Follow Biosafety Level 3 precautions
• A live attenuated vaccine applied intradermally to high-risk individuals (e.g., military personnel) is not available for general use.
EPIDEMIOLOGY
• Predominant age: All ages; more likely to occur in young adults with outdoor interests
• Predominant sex: Male Female
Incidence
0.1/100,000; high rate of asymptomatic infection in endemic areas
Prevalence
~200 cases reported annually in US; likely an under-reported disease.
RISK FACTORS
• Location in endemic area; 50% of US cases in Arkansas, Missouri, Oklahoma, Tennessee, and Texas; also in South Dakota, Montana, Kansas, Colorado, and Illinois
• Non-US cases occur in Eastern Europe, China, Japan, and northern Europe, with predilection for rural areas.
• Outdoor work
• Rural residence
• Handling wild game or infected hay
• Laboratory work with the causative organism
PATHOPHYSIOLOGY
• Acquired through arthropod, fly, or mosquito vector (see "Etiology").
• Depending on route of infection, may cause a respiratory illness septicemia, or local ulceration and lymphadenopathy.
• Of the 2 subspecies, tularensis is more virulent than holarctica.
ETIOLOGY
Inoculation of F. tularensis via
• Tick bite (most common)
• Deer fly (Chrysops) bite (less common than via tick bites)
• Mosquitoes, especially in Eastern Europe
• Aerosol inhalation, from contaminated dust, hay, or pelts
• Contact of skin or mucous membranes with blood or tissue of infected carcass (e.g., pathogen can penetrate unbroken skin)
• Ingestion of undercooked meat of infected animals
• Ingestion of contaminated water
• Laboratory-acquired infections (usually respiratory)
ASSOCIATED CONDITIONS
• Other arthropod-borne diseases
• Tularemic conjunctivitis
• Bacteremia/septicemia
• Lymphadenopathy
• Pneumonia
DIAGNOSIS
SIGNS AND SYMPTOMS
• Nearly all patients suffer fever, chills, fatigue, and malaise; rash/ulcer may be present.
• Ulceroglandular at bite site (75% of cases)
- Nonhealing ulcer
- Regional adenopathy
• Glandular
- Localized adenopathy, sometimes suppurative
- Usually no ulcer
• Typhoidal
- Systemic febrile illness
- Fulminating sepsis
- Pleuropulmonary disease
- Usually no ulcer
• Oropharyngeal
- Exudative pharyngitis
- Gastrointestinal symptoms
- Cervical adenopathy
• Oculoglandular
- Purulent conjunctivitis
- Regional adenopathy
History
• Thorough history of patient's contact with known vectors, reservoirs (e.g., game animals, wild rodents), lab exposure, or exposure to infected materials such as water or hay Social history including place of residence and leisure activities
• Travel history focusing on known risk factors and countries/states of high prevalence
Physical Exam
Focused exam based on symptoms
• Presence of fever
• Skin: Look for nonhealing ulcer
• Eyes: Conjunctivitis
• Throat: Pharyngitis
• Gastrointestinal: If nausea, vomiting, diarrhea
• Lymphatic system: Lymphadenopathy
• Pulmonary: Findings suggestive of pneumonia
TESTS
• Referral to specialized lab for ELISA-based serological testing or polymerase chain reaction (PCR)
• Pleomorphic Gram-negative coccobacilli
• Culture of ulcer exudate (2 distinct varieties of the organism exist)
- Jellison Type A biovar tularensis is more virulent and is prevalent in North America.
- Jellison Type B biovar holarctica is less virulent and is prevalent in Europe and Asia.
Lab
• 4-fold rise in antibody titer (peak, 4-8 weeks)
• Convalescent titer of 160
• Elevated ESR
• Normal leukocyte count, left shift
• PCR, if available
• Disorders that may alter lab results: Brucella antibodies may cross-react
• ELISA-based serologic testing is more specific.
Imaging
Chest radiograph may show ill-defined infiltrates, lobar consolidation, or pleural effusion.
Diagnostic Procedures/Surgery
• Lymph node aspiration done once antibiotic therapy has been started to avoid bacteremia
• Thoracentesis
• Extreme care should be taken when handling infected material due to concern for aerosolization.
Pathological Findings
• Necrotic areas in liver, spleen, and other organs
• Caseating granulomata
• Microscopic foci with polymorphonuclear leukocytes, macrophages, giant cells
DIFFERENTIAL DIAGNOSIS
• Ulceroglandular/glandular
- Staphylococcal infections
- Streptococcal infections
- Cat-scratch disease
- Lymphoma
- Pasteurella infections
- Lymphogranuloma venereum
- Sporotrichosis
- Anthrax
- Plague
- Toxoplasmosis
• Typhoidal
- Legionellosis
- Rocky Mountain spotted fever
- Ehrlichiosis
- Borreliosis (including Lyme disease)
- Infectious mononucleosis
- Nontyphoid salmonellosis
- Typhoid fever
- Brucellosis
- Q fever
- Psittacosis
- Tick-borne typhus
- Viral pneumonia
- Tuberculosis
• Oropharyngeal
- Streptococcal pharyngitis
- Viral pharyngitis
- Diphtheric pharyngitis
- Infectious mononucleosis
• Oculoglandular
- Bacterial (e.g., gonorrheal) or viral (e.g., HSV) conjunctivitis
TREATMENT
STABILIZATION
Inpatient or outpatient, depending on severity
GENERAL MEASURES
• Isolation not needed for patient, but handle secretions carefully
• Hydration, fever control, antibiotics
• Wet saline dressings for skin lesions
• Recovery requires intact cell-mediated immunity
• Bacterium is readily killed off by heat (56C for 10 minutes). May remain viable frozen 3 years
Diet
As tolerated, high calorie, easily digestible
Nursing
Monitor for fever or shortness of breath (pneumonia risk) or septicemia
MEDICATION (DRUGS)
First Line
• Aminoglycosides (streptomycin or gentamicin) are the antimicrobials of choice
- Streptomycin: 15-20 mg/kg/d IM, divided b.i.d., for 7-14 days, not to exceed 2 g/d
- Gentamicin: 3-5 mg/kg/d; divided b.i.d. dosing may be possible.
- Fluoroquinolones are gaining acceptance, and may be used as alternative therapy.
• Contraindications
- Known hypersensitivity, pregnancy
- Doxycycline or ciprofloxacin are considered drugs of choice in mass-casualty situation (e.g., biowarfare). Prophylactic use in postexposure period is suggested
• Precautions
- Long-term therapy may damage the 8th cranial nerve.
- Reduce dosage in patients with known renal dysfunction.
- Long-term therapy may induce renal dysfunction.
- Use cautiously, with care postanesthesia (respiratory paralysis), and in patients with myasthenia gravis.
• Significant possible interactions
- Other aminoglycosides, cephaloridine, polymyxin B, amphotericin B, colistin, muscle relaxants, paralyzing anesthetic agents
• -Lactams (e.g., penicillin derivatives), most cephalosporins, and many macrolides are ineffective or have resistance.
Second Line
• Chloramphenicol: May be difficult to obtain
• Tetracyclines: Higher relapse rate
• Postexposure prophylaxis (effective if administered within 24 hours of an aerosol exposure in a mass-casualty situation)
- Ciprofloxacin: 500 mg PO b.i.d. for 10 days
- Doxycycline (Doryx, Vibra-Tabs, Vibramycin): 100 mg PO b.i.d. for 14-21 days
ALERT
Pregnancy Considerations
Aminoglycosides and quinolones all carry cautions for use in pregnant or pediatric patients
SURGERY
Incision and drainage of abscesses if needed
FOLLOW-UP
DISPOSITION
Admission Criteria
• Fever with shortness of breath
• Concern for septicemia
• Need for surgery
• Risk of biowarfare
Discharge Criteria
• Improvement in symptoms
• Ability to tolerate oral antibiotics
• Compliance
Issues for Referral
• Considered infectious disease referral
• Appropriate public health authority (e.g., state, CDC, WHO) notified of suspected cases
PROGNOSIS
• Cure, if disorder is treated early and vigorously
• Immunity is life-long
• Mortality: 1-3%, higher in typhoidal disease
COMPLICATIONS
• Lung abscess
• Adult respiratory distress syndrome
• Hepatic dysfunction
• Rhabdomyolysis
• Renal failure
• Osteomyelitis, meningitis, endocarditis, pericarditis, peritonitis, conjunctivitis
• Mediastinitis
• Drug-induced side effects (e.g., diarrhea, renal failure)
PATIENT MONITORING
• Monitor function of 8th cranial nerve during long-term therapy with aminoglycosides.
• Monitor renal function during long-term therapy with aminoglycosides or quinolones.
REFERENCES
1. Eliasson H, Broman T, Forsman M, Back E. Tularemia: Current epidemiology and disease management. Infect Dis Clin North Am. 2006;20(2).
2. Tularemia. In: Darling RG, Woods JB, eds. USAMRIID Medical Management of Biological Casualties Handbook, 5th ed. Fort Detrick, Maryland:, 2004.
3. Sjostedt A. Tularemia. In: Heymann DL, ed. Control of Communicable Diseases Manual. Washington, DC: APHA Press, 2004.
4. Cronquist SD. Tularemia: The disease and the weapon. Dermatol Clin. 2004;22(3):313-320.
5. Farlow J, Wagner DM, Dukerich M, et al. Francisella tularensis in the United States. Emerg Infect Dis. 2005;11(12):1835-1841.
ADDITIONAL READING
Public health response to biological and chemical weapons: WHO guidance. World Health Organization, Geneva, Switzerland, 2004.
MISCELLANEOUS
• See also: Bartonella infections; Diphtheria; Ehrlichiosis; Lymphogranuloma venereum; Plague; Psittacosis; Rocky Mountain spotted fever; Toxoplasmosis; Typhus fevers
• Other notes: Incidence is higher in summer and fall; discussed as a possible bioweapon.
TUBEROUS SCLEROSIS COMPLEX
TUBEROUS SCLEROSIS COMPLEX - Nuhad D. Dinno, MD
BASICS
DESCRIPTION
• 1 of the neurocutaneous syndromes (phakomatoses).
• A genetic developmental disorder with variable presentations, a broad clinical spectrum, and multiorgan involvement.
• Organ system changes may be few and subtle but can encompass multiple types of cutaneous lesions and tumor formation in the CNS, skin, retina, heart, lung, viscera, liver, kidney, bone, teeth, and nails. Other phakomatoses include neurofibromatosis, Sturge-Weber disease, von Hippel-Lindau syndrome, and ataxia-telangiectasia.
• System(s) Affected: Cardiovascular; Musculoskeletal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
• Synonym(s): Bourneville disease
ALERT
Pregnancy Considerations
• Genetic counseling
• Prenatal testing by ultrasonography for tumors is available, but sensitivity is unknown. Prenatal DNA analysis is available to families previously enrolled in a research protocol.
GENERAL PREVENTION
Genetic counseling
EPIDEMIOLOGY
• Predominant age: Clinical expression is variable, so diagnosis may be delayed. Usually diagnosed during the 1st decade of life.
• Predominant sex: Male = Female (but autism more common in male patients)
Prevalence
Reported to affect 1/5,800-1/30,000 in the general population
RISK FACTORS
Family history
Genetics
• Autosomal dominant with variable penetrance
• 2/3 of cases result from new genetic mutations.
• 2 chromosomal loci have been mapped: Tuberous sclerosis complex 1 (locus 9q34) and tuberous sclerosis complex 2 (locus 16p13.3).
ETIOLOGY
Congenital
DIAGNOSIS
SIGNS AND SYMPTOMS
• Most cases have more than one of the following findings
- Angiofibromata (termed adenoma sebaceum and ranging from 0.1-1.0 cm) and often present as facial lesions in a "butterfly" distribution (80%)
- Hypopigmented areas, mainly on trunk and extremities, are often the 1st sign (e.g., ash-leaf spots); present at birth or shortly after (50%)
- Seizure disorders including myoclonic (90%)
- Renal cysts (50-80%)
- Pulmonary lymphangiomatosis (10%)
- CNS periventricular calcifications (50-80%)
- Retinal astrocytomas and hamartomas (50-80%)
- Cardiac rhabdomyomas (50%)
- Mental retardation (60-70%)
- Autism (10-20%)
- Ungual fibromas, multiple (20%)
- Dental pits
- Liver hamartomas (10%)
• Any combination of the above stigmata may be present at, or shortly after, birth or may only become apparent in later childhood or adulthood.
TESTS
Must rely mainly on clinical diagnostic criteria until a reliable molecular marker is found.
Lab
• Abnormal electroencephalographic results
• Research to isolate and determine reliable molecular marker and gene seems promising.
Imaging
• MRI and CT have become primary diagnostic techniques in this disorder.
• With gadolinium enhancement, MRI provides more detailed imaging of characteristic subependymal nodules and cortical white matter tubers.
• Fetal cardiac rhabdomyomas can be seen sonographically during late gestation.
• EEG
• MRI with gadolinium contrast
• Renal CT, ultrasound
• ECG
Diagnostic Procedures/Surgery
• Woods lamp evaluation for ash-leaf spots
• Biopsy of indeterminate lesions
• Molecular testing generally available on research basis only, although now more routinely offered to families with diagnosed tuberous sclerosis complex 1 or tuberous sclerosis complex 2 mutation
• Neurodevelopmental testing as age-appropriate.
• Screening for neurodevelopmental and behavioral difficulties at time of diagnosis
Pathological Findings
• Nodular lesions made up largely of irregular groups of glial fibrils, ganglion cells, and atypical cells thought to result from faults in developing tissue combinations (e.g., hamartomas)
• Lesions may be sparse at birth.
• Calcification of subependymal lesions may not occur until several months after birth.
• Facial angiofibromas, ungual fibromas, and renal angiomyolipomas are specific lesions that may develop months after birth.
• ~1% of affected patients present with tuberous sclerosis lymphangioleiomyomatosis, usually women of reproductive age
• Not practical to have age-specific criteria
DIFFERENTIAL DIAGNOSIS
• Polycystic kidney disease, renal hamartomas
• Other causes of seizure disorders, mental retardation, autistic behavior, or traumatic ungual fibromata
• Other neurocutaneous syndromes (e.g., the phacomatoses)
TREATMENT
STABILIZATION
Outpatient, except for complications for severely involved manifestations or uncontrolled seizures
GENERAL MEASURES
• Team approach with involvement of primary care providers, neurologic, orthopedic, surgical, and radiologic specialists
• Physical, occupational, and speech therapy
• Social workers for home care
• Vocational training support
• Periodic reassessment in at-risk families
• Genetic counseling for patient and family
• Neurosurgical consideration for uncontrollable seizures
Diet
No restrictions. Special diets, such as a ketogenic diet, have been used for seizure control.
Activity
Determined by degree and complexity of involvement
MEDICATION (DRUGS)
First Line
• Anticonvulsants for seizure control
• Antibiotic prophylaxis for surgery if indicated
• Precautions: Refer to the manufacturer's profile for each drug.
• Significant possible interactions: Knowledge of anticonvulsant used is necessary to avoid drug interactions, especially with antibiotics.
• Refer to the manufacturer's profile for each drug.
Second Line
Refer to http://clinicaltrials.gov
SURGERY
Surgical excision of tumors where and when appropriate
FOLLOW-UP
PROGNOSIS
Variable; shortened longevity compared with expectations in general population
COMPLICATIONS
See "Signs and Symptoms."
PATIENT MONITORING
• Clinical features and symptoms should be reviewed and updated periodically.
• Periodic reassessment of at-risk patients
REFERENCES
1. Aicardi J. Tuberous sclerosis. Int Pediatr. 1993;8:2:171-175.
2. Perspective Newsletter, National Tuberous Sclerosis Association, Spring/Summer/Fall/Winter Publications.
3. Roach ES, et al. Tuberous sclerosis consensus conference: Recommendations for diagnostic evaluation. J Child Neurol. 1999;14:401-407.
4. Caldemeyer KS, Mirowski GW. Tuberous sclerosis. Part 1: Clinical and central nervous system findings. J Amer Acad Dermatol. 2001;45:448-449.
5. Baker P, Piven J, Sato Y. Autism and tuberous sclerosis complex: Prevalence and clinical features. J Autism Dev Disord. 1998;28:279-285.
6. Roach ES, Sparagana P. Diagnosis of Tuberous Sclerosis complex. J Child Neurol. 2004(9): 643-649.
MISCELLANEOUS
See also: Neurofibromatosis (Types 1 and 2)
BASICS
DESCRIPTION
• 1 of the neurocutaneous syndromes (phakomatoses).
• A genetic developmental disorder with variable presentations, a broad clinical spectrum, and multiorgan involvement.
• Organ system changes may be few and subtle but can encompass multiple types of cutaneous lesions and tumor formation in the CNS, skin, retina, heart, lung, viscera, liver, kidney, bone, teeth, and nails. Other phakomatoses include neurofibromatosis, Sturge-Weber disease, von Hippel-Lindau syndrome, and ataxia-telangiectasia.
• System(s) Affected: Cardiovascular; Musculoskeletal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
• Synonym(s): Bourneville disease
ALERT
Pregnancy Considerations
• Genetic counseling
• Prenatal testing by ultrasonography for tumors is available, but sensitivity is unknown. Prenatal DNA analysis is available to families previously enrolled in a research protocol.
GENERAL PREVENTION
Genetic counseling
EPIDEMIOLOGY
• Predominant age: Clinical expression is variable, so diagnosis may be delayed. Usually diagnosed during the 1st decade of life.
• Predominant sex: Male = Female (but autism more common in male patients)
Prevalence
Reported to affect 1/5,800-1/30,000 in the general population
RISK FACTORS
Family history
Genetics
• Autosomal dominant with variable penetrance
• 2/3 of cases result from new genetic mutations.
• 2 chromosomal loci have been mapped: Tuberous sclerosis complex 1 (locus 9q34) and tuberous sclerosis complex 2 (locus 16p13.3).
ETIOLOGY
Congenital
DIAGNOSIS
SIGNS AND SYMPTOMS
• Most cases have more than one of the following findings
- Angiofibromata (termed adenoma sebaceum and ranging from 0.1-1.0 cm) and often present as facial lesions in a "butterfly" distribution (80%)
- Hypopigmented areas, mainly on trunk and extremities, are often the 1st sign (e.g., ash-leaf spots); present at birth or shortly after (50%)
- Seizure disorders including myoclonic (90%)
- Renal cysts (50-80%)
- Pulmonary lymphangiomatosis (10%)
- CNS periventricular calcifications (50-80%)
- Retinal astrocytomas and hamartomas (50-80%)
- Cardiac rhabdomyomas (50%)
- Mental retardation (60-70%)
- Autism (10-20%)
- Ungual fibromas, multiple (20%)
- Dental pits
- Liver hamartomas (10%)
• Any combination of the above stigmata may be present at, or shortly after, birth or may only become apparent in later childhood or adulthood.
TESTS
Must rely mainly on clinical diagnostic criteria until a reliable molecular marker is found.
Lab
• Abnormal electroencephalographic results
• Research to isolate and determine reliable molecular marker and gene seems promising.
Imaging
• MRI and CT have become primary diagnostic techniques in this disorder.
• With gadolinium enhancement, MRI provides more detailed imaging of characteristic subependymal nodules and cortical white matter tubers.
• Fetal cardiac rhabdomyomas can be seen sonographically during late gestation.
• EEG
• MRI with gadolinium contrast
• Renal CT, ultrasound
• ECG
Diagnostic Procedures/Surgery
• Woods lamp evaluation for ash-leaf spots
• Biopsy of indeterminate lesions
• Molecular testing generally available on research basis only, although now more routinely offered to families with diagnosed tuberous sclerosis complex 1 or tuberous sclerosis complex 2 mutation
• Neurodevelopmental testing as age-appropriate.
• Screening for neurodevelopmental and behavioral difficulties at time of diagnosis
Pathological Findings
• Nodular lesions made up largely of irregular groups of glial fibrils, ganglion cells, and atypical cells thought to result from faults in developing tissue combinations (e.g., hamartomas)
• Lesions may be sparse at birth.
• Calcification of subependymal lesions may not occur until several months after birth.
• Facial angiofibromas, ungual fibromas, and renal angiomyolipomas are specific lesions that may develop months after birth.
• ~1% of affected patients present with tuberous sclerosis lymphangioleiomyomatosis, usually women of reproductive age
• Not practical to have age-specific criteria
DIFFERENTIAL DIAGNOSIS
• Polycystic kidney disease, renal hamartomas
• Other causes of seizure disorders, mental retardation, autistic behavior, or traumatic ungual fibromata
• Other neurocutaneous syndromes (e.g., the phacomatoses)
TREATMENT
STABILIZATION
Outpatient, except for complications for severely involved manifestations or uncontrolled seizures
GENERAL MEASURES
• Team approach with involvement of primary care providers, neurologic, orthopedic, surgical, and radiologic specialists
• Physical, occupational, and speech therapy
• Social workers for home care
• Vocational training support
• Periodic reassessment in at-risk families
• Genetic counseling for patient and family
• Neurosurgical consideration for uncontrollable seizures
Diet
No restrictions. Special diets, such as a ketogenic diet, have been used for seizure control.
Activity
Determined by degree and complexity of involvement
MEDICATION (DRUGS)
First Line
• Anticonvulsants for seizure control
• Antibiotic prophylaxis for surgery if indicated
• Precautions: Refer to the manufacturer's profile for each drug.
• Significant possible interactions: Knowledge of anticonvulsant used is necessary to avoid drug interactions, especially with antibiotics.
• Refer to the manufacturer's profile for each drug.
Second Line
Refer to http://clinicaltrials.gov
SURGERY
Surgical excision of tumors where and when appropriate
FOLLOW-UP
PROGNOSIS
Variable; shortened longevity compared with expectations in general population
COMPLICATIONS
See "Signs and Symptoms."
PATIENT MONITORING
• Clinical features and symptoms should be reviewed and updated periodically.
• Periodic reassessment of at-risk patients
REFERENCES
1. Aicardi J. Tuberous sclerosis. Int Pediatr. 1993;8:2:171-175.
2. Perspective Newsletter, National Tuberous Sclerosis Association, Spring/Summer/Fall/Winter Publications.
3. Roach ES, et al. Tuberous sclerosis consensus conference: Recommendations for diagnostic evaluation. J Child Neurol. 1999;14:401-407.
4. Caldemeyer KS, Mirowski GW. Tuberous sclerosis. Part 1: Clinical and central nervous system findings. J Amer Acad Dermatol. 2001;45:448-449.
5. Baker P, Piven J, Sato Y. Autism and tuberous sclerosis complex: Prevalence and clinical features. J Autism Dev Disord. 1998;28:279-285.
6. Roach ES, Sparagana P. Diagnosis of Tuberous Sclerosis complex. J Child Neurol. 2004(9): 643-649.
MISCELLANEOUS
See also: Neurofibromatosis (Types 1 and 2)
TUBERCULOSIS
TUBERCULOSIS - Katherine Berg, MD
BASICS
DESCRIPTION
Common disease transmitted by inhaling airborne bacilli from a person with active tuberculosis. Bacilli multiply in alveoli, are carried by macrophages, lymphatics, and blood to distant sites. Tissue hypersensitivity usually halts infection within 10 weeks.
• Latent infection
- Asymptomatic, with positive PPD
- Negative chest radiograph
- Noninfectious
• Active disease
- Occurs in 10% of infected individuals without preventive therapy
- Risk increases with immunosuppression and is highest within 2 years of infection
- 85% of cases are pulmonary, which is contagious.
• Primary: Disease resulting from initial infection.
• Recrudescent: Active disease occurring after period of latent, asymptomatic infection
• Miliary: Disseminated disease
• Systems Affected: Potentially any via hematogenous spread
ALERT
Pediatric Considerations
• Emphasize DOT (directly observed therapy)
• Caution with ethambutol
• Children on medication may attend school.
• Disseminated TB more common in infants; prompt treatment with 4 drugs if TB suspected
• Congenital infection may occur with miliary TB or endometrial TB in mother. If suspected, get PPD, chest radiograph, lumbar puncture, culture placenta in infant, then start treatment promptly.
• Consider BCG if unavoidable contact with TB
GENERAL PREVENTION
• Treat those with latent TB infection.
• Identify and test all close contacts of infected person.
• BCG vaccine: Live attenuated Mycobacterium bovis
- 50% efficacy preventing pulmonary disease, prevents 80% of TB meningitis and miliary disease in children
- In the US, consider BCG for children with negative PPD and HIV tests with unavoidable high risk, and for health care workers at high risk for drug-resistant infection (1).
- Used more commonly in countries where TB is endemic.
EPIDEMIOLOGY
• 1/3 of world's population infected with TB bacillus
• Higher incidence in ethnic minorities and medically underserved populations.
Incidence
• The Americas: 41 per 100,000
• Worldwide: 140 per 100,000
• In US, rate of decline of incidence slowing since 2000 (3.8% decrease per year as opposed to 7.1% per year in years 1993-2000)
Prevalence
• The Americas: 53 per 100,000
• Worldwide: 229 per 100,000
RISK FACTORS
• For infection
- Demographics: Homeless, minority
- Institutionalization (e.g., prison, nursing home)
- Close contact with infected individual
- Immigrant within 5 years (from Asia, Africa, Latin America, former Soviet Union states)
- Health care workers
• For development of disease once infected
- HIV; lymphoma; diabetes mellitus; chronic renal failure; cancer of head, neck, or lung
- Gastrectomy
- Steroids, immunosuppressive drugs
- IV drug abuse, malnutrition
ETIOLOGY
• Mycobacterium tuberculosis
• Mycobacterium bovis
• Mycobacterium africanum
ASSOCIATED CONDITIONS
HIV infection (emphasize DOT; most recommendations remain the same)
DIAGNOSIS
SIGNS AND SYMPTOMS
• Cough
• Hemoptysis
• Fever and night sweats
• Weight loss
• Malaise
• Painless adenopathy
• Pleuritic chest pain
• Hepatosplenomegaly
• Late findings: Renal, bone, or CNS disease
History
• Recent travel to or immigration from high-prevalence country
• Exposure to high-risk populations (see "Risk Factors"), or to known infected person
• HIV status/risk factors
Physical Exam
• Often normal
• May note rales on lung exam.
• Specific findings vary based on organ involvement.
TESTS
Lab
• Persons with TB should be tested for HIV; if positive, get CD4 count.
• Baseline liver enzymes, bilirubin, creatinine, CBC with platelet count
• If using ethambutol: Baseline visual acuity and color discrimination
• If high risk: Test for hepatitis B and C
• If extrapulmonary suspected: Urine, CSF, bone marrow, and liver biopsy for culture
• Nonspecific laboratory findings include
- Anemia
- Monocytosis
- Thrombocytosis
- Hypergammaglobulinemia
- SIADH
- Sterile pyuria
- Steroids: False-negative skin test
• Factors that may yield false-negative skin test
- Recent viral infections
- New (10 weeks) infection
- Severe malnutrition
- HIV
- Anergy
- Age 6 months
- Overwhelming TB
Imaging
• Chest radiograph
- With primary TB: May show infiltrate with or without effusion, atelectasis, or adenopathy
- With recrudescent TB: Cavitary lesions and upper-lobe disease with hilar adenopathy common
- HIV: Atypical findings with primary infection, right upper-lobe atelectasis
• CT chest: Good sensitivity
Diagnostic Procedures/Surgery
• PPD: 5 units (0.1 cc) intermediate-strength intradermal injection into volar forearm. Measure induration at 48-72 h
• PPD positive if induration
- >5 mm and HIV infection (or suspected), immunosuppressed, recent TB contact, clinical evidence of disease on chest film
- >10 mm and age 4 years or other risk factors
- >15 mm and age >4 years and no risk factors
- 2-step test if patient has no recent PPD, age >55, nursing home resident, prison inmate, or health care worker. Administer second test 1-3 weeks after initial one; interpret as usual.
• Drugs that may alter PPD results
- BCG: False-positive skin test, but unreliable and should not influence decision to treat latent tuberculosis infection
QuantiFERON whole blood assay not affected by BCG vaccine (2)[A]
• 3 different morning sputum samples for acid-fast bacilli (AFB) stain and culture; use aerosol induction, gastric aspirate (children), or bronchoalveolar lavage if needed
• If positive AFB, begin treatment immediately
• Culture and sensitivity guide treatment
Pathological Findings
• AFB stains positive
• Biopsy may show granulomas with central caseating necrosis.
DIFFERENTIAL DIAGNOSIS
• Other pneumonias
• Lymphomas
• Fungal infections, especially other atypical Mycobacteria or Nocardia
TREATMENT
GENERAL MEASURES
• If clinical suspicion, treat immediately
• Prescribing physician responsible for treatment completion.
• Inpatient: Use personal sealed respirators, negative pressure ventilation, ultraviolet
• Ambulatory patients use mask and tissues
• Not infectious if: Favorable clinical response after 2-3 weeks of therapy and 3 negative AFB smears
• Age no longer a factor in the treatment of latent tuberculosis
Activity
Respiratory isolation for infectious pulmonary TB until clinical response and 3 negative AFB smears
MEDICATION (DRUGS)
First Line
• Regimen 1 (preferred)
- Initial phase: Isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) once daily for 8 weeks
- Continuation phase: INH/RIF daily for 18 weeks. Or INH/RIF twice weekly for 18 weeks (only use for HIV+ if CD4>100) Or INH/ Rifapentine once weekly for 18 weeks (acceptable alternative for HIV- patients only) (1)[A]
• Regimen 2
- Initial phase: INH/RIF/PZA/EMB daily for 2 weeks, then twice weekly for 6 weeks
- Continuation phase: INH/RIF twice weekly for 18 wks (HIV+ patients only if CD4>100) or INH/Rifapentine once weekly for 18 weeks (acceptable alternative for HIV- patients only) (1)[A]
• Regimen 3 (acceptable alternative)
- Initial phase: INH/RIF/PZA/EMB daily for 8 weeks
- Continuation phase: INH/RIF 3 times weekly for 18 weeks (1)[A]
• Regimen 4 (only when unable to give preferred regimen)
- Initial phase: INH/RIF/EMB daily for 8 weeks
- Continuation phase: INH/RIF daily or twice weekly for 31 weeks (1)[B]
- No studies proving efficacy of 5 times weekly regimen, but clinical evidence suggests it. [C] Directly observed therapy required for nondaily regimens. (1)
• Latent tuberculosis should be treated with Isoniazid 300 mg/d for adults, and 10-15 mg/kg (not to exceed 300 mg/d) in children for 6-12 months with DOT. Dosing
• INH: Scored tabs 50/100/300 mg, syrup 10 mg/mL, or aqueous solution 100 mg/mL
- Daily dose: Adult 5 mg/kg (max 300 mg); pediatric 10-15 mg/kg (max 300 mg)
- 3 times weekly: Adult 15 mg/kg (max 900 mg)
- Twice weekly: Adult 15 mg/kg, (max 900 mg); pediatric 20-30 mg/kg (max 900 mg)
- Weekly: Adult only, 15 mg/kg (max 900 mg);
- Consider pyridoxine 10-50 mg/d
• RIF: Capsules 150/300 mg, powder for oral suspension, or IV aqueous
- Daily or twice weekly dose: Adult and pediatric 10-20 mg/kg (maximum 600 mg)
• PZA: Scored tabs 500 mg. Dosed by weight
- Adults 40-55 kg
Daily: 18-25 mg/kg, max 1 g
3 times weekly: 27-37 mg/kg, max 1.5 g
Twice weekly: 36-50 mg/kg, max 2 g
- Adults 56-75 kg
Daily: 20-27 mg/kg, max 1.5 g
3 times weekly: 33-45 mg/kg, max 2.5 g
Twice weekly: 40-54 mg/kg, max 3 g
- Adults >75 kg
Daily: 22-26 mg/kg, max 2 g
3 times weekly: 33-40 mg/kg, max 3 g
Twice weekly: 44-53 mg/kg, max 4 g
- Pediatric daily: 15-30 mg/kg (maximum 2 g)
- Pediatric twice weekly: 50 mg/kg (maximum 4 g)
• Rifabutin (Mycobutin): Capsules 150 mg
- Daily or twice weekly: Adult 5 mg/kg, max 300 mg
• Rifapentine (Priftine): Tablet 150 mg; for continuation phase only
- HIV- adults: 600 mg once weekly, given with INH. Not effective if HIV+. (1)[A]
• EMB: Tablets 100/400 mg bacteriostatic. Dose based on weight.
- Adults 40-55 kg
Daily: 15-20 mg/kg, max 800 mg
3 times weekly: 22-30 mg/kg, max 1.2 g
Twice weekly: 36-50 mg/kg, max 2 g
- Adults 56-75 kg
Daily: 16-22 mg/kg, max 1.2 g
3 times weekly: 27-36 mg/kg, max 2 g
Twice weekly: 37-50 mg/kg, max 2.8 g
- Adults >75 kg
Daily: 22-26 mg/kg, max 2.6 g
3 times weekly: 33-40 mg/kg, max 2.4 g
Twice weekly: 44-53 mg/kg, max 4 g
- Pediatrics
Daily: 15-20 mg/kg, max 1 g
Twice weekly: 50 mg/kg, max 4 g
• Contraindications
- RIF: Avoid if patient taking antiretrovirals
- EMB: May cause optic neuritis. Avoid unless patient old enough to cooperate for visual acuity and color testing
• Precautions
- INH, RIF, PZA: May cause hepatitis. Caution if liver disease.
- RIF: Colors urine, tears, and secretions orange. Can stain contact lenses.
- INH: Peripheral neuritis and hypersensitivity possible. Treat with pyridoxine.
- PZA: May increase uric acid. Unclear safety during pregnancy [C]
• Significant possible interactions: Rifamycins alter level of phenytoin, antivirals, and other drugs metabolized by liver and may inactivate birth control pills (recommend a barrier method).
Second Line
• Steroids: Use only with concurrent anti-TB therapy. Recommended for TB meningitis or pericarditis. (3)[B]
• Streptomycin: Cautionototoxic and nephrotoxic; do not use in pregnancy.
ALERT
Pregnancy Considerations
• Treat pregnant women with INH, RIF, and EMB; add pyridoxine.
• Avoid streptomycin due to ototoxicity.
• Use pyrazinamide with caution.
• Breast-feeding OK while taking TB drugs.
SURGERY
For extrapulmonary complications (e.g., spinal cord compression, constrictive pericarditis)
FOLLOW-UP
PROGNOSIS
Generally, few complications and full resolution if drugs taken for full course as prescribed
COMPLICATIONS
• Cavitary lesions can be secondarily infected.
• Drug resistance: Drug resistance declining in US. At risk if HIV+, or treatment taken improperly, or if from area with high incidence of resistance
PATIENT MONITORING
• Assess monthly for treatment adherence and adverse effects.
• Check liver enzymes if symptomatic, HIV+, chronic liver disease, alcohol use, pregnant or postpartum. Temporarily discontinue medications if enzymes are 5 times normal.
• If culture is positive after 2 months of therapy, reassess drug sensitivity and initiate DOT.
• Chest radiograph at 3 months
REFERENCES
1. Potter B. Management of active TB. Am Fam Physician 2005;72(11).
2. Centers for Disease Control. Guideline for using the QuantiFERON-TB gold test for detecting mycobacterium tubercular infection. United States. MMWR 2005;54(RR15): 49-55.
3. Golden M. Extrapulmonary TB; an overview. Am Fam Physician 2005;72(9).
MISCELLANEOUS
See also: Tuberculosis, CNS; Tuberculosis, latent; Tuberculosis, miliary
BASICS
DESCRIPTION
Common disease transmitted by inhaling airborne bacilli from a person with active tuberculosis. Bacilli multiply in alveoli, are carried by macrophages, lymphatics, and blood to distant sites. Tissue hypersensitivity usually halts infection within 10 weeks.
• Latent infection
- Asymptomatic, with positive PPD
- Negative chest radiograph
- Noninfectious
• Active disease
- Occurs in 10% of infected individuals without preventive therapy
- Risk increases with immunosuppression and is highest within 2 years of infection
- 85% of cases are pulmonary, which is contagious.
• Primary: Disease resulting from initial infection.
• Recrudescent: Active disease occurring after period of latent, asymptomatic infection
• Miliary: Disseminated disease
• Systems Affected: Potentially any via hematogenous spread
ALERT
Pediatric Considerations
• Emphasize DOT (directly observed therapy)
• Caution with ethambutol
• Children on medication may attend school.
• Disseminated TB more common in infants; prompt treatment with 4 drugs if TB suspected
• Congenital infection may occur with miliary TB or endometrial TB in mother. If suspected, get PPD, chest radiograph, lumbar puncture, culture placenta in infant, then start treatment promptly.
• Consider BCG if unavoidable contact with TB
GENERAL PREVENTION
• Treat those with latent TB infection.
• Identify and test all close contacts of infected person.
• BCG vaccine: Live attenuated Mycobacterium bovis
- 50% efficacy preventing pulmonary disease, prevents 80% of TB meningitis and miliary disease in children
- In the US, consider BCG for children with negative PPD and HIV tests with unavoidable high risk, and for health care workers at high risk for drug-resistant infection (1).
- Used more commonly in countries where TB is endemic.
EPIDEMIOLOGY
• 1/3 of world's population infected with TB bacillus
• Higher incidence in ethnic minorities and medically underserved populations.
Incidence
• The Americas: 41 per 100,000
• Worldwide: 140 per 100,000
• In US, rate of decline of incidence slowing since 2000 (3.8% decrease per year as opposed to 7.1% per year in years 1993-2000)
Prevalence
• The Americas: 53 per 100,000
• Worldwide: 229 per 100,000
RISK FACTORS
• For infection
- Demographics: Homeless, minority
- Institutionalization (e.g., prison, nursing home)
- Close contact with infected individual
- Immigrant within 5 years (from Asia, Africa, Latin America, former Soviet Union states)
- Health care workers
• For development of disease once infected
- HIV; lymphoma; diabetes mellitus; chronic renal failure; cancer of head, neck, or lung
- Gastrectomy
- Steroids, immunosuppressive drugs
- IV drug abuse, malnutrition
ETIOLOGY
• Mycobacterium tuberculosis
• Mycobacterium bovis
• Mycobacterium africanum
ASSOCIATED CONDITIONS
HIV infection (emphasize DOT; most recommendations remain the same)
DIAGNOSIS
SIGNS AND SYMPTOMS
• Cough
• Hemoptysis
• Fever and night sweats
• Weight loss
• Malaise
• Painless adenopathy
• Pleuritic chest pain
• Hepatosplenomegaly
• Late findings: Renal, bone, or CNS disease
History
• Recent travel to or immigration from high-prevalence country
• Exposure to high-risk populations (see "Risk Factors"), or to known infected person
• HIV status/risk factors
Physical Exam
• Often normal
• May note rales on lung exam.
• Specific findings vary based on organ involvement.
TESTS
Lab
• Persons with TB should be tested for HIV; if positive, get CD4 count.
• Baseline liver enzymes, bilirubin, creatinine, CBC with platelet count
• If using ethambutol: Baseline visual acuity and color discrimination
• If high risk: Test for hepatitis B and C
• If extrapulmonary suspected: Urine, CSF, bone marrow, and liver biopsy for culture
• Nonspecific laboratory findings include
- Anemia
- Monocytosis
- Thrombocytosis
- Hypergammaglobulinemia
- SIADH
- Sterile pyuria
- Steroids: False-negative skin test
• Factors that may yield false-negative skin test
- Recent viral infections
- New (10 weeks) infection
- Severe malnutrition
- HIV
- Anergy
- Age 6 months
- Overwhelming TB
Imaging
• Chest radiograph
- With primary TB: May show infiltrate with or without effusion, atelectasis, or adenopathy
- With recrudescent TB: Cavitary lesions and upper-lobe disease with hilar adenopathy common
- HIV: Atypical findings with primary infection, right upper-lobe atelectasis
• CT chest: Good sensitivity
Diagnostic Procedures/Surgery
• PPD: 5 units (0.1 cc) intermediate-strength intradermal injection into volar forearm. Measure induration at 48-72 h
• PPD positive if induration
- >5 mm and HIV infection (or suspected), immunosuppressed, recent TB contact, clinical evidence of disease on chest film
- >10 mm and age 4 years or other risk factors
- >15 mm and age >4 years and no risk factors
- 2-step test if patient has no recent PPD, age >55, nursing home resident, prison inmate, or health care worker. Administer second test 1-3 weeks after initial one; interpret as usual.
• Drugs that may alter PPD results
- BCG: False-positive skin test, but unreliable and should not influence decision to treat latent tuberculosis infection
QuantiFERON whole blood assay not affected by BCG vaccine (2)[A]
• 3 different morning sputum samples for acid-fast bacilli (AFB) stain and culture; use aerosol induction, gastric aspirate (children), or bronchoalveolar lavage if needed
• If positive AFB, begin treatment immediately
• Culture and sensitivity guide treatment
Pathological Findings
• AFB stains positive
• Biopsy may show granulomas with central caseating necrosis.
DIFFERENTIAL DIAGNOSIS
• Other pneumonias
• Lymphomas
• Fungal infections, especially other atypical Mycobacteria or Nocardia
TREATMENT
GENERAL MEASURES
• If clinical suspicion, treat immediately
• Prescribing physician responsible for treatment completion.
• Inpatient: Use personal sealed respirators, negative pressure ventilation, ultraviolet
• Ambulatory patients use mask and tissues
• Not infectious if: Favorable clinical response after 2-3 weeks of therapy and 3 negative AFB smears
• Age no longer a factor in the treatment of latent tuberculosis
Activity
Respiratory isolation for infectious pulmonary TB until clinical response and 3 negative AFB smears
MEDICATION (DRUGS)
First Line
• Regimen 1 (preferred)
- Initial phase: Isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) once daily for 8 weeks
- Continuation phase: INH/RIF daily for 18 weeks. Or INH/RIF twice weekly for 18 weeks (only use for HIV+ if CD4>100) Or INH/ Rifapentine once weekly for 18 weeks (acceptable alternative for HIV- patients only) (1)[A]
• Regimen 2
- Initial phase: INH/RIF/PZA/EMB daily for 2 weeks, then twice weekly for 6 weeks
- Continuation phase: INH/RIF twice weekly for 18 wks (HIV+ patients only if CD4>100) or INH/Rifapentine once weekly for 18 weeks (acceptable alternative for HIV- patients only) (1)[A]
• Regimen 3 (acceptable alternative)
- Initial phase: INH/RIF/PZA/EMB daily for 8 weeks
- Continuation phase: INH/RIF 3 times weekly for 18 weeks (1)[A]
• Regimen 4 (only when unable to give preferred regimen)
- Initial phase: INH/RIF/EMB daily for 8 weeks
- Continuation phase: INH/RIF daily or twice weekly for 31 weeks (1)[B]
- No studies proving efficacy of 5 times weekly regimen, but clinical evidence suggests it. [C] Directly observed therapy required for nondaily regimens. (1)
• Latent tuberculosis should be treated with Isoniazid 300 mg/d for adults, and 10-15 mg/kg (not to exceed 300 mg/d) in children for 6-12 months with DOT. Dosing
• INH: Scored tabs 50/100/300 mg, syrup 10 mg/mL, or aqueous solution 100 mg/mL
- Daily dose: Adult 5 mg/kg (max 300 mg); pediatric 10-15 mg/kg (max 300 mg)
- 3 times weekly: Adult 15 mg/kg (max 900 mg)
- Twice weekly: Adult 15 mg/kg, (max 900 mg); pediatric 20-30 mg/kg (max 900 mg)
- Weekly: Adult only, 15 mg/kg (max 900 mg);
- Consider pyridoxine 10-50 mg/d
• RIF: Capsules 150/300 mg, powder for oral suspension, or IV aqueous
- Daily or twice weekly dose: Adult and pediatric 10-20 mg/kg (maximum 600 mg)
• PZA: Scored tabs 500 mg. Dosed by weight
- Adults 40-55 kg
Daily: 18-25 mg/kg, max 1 g
3 times weekly: 27-37 mg/kg, max 1.5 g
Twice weekly: 36-50 mg/kg, max 2 g
- Adults 56-75 kg
Daily: 20-27 mg/kg, max 1.5 g
3 times weekly: 33-45 mg/kg, max 2.5 g
Twice weekly: 40-54 mg/kg, max 3 g
- Adults >75 kg
Daily: 22-26 mg/kg, max 2 g
3 times weekly: 33-40 mg/kg, max 3 g
Twice weekly: 44-53 mg/kg, max 4 g
- Pediatric daily: 15-30 mg/kg (maximum 2 g)
- Pediatric twice weekly: 50 mg/kg (maximum 4 g)
• Rifabutin (Mycobutin): Capsules 150 mg
- Daily or twice weekly: Adult 5 mg/kg, max 300 mg
• Rifapentine (Priftine): Tablet 150 mg; for continuation phase only
- HIV- adults: 600 mg once weekly, given with INH. Not effective if HIV+. (1)[A]
• EMB: Tablets 100/400 mg bacteriostatic. Dose based on weight.
- Adults 40-55 kg
Daily: 15-20 mg/kg, max 800 mg
3 times weekly: 22-30 mg/kg, max 1.2 g
Twice weekly: 36-50 mg/kg, max 2 g
- Adults 56-75 kg
Daily: 16-22 mg/kg, max 1.2 g
3 times weekly: 27-36 mg/kg, max 2 g
Twice weekly: 37-50 mg/kg, max 2.8 g
- Adults >75 kg
Daily: 22-26 mg/kg, max 2.6 g
3 times weekly: 33-40 mg/kg, max 2.4 g
Twice weekly: 44-53 mg/kg, max 4 g
- Pediatrics
Daily: 15-20 mg/kg, max 1 g
Twice weekly: 50 mg/kg, max 4 g
• Contraindications
- RIF: Avoid if patient taking antiretrovirals
- EMB: May cause optic neuritis. Avoid unless patient old enough to cooperate for visual acuity and color testing
• Precautions
- INH, RIF, PZA: May cause hepatitis. Caution if liver disease.
- RIF: Colors urine, tears, and secretions orange. Can stain contact lenses.
- INH: Peripheral neuritis and hypersensitivity possible. Treat with pyridoxine.
- PZA: May increase uric acid. Unclear safety during pregnancy [C]
• Significant possible interactions: Rifamycins alter level of phenytoin, antivirals, and other drugs metabolized by liver and may inactivate birth control pills (recommend a barrier method).
Second Line
• Steroids: Use only with concurrent anti-TB therapy. Recommended for TB meningitis or pericarditis. (3)[B]
• Streptomycin: Cautionototoxic and nephrotoxic; do not use in pregnancy.
ALERT
Pregnancy Considerations
• Treat pregnant women with INH, RIF, and EMB; add pyridoxine.
• Avoid streptomycin due to ototoxicity.
• Use pyrazinamide with caution.
• Breast-feeding OK while taking TB drugs.
SURGERY
For extrapulmonary complications (e.g., spinal cord compression, constrictive pericarditis)
FOLLOW-UP
PROGNOSIS
Generally, few complications and full resolution if drugs taken for full course as prescribed
COMPLICATIONS
• Cavitary lesions can be secondarily infected.
• Drug resistance: Drug resistance declining in US. At risk if HIV+, or treatment taken improperly, or if from area with high incidence of resistance
PATIENT MONITORING
• Assess monthly for treatment adherence and adverse effects.
• Check liver enzymes if symptomatic, HIV+, chronic liver disease, alcohol use, pregnant or postpartum. Temporarily discontinue medications if enzymes are 5 times normal.
• If culture is positive after 2 months of therapy, reassess drug sensitivity and initiate DOT.
• Chest radiograph at 3 months
REFERENCES
1. Potter B. Management of active TB. Am Fam Physician 2005;72(11).
2. Centers for Disease Control. Guideline for using the QuantiFERON-TB gold test for detecting mycobacterium tubercular infection. United States. MMWR 2005;54(RR15): 49-55.
3. Golden M. Extrapulmonary TB; an overview. Am Fam Physician 2005;72(9).
MISCELLANEOUS
See also: Tuberculosis, CNS; Tuberculosis, latent; Tuberculosis, miliary
TUBERCULOSIS, MILIARY
TUBERCULOSIS, MILIARY - Katherine Berg, MD
BASICS
DESCRIPTION
• Any progressive, disseminated form of TB, resulting from uncontrolled hematogenous spread of Mycobacterium tuberculosis. Originally named for "millet seed" appearance of nodules often found in lungs. 3 types
- Acute: Usually with primary infection. Rapidly progressive, more severe type
- Late generalized: Occurs after years of latent infection. Chronic, more indolent course
- Anergic: Rare. Microabscesses form in place of granulomas. Generally a reactivation of old disease, older patients
• System(s) Affected: Most commonly Pulmonary; Lymphatic; CNS (TB meningitis); Hepatic; Splenic; and Bone Marrow.
• Multiorgan failure and ARDS also known to occur
• Synonym(s): Disseminated TB
GENERAL PREVENTION
• BCG vaccine
- 78% effective preventing severe meningeal and miliary TB in children (1)[B]
• Treatment of latent TB infection with INH (see "Tuberculosis, latent")
EPIDEMIOLOGY
• 1-3% of all TB cases (See "Tuberculosis" chapter)
• 10% of pulmonary TB cases and 38% of extrapulmonary cases in AIDS population (2)
• Gender: Male > Female (as in all types of TB)
RISK FACTORS
Within TB-infected population, risk factors for miliary disease include
• HIV infection/AIDS
• Young age (especially 1 year) or old age
• Iatrogenic immunosuppression (i.e., organ transplant patients, chronic corticosteroid use)
• Diabetes mellitus
• Pregnancy
• Chronic renal failure
• Protein malnutrition
PATHOPHYSIOLOGY
• Lymphatic or hematogenous spread from a local focus, with failure of the body to halt infection by granulomatous encapsulation.
• Commonly affects the more vascular organs (i.e., spleen, liver, brain, bone marrow)
• Iatrogenic disease also reported after solid organ transplants, urethral catheterization, and cardiac valve transplants.
ETIOLOGY
TB infection in the context of impaired cell-mediated immunity
• Primary infection in immunocompromised host, or recrudescent infection in once-healthy host with new health impairment.
• Iatrogenic infection as above.
ASSOCIATED CONDITIONS
HIV/AIDS: See "Special Considerations"
DIAGNOSIS
PRE HOSPITAL
• Diagnosis often is impeded by low suspicion and delay in collecting fluid/tissue samples for AFB smear and culture.
• Identify and test any close contacts.
SIGNS AND SYMPTOMS
Presentation extremely variable, but may include
• Night sweats (near 100%)
• Fever (96%)
• Weight loss, anorexia (92%)
• Tachypnea, tachycardia (77%)
• Cough, dyspnea (72%)
• Hepatomegaly (52%)
• Neurological/HA/mental status changes (25%)
• Chills
• Single or multiorgan failure
• Severe disease resulting in septic shock and ARDS has been reported.
• Chest pain
History
Ask about risk factors
Physical Exam
• Vital signs: Fever, tachycardia, tachypnea common
• Pulmonary: Rales (50%)
• Hepatosplenomegaly common
• Should have ophthalmologist do dilated funduscopic exam to look for choroidal tubercles (found in 50% postmortem) (3)[B]
• Evaluate for meningeal signs
TESTS
• PPD positive in 50% of cases
• Sputum for AFB smear and culture
• Gastric washings (especially in children), CSF, blood cxs, or bone and liver biopsy also for smear and culture
• Test for HIV (4)[C]
ALERT
Pediatric Considerations
May need to culture samples from infected adult contact, because samples can be difficult to obtain in pediatric cases.
Lab
Abnormal lab findings may include
• Normochromic anemia
• Leucopenia or leukocytosis
• Elevated ESR
• Hyponatremia
Imaging
• Chest radiograph: Faint, reticulonodular infiltrate, uniform distribution. Often mediastinal/hilar adenopathy
• Chest CT: Numerous 2-3 mm nodules scattered throughout lungs in >85% of patients
• Abdominal/pelvic CT: If suspicious of other organ involvement.
• Brain MRI: Cerebral nodules or tuberculoma
- Only if neurological symptoms present
Diagnostic Procedures/Surgery
• See "Tuberculosis" chapter.
• Collect samples for AFB/culture. (4)[A] Sampling fluids from multiple sites greatly improves yield for AFB smear and culture.
- Sputum culture positive in 62% (smear in 33%)
- BAL culture positive in 55% (smear in 27%)
- Gastric aspirate culture positive in 100% (smear in 43%)
- CSF culture positive in 60% (smear in 8%) (5)
• Biopsy organs based on symptoms
Pathological Findings
• Caseating granulomas on tissue biopsy (liver most common site)
• Microabscesses with neutrophilic response in acute type
• Can see mycotic aneurysms if disease affects aorta
• TB pericarditis diagnosed by pericardial biopsy
DIFFERENTIAL DIAGNOSIS
• Other pneumonias
• Lymphoma
• Metastatic carcinoma
• Sarcoidosis
TREATMENT
GENERAL MEASURES
• See "Tuberculosis" chapter
• Respiratory isolation until clinically responding and 3 negative AFB smears (4)[B]
• ARDS/organ failure may complicate treatment.
• If CNS involvement, extended treatment is advised (9-12 months). (6)[C]
Diet
Some evidence suggests that high-cholesterol diet accelerates sterilization of sputum in pulmonary TB patients.
Activity
Respiratory isolation if pulmonary disease
• Negative pressure room
• TB mask when out of room
MEDICATION (DRUGS)
• All drug regimens same as those for general tuberculosis.
• Adherence extremely important to prevent drug resistance. Responsibility is the provider's.
First Line
• Regimen 1 (preferred)
- Initial phase: Isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) once daily for 8 weeks
- Continuation phase: INH/RIF daily for 18 weeks. Or INH/RIF twice weekly for 18 weeks (only use for HIV+ if CD4>100); or INH/ rifapentine once weekly for 18 weeks (acceptable alternative for HIV- patients only) (7)[A]
• Regimen 2
- Initial phase: INH/RIF/PZA/EMB daily for 2 weeks, then twice weekly for 6 weeks
- Continuation phase: INH/RIF twice weekly for 18 weeks (HIV+ patients only if CD4>100) or INH/rifapentine once weekly for 18 weeks (acceptable alternative for HIV- patients only) (7)[A]
• Regimen 3 (acceptable alternative)
- Initial phase: INH/RIF/PZA/EMB daily for 8 weeks
- Continuation phase: INH/RIF 3 times weekly for 18 weeks (7)[A]
• Regimen 4 (only when unable to give preferred regimen)
- Initial phase: INH/RIF/EMB daily for 8 weeks
- Continuation phase: INH/RIF daily or twice weekly for 31 weeks (7)[B]
• No studies proving efficacy of 5 times a week regimen, but clinical evidence suggests it. [C]
• Directly observed therapy required for non-daily regimens (7).
• Dosing
• INH: Scored tabs 50/100/300 mg, syrup 10 mg/mL, or aqueous solution 100 mg/mL
- Daily dose: Adult 5 mg/kg (max 300 mg); pediatric 10 to 15 mg/kg (max 300 mg)
- 3 times weekly: Adult 15 mg/kg (max 900 mg)
- Twice weekly: Adult 15 mg/kg (max 900 mg); pediatric 20-30 mg/kg (max 900 mg)
- Weekly: Adult only, 15 mg/kg (max 900 mg)
- Consider pyridoxine 10-50 mg/d
• RIF: Capsules 150/300 mg, powder for oral suspension, or IV aqueous
- Daily or twice weekly dose: Adult and pediatric 10-20 mg/kg (maximum 600 mg)
• PZA: Scored tabs 500 mg. Dosed by weight
- Adults 40-55 kg
Daily: 18-25 mg/kg, max 1 g
3 times weekly: 27-37 mg/kg, max 1.5 g
Twice weekly: 36-50 mg/kg, max 2 g
- Adults 56-75 kg
Daily: 20-27 mg/kg, max 1.5 g
3 times weekly: 33-45 mg/kg, max 2.5 g
Twice weekly: 40-54 mg/kg, max 3 g
- Adults > 75 kg
Daily: 22-26 mg/kg, max 2 g
3 times weekly: 33-40 mg/kg, max 3 g
Twice weekly: 44-53 mg/kg, max 4 g
- Pediatric daily: 15 to 30 mg/kg (maximum 2 g)
- Pediatric twice weekly: 50 mg/kg (maximum 4 g)
• Rifabutin (Mycobutin): Capsules 150 mg
- Daily or twice weekly: Adult 5 mg/kg, max 300 mg
• Rifapentine (Priftine): Tablet 150 mg; for continuation phase only
- HIV- adults: 600 mg once weekly, given with INH. Not effective if HIV+. (7)[A]
• EMB: Tablets 100/400 mg bacteriostatic. Dose based on weight
- Adults 40-55 kg
Daily: 15-20 mg/kg, max 800 mg
3 times weekly: 22-30 mg/kg, max 1.2 g
Twice weekly: 36-50 mg/kg, max 2 g
- Adults 56-75 kg
Daily: 16-22 mg/kg, max 1.2 g
3 times weekly: 27-36 mg/kg, max 2 g
Twice weekly: 37-50 mg/kg, max 2.8 g
- Adults >75 kg
Daily: 22-26 mg/kg, max 2.6 g
3 times weekly: 33-40 mg/kg, max 2.4 g
Twice weekly: 44-53 mg/kg, max 4 g
- Pediatrics
Daily: 15-20 mg/kg, max 1 g
Twice weekly: 50 mg/kg, max 4 g
• Contraindications
- RIF: Avoid if patient taking antiretrovirals
- EMB: May cause optic neuritis. Avoid unless patient old enough to cooperate for visual acuity and color testing
• Precautions
- INH, RIF, PZA: May cause hepatitis. Caution if liver disease.
- RIF: Colors urine, tears, and secretions orange. Can stain contact lenses.
- INH: Peripheral neuritis and hypersensitivity possible. Treat with pyridoxine.
- PZA: May increase uric acid. Unclear safety during pregnancy [C]
• Significant possible interactions: Rifamycins alter level of phenytoin, antivirals, and other drugs metabolized by liver and may inactivate birth control pills (recommend a barrier method).
Second Line
• Corticosteroids: Use only with concurrent anti-TB therapy. Recommended for TB meningitis, pericarditis, or severe miliary disease (3)[B]
- Reduce fluid reaccumulation in pericarditis, but no proven mortality benefit. (2)[B]
- Also for HIV+ population (see "Considerations" below)
• Streptomycin: Cautionototoxic and nephrotoxic; do not use in pregnancy.
ALERT
Geriatric Considerations
See "Tuberculosis" chapter.
Pediatric Considerations
See "Tuberculosis" chapter.
Pregnancy Considerations
See "Tuberculosis" chapter.
• If CD4, 100, risk of developing resistance to RIF if given 3 times weekly.
• INH/Rifapentine once weekly continuation phase contraindicated.
• Paradoxical worsening of disease may occur during treatment; this is thought due to immune reconstitution while on antiretrovirals.
- If mild, treat with NSAIDs
- If severe, prednisone (1-2 mg/kg for 2 weeks, then taper) has been shown helpful) (6)[C]
Second Line
• Corticosteroids shown effective for TB pericarditis and meningitis, and miliary TB (2)[B]
• Streptomycin-resistance has increased in recent years. Contraindicated in pregnancy; it causes ototoxicity in fetus.
SURGERY
Case-specific, depending on location of disease.
FOLLOW-UP
As for general TB.
DISPOSITION
Issues for Referral
ID specialist helpful for patients also on antiretrovirals, because doses may need adjusting
PROGNOSIS
• Mortality: 16-38%
• If ARDS develops, mortality is 80-100%
COMPLICATIONS
• ARDS with refractory hypoxemia can occur
• Multidrug resistant TB rare in the US, but increasing elsewhere.
PATIENT MONITORING
See "Tuberculosis" chapter.
REFERENCES
1. Coditz. Efficacy of BCG vaccine in the prevention of TB. JAMA 1994;271(9):698-702.
2. Golden M. Extrapulmonary TB; an overview. Am Fam Physician 2005;72(9).
3. Slavin. Late generalized TB; a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine 1980;59(5):352-366.
4. Horsburgh et al. Treatment guidelines for treatment of TB. Clin Infect Dis 2000;31:633-6392000.
5. Maartens. Miliary TB; rapid diagnosis, hematologic abnormalities and outcome in 109 treated adults. Am J Med 1990;89(3):291-296.
6. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR 2003;52(RR11):1-77.
7. Potter B. Management of active TB. Am Fam Physician 2005;72(11).
BASICS
DESCRIPTION
• Any progressive, disseminated form of TB, resulting from uncontrolled hematogenous spread of Mycobacterium tuberculosis. Originally named for "millet seed" appearance of nodules often found in lungs. 3 types
- Acute: Usually with primary infection. Rapidly progressive, more severe type
- Late generalized: Occurs after years of latent infection. Chronic, more indolent course
- Anergic: Rare. Microabscesses form in place of granulomas. Generally a reactivation of old disease, older patients
• System(s) Affected: Most commonly Pulmonary; Lymphatic; CNS (TB meningitis); Hepatic; Splenic; and Bone Marrow.
• Multiorgan failure and ARDS also known to occur
• Synonym(s): Disseminated TB
GENERAL PREVENTION
• BCG vaccine
- 78% effective preventing severe meningeal and miliary TB in children (1)[B]
• Treatment of latent TB infection with INH (see "Tuberculosis, latent")
EPIDEMIOLOGY
• 1-3% of all TB cases (See "Tuberculosis" chapter)
• 10% of pulmonary TB cases and 38% of extrapulmonary cases in AIDS population (2)
• Gender: Male > Female (as in all types of TB)
RISK FACTORS
Within TB-infected population, risk factors for miliary disease include
• HIV infection/AIDS
• Young age (especially 1 year) or old age
• Iatrogenic immunosuppression (i.e., organ transplant patients, chronic corticosteroid use)
• Diabetes mellitus
• Pregnancy
• Chronic renal failure
• Protein malnutrition
PATHOPHYSIOLOGY
• Lymphatic or hematogenous spread from a local focus, with failure of the body to halt infection by granulomatous encapsulation.
• Commonly affects the more vascular organs (i.e., spleen, liver, brain, bone marrow)
• Iatrogenic disease also reported after solid organ transplants, urethral catheterization, and cardiac valve transplants.
ETIOLOGY
TB infection in the context of impaired cell-mediated immunity
• Primary infection in immunocompromised host, or recrudescent infection in once-healthy host with new health impairment.
• Iatrogenic infection as above.
ASSOCIATED CONDITIONS
HIV/AIDS: See "Special Considerations"
DIAGNOSIS
PRE HOSPITAL
• Diagnosis often is impeded by low suspicion and delay in collecting fluid/tissue samples for AFB smear and culture.
• Identify and test any close contacts.
SIGNS AND SYMPTOMS
Presentation extremely variable, but may include
• Night sweats (near 100%)
• Fever (96%)
• Weight loss, anorexia (92%)
• Tachypnea, tachycardia (77%)
• Cough, dyspnea (72%)
• Hepatomegaly (52%)
• Neurological/HA/mental status changes (25%)
• Chills
• Single or multiorgan failure
• Severe disease resulting in septic shock and ARDS has been reported.
• Chest pain
History
Ask about risk factors
Physical Exam
• Vital signs: Fever, tachycardia, tachypnea common
• Pulmonary: Rales (50%)
• Hepatosplenomegaly common
• Should have ophthalmologist do dilated funduscopic exam to look for choroidal tubercles (found in 50% postmortem) (3)[B]
• Evaluate for meningeal signs
TESTS
• PPD positive in 50% of cases
• Sputum for AFB smear and culture
• Gastric washings (especially in children), CSF, blood cxs, or bone and liver biopsy also for smear and culture
• Test for HIV (4)[C]
ALERT
Pediatric Considerations
May need to culture samples from infected adult contact, because samples can be difficult to obtain in pediatric cases.
Lab
Abnormal lab findings may include
• Normochromic anemia
• Leucopenia or leukocytosis
• Elevated ESR
• Hyponatremia
Imaging
• Chest radiograph: Faint, reticulonodular infiltrate, uniform distribution. Often mediastinal/hilar adenopathy
• Chest CT: Numerous 2-3 mm nodules scattered throughout lungs in >85% of patients
• Abdominal/pelvic CT: If suspicious of other organ involvement.
• Brain MRI: Cerebral nodules or tuberculoma
- Only if neurological symptoms present
Diagnostic Procedures/Surgery
• See "Tuberculosis" chapter.
• Collect samples for AFB/culture. (4)[A] Sampling fluids from multiple sites greatly improves yield for AFB smear and culture.
- Sputum culture positive in 62% (smear in 33%)
- BAL culture positive in 55% (smear in 27%)
- Gastric aspirate culture positive in 100% (smear in 43%)
- CSF culture positive in 60% (smear in 8%) (5)
• Biopsy organs based on symptoms
Pathological Findings
• Caseating granulomas on tissue biopsy (liver most common site)
• Microabscesses with neutrophilic response in acute type
• Can see mycotic aneurysms if disease affects aorta
• TB pericarditis diagnosed by pericardial biopsy
DIFFERENTIAL DIAGNOSIS
• Other pneumonias
• Lymphoma
• Metastatic carcinoma
• Sarcoidosis
TREATMENT
GENERAL MEASURES
• See "Tuberculosis" chapter
• Respiratory isolation until clinically responding and 3 negative AFB smears (4)[B]
• ARDS/organ failure may complicate treatment.
• If CNS involvement, extended treatment is advised (9-12 months). (6)[C]
Diet
Some evidence suggests that high-cholesterol diet accelerates sterilization of sputum in pulmonary TB patients.
Activity
Respiratory isolation if pulmonary disease
• Negative pressure room
• TB mask when out of room
MEDICATION (DRUGS)
• All drug regimens same as those for general tuberculosis.
• Adherence extremely important to prevent drug resistance. Responsibility is the provider's.
First Line
• Regimen 1 (preferred)
- Initial phase: Isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) once daily for 8 weeks
- Continuation phase: INH/RIF daily for 18 weeks. Or INH/RIF twice weekly for 18 weeks (only use for HIV+ if CD4>100); or INH/ rifapentine once weekly for 18 weeks (acceptable alternative for HIV- patients only) (7)[A]
• Regimen 2
- Initial phase: INH/RIF/PZA/EMB daily for 2 weeks, then twice weekly for 6 weeks
- Continuation phase: INH/RIF twice weekly for 18 weeks (HIV+ patients only if CD4>100) or INH/rifapentine once weekly for 18 weeks (acceptable alternative for HIV- patients only) (7)[A]
• Regimen 3 (acceptable alternative)
- Initial phase: INH/RIF/PZA/EMB daily for 8 weeks
- Continuation phase: INH/RIF 3 times weekly for 18 weeks (7)[A]
• Regimen 4 (only when unable to give preferred regimen)
- Initial phase: INH/RIF/EMB daily for 8 weeks
- Continuation phase: INH/RIF daily or twice weekly for 31 weeks (7)[B]
• No studies proving efficacy of 5 times a week regimen, but clinical evidence suggests it. [C]
• Directly observed therapy required for non-daily regimens (7).
• Dosing
• INH: Scored tabs 50/100/300 mg, syrup 10 mg/mL, or aqueous solution 100 mg/mL
- Daily dose: Adult 5 mg/kg (max 300 mg); pediatric 10 to 15 mg/kg (max 300 mg)
- 3 times weekly: Adult 15 mg/kg (max 900 mg)
- Twice weekly: Adult 15 mg/kg (max 900 mg); pediatric 20-30 mg/kg (max 900 mg)
- Weekly: Adult only, 15 mg/kg (max 900 mg)
- Consider pyridoxine 10-50 mg/d
• RIF: Capsules 150/300 mg, powder for oral suspension, or IV aqueous
- Daily or twice weekly dose: Adult and pediatric 10-20 mg/kg (maximum 600 mg)
• PZA: Scored tabs 500 mg. Dosed by weight
- Adults 40-55 kg
Daily: 18-25 mg/kg, max 1 g
3 times weekly: 27-37 mg/kg, max 1.5 g
Twice weekly: 36-50 mg/kg, max 2 g
- Adults 56-75 kg
Daily: 20-27 mg/kg, max 1.5 g
3 times weekly: 33-45 mg/kg, max 2.5 g
Twice weekly: 40-54 mg/kg, max 3 g
- Adults > 75 kg
Daily: 22-26 mg/kg, max 2 g
3 times weekly: 33-40 mg/kg, max 3 g
Twice weekly: 44-53 mg/kg, max 4 g
- Pediatric daily: 15 to 30 mg/kg (maximum 2 g)
- Pediatric twice weekly: 50 mg/kg (maximum 4 g)
• Rifabutin (Mycobutin): Capsules 150 mg
- Daily or twice weekly: Adult 5 mg/kg, max 300 mg
• Rifapentine (Priftine): Tablet 150 mg; for continuation phase only
- HIV- adults: 600 mg once weekly, given with INH. Not effective if HIV+. (7)[A]
• EMB: Tablets 100/400 mg bacteriostatic. Dose based on weight
- Adults 40-55 kg
Daily: 15-20 mg/kg, max 800 mg
3 times weekly: 22-30 mg/kg, max 1.2 g
Twice weekly: 36-50 mg/kg, max 2 g
- Adults 56-75 kg
Daily: 16-22 mg/kg, max 1.2 g
3 times weekly: 27-36 mg/kg, max 2 g
Twice weekly: 37-50 mg/kg, max 2.8 g
- Adults >75 kg
Daily: 22-26 mg/kg, max 2.6 g
3 times weekly: 33-40 mg/kg, max 2.4 g
Twice weekly: 44-53 mg/kg, max 4 g
- Pediatrics
Daily: 15-20 mg/kg, max 1 g
Twice weekly: 50 mg/kg, max 4 g
• Contraindications
- RIF: Avoid if patient taking antiretrovirals
- EMB: May cause optic neuritis. Avoid unless patient old enough to cooperate for visual acuity and color testing
• Precautions
- INH, RIF, PZA: May cause hepatitis. Caution if liver disease.
- RIF: Colors urine, tears, and secretions orange. Can stain contact lenses.
- INH: Peripheral neuritis and hypersensitivity possible. Treat with pyridoxine.
- PZA: May increase uric acid. Unclear safety during pregnancy [C]
• Significant possible interactions: Rifamycins alter level of phenytoin, antivirals, and other drugs metabolized by liver and may inactivate birth control pills (recommend a barrier method).
Second Line
• Corticosteroids: Use only with concurrent anti-TB therapy. Recommended for TB meningitis, pericarditis, or severe miliary disease (3)[B]
- Reduce fluid reaccumulation in pericarditis, but no proven mortality benefit. (2)[B]
- Also for HIV+ population (see "Considerations" below)
• Streptomycin: Cautionototoxic and nephrotoxic; do not use in pregnancy.
ALERT
Geriatric Considerations
See "Tuberculosis" chapter.
Pediatric Considerations
See "Tuberculosis" chapter.
Pregnancy Considerations
See "Tuberculosis" chapter.
• If CD4, 100, risk of developing resistance to RIF if given 3 times weekly.
• INH/Rifapentine once weekly continuation phase contraindicated.
• Paradoxical worsening of disease may occur during treatment; this is thought due to immune reconstitution while on antiretrovirals.
- If mild, treat with NSAIDs
- If severe, prednisone (1-2 mg/kg for 2 weeks, then taper) has been shown helpful) (6)[C]
Second Line
• Corticosteroids shown effective for TB pericarditis and meningitis, and miliary TB (2)[B]
• Streptomycin-resistance has increased in recent years. Contraindicated in pregnancy; it causes ototoxicity in fetus.
SURGERY
Case-specific, depending on location of disease.
FOLLOW-UP
As for general TB.
DISPOSITION
Issues for Referral
ID specialist helpful for patients also on antiretrovirals, because doses may need adjusting
PROGNOSIS
• Mortality: 16-38%
• If ARDS develops, mortality is 80-100%
COMPLICATIONS
• ARDS with refractory hypoxemia can occur
• Multidrug resistant TB rare in the US, but increasing elsewhere.
PATIENT MONITORING
See "Tuberculosis" chapter.
REFERENCES
1. Coditz. Efficacy of BCG vaccine in the prevention of TB. JAMA 1994;271(9):698-702.
2. Golden M. Extrapulmonary TB; an overview. Am Fam Physician 2005;72(9).
3. Slavin. Late generalized TB; a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine 1980;59(5):352-366.
4. Horsburgh et al. Treatment guidelines for treatment of TB. Clin Infect Dis 2000;31:633-6392000.
5. Maartens. Miliary TB; rapid diagnosis, hematologic abnormalities and outcome in 109 treated adults. Am J Med 1990;89(3):291-296.
6. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR 2003;52(RR11):1-77.
7. Potter B. Management of active TB. Am Fam Physician 2005;72(11).
TUBERCULOSIS, LATENT
TUBERCULOSIS, LATENT - Kay A. Bauman, MD, MPH
BASICS
DESCRIPTION
Tuberculosis (TB) is a common infection transmitted by inhaling airborne bacilli from a person with active tuberculosis. The bacilli multiply in the alveolus and are carried by macrophages, lymphatics, and blood to distant sites (e.g., lung pleura, brain, kidney, bone). Tissue hypersensitivity halts infection within 10 weeks.
• Latent tuberculosis infection (LTBI) is asymptomatic, noninfectious, and usually detected by a positive skin test (evidence of prior TB infection by purified protein derivative [PPD] or chest radiograph, but acid-fast bacilli smear and culture are negative and chest radiograph does not suggest active TB).
• TB: Active disease occurs in 5-10% of infected individuals without preventive therapy. (1) Chance of disease increases with immunosuppression and is highest for all individuals within 2 years after infection; 85% of the cases are pulmonary, which is infectious.
• Recrudescent TB: The active disease occurs after a period of latent asymptomatic infection.
• System(s) Affected: Asymptomatic
GENERAL PREVENTION
Treatment of LTBI is also preventive: To decrease the incidence of TB in both the individuals treated and to decrease the risk to close contacts should active TB occur.
EPIDEMIOLOGY
• TB screening of high risk groups (e.g., recent immigrants from Asia, Latin America, and Africa; pockets of homelessness; history of drug use; history of incarceration). (1)
• Recrudescent disease: Adults and elderly, HIV infected, those newly exposed, including pediatric population
• Predominant sex: Male > Female
Prevalence
In the US, 10-15 million people have the latent infection. (1)
RISK FACTORS
• Immigrant within 5 years (from Asia, Africa, Latin America); including migrant workers
• HIV infection, immunosuppression
• Close contact with infected individual
• Institutional environment (e.g., prison, nursing home)
• Use of illicit drugs
• Lower socioeconomic or homeless
• Health care workers
• Chronic disease such as diabetes mellitus, end-stage renal disease, canceror silicosis.
ETIOLOGY
Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium africanum
ASSOCIATED CONDITIONS
• HIV infection (see "Tests")
• Immune suppression
DIAGNOSIS
SIGNS AND SYMPTOMS
None
History
History of recent immigration from a high-risk area, history of IV drug use and/or drug treatment, HIV, homelessness, recent incarceration (1)
TESTS
• HIV test recommended to assess risk for active TB in men who have sex with men or persons with a history of IV drug use
• PPD: 5 units (0.1 mL) intermediate strength intradermal volar forearm. Measure induration at 48-72 hours.
- Positive if induration is >5 mm and patient has HIV infection (or suspected) (2), is immunosuppressed, had recent close TB contact, or has clinical evidence of active or old disease on chest radiograph; induration is >10 mm and patient is 4 years old or has other risk factors noted above; or induration is >15 mm and patient is >4 years old and has no risk factors (3)
- Negative if induration is 5 mm on initial test and, if indicated, on 2nd test. Utilize the 2-step test if patient has had no recent PPD and is >55 years old, or is a nursing home resident, prison inmate, or health care worker (administer a 2nd intradermal test 1-3 weeks after initial test; measure and interpret as usual). (3)
- The interferon-gamma blood test or QuantiFERON-TB and QuantiFERON-TB GOLD, measure the release of interferon-gamma by sensitized lymphocytes when exposed to antigens of M. tuberculosis. It is unaffected by prior Bacillus Calmette-Guerin (BCG) vaccination, requires only 1 patient visit, has improved sensitivity and specificity, but is costly. (4)
- Do not use BCG vaccination as a reason to ignore a positive PPD in adults and forego recommendation for treatment.
• The multiple puncture (Tine) test is not recommended.
Lab
• None routinely recommended
- BCG vaccine: False-positive skin test but unreliable and should not influence decision to treat LTBI
- Steroids: False-negative skin test
- Measles vaccine: May suppress tuberculin activity; simultaneous PPD and measles vaccine recommended; if not simultaneous, defer PPD 4-6 weeks after measles vaccine
• Disorders that may alter results: False-negative skin test
- Recent viral infection
- New (10 weeks) infection
- Severe malnutrition
- HIV
- Anergy
- Age 6 months
- Overwhelming TB
Imaging
• Chest radiography required to rule out TB in asymptomatic infected persons
• CT of the chest-good sensitivity
DIFFERENTIAL DIAGNOSIS
Fungal infections, especially other atypical mycobacteria or nocardia
TREATMENT
GENERAL MEASURES
• Treat LTBI at any age if patient has HIV, has had close TB contact, is a recent converter (2 years), is an IV drug user, has an abnormal chest radiograph, has a high-risk medical condition, or is in another high-risk group. (1) Use isoniazid (INH) daily for 9 months [A] or an accepted alternative
- INH twice weekly for 9 months with directly observed treatment (DOT) [B]
- INH daily or twice weekly for 6 months with DOT (B)
- Rifampin (RIF) daily for 4 months [B] RIF plus pyrazinamide (PZA) daily for 2 months or twice weekly for 2-3 months [D]; special monitoring for hepatic toxicity required (preferred if patient is INH resistant). For inactive pulmonary TB on chest radiograph, use INH for 9 months
- Consider INH resistance
- DOT is recommended if patient adherence is not assured
• Careful reevaluation required; change to twice weekly dosing only if using DOT
• Treat LTBI during pregnancy if patient has recent infection or is HIV positive (use INH with pyridoxine and monitor liver enzymes); otherwise, treatment may be postponed until postpartum (2)
Diet
Regular, consider pyridoxine supplement: 10-50 mg/d
Activity
• As tolerated
• No isolation required
ALERT
Geriatric Considerations
• Before entering a chronic care facility, patients should have a PPD using 2-step protocols.
• INH side effects are more pronounced.
Pediatric Considerations
• Protocol for newborn with mother/household contact with infection or disease
- If mother or household contact has LTBI, skin test all household contacts and treat any with positive PPD
- If contact has abnormal chest radiograph, separate infant until infectious status known; if not contagious, monitor infant PPD (5)
- If mother has disease and is possibly contagious, evaluate infant for congenital TB and test for HIV; separate newborn until mother is noninfectious (5)
- If congenital TB is suspected, treat.
- If there is no congenital disease, start INH and repeat PPD after 3-4 months. If positive, reassess infant and finish 9 months INH. If PPD is negative and source is noninfectious, stop INH and monitor infant. (5)
• Consider BCG
MEDICATION (DRUGS)
• INH scored tablets: 100 mg, 300 mg, or syrup 10 mg/mL
- Daily: Adult 300 mg; pediatric 10-15 mg/kg (maximum 300 mg) (3,5)
- Twice weekly: Adult 15 mg/kg; pediatric 20-30 mg/kg (maximum 900 mg) (3,5)
• RIF capsules: 150/300 or syrup 10 mg/mL
- Daily: Adult 600 mg; pediatric 10-20 mg/kg (maximum 600 mg) (3,5)
- Twice weekly: Adult 600 mg; pediatric 10-20 mg/kg (maximum 600 mg) (3,5)
• PZA scored tablets: 500 mg
- Daily: Adult 15-25 mg/kg (maximum 2 g); pediatric 20-40 mg/kg (maximum 2 g) (3,5)
- Twice weekly: Adult 50 mg/kg; pediatric 50 mg/kg (maximum 4 g)
• Precautions
- RIF and PZA may cause hepatitis. (3)
- Follow liver function if the patient has history of liver dysfunction or new signs develop.
- RIF colors urine, tears, and secretions orange. May permanently stain contact lenses. (3)
- INH: Peripheral neuritis and hypersensitivity are possible. Consider pyridoxine. (3)
- PZA may increase uric acid. (3)
- Avoid PZA during pregnancy.
• Significant possible interactions: RIF alters the level of phenytoin (Dilantin), antivirals (3), and other drugs metabolized by the liver; may inactivate birth control pills (recommend barrier method).
• Women may breast-feed while taking TB drugs.
FOLLOW-UP
PROGNOSIS
Generally few complications and effective if drugs are taken for full course as prescribed
COMPLICATIONS
Recrudescent TB
PATIENT MONITORING
• During preventive therapy for LTBI: Initial monthly visits to assess adherence to regimen and to monitor for hepatitis and neuropathy; if stable, can monitor less frequently.
• If patient remains asymptomatic, repeat chest radiograph is not needed.
• Check liver enzymes if patient is symptomatic, is HIV positive, has chronic liver disease, uses alcohol, or is pregnant or postpartum, and modify drugs if needed.
• RIF plus PZA treatment of LTBI requires special monitoring. Dispense only 2-week supply of RIF-PZA. Reevaluate in person at 2, 4, 6, and 8 weeks; test liver enzymes and bilirubin at baseline 2, 4, and 6 weeks. Stop treatment if bilirubin is above normal or symptoms of hepatitis with enzymes are above normal or enzymes are 5 times normal. (5)
REFERENCES
1. Centers for Disease Control and Prevention. Controlling Tuberculosis in the United States: Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2005;54(RR-12):1-80.
2. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: Principles and revised recommendations. MMWR Recomm Rep. 1998;47(RR-20):1-58.
3. Blumberg HM, Leonard MK, Jasmer RM. Update on the treatment of tuberculosis. Part II. Dis Mon. 1997;43:181-274.
4. Campos-Outcalt D. When, and when not, to use the interferon-gamma TB blood test. J Fam Pract. 2005;54:873-875.
5. American Academy of Pediatrics. Report of the Committee on Infectious Diseases (Red Book). Elk Grove Village, IL: American Academy of Pediatrics; 2003.
6. Centers for Disease Control and Prevention. Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection United States, 2003. MMWR. 2003;52:735-738.
MISCELLANEOUS
• BCG vaccine, live attenuated M. bovis: Used more commonly in developing countries to prevent complications of TB
• See also: Tuberculosis
BASICS
DESCRIPTION
Tuberculosis (TB) is a common infection transmitted by inhaling airborne bacilli from a person with active tuberculosis. The bacilli multiply in the alveolus and are carried by macrophages, lymphatics, and blood to distant sites (e.g., lung pleura, brain, kidney, bone). Tissue hypersensitivity halts infection within 10 weeks.
• Latent tuberculosis infection (LTBI) is asymptomatic, noninfectious, and usually detected by a positive skin test (evidence of prior TB infection by purified protein derivative [PPD] or chest radiograph, but acid-fast bacilli smear and culture are negative and chest radiograph does not suggest active TB).
• TB: Active disease occurs in 5-10% of infected individuals without preventive therapy. (1) Chance of disease increases with immunosuppression and is highest for all individuals within 2 years after infection; 85% of the cases are pulmonary, which is infectious.
• Recrudescent TB: The active disease occurs after a period of latent asymptomatic infection.
• System(s) Affected: Asymptomatic
GENERAL PREVENTION
Treatment of LTBI is also preventive: To decrease the incidence of TB in both the individuals treated and to decrease the risk to close contacts should active TB occur.
EPIDEMIOLOGY
• TB screening of high risk groups (e.g., recent immigrants from Asia, Latin America, and Africa; pockets of homelessness; history of drug use; history of incarceration). (1)
• Recrudescent disease: Adults and elderly, HIV infected, those newly exposed, including pediatric population
• Predominant sex: Male > Female
Prevalence
In the US, 10-15 million people have the latent infection. (1)
RISK FACTORS
• Immigrant within 5 years (from Asia, Africa, Latin America); including migrant workers
• HIV infection, immunosuppression
• Close contact with infected individual
• Institutional environment (e.g., prison, nursing home)
• Use of illicit drugs
• Lower socioeconomic or homeless
• Health care workers
• Chronic disease such as diabetes mellitus, end-stage renal disease, canceror silicosis.
ETIOLOGY
Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium africanum
ASSOCIATED CONDITIONS
• HIV infection (see "Tests")
• Immune suppression
DIAGNOSIS
SIGNS AND SYMPTOMS
None
History
History of recent immigration from a high-risk area, history of IV drug use and/or drug treatment, HIV, homelessness, recent incarceration (1)
TESTS
• HIV test recommended to assess risk for active TB in men who have sex with men or persons with a history of IV drug use
• PPD: 5 units (0.1 mL) intermediate strength intradermal volar forearm. Measure induration at 48-72 hours.
- Positive if induration is >5 mm and patient has HIV infection (or suspected) (2), is immunosuppressed, had recent close TB contact, or has clinical evidence of active or old disease on chest radiograph; induration is >10 mm and patient is 4 years old or has other risk factors noted above; or induration is >15 mm and patient is >4 years old and has no risk factors (3)
- Negative if induration is 5 mm on initial test and, if indicated, on 2nd test. Utilize the 2-step test if patient has had no recent PPD and is >55 years old, or is a nursing home resident, prison inmate, or health care worker (administer a 2nd intradermal test 1-3 weeks after initial test; measure and interpret as usual). (3)
- The interferon-gamma blood test or QuantiFERON-TB and QuantiFERON-TB GOLD, measure the release of interferon-gamma by sensitized lymphocytes when exposed to antigens of M. tuberculosis. It is unaffected by prior Bacillus Calmette-Guerin (BCG) vaccination, requires only 1 patient visit, has improved sensitivity and specificity, but is costly. (4)
- Do not use BCG vaccination as a reason to ignore a positive PPD in adults and forego recommendation for treatment.
• The multiple puncture (Tine) test is not recommended.
Lab
• None routinely recommended
- BCG vaccine: False-positive skin test but unreliable and should not influence decision to treat LTBI
- Steroids: False-negative skin test
- Measles vaccine: May suppress tuberculin activity; simultaneous PPD and measles vaccine recommended; if not simultaneous, defer PPD 4-6 weeks after measles vaccine
• Disorders that may alter results: False-negative skin test
- Recent viral infection
- New (10 weeks) infection
- Severe malnutrition
- HIV
- Anergy
- Age 6 months
- Overwhelming TB
Imaging
• Chest radiography required to rule out TB in asymptomatic infected persons
• CT of the chest-good sensitivity
DIFFERENTIAL DIAGNOSIS
Fungal infections, especially other atypical mycobacteria or nocardia
TREATMENT
GENERAL MEASURES
• Treat LTBI at any age if patient has HIV, has had close TB contact, is a recent converter (2 years), is an IV drug user, has an abnormal chest radiograph, has a high-risk medical condition, or is in another high-risk group. (1) Use isoniazid (INH) daily for 9 months [A] or an accepted alternative
- INH twice weekly for 9 months with directly observed treatment (DOT) [B]
- INH daily or twice weekly for 6 months with DOT (B)
- Rifampin (RIF) daily for 4 months [B] RIF plus pyrazinamide (PZA) daily for 2 months or twice weekly for 2-3 months [D]; special monitoring for hepatic toxicity required (preferred if patient is INH resistant). For inactive pulmonary TB on chest radiograph, use INH for 9 months
- Consider INH resistance
- DOT is recommended if patient adherence is not assured
• Careful reevaluation required; change to twice weekly dosing only if using DOT
• Treat LTBI during pregnancy if patient has recent infection or is HIV positive (use INH with pyridoxine and monitor liver enzymes); otherwise, treatment may be postponed until postpartum (2)
Diet
Regular, consider pyridoxine supplement: 10-50 mg/d
Activity
• As tolerated
• No isolation required
ALERT
Geriatric Considerations
• Before entering a chronic care facility, patients should have a PPD using 2-step protocols.
• INH side effects are more pronounced.
Pediatric Considerations
• Protocol for newborn with mother/household contact with infection or disease
- If mother or household contact has LTBI, skin test all household contacts and treat any with positive PPD
- If contact has abnormal chest radiograph, separate infant until infectious status known; if not contagious, monitor infant PPD (5)
- If mother has disease and is possibly contagious, evaluate infant for congenital TB and test for HIV; separate newborn until mother is noninfectious (5)
- If congenital TB is suspected, treat.
- If there is no congenital disease, start INH and repeat PPD after 3-4 months. If positive, reassess infant and finish 9 months INH. If PPD is negative and source is noninfectious, stop INH and monitor infant. (5)
• Consider BCG
MEDICATION (DRUGS)
• INH scored tablets: 100 mg, 300 mg, or syrup 10 mg/mL
- Daily: Adult 300 mg; pediatric 10-15 mg/kg (maximum 300 mg) (3,5)
- Twice weekly: Adult 15 mg/kg; pediatric 20-30 mg/kg (maximum 900 mg) (3,5)
• RIF capsules: 150/300 or syrup 10 mg/mL
- Daily: Adult 600 mg; pediatric 10-20 mg/kg (maximum 600 mg) (3,5)
- Twice weekly: Adult 600 mg; pediatric 10-20 mg/kg (maximum 600 mg) (3,5)
• PZA scored tablets: 500 mg
- Daily: Adult 15-25 mg/kg (maximum 2 g); pediatric 20-40 mg/kg (maximum 2 g) (3,5)
- Twice weekly: Adult 50 mg/kg; pediatric 50 mg/kg (maximum 4 g)
• Precautions
- RIF and PZA may cause hepatitis. (3)
- Follow liver function if the patient has history of liver dysfunction or new signs develop.
- RIF colors urine, tears, and secretions orange. May permanently stain contact lenses. (3)
- INH: Peripheral neuritis and hypersensitivity are possible. Consider pyridoxine. (3)
- PZA may increase uric acid. (3)
- Avoid PZA during pregnancy.
• Significant possible interactions: RIF alters the level of phenytoin (Dilantin), antivirals (3), and other drugs metabolized by the liver; may inactivate birth control pills (recommend barrier method).
• Women may breast-feed while taking TB drugs.
FOLLOW-UP
PROGNOSIS
Generally few complications and effective if drugs are taken for full course as prescribed
COMPLICATIONS
Recrudescent TB
PATIENT MONITORING
• During preventive therapy for LTBI: Initial monthly visits to assess adherence to regimen and to monitor for hepatitis and neuropathy; if stable, can monitor less frequently.
• If patient remains asymptomatic, repeat chest radiograph is not needed.
• Check liver enzymes if patient is symptomatic, is HIV positive, has chronic liver disease, uses alcohol, or is pregnant or postpartum, and modify drugs if needed.
• RIF plus PZA treatment of LTBI requires special monitoring. Dispense only 2-week supply of RIF-PZA. Reevaluate in person at 2, 4, 6, and 8 weeks; test liver enzymes and bilirubin at baseline 2, 4, and 6 weeks. Stop treatment if bilirubin is above normal or symptoms of hepatitis with enzymes are above normal or enzymes are 5 times normal. (5)
REFERENCES
1. Centers for Disease Control and Prevention. Controlling Tuberculosis in the United States: Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2005;54(RR-12):1-80.
2. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: Principles and revised recommendations. MMWR Recomm Rep. 1998;47(RR-20):1-58.
3. Blumberg HM, Leonard MK, Jasmer RM. Update on the treatment of tuberculosis. Part II. Dis Mon. 1997;43:181-274.
4. Campos-Outcalt D. When, and when not, to use the interferon-gamma TB blood test. J Fam Pract. 2005;54:873-875.
5. American Academy of Pediatrics. Report of the Committee on Infectious Diseases (Red Book). Elk Grove Village, IL: American Academy of Pediatrics; 2003.
6. Centers for Disease Control and Prevention. Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection United States, 2003. MMWR. 2003;52:735-738.
MISCELLANEOUS
• BCG vaccine, live attenuated M. bovis: Used more commonly in developing countries to prevent complications of TB
• See also: Tuberculosis
TUBERCULOSIS
TUBERCULOSIS, CNS - Linda M. Spooner, PharmD, BCPS; Edward Liu, MD
BASICS
DESCRIPTION
• Tuberculosis (TB) of the CNS is a granulomatous infection of the brain, meninges, or spinal cord caused by Mycobacterium tuberculosis. Clinical forms include tuberculous meningitis, intracranial tuberculoma, spinal tuberculoma, and spinal tuberculous arachnoiditis.
• Uncommon manifestations of CNS TB: En-plaque granulomas, tuberculous abscesses, pituitary TB, and tuberculous ventriculitis. Spinal cord infection is less common but results in arachnoiditis, focal intramedullary tuberculomas, or abscesses.
• System(s) Affected: Endocrine/Metabolic, Nervous
GENERAL PREVENTION
• Treatment of other sites of infection
• Aggressive and complete antitubercular therapy to prevent recurrence or major sequelae
EPIDEMIOLOGY
• Predominant age
- Tuberculous meningitis: Highest incidence in 1st 3 years of life in TB-endemic areas; highest incidence in adults in countries with low incidence of TB (e.g., U.S.)
- Intracranial tuberculomas: Majority of patients are 30 years of age
• Predominant sex: Male = Female
Incidence
• In the US: The incidence of TB is 4.8/100,000. CNS involvement: 15% of extrapulmonary TB cases
• Worldwide, the incidence of TB continues to increase, with an overall incidence of 140/100,000. CNS tuberculomas account for ~20% of all intracranial mass lesions.
• In developing countries, intracranial tuberculomas occur in ~ 20% of TB meningitis.
Prevalence
• 1.7 billion worldwide are infected with TB.
• Prevalence of CNS TB varies depending on region of the world, public health infrastructure, and socioeconomic status.
RISK FACTORS
• CNS TB more common in immunosuppressed patients (e.g., old or young, HIV+ patients, diabetics, users of steroids or cytotoxic drugs)
• Immigrants from TB-endemic areas
• History of pulmonary TB
• Exposure to population with high rates of TB (e.g., health care professionals, prison workers)
Genetics
Host immune response is related to incompletely understood genetic factors.
PATHOPHYSIOLOGY
• Tuberculous infection spreads hematogenously to the CNS, generally from a pulmonary focus. Infection starts as a subpial or subependymal cortical focus (Rich focus).
• Meningitis results from rupture of a Rich focus into the subarachnoid space. Meningitis causes communicating or obstructive hydrocephalus and cranial neuropathies.
• Tuberculomas result from coalescence of granulomas or as a paradoxical reaction despite adequate drug therapy.
ETIOLOGY
Mycobacterium tuberculosis
ASSOCIATED CONDITIONS
• HIV
• Deep cerebral infarcts
• TB osteomyelitis of spine
DIAGNOSIS
SIGNS AND SYMPTOMS
• Malaise
• Fever
• Headache
• Meningismus
• Vomiting
• Confusion/decreased consciousness
• Cranial nerve palsy
• Coma
• Hemiparesis
• Hyponatremia secondary to syndrome of inappropriate antidiuretic hormone (SIADH)
• Seizures
• Signs of extracranial TB
TESTS
• PCR of CSF has sensitivity of 56% and specificity of 98%. (1)[A]
• Culture (M. tuberculosis direct test [MTD]) with Ziehl-Neelsen (ZN) staining of CSF have similar accuracy prior to treatment initiation. (1)[B]
Lab
• General labs
- Purified protein derivative (PPD) tuberculin skin test may be of limited value in many patients, since active TB infection may suppress reactivity (anergy). (2)[C]
• CSF study in tuberculous meningitis
- Moderate elevation in protein
- Lymphocytic predominance
- Normal or slightly low glucose
- Tubercle bacilli found on direct smear in 10-20%, depending on quality
- Cultures grow in 4-8 wks but DNA probes may provide preliminary identification
• CSF study in tuberculomas
- Isolated from subarachnoid space due to thick capsule, so rare CSF changes seen
• Drugs that may alter lab results
- Steroids may alter CSF and give false negative skin test results.
- Antituberculous therapy
• Disorders that may alter lab results
• Immunodeficient states (e.g., HIV) may give false negative skin test results.
ALERT
Geriatric Considerations
May have atypical clinical presentation and CSF findings
Imaging
• CT scan of head with contrast
- Useful for revealing
Hydrocephalus
Tuberculomas
Cerebral edema
Basilar meningeal involvement
Response to treatment
- Can be normal
• MRI scan
- In tuberculous meningitis, MRI more sensitive in demonstrating early infarcts or brainstem, midbrain, basal ganglion lesions than CT
- Solid tuberculomas iso- or hypointense on T1-weighted images and hyperintense on T2 with ring enhancement.
Diagnostic Procedures/Surgery
• Need lumbar puncture for diagnosis and monitoring response to therapy. (3)[C]
• CT-guided stereotactic brain biopsy is helpful in differentiating tuberculomas from other space-occupying lesions. (4)[A]
Pathological Findings
• In tuberculous meningitis
- Thick tubercular exudates seen in the basal cisterns and sylvian fissures
- Hydrocephalus common
- Exudates in basal cisterns compress vessels, with subsequent ischemia
• In tuberculoma
- Well-defined avascular lesions composed of a necrotic caseous center surrounded by a tuberculous granulation tissue; TB bacilli can be present in this granulation tissue.
- Surrounding brain shows edema.
- Occurs at any site; may adhere to dura
• Tuberculous bacilli are difficult to culture from tuberculomas.
• Immunohistochemical demonstration of mycobacterial antigen is possible from tuberculoma tissue.
DIFFERENTIAL DIAGNOSIS
• Tuberculous meningitis
- Meningitis (e.g., chronic, viral, fungal, bacterial, carcinomatous)
- Sarcoidosis
- Lymphoma
• Intracranial tuberculoma
- Granulomas (e.g., sarcoid, fungal)
- Pyogenic abscess
- Metastasis
- Glioma
• Spinal tuberculoma
- Intramedullary tumors
- Syringomyelia
- Spinal abscess
- Myelitis
TREATMENT
• Best evidence suggests that Initial treatment should include 4-drug therapy with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 7-10 months. Optimal treatment duration is unknown. (3)[B]
• Adjunctive dexamethasone is recommended for tuberculous meningitis and tuberculoma. (5)[A]
STABILIZATION
Often inpatient care needed
GENERAL MEASURES
• Look for other foci of infection.
• Seizure precautions.
• Neuropsychological surveillance is essential.
• Concurrent treatment of HIV, if present.
Diet
Pyridoxine supplementation (25 mg/d) in patients may prevent neuropathy (poor nutritional status, diabetes, HIV infection, pregnancy, alcohol use), especially if taking isoniazid. (3)[C]
Activity
• Appropriate restriction if seizures are present
• Isolation required only if pulmonary disease
ALERT
Pregnancy Considerations
Breast-feeding is not contraindicated. (3)[C]
MEDICATION (DRUGS)
First Line
• Antituberculous medications
- Ist-line agents used in CNS TB are
Isoniazid (INH): Adults: 5 mg/kg PO or IM daily (max 300 mg/d); children: 10-15 mg/kg/d PO or IM (max 300 mg/d)
Rifampin (RIF): Adults: 10 mg/kg/d PO or IV (max 600 mg/d); children: 10-20 mg/kg/d PO or IV (max 600 mg/d)
Ethambutol (EMB): Adults: body weight (BW) 40-55 kg, 800 mg/d PO; BW 56-75 kg, 1200 mg/d PO; BW 76-90 kg, 1600 mg; children: 15-20 mg/kg/d (max 1000 mg/d)
Pyrazinamide (PZA): Adults: BW 40-55 kg, 1000 mg/d PO; BW 56-75 kg, 1500 mg/d PO; BW 76-90 kg, 2000 mg/d PO; children: 15-30 mg/kg/d (max 2000 mg/d)
- Usual regimen: INH + RIF + EMB + PZA for 2 months, followed by INH + RIF for 7-10 months (3)[B]
- Other drugs are added when drug resistance is suspected.
• Corticosteroids
- Steroids are recommended for patients with meningitis (5)[A] or tuberculoma. (3)[C]
- Dosing (IV or PO)
Adults and children >25 kg: 12 mg/d dexamethasone
Children 25 kg: 8 mg/d
- Continue full-dose steroids for 3 weeks, followed by taper over 3 more weeks.
• Anticonvulsants
- High incidence of seizures in tuberculomas requires the routine use of anticonvulsants.
- Phenytoin or carbamazepine
• Diuretics
- Furosemide or acetazolamide used for communicating hydrocephalus. (6)[C]
• Contraindications
- INH: Acute liver disease, previous INH-associated hepatitis
- RIF: Concomitant use of some HIV antiretrovirals, hypersensitivity to RIF
- EMB: Optic neuritis, patients unable to report visual adverse effects (e.g., young children)
- PZA: Severe hepatic dysfunction
• Precautions
- INH: Peripheral neuropathy, rash, elevated liver function tests, psychosis, lupuslike syndrome, hepatitis, seizures, optic neuritis
- RIF: Hepatotoxicity, red-orange colored body fluids, gastrointestinal distress
- EMB: Optic neuritis (color blindness, decreased visual acuity), rash, dizziness, hyperuricemia
- PZA: Transient rash, hyperuricemia, hepatotoxicity, arthralgias
• Significant possible interactions
- INH inhibits the metabolism of phenytoin, carbamazepine, warfarin, and theophylline, resulting in elevated serum concentrations of these drugs. Monitor closely.
- RIF has numerous significant drug interactions due to its potent hepatic enzyme-inducing effects. Consult prescribing information for details.
- Antacids decrease the absorption of EMB.
Second Line
• 2nd-line drugs include streptomycin, ethionamide, kanamycin, capreomycin, cycloserine, and fluoroquinolones.
• Reserved for patients with resistant TB or intolerance to 1st-line agents (3)[C]
ALERT
Pregnancy Considerations
• Streptomycin and fluoroquinolones are not recommended.
• Anticonvulsants must be properly chosen.
SURGERY
• Tuberculous meningitis
- Surgical diversion of CSF when tuberculous meningitis associated with symptomatic elevated intracranial pressure and noncommunicating hydrocephalus (ventriculoperitoneal shunt preferred) (7)[B]
• Tuberculoma
- Surgical intervention for decompression or debulking of large, symptomatic tuberculomas is required. (8)[C]
- Surgery considered for treatment failures or to relieve elevated intracranial pressure. Antituberculous therapy is continued to prevent seeding of meninges. (2)[C]
FOLLOW-UP
PROGNOSIS
• In tuberculous meningitis and tuberculomas, prognosis depends on age, duration of symptoms, and neurologic status.
• 10-30% of patients have permanent neurologic deficits.
COMPLICATIONS
• Visual deterioration
• Focal deficits
• Cognitive deterioration
• Paraplegia
• Hormonal deficiencies
• Shunt block
• Shunt infection
• Side effects of antituberculous therapy
PATIENT MONITORING
• Liver function tests
• Uric acid
• Assessment of peripheral neuropathy
• Monthly visual acuity and red-green color discrimination testing if receiving EMB therapy
• Anticonvulsant medication serum levels
• Attention to possible drug-drug interactions.
• Contrast-enhanced CT scan in patients with tuberculoma on medical treatment every 3-6 months until complete resolution of symptoms
• Hormonal evaluation (e.g., thyroid-stimulating hormone, cortisol, prolactin) in pituitary TB
REFERENCES
1. Thwaites GE, Hien TT. Tuberculous meningitis: Many questions, too few answers. Lancet Neurol 2005;4:160-170.
2. Afghani B, Lieberman JM. Paradoxical enlargement or development of intracranial tuberculomas during therapy: Case report and review. Clin Infect Dis 1994;19:1092-1099.
3. American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-77.
4. Gropper MR, Schulder M, Sharan AD, Cho E-S. Central nervous system tuberculosis: Medical management and surgical indications. Surg Neurol 1995;44:378-385.
5. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Database Syst Rev 2000;(3):CD02244.
6. Donald PR, Schoeman JF. Tuberculous meningitis. N Engl J Med 2004;351:1719-1720.
7. Thwaites G, Chau TTH, Mai NTH, Drobinewski F, McAdam K, Farrar J. Tuberculous meningitis. J Neurol Neurosurg Psychiatry 2000;68:289-299.
8. Jain SK, Kwon P, Moss WJ. Management and outcomes of intracranial tuberculomas developing during antituberculous therapy: Case report and review. Clin Pediatr 2005;44:443-450.
MISCELLANEOUS
See also: Tuberculosis
BASICS
DESCRIPTION
• Tuberculosis (TB) of the CNS is a granulomatous infection of the brain, meninges, or spinal cord caused by Mycobacterium tuberculosis. Clinical forms include tuberculous meningitis, intracranial tuberculoma, spinal tuberculoma, and spinal tuberculous arachnoiditis.
• Uncommon manifestations of CNS TB: En-plaque granulomas, tuberculous abscesses, pituitary TB, and tuberculous ventriculitis. Spinal cord infection is less common but results in arachnoiditis, focal intramedullary tuberculomas, or abscesses.
• System(s) Affected: Endocrine/Metabolic, Nervous
GENERAL PREVENTION
• Treatment of other sites of infection
• Aggressive and complete antitubercular therapy to prevent recurrence or major sequelae
EPIDEMIOLOGY
• Predominant age
- Tuberculous meningitis: Highest incidence in 1st 3 years of life in TB-endemic areas; highest incidence in adults in countries with low incidence of TB (e.g., U.S.)
- Intracranial tuberculomas: Majority of patients are 30 years of age
• Predominant sex: Male = Female
Incidence
• In the US: The incidence of TB is 4.8/100,000. CNS involvement: 15% of extrapulmonary TB cases
• Worldwide, the incidence of TB continues to increase, with an overall incidence of 140/100,000. CNS tuberculomas account for ~20% of all intracranial mass lesions.
• In developing countries, intracranial tuberculomas occur in ~ 20% of TB meningitis.
Prevalence
• 1.7 billion worldwide are infected with TB.
• Prevalence of CNS TB varies depending on region of the world, public health infrastructure, and socioeconomic status.
RISK FACTORS
• CNS TB more common in immunosuppressed patients (e.g., old or young, HIV+ patients, diabetics, users of steroids or cytotoxic drugs)
• Immigrants from TB-endemic areas
• History of pulmonary TB
• Exposure to population with high rates of TB (e.g., health care professionals, prison workers)
Genetics
Host immune response is related to incompletely understood genetic factors.
PATHOPHYSIOLOGY
• Tuberculous infection spreads hematogenously to the CNS, generally from a pulmonary focus. Infection starts as a subpial or subependymal cortical focus (Rich focus).
• Meningitis results from rupture of a Rich focus into the subarachnoid space. Meningitis causes communicating or obstructive hydrocephalus and cranial neuropathies.
• Tuberculomas result from coalescence of granulomas or as a paradoxical reaction despite adequate drug therapy.
ETIOLOGY
Mycobacterium tuberculosis
ASSOCIATED CONDITIONS
• HIV
• Deep cerebral infarcts
• TB osteomyelitis of spine
DIAGNOSIS
SIGNS AND SYMPTOMS
• Malaise
• Fever
• Headache
• Meningismus
• Vomiting
• Confusion/decreased consciousness
• Cranial nerve palsy
• Coma
• Hemiparesis
• Hyponatremia secondary to syndrome of inappropriate antidiuretic hormone (SIADH)
• Seizures
• Signs of extracranial TB
TESTS
• PCR of CSF has sensitivity of 56% and specificity of 98%. (1)[A]
• Culture (M. tuberculosis direct test [MTD]) with Ziehl-Neelsen (ZN) staining of CSF have similar accuracy prior to treatment initiation. (1)[B]
Lab
• General labs
- Purified protein derivative (PPD) tuberculin skin test may be of limited value in many patients, since active TB infection may suppress reactivity (anergy). (2)[C]
• CSF study in tuberculous meningitis
- Moderate elevation in protein
- Lymphocytic predominance
- Normal or slightly low glucose
- Tubercle bacilli found on direct smear in 10-20%, depending on quality
- Cultures grow in 4-8 wks but DNA probes may provide preliminary identification
• CSF study in tuberculomas
- Isolated from subarachnoid space due to thick capsule, so rare CSF changes seen
• Drugs that may alter lab results
- Steroids may alter CSF and give false negative skin test results.
- Antituberculous therapy
• Disorders that may alter lab results
• Immunodeficient states (e.g., HIV) may give false negative skin test results.
ALERT
Geriatric Considerations
May have atypical clinical presentation and CSF findings
Imaging
• CT scan of head with contrast
- Useful for revealing
Hydrocephalus
Tuberculomas
Cerebral edema
Basilar meningeal involvement
Response to treatment
- Can be normal
• MRI scan
- In tuberculous meningitis, MRI more sensitive in demonstrating early infarcts or brainstem, midbrain, basal ganglion lesions than CT
- Solid tuberculomas iso- or hypointense on T1-weighted images and hyperintense on T2 with ring enhancement.
Diagnostic Procedures/Surgery
• Need lumbar puncture for diagnosis and monitoring response to therapy. (3)[C]
• CT-guided stereotactic brain biopsy is helpful in differentiating tuberculomas from other space-occupying lesions. (4)[A]
Pathological Findings
• In tuberculous meningitis
- Thick tubercular exudates seen in the basal cisterns and sylvian fissures
- Hydrocephalus common
- Exudates in basal cisterns compress vessels, with subsequent ischemia
• In tuberculoma
- Well-defined avascular lesions composed of a necrotic caseous center surrounded by a tuberculous granulation tissue; TB bacilli can be present in this granulation tissue.
- Surrounding brain shows edema.
- Occurs at any site; may adhere to dura
• Tuberculous bacilli are difficult to culture from tuberculomas.
• Immunohistochemical demonstration of mycobacterial antigen is possible from tuberculoma tissue.
DIFFERENTIAL DIAGNOSIS
• Tuberculous meningitis
- Meningitis (e.g., chronic, viral, fungal, bacterial, carcinomatous)
- Sarcoidosis
- Lymphoma
• Intracranial tuberculoma
- Granulomas (e.g., sarcoid, fungal)
- Pyogenic abscess
- Metastasis
- Glioma
• Spinal tuberculoma
- Intramedullary tumors
- Syringomyelia
- Spinal abscess
- Myelitis
TREATMENT
• Best evidence suggests that Initial treatment should include 4-drug therapy with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 7-10 months. Optimal treatment duration is unknown. (3)[B]
• Adjunctive dexamethasone is recommended for tuberculous meningitis and tuberculoma. (5)[A]
STABILIZATION
Often inpatient care needed
GENERAL MEASURES
• Look for other foci of infection.
• Seizure precautions.
• Neuropsychological surveillance is essential.
• Concurrent treatment of HIV, if present.
Diet
Pyridoxine supplementation (25 mg/d) in patients may prevent neuropathy (poor nutritional status, diabetes, HIV infection, pregnancy, alcohol use), especially if taking isoniazid. (3)[C]
Activity
• Appropriate restriction if seizures are present
• Isolation required only if pulmonary disease
ALERT
Pregnancy Considerations
Breast-feeding is not contraindicated. (3)[C]
MEDICATION (DRUGS)
First Line
• Antituberculous medications
- Ist-line agents used in CNS TB are
Isoniazid (INH): Adults: 5 mg/kg PO or IM daily (max 300 mg/d); children: 10-15 mg/kg/d PO or IM (max 300 mg/d)
Rifampin (RIF): Adults: 10 mg/kg/d PO or IV (max 600 mg/d); children: 10-20 mg/kg/d PO or IV (max 600 mg/d)
Ethambutol (EMB): Adults: body weight (BW) 40-55 kg, 800 mg/d PO; BW 56-75 kg, 1200 mg/d PO; BW 76-90 kg, 1600 mg; children: 15-20 mg/kg/d (max 1000 mg/d)
Pyrazinamide (PZA): Adults: BW 40-55 kg, 1000 mg/d PO; BW 56-75 kg, 1500 mg/d PO; BW 76-90 kg, 2000 mg/d PO; children: 15-30 mg/kg/d (max 2000 mg/d)
- Usual regimen: INH + RIF + EMB + PZA for 2 months, followed by INH + RIF for 7-10 months (3)[B]
- Other drugs are added when drug resistance is suspected.
• Corticosteroids
- Steroids are recommended for patients with meningitis (5)[A] or tuberculoma. (3)[C]
- Dosing (IV or PO)
Adults and children >25 kg: 12 mg/d dexamethasone
Children 25 kg: 8 mg/d
- Continue full-dose steroids for 3 weeks, followed by taper over 3 more weeks.
• Anticonvulsants
- High incidence of seizures in tuberculomas requires the routine use of anticonvulsants.
- Phenytoin or carbamazepine
• Diuretics
- Furosemide or acetazolamide used for communicating hydrocephalus. (6)[C]
• Contraindications
- INH: Acute liver disease, previous INH-associated hepatitis
- RIF: Concomitant use of some HIV antiretrovirals, hypersensitivity to RIF
- EMB: Optic neuritis, patients unable to report visual adverse effects (e.g., young children)
- PZA: Severe hepatic dysfunction
• Precautions
- INH: Peripheral neuropathy, rash, elevated liver function tests, psychosis, lupuslike syndrome, hepatitis, seizures, optic neuritis
- RIF: Hepatotoxicity, red-orange colored body fluids, gastrointestinal distress
- EMB: Optic neuritis (color blindness, decreased visual acuity), rash, dizziness, hyperuricemia
- PZA: Transient rash, hyperuricemia, hepatotoxicity, arthralgias
• Significant possible interactions
- INH inhibits the metabolism of phenytoin, carbamazepine, warfarin, and theophylline, resulting in elevated serum concentrations of these drugs. Monitor closely.
- RIF has numerous significant drug interactions due to its potent hepatic enzyme-inducing effects. Consult prescribing information for details.
- Antacids decrease the absorption of EMB.
Second Line
• 2nd-line drugs include streptomycin, ethionamide, kanamycin, capreomycin, cycloserine, and fluoroquinolones.
• Reserved for patients with resistant TB or intolerance to 1st-line agents (3)[C]
ALERT
Pregnancy Considerations
• Streptomycin and fluoroquinolones are not recommended.
• Anticonvulsants must be properly chosen.
SURGERY
• Tuberculous meningitis
- Surgical diversion of CSF when tuberculous meningitis associated with symptomatic elevated intracranial pressure and noncommunicating hydrocephalus (ventriculoperitoneal shunt preferred) (7)[B]
• Tuberculoma
- Surgical intervention for decompression or debulking of large, symptomatic tuberculomas is required. (8)[C]
- Surgery considered for treatment failures or to relieve elevated intracranial pressure. Antituberculous therapy is continued to prevent seeding of meninges. (2)[C]
FOLLOW-UP
PROGNOSIS
• In tuberculous meningitis and tuberculomas, prognosis depends on age, duration of symptoms, and neurologic status.
• 10-30% of patients have permanent neurologic deficits.
COMPLICATIONS
• Visual deterioration
• Focal deficits
• Cognitive deterioration
• Paraplegia
• Hormonal deficiencies
• Shunt block
• Shunt infection
• Side effects of antituberculous therapy
PATIENT MONITORING
• Liver function tests
• Uric acid
• Assessment of peripheral neuropathy
• Monthly visual acuity and red-green color discrimination testing if receiving EMB therapy
• Anticonvulsant medication serum levels
• Attention to possible drug-drug interactions.
• Contrast-enhanced CT scan in patients with tuberculoma on medical treatment every 3-6 months until complete resolution of symptoms
• Hormonal evaluation (e.g., thyroid-stimulating hormone, cortisol, prolactin) in pituitary TB
REFERENCES
1. Thwaites GE, Hien TT. Tuberculous meningitis: Many questions, too few answers. Lancet Neurol 2005;4:160-170.
2. Afghani B, Lieberman JM. Paradoxical enlargement or development of intracranial tuberculomas during therapy: Case report and review. Clin Infect Dis 1994;19:1092-1099.
3. American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-77.
4. Gropper MR, Schulder M, Sharan AD, Cho E-S. Central nervous system tuberculosis: Medical management and surgical indications. Surg Neurol 1995;44:378-385.
5. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Database Syst Rev 2000;(3):CD02244.
6. Donald PR, Schoeman JF. Tuberculous meningitis. N Engl J Med 2004;351:1719-1720.
7. Thwaites G, Chau TTH, Mai NTH, Drobinewski F, McAdam K, Farrar J. Tuberculous meningitis. J Neurol Neurosurg Psychiatry 2000;68:289-299.
8. Jain SK, Kwon P, Moss WJ. Management and outcomes of intracranial tuberculomas developing during antituberculous therapy: Case report and review. Clin Pediatr 2005;44:443-450.
MISCELLANEOUS
See also: Tuberculosis
