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Program Director, Roseman University of Health Sciences

The lesions of polyarteritis affect arteries of medium and small caliber, especially at bifurcations and branchings. The segmental process involves the media, with edema, fibrinous exudation, fibrinoid necrosis, and infiltration of polymorphonuclear neutrophils, and extends to the adventitia and intima. Subsequently the regions of fibrinoid necrosis are replaced by granulation tissue, and the intima proliferates. Finally, the involved segment is replaced by scar tissue with associated intimal thickening and periarterial fibrosis. These changes produce partial occlusion, thrombosis and infarction, and palpable or visible aneurysms with occasional rupture. In allergic angiitis and granulomatosis the acute fibrinoid necrosis with cellular infiltration involves arterioles and venules as well as medium-sized muscular arteries. It is characteristic of the polyarteritis nodosa group for the vascular lesions to be in different stages of evolution, i. In allergic angiitis and granulomatosis, the pulmonary granulomatous lesions in vascular and extravascular sites are accompanied by intense eosinophilic infiltration. The widespread distribution of the arterial lesions produces diverse clinical manifestations that reflect the particular organ systems in which the arterial supply has been impaired. Among the early symptoms and signs of polyarteritis nodosa are fever, weight loss, and pain in viscera and/or the musculoskeletal system. Striking and specific initial signs may relate to abdominal pain, acute glomerulitis, polyneuritis on occasion, or myocardial infarction. Pulmonary manifestations, especially intractable bronchial asthma, would indicate allergic angiitis and granulomatosis rather than classic polyarteritis nodosa. Renal involvement in two forms, renal polyarteritis and glomerulitis, may occur separately or together. Approximately 70% of patients with polyarteritis nodosa and renal disease have renal vasculitis, whereas the other 30% have glomerulitis. Manifestations of the renal involvement include intermittent proteinuria and microscopic hematuria with occasional hyaline and granular casts. The glomerulitis is manifested by microscopic and even macroscopic hematuria, proteinuria, cellular casts, and progressive renal failure. Renal involvement is the cause of death in about two thirds of patients with classic polyarteritis nodosa and about one third with allergic angiitis and granulomatosis. The principal manifestation is pain; anorexia, nausea, and vomiting are less prominent. Impaired arterial blood supply to the bowel can produce mucosal ulceration, perforation, or infarction with melena or bloody diarrhea. Involvement of the appendix, gallbladder, or pancreas can simulate appendicitis, cholecystitis, or hemorrhagic pancreatitis. Liver involvement can range from hepatomegaly with or without jaundice to signs of extensive hepatic necrosis. No consistent relationship has been seen between the development of necrotizing vasculitis and the appearance of liver disease in patients with hepatitis B antigenemia. Some of the combinations observed include necrotizing vasculitis as the initial clinical finding superimposed on chronic active hepatitis or appearing simultaneously with acute hepatitis. Headache, seizures, and retinal hemorrhage and exudate occur with or without localizing signs referable to the cerebrum, cerebellum, or brain stem; meningeal irritation may occur as a result of subarachnoid hemorrhage. The peripheral neuropathy is usually asymmetrical, with both sensory and motor distribution. The former can be extremely painful, but the latter has attendant muscular degeneration that can be so severe that it dominates the clinical picture. Arthralgias are migratory, generally without swelling, and thought to be due to small, localized arterial lesions. Muscle pain or weakness reflects either direct involvement of the arterial supply or a peripheral neuropathy. Polyarteritis of the coronary arteries and their branches has a frequency approaching that of renal polyarteritis, and heart failure is responsible for or contributes to death in one sixth to one half of the cases. Clinical manifestations are partial or complete arterial occlusion, as modified by the superimposition of renal hypertension and an appreciable incidence of acute pericarditis without effusion.

Isolated cases of blastomycosis have been reported worldwide, including Africa and Central and South America; however, the disease is concentrated or endemic in the South and North Central United States, especially in areas bordering the Mississippi and Ohio river basins, and the Great Lakes. In these endemic areas, infection occurs both sporadically and epidemically; small point-source outbreaks of blastomycosis have been associated with recreational or occupational activities in wooded areas along waterways. It is not surprising, therefore, that persons with occupational or avocational exposure to soil and the outdoors appear to be at highest risk of acquiring infection. Data from point-source outbreaks indicate that the median incubation period from exposure to infection is about 43 days, with a range of 3 weeks to 3 months. Animals, especially dogs and horses, are also susceptible to infection, which may progress to clinical disease. This observation suggests that reactivation blastomycosis may be more common than previously suspected. Humans and animals, for the most part, acquire infection by inhaling aerosolized conidia that convert to the yeast form in the lungs at body temperature. The clinical manifestations of disease at body sites other than lung (and rarely skin) result from the hematogenous spread of organisms. T-cell-mediated immunity appears to be the most important arm of host defense against B. In vivo and in vitro studies indicate that macrophages, stimulated by lymphokines, are more effective in inhibiting or killing this yeast than are granulocytes. A growth-inhibiting or protective role of humoral immunity in blastomycosis has not been established. The typical histopathologic picture of pulmonary blastomycosis and other nonmucocutaneous sites of disease consists of noncaseating granulomas as well as clusters of neutrophils. By contrast, cutaneous and mucous membrane lesions are characterized by pseudoepitheliomatous hyperplasia with microabscesses. In general, blastomycosis is a chronic indolent systemic fungal disease associated with a variety of pulmonary and extrapulmonary manifestations. Among the latter, cutaneous disease predominates, occurring in about 40 to 80% of cases. Extrapulmonary disease may occur in the absence of clinical or radiologic evidence of lung disease. Most primary infections are believed to be either asymptomatic or unrecognized as being due to B. In patients with proven acute pulmonary blastomycosis, the radiologic findings usually consist of infiltrative or nodular air space opacities, most often in the lower lobes. By contrast, chronic pulmonary blastomycosis, which is found in about 75% of cases, usually manifests as a chronic pneumonia syndrome, characterized by productive cough, pleuritic chest pain, dyspnea, weight loss, and low-grade fever. Although the disease has no distinguishing radiologic characteristics, consolidation, one or more fibronodular infiltrates, or mass lesions (with or without cavitation) are common, often mimicking the findings in other granulomatous diseases or lung cancer. Patients with overwhelming pulmonary blastomycosis may develop diffuse, bilateral, interstitial alveolar infiltrates on the chest radiograph and clinical evidence of acute respiratory distress syndrome. The cutaneous lesions, which often prompt the patient with blastomycosis to seek medical evaluation initially, are of two general types, verrucous and ulcerative; both types tend to occur more commonly on exposed parts. The verrucous lesions, which begin as papulopustules, are more characteristic; these progress slowly over weeks to months to become crusted, heaped-up, and warty in appearance, often with a reddish-black or violaceous hue, an area of central healing and scarring, and a well-circumscribed outer border. Microabscesses, manifested by black dots on the surface, are typically located at the periphery of verrucous lesions; removing the crusted eschar often reveals purulent material in which the yeast form of the organism can be demonstrated by wet preparation. Ulcerative lesions overlying a bed of friable red granulation tissue are less common. Occasionally, mucosal ulcerations may be found in the mouth, nose, or larynx, mimicking the mucocutaneous lesions of histoplasmosis. After lung and skin disease, bone and joint involvement is next most common and is seen in up to 25% of cases. Osteolytic lesions, with or without sclerotic margins, are typically located in long bones and vertebrae. Often, patients with bone disease present as a result of overlying chronic draining sinuses or contiguous soft tissue lesions rather than bone pain. Septic arthritis, which is much less common than osteomyelitis, is frequently secondary to contiguous extension.

Hypogonadism causes diminished libido, impotence, infertility, and rarely gynecomastia or galactorrhea. Hyperprolactinemia is found in up to 5% of men being evaluated for sexual dysfunction. There are four primary categories of causes of hyperprolactinemia that must be distinguished if the correct therapy is to be instituted: (1) physiologic/metabolic hyperprolactinemia; (2) pharmacologic hyperprolactinemia; (3) hypothalamic or pituitary stalk compression; and (4) prolactinoma (see Table 237-2). In most cases, the degree of hyperprolactinemia caused by drugs is less than 100 ng/mL. A variety of suprasellar and parasellar mass lesions cause hyperprolactinemia (generally between 20-100 ng/mL) because of compression of the hypothalamus or pituitary stalk. When no pituitary lesions are seen by radiographic studies and physiologic and pharmacologic causes of hyperprolactinemia cannot be identified, the diagnosis of idiopathic hyperprolactinemia is made. Whether such patients should be treated depends on the clinical effects of hyperprolactinemia. Although large prolactinomas clearly must evolve from smaller lesions, it is uncommon (approximately 7%) for microprolactinomas to progress to macroadenomas. Because of the slow rate of growth, it is reasonable to monitor patients with microprolactinomas without treatment unless the hyperprolactinemia is causing symptoms that warrant therapy. When hyperprolactinemia causes hypogonadism, osteopenia, or infertility, a dopamine agonist such as bromocriptine or cabergoline is the therapy of choice. After adaptation to the drug, the dose can be increased gradually over several weeks. Dopamine agonists may cause a considerable reduction in tumor size in patients with macroprolactinomas, about 40% having a more than 50% reduction in tumor size, about 25% having a 25 to 50% reduction in tumor size, and the remainder having little or no response. Visual field defects are a very sensitive index of tumor size, and improvements can be seen in about 90% of patients. Thus, it is reasonable to use bromocriptine as first-line therapy even in patients with visual field defects as long as visual acuity is not threatened by rapid progression or recent tumor hemorrhage. In patients with very large tumors who have excellent tumor size reduction, stopping therapy must be done very cautiously, if at all. Cabergoline is a new dopamine agonist that is even more effective and has less adverse side effects than bromocriptine and has the additional advantage in only having to be taken once or twice weekly. In some cases, prolactinomas appear to be resistant to a dopamine agonist, but it is important to ensure compliance and to be certain that the underlying lesion is a prolactinoma and not some other cause of hyperprolactinemia. Although initial remission rates (70 to 80%) for transsphenoidal surgery of microprolactinomas are good, there is long-term recurrence in about 20% of patients. For macroprolactinomas, the initial remission rates are closer to 30%, with a similar recurrence rate. Radiation therapy is reserved for those patients with macroadenomas not responding to either medical or surgical treatment. Bromocriptine therapy for infertility, or when there is a possibility of pregnancy, deserves special consideration. Bromocriptine can induce ovulation in 80 to 90% of patients with hyperprolactinemia. Although bromocriptine has not been associated with congenital malformations or complications during pregnancy, most physicians and patients prefer to avoid its use during pregnancy if possible. A form of barrier contraception is usually recommended until two to three regular menstrual cycles have occurred. Subsequently, pregnancy can be confirmed if a menstrual period is missed, allowing discontinuation of bromocriptine with exposure of the fetus to the drug for only 3 to 5 weeks. At present, the safety data for pregnancy outcome are much more limited for cabergoline; therefore, bromocriptine is the preferred drug when fertility is desired. Less than 2% of patients with microadenomas, but 15% of patients with macroadenomas develop symptoms of tumor enlargement (headaches, visual field defects) during pregnancy. If there is evidence of visual field compromise or tumor growth, bromocriptine therapy should be restarted to shrink the tumor. Because problems of tumor growth occur most often in patients with macroadenomas, consideration should be given to the option of transsphenoidal decompression before pregnancy in women with large tumors, as long as fertility can be preserved.

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