Isolated angiitis of the central nervous systen is a recently recognized vasculitic disorder primarily involving the central nervous system Typical

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patients are in their forties or fifties. Onset is highly variable, usually with a prodrome of 6 months. The most common symptoms are headaches, which can spontaneously remit for long periods. Nonfocal neurologic deficits are characteristic, including a decrease in cognitive function. Any anatomic area can be involved with signs and symptoms, which range from transient ischemic attacks, strokes, paraparesis, and cranial neuropathies to seizures. Cerebrospinal fluid analysis findings are abnormal in more than 90% of patients and include modest pleocytosis, normal glucose levels, and increased protein. The cerebrospinal fluid should be cultured and infection ruled out. MRI and CT have made diagnosis easier; suggestive findings include multiple, bilateral supratentorial infarcts. Angiography has proved less useful. Histologic confirmation through leptomeningeal biopsy is the gold standard. Therapy is with corticosteroids and cyclophosphamide (CTX) and is usually continued for 6 to 12 months after remission.

XI. Polyarteritis nodosa is an acute necrotizing vasculitis of medium-sized and small arteries. Before the 1994 International Chapel Hill Consensus Conference, PAN also included microscopic polyangiitis. After this conference, microscopic polyangiitis was separated from PAN, with involvement of vessels smaller than arterioles indicating microscopic polyangiitis and not PAN. Most series, however, still consider renal involvement with a pattern of microscopic polyangiitis to be part of PAN.

A. Etiology. In most cases, the etiology of PAN is not known; some cases, however, are a consequence of hepatitis B viral infection. In France, hepatitis B-related PAN formerly accounted for about one-third of all cases of PAN, but there has been a decrease in the number of cases since the development of vaccines against hepatitis B. Other viruses (human immunodeficiency virus, cytomegalovirus, parvovirus B19, human T-lymphotrophic virus type 1, hepatitis C virus) are also implicated as etiologic agents.

B. The pathologic lesion that best defines PAN is a focal, segmental, necrotizing vasculitis of medium-sized and small vessels. The existence of uninvolved segments just next to the diseased areas is typical of PAN. The lesion may occur in any artery of the body, but involvement of the aorta and pulmonary arteries is rare. Arterial aneurysms and thromboses can occur at the site of the vascular lesion.

C. Clinical presentation. The majority of patients present with constitutional symptoms (malaise, fever, weight loss), peripheral neuropathy, and gastrointestinal or cutaneous involvement. Peripheral neuropathy is most commonly in the form of painful mononeuritis multiplex or multiple mononeuropathies. Cutaneous lesions are present in 27% to 60% of patients. Vascular purpura is typically papulopetechial. Inflammatory lesions are infrequent, but when present they are the ideal site for biopsy. Livedo reticularis is common. When possible, the biopsy specimen should include the dermis to detect medium-sized vessel involvement. Myalgias and arthralgias are also common. Kidney involvement is diverse and can be vascular or glomerular. According to the type of tissue involvement, it is possible to diagnose two different diseases: microscopic polyangiitis when glomerulonephritis is seen, and PAN when vascular nephropathy is observed. Gastrointestinal involvement can be severe and present with abdominal pain, bleeding, and bowel perforation. Orchitis and epididymitis are also seen in PAN. Although the spectrum of the clinical presentation may vary, most patients will have severe manifestations and appear acutely ill.

D. Laboratory studies. The ESR is usually high. Positivity for ANCA is rare in PAN. Hepatitis B surface antigen (HBsAg) should be sought in all cases. Angiography often shows microaneurysms and stenoses in medium-sized vessels. Although the diagnosis of PAN is clinical, it is useful to demonstrate vasculitis in biopsy specimens. Skin, skeletal muscle, sural nerve, and kidney are the usual sites. Biopsy specimens of apparently unaffected muscles may reveal vasculitis in a small fraction of patients.

E. Treatment. Initial management of PAN without hepatitis B is with high-dose corticosteroids (40 to 60 mg/d). CTX is added for severe cases. Traditionally, oral CTX has been used, but recent studies have shown that IV administration can be as effective as the oral with fewer side effects. In hepatitis B-related PAN, corticosteroids and CTX may allow the virus to persist, which can lead to chronic hepatitis and liver cirrhosis. Good results have been reported treating these patients with a combination of antiviral agents, plasma exchange, and corticosteroids. Relapses are rare in patients who achieve remission.

XII. Kawasaki disease is an acute febrile disease occurring most commonly in infants and children under the age of 5. The first case was described in Japan in 1961.

A. Clinical presentation. Vasculitis, especially of the coronary arteries, is the most serious and life-threatening complication. The onset is typically abrupt, with remitting or continuous high fever that generally lasts 1 to 2 weeks. Within 2 to 4 days of onset, bilateral conjunctival congestion occurs. Dryness, redness, and fissuring of the lips are observed within 2 to 5 days, and a "strawberry" tongue (as in scarlet fever) can be seen. Painful cervical lymphadenopathy appears shortly before or simultaneously with the fever. Exanthema of the trunk and reddening of the palms and soles with consequent desquamation are usual. Cardiovascular involvement can include carditis with heart murmurs and electrocardiographic changes. Coronary artery lesions with dilatation or aneurysms may be seen on echocardiography. Other symptoms include abdominal pain, vomiting, diarrhea, and arthritis. Kawasaki disease should be included in the differential diagnosis of all febrile illnesses associated with rash in children. The angiitis of Kawasaki disease usually lasts about 7 weeks and is most commonly seen in the medium-sized and large arteries, including the coronary and iliac arteries.

B. The etiology of Kawasaki disease is not known. Although many hypotheses involving an infectious cause have been proposed, none has been confirmed.

C. Treatment. Management is supportive in uncomplicated cases. Coronary artery involvement should assessed with two-dimensional echocardiography weekly for the first month. If changes are detected, high-dose IV gamma globulin as a single infusion of 2 g/kg is given. Low-dose aspirin (3 to 5 mg/kg daily) is used until the coronary artery changes regress. Long-term management should include coronary angiography and follow-up for coronary artherosclerosis.

XIII. Wegener's granulomatosis is a relatively rare disease (3 per 100,000 in the United States) with the classic triad of necrotizing granulomatous vasculitis of the upper and lower airways, systemic vasculitis, and focal necrotizing glomerulonephritis. A less aggressive, milder form of WG exists (limited WG), with involvement predominantly in the lungs and an absence of glomerulonephritis, that carries a better prognosis. WG affects male and female subjects at about the same rate, and about 80% to 90% of the patients are white.

A. Clinical presentation. The diagnosis is usually made within 6 months of initial symptoms, but unusual presentations of the mild form may elude diagnosis for years. It is important to distinguish WG from other pulmonary-renal syndromes, such as Goodpasture's syndrome and SLE. Most patients seek care because of upper and lower respiratory tract symptoms. Sinus pain, purulent sinus drainage, nasal mucosal ulceration, and otitis media are common; tracheal inflammation can lead to subglottic stenosis. At presentation, 80% of patients have no renal involvement and 50% have no overt lung disease; however, pulmonary problems, renal problems, or both eventually develop in more than 80% of patients. The glomerulonephritis is characterized by focal necrosis, crescent formation, and an absence or paucity of immunoglobulin deposits. Identical "pauci-immune" necrotizing glomerulonephritis occurs in CSS and microscopic polyangiitis, the other two ANCA-associated small-vessel vasculitides. Other WG manifestations include ocular inflammation, cutaneous purpura, peripheral neuropathy, arthritis, and diverse abdominal visceral involvement. Necrotizing granulomatous pulmonary inflammation produces radiographic densities, and the lesions may cavitate. Alveolar capillaritis can cause pulmonary hemorrhage with irregular infiltrates. Massive pulmonary hemorrhage is a life-threatening manifestation and requires aggressive immunosuppressive treatment.

B. Laboratory data. Patients usually have normochromic, normocytic anemia, leukocytosis, thrombocytosis, and an elevated ESR. WG, in contrast to the immune complex vasculitides, is associated with antineutrophil cytoplasmic antibody (ANCA), especially c-ANCA, which has a 98% specificity but a 30% to 99% sensitivity. Titers are usually associated with disease activity; consequently, only 30% to 40% of patients with limited WG or generalized WG in remission have c-ANCA positivity. A small minority (5%) can be positive for p-ANCA also. The limited form of the disease can be difficult to diagnose on clinical grounds, and the presence of c-ANCA may strongly influence the diagnosis. The strongest diagnostic evidence nonetheless comes from biopsy specimens of the involved tissues, which show granulomas. Lymphomatoid granulomatosis and necrotizing sarcoidosis may be confused with WG. The causative agent(s) leading to granuloma formation are unknown.

C. Treatment. Patients are initially given oral cyclophosphamide (2 mg/kg daily) and oral prednisone (1 mg/kg daily). The prednisone is changed to an alternate-day regimen in about 4 to 6 weeks, and then the dose is gradually tapered. Cyclophosphamide is continued for at least 1 year after complete clinical remission. Leukocyte count is a guide to cyclophosphamide dose adjustment, and one should aim to keep the neutrophil count above 3,000/mm 3 An increased risk for infection, especially with Pneumocystis carinii, and bladder cancer should be kept in mind at all times. When compared with oral cyclophosphamide and corticosteroids, pulse IV cyclophosphamide and corticosteroids are equally effective in achieving initial remission; however, in the long term, treatment with pulse cyclophosphamide does not maintain remission or prevent relapses to the degree that oral cyclophosphamide treatment does. Methotrexate and azathioprine are alternatives to cyclophosphamide in less severe forms of WG, and both have been used for maintenance after achievement of remission in generalized WG. Relapses are associated with respiratory tract infections and with chronic nasal carriage of Staphylococcus aureus. Some studies suggest that trimethoprim/sulfamethoxazole may be useful in inducing remission in the initial phases of WG or in preventing relapses.

XIV. Microscopic polyangiitis is a pauci-immune necrotizing vasculitis of the small vessels without evidence of granulomatous inflammation. ANCA positivity is common.

A. Clinical presentation. Pulmonary and renal involvement are commonly seen, with approximately 90% of patients having glomerulonephritis. Microscopic polyangiitis is the most common cause of pulmonary-renal syndrome. Alveolar hemorrhage can complicate the picture. The onset is usually insidious and the prognosis is more guarded than in classic PAN.

B. Laboratory studies. More than 80% of patients have ANCA, most often p-ANCA. This helps to distinguish microscopic polyangiitis from ANCA-negative small-vessel vasculitis but does not distinguish it from other ANCA-related vasculitides. Pathologically, microscopic polyangiitis can cause a necrotizing vasculitis identical to PAN. At the Chapel Hill Consensus Conference, microscopic polyangiitis and PAN were distinguished by the absence of vasculitis in vessels other than arteries in PAN and the presence of vasculitis in vessels smaller than arteries (arterioles, venules, and capillaries) in microscopic polyangiitis. By this definition, the presence of glomerulonephritis or pulmonary alveolar capillaritis would exclude a diagnosis of PAN.

C. Treatment of microscopic polyangiitis includes corticosteroids and cytotoxic agents; doses and duration of treatment are similar to those used for WG.

High-dose IV steroids, followed by oral steroids and oral or IV cyclophosphamide in cases with major organ involvement, is a useful treatment strategy. About one-third of patients relapse and are treated with a repeated regimen similar to the induction therapy.

XV. Churg-Strauss syndrome is a rare disorder characterized by hypereosinophilia, systemic vasculitis, and necrotizing granulomatous inflammation that occurs in people with asthma and allergic rhinitis. Pulmonary infiltrates occur in up to 90% of patients, and a cutaneous eruption is seen in 70%. Cardiac manifestations (pericarditis, cardiomyopathy, and myocardial infarction) account for about half of deaths. Peripheral neuropathy is found in 70% of patients; its occurrence in susceptible patients is highly suggestive of CSS. Renal disease, seldom seen, is generally mild.

A. Laboratory findings. Approximately 70% of patients have ANCA, more commonly p-ANCA; virtually all have eosinophilia. Anemia and an elevated ESR are also found with active disease. The diagnosis of vasculitis should be substantiated by biopsy of one of the involved tissues.

B. The differential diagnosis of CSS includes WG, microscopic polyangiitis, PAN, chronic eosinophilic pneumonia, and the idiopathic hypereosinophilic syndrome. Neither asthma nor a history of allergies is a prominent feature of WG, in which eosinophilia is rarely found. Renal involvement is less severe in CSS, and the histopathologic features of the granulomatous lesions of CSS and WG are very different. The absence of vasculitis or granuloma formation in chronic eosinophilic pneumonia and in the idiopathic hypereosinophilic syndrome helps to differentiate these entities from CSS.

C. Treatment. Most cases of CSS respond well to corticosteroids. Initial management requires high doses of prednisone (1 mg/kg daily) or the equivalent; methylprednisolone pulses have also been used. Life-threatening complications call for cyclophosphamide in addition to steroids. Both oral and IV pulse cyclophosphamide has been used, with differing rates of success. Relapses are rare after complete remissions.

XVI. Henoch-Schonlein purpura is the most common vasculitis of childhood. Half of the time, it is preceded by an upper respiratory tract infection, but the etiology remains unknown. Boys and girls are affected equally. The median age of onset is 4 years. It follows a self-limiting course in most patients. HSP can accompany familial Mediterranean fever in those regions where the latter is endemic.

A. Clinical presentation. The classic triad is palpable purpura with a normal platelet count, colicky abdominal pain, and arthritis. Palpable purpura occurs in 100% of patients but is the presenting symptom in only half. Dependent areas are usually involved, and involvement of the buttocks is common. Arthritis is transient and usually involves the knees and ankles; there are no permanent sequelae. Up to one-third of patients may experience hemoptysis and half have occult gastrointestinal bleeding, but serious hemorrhage is rare. Ten percent to fifty percent have renal involvement, ranging from transient isolated microscopic hematuria to rapidly progressive glomerulonephritis. HSP and immunoglobulin A (IgA) nephropathy are similar, but the latter is confined to the kidney, whereas the former is a systemic disease.

B. The diagnosis is made on clinical grounds. Laboratory tests may indicate the organs involved and are mostly used to rule out other causes.

C. Treatment is largely supportive and includes hydration and monitoring. Nonsteroidal antiinflammatory drugs (NSAIDs) can be used for joint pain and will not aggravate the purpura. However, they should be avoided if renal insufficiency is present. Corticosteroids have been used in the management of abdominal pain, edema, and nephritis.

XVII. Cryoglobulinemic vasculitis Cryoglobulins are circulating immunoglobulins that precipitate at low temperatures. They are grouped into three categories: type 1, composed of a single monoclonal immunoglobulin; type 2, characterized by polyclonal IgG; and type 3, which is monoclonal or polyclonal IgM. The IgM is an auto-antibody with rheumatoid factor activity. Mixed cryoglobulins lead to immune complex disease by depositing in the vessels, activating complement, and causing inflammation.

A. Clinical presentation. The most frequent manifestations are palpable purpura, arthralgias, and nephritis. Histologic section reveals leukocytoclastic vasculitis. Skin ulcers, Raynaud's phenomenon, hepatic abnormalities, and splenomegaly can also be seen. Hepatitis C virus has been detected in more than 90% of patients with mixed cryoglobulins in various population studies, but the exact pathogenic role of hepatitis C virus in this setting is still unclear. Mixed cryoglobulins and rheumatoid factor are typically detectable in the serum. For reliable detection, blood must be maintained at 37°C during transport and clotting. Serum must then be stored at 4°C for at least 7 days for cryoglobulins to be observed.

B. Cryocrit, a method for detecting and quantifying cryoglobulins, measures the percentage of packed cryoglobulins in graduated test tubes after cold incubation and centrifugation of the serum. The cryocrit is usually between 1% and 3% in type 3 and between 2% and 7% in type 2, and it may be up to 50% in type 1 cryoglobulinemia. There is, however, no correlation between the cryocrit and disease severity. Very low levels of C4 and normal or slightly low levels of C3 are common and aid in the diagnosis. The main cause of morbidity is renal involvement.

C. Treatment. Mild disease with purpura and arthralgias is usually treated with NSAIDs. Serious visceral involvement, such as glomerulonephritis, calls for treatment with corticosteroids and cytotoxic drugs such as CTX and azathioprine. Plasmapheresis has also been used with some success. Recently, interferon-alfa has been successfully used in patients with cryoglobulinemic vasculitis associated with hepatitis C infection. However, further studies are still needed.

XVIII. Pseudovasculitis. These are conditions that obstruct blood flow in vessels without an accompanying inflammation of the vessel wall. They need to be kept in the differential diagnosis of any suspected vasculitis. A useful mnemonic to recall the more frequently seen pseudovasculitic conditions is AMACEC (anti-phospholipid antibody syndrome, myxoma, amyloidosis, cholesterol emboli, endocarditis, and calciphylaxis).

A. Anti-phospholipid antibody syndrome causes both large- and small-vessel occlusions, leading to gangrene, livedo, and skin ulcers. Signs of inflammation, including a raised ESR, are usually absent. It should be kept in mind that anti-phospholipid antibody syndrome may also be seen in the setting of true vasculitis, as in patients with SLE.

B. Myxomas are benign cardiac tumors, most commonly found in the left atrium. They can cause extracardiac symptoms of petechial skin rashes, Raynaud's phenomenon, glomerulonephritis, arthritis, myositis, pleurisy, and pericarditis, often accompanied by fever, increased ESR, leukocytosis, hypocomplementemia, positivity for aNa, and thrombocytopenia. Diagnosis is usually made with echocardiography.

C. Amyloidosis can also sometimes mimic vasculitis and be accompanied by PMR and GCA-type symptoms of scalp tenderness and claudication of the jaw. Histology shows amyloid deposits in the vessel walls.

D. Cholesterol embolism is caused by the shedding of cholesterol crystals from atheromatous plaques. It is most commonly seen in elderly men. It is usually seen in the setting of diffuse atherosclerosis, commonly after abdominal surgery or diagnostic angiography, during which emboli become dislodged. When emboli occlude small arteries, the symptoms are indistinguishable from those of true vasculitis. Livedo reticularis in the lower extremities is common. More serious complications are occlusion of intestinal or coronary arteries. Renal failure may develop. Myalgias with muscle tenderness are common. The key element in diagnosis is clinical suspicion. Histologic demonstration of cholesterol emboli may be diagnostic. Treatment is by excision of the atheromatous plaque. Steroids are not helpful, and anticoagulation should be avoided.

E. Infective endocarditis is associated with a true vasculitis and embolic phenomena. True vasculitic lesions can be caused by an immune complex vasculitis. Emboli occluding the vessel lumen are more common. Skin, brain, spleen, and kidney are the organs frequently involved. Patients can also have arthralgias, arthritis, and an increased acute-phase response and be positive for rheumatoid factor, which make diagnosis difficult; SLE may also be suggested, given that these patients commonly have valvular disease.

F. Calciphylaxis is a rare and potentially lethal syndrome, almost always associated with chronic renal failure. Even though calcifications develop in many patients with chronic renal failure, in some, a severe condition develops that is characterized by skin necrosis and gangrene of the extremities. Organ involvement can also occur. Calciphylaxis is thought to be a hypersensitivity reaction involving parathyroid hormone, vitamin D, and hypercalcemia. Treatment is aimed at local management of skin ulcers and at keeping the calcium/phosphate product low.

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