edema, cotton-wool spots, irregular caliber of retinal vessels, and retinal vascular occlusion [300, 304, 305]. Sometimes, retinopathy may be secondary to concomitant hypertension. Papilledema or papillitis due to optic nerve vasculitis may occur and inßammation of orbital vessels may lead to exophthalmos [300, 301, 306Ð308]. Vasculitic involvement of the central and peripheral nervous system may produce third, Þfth, sixth, and seventh nerve palsies, homonymous hemianopia, nystagmus, amaurosis fugax, and HornerÕs syndrome [306]. Anterior uveal vascular inßammation is occasionally seen as anterior uveitis with leakage of protein into the anterior chamber [304, 309]. Conjunctival infarction may produce pale yellow, raised and friable conjunctival lesions, chemosis, and subconjunctival hemorrhages [309]. Vascular inßammation of episcleral, scleral, and limbal vessels may lead to episcleritis, scleritis, and sclerokeratitis [303, 304, 310Ð312]. Ocular involvement may be the Þrst manifestation of PAN [203, 311, 313].

Scleritis

The reported incidence of PAN in patients with scleritis ranges from 0.68 to 6.45% [121Ð124]. Necrotizing anterior scleritis, often associated with PUK, is the most frequent type of scleritis in patients with PAN [310Ð312]. Scleritis becomes extremely painful and is highly destructive unless correct diagnosis and control of the underlying systemic disease are achieved. Corneal ulceration is progressive, both circumferentially and centrally, with undermining of the central edge of the ulcer, resulting in overhanging lip of the cornea. Scleral involvement helps to distinguish classic MoorenÕs ulcer from sclerokeratitis associated with vasculitic diseases, such as RA, GPA (Wegener), or PAN. In most cases, sclerokeratitis present after PAN diagnosis, but occasionally may be the presenting manifestation of the disease [203, 311, 313]. The ophthalmologist may play an important role in the diagnosis and management of a patient with this potentially lethal vasculitic disease. In our series of 500 patients with scleritis, there were no patients with PAN. However, in our prior series [123], PAN was diagnosed in two patients (1.16%): one man and

one woman, with a mean age of 58 years. One patient had unilateral diffuse scleritis and the other patient had unilateral necrotizing scleritis with PUK. PAN had already been diagnosed 1 year before the onset of nodular scleritis in the Þrst patient. Necrotizing scleritis with PUK was the Þrst manifestation whose study led to the diagnosis of PAN in the second patient; biopsy of an elbow nodule compatible with PAN and saccular aneurysms in the superior mesenteric artery in the setting of systemic clinical Þndings, such as constitutional symptoms, dizziness, profound quadriceps muscle weakness, tinnitus, skin lesions, and grand mal seizure, conÞrmed the diagnosis of PAN. Prompt and aggressive therapy improved the ocular and systemic prognoses. The ophthalmologist may play an important role in the diagnosis and management of a patient with this potentially lethal vasculitic disease.

Episcleritis

Although histological involvement of episcleral vessels is frequently seen, episcleritis is less often detected clinically [298, 303]. It may be simple or diffuse, and recurrent [204]. Episcleritis in patients with PAN is less common than scleritis [122]. There were no patients with PAN in our series of patients with episcleritis.

6.1.8.4 Laboratory and Angiographic Findings

There are no laboratory tests that can conÞrm the diagnosis of PAN. Leukocytosis, anemia, and an elevated ESR may be seen. Eosinophilia is seen only rarely and, when present at high levels, suggests the diagnosis of ChurgÐStrauss syndrome. Hypergammaglobulinemia may be present, and up to 30% of patients have a positive test for hepatitis B surface antigen. Antibodies against myeloperoxidase or proteinase-3 (PR-3) (ANCA) are rarely found in patients with PAN.

In cases with urinary sediment red cells, red cell casts, or proteinuria, renal disease must be suspected. The angiographic Þnding of small, aneurysmal dilatations in renal, hepatic, and gastrointestinal vessels may be helpful in establishing the diagnosis, although they may also be found in SLE [314] and Þbromuscular dysplasia [315].

6.1.8.5 Diagnosis

The diagnosis of PAN is based on the histological Þnding of necrotizing vasculitis of smalland medium-sized muscular arteries in patients with compatible multisystem clinical Þndings. Biopsy of symptomatic areas, such as skin, testes, epididymus, skeletal muscle, or peripheral nerves, provides the highest diagnostic yield [316Ð318]. Blind biopsy of asymptomatic organs rarely establish the diagnosis. In the absence of easily accessible tissue for biopsy, the angiographic demonstration of involved vessels, particularly in the form of aneurysms of smalland mediumsized arteries in the renal, hepatic, and visceral vasculature, is sufÞcient to make the diagnosis. Aneurysms of vessels are not pathognomonic of PAN; furthermore, aneurysms need not always be present, and angiographic Þndings may be limited to stenotic segments and obliteration of vessels.

6.1.9Allergic Granulomatous Angiitis (Churg–Strauss Syndrome)

Allergic granulomatous angiitis (ChurgÐStrauss syndrome) is a vasculitic disease similar to classic PAN in that it may affect any organ of the body; however, unlike classic PAN, pulmonary involvement is a sine qua non of this syndrome. ChurgÐStrauss syndrome is characterized, as it was originally described [319], by asthma, eosinophilia, pulmonary inÞltrations, vasculitis, and extravascular granulomas.

6.1.9.1 Epidemiology

Although there are no epidemiologic studies, ChurgÐStrauss syndrome is an uncommon disease. Age at the onset ranges from 15 to 70 years and men are twice as likely to be affected as women.

6.1.9.2 Systemic Manifestations

Lung involvement is predominant and usually the Þrst manifestation of the disease. There is often a history of asthma or atopy, or both, sometimes with bronchitis and pneumonitis. After a mean duration of asthma of 8 years [320], constitutional symptoms, such as fever, malaise, and

weight loss, may appear, heralding the onset of systemic manifestations in skin, peripheral nerves, heart, gastrointestinal tract, and kidney [320, 321]. At this time, chest X-rays may show evanescent pulmonary inÞltrates (LšfßerÕs syndrome), massive nodular inÞltrates without cavitation, or diffuse intertstitial lung disease. Systemic Þndings include (1) skin lesions, such as subcutaneous nodules, purpura, or ulcerations;

(2) peripheral neuropathy, such as mononeuritis multiplex; (3) heart abnormalities, such as congestive heart failure; (4) gastrointestinal involvement, such as infarction, ulceration, or perforation of the stomach, small bowel, or large bowel; and

(5) renal disease with eosinophilic granulomatous involvement of the prostate and lower urinary tract.

Polyarthralgias and arthritis are uncommon in ChurgÐStrauss syndrome. Central nervous system abnormalities, such as seizures, are unusual.

6.1.9.3 Ocular Manifestations

Ocular manifestations in ChurgÐStrauss syndrome are rare. A necrotizing eosinophilic granulomatous process may involve conjunctiva [322], cornea, uveal tract, retina, and optic nerve [323]. Episcleritis and scleritis may occur as part of the ocular involvement [323]. Because ocular abnormalities may be the initial manifestation of the disease [322], their recognition may lead to early ChurgÐStrauss syndrome diagnosis and prompt initiation of therapy. There are no cases of ChurgÐ Strauss syndrome in our series of scleritis or episcleritis.

6.1.9.4 Laboratory Findings

The characteristic laboratory Þnding is eosinophilia, which reaches levels >1,000 cells/ml in >80% of patients. In the original description by Churg and Strauss [319], eosinophil counts ranged from 5,000 to 20,000 eosinophils per millimetre [7]. With patient improvement, eosinophilia decreases. Elevated serum IgE and anemia also may be found [320]. Evidence of inßammation as evidenced by elevated ESR, Þbrinogen, or a2 globulins can be found in 81% of patients. The other laboratory Þndings reßect the organ systems involved. Approximately 48% of patients