Cerebral vasculitis

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 31

Cerebral vasculitis HAROLD P. ADAMS, JR.* Division of Cerebrovascular Diseases, Department of Neurology, Carver College of Medicine, University of Iowa Health Care Stroke Center, University of Iowa, Iowa City, IA, USA

INTRODUCTION AND GENERAL COMMENTS The term cerebral vasculitis (arteritis, angiitis) encompasses several inflammatory vasculitides that lead to stenosis, occlusion, or rupture of an artery, capillary, or venule in the central nervous system (Lie, 1997). These diseases also affect the peripheral nervous system. The vascular pathological findings that may be detected include fibrinoid necrosis of the arterial wall, formation of giant cells, or non-necrotizing vasculopathy without granuloma or giant cell formation (Guillevin and Lhote, 1997; Rossi and Di Comite, 2009). Vasculitis also leads to the pathological change of angiogenesis that appears to be a compensatory response to secondary tissue ischemia. Intracranial vasculitis may lead to thrombosis of arteries and veins, including the dural sinuses. The disease may lead to granulomatous meningeal involvement and the direct effects of released cytokines may induce neurologic dysfunction (Rossi and Di Comite, 2009). The clinical course of cerebral vasculitis ranges from fulminant to indolent and may be marked by fluctuations in clinical signs. The neurologic presentations of vasculitis include peripheral neuropathy (polyneuropathy, mononeuropathy, or mononeuropathy multiplex), cranial neuropathy, muscle disease, visual loss, encephalopathy, seizures, headache, venous thrombosis, and ischemic or hemorrhagic stroke (Moore and Cupps, 1983; Sigal, 1987; Berlit et al., 1993; Ferro, 1998; Moore and Richardson, 1998; Finsterer, 2009; Rossi and Di Comite, 2009). Most physicians will see a few cases during their professional career. However, vasculitis accounts for a limited number of cases of either hemorrhagic or ischemic stroke. Rarely, the spinal cord may be affected (Ropper et al., 2003). Many patients also have evidence of vasculitic involvement of other organs including skin, kidney,

lungs, sinuses, cardiovascular system, or joints. A primary vasculitis may occur without any identified underlying cause. Vasculitis may be secondary to a malignancy, drugs of abuse, or medications. In addition, cerebral vasculitis may be secondary to an infectious disease or a noninfectious inflammatory disorder that may be isolated to the central nervous system or a part of a multisystem disorder. Because vasculitis affecting the brain is relatively uncommon and because the neurologic symptoms are relatively nonspecific, an accurate diagnosis may be challenging (Ferro, 1998; Rossi and Di Comite, 2009). The problems in diagnosis are augmented because the results of ancillary testing often are not sufficiently precise to point to cerebral vasculitis. As a result, cerebral vasculitis is both over- and underdiagnosed. The differential diagnosis of cerebral vasculitis is broad (Table 31.1). The diagnosis of primary (isolated) vasculitis of the central nervous system is especially difficult because of the absence of symptoms or signs in other parts of the body (Moore, 1989). On the other hand, the multisystem diseases that may lead to cerebral vasculitis often have rather stereotyped constellations of findings. They usually have specific abnormalities detected on serologic testing. Thus, the diagnosis of these disorders is somewhat easier to achieve. The components of the evaluation of a patient with suspected cerebral vasculitis are outlined in Table 31.2 (Ferro, 1998). Brain imaging (computed tomography (CT) and magnetic resonance imaging (MRI)) is usually performed and in general, MRI is more sensitive than CT (Kuker, 2007a, b; Birnbaum and Hellmann, 2009). While some patients’ scans may be normal, most show changes such as multiple small intraparenchymal (gray or white matter) lesions consistent with ischemic stroke. These lesions do

*Correspondence to: Harold P. Adams, Jr., M.D., Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa, 52242, USA. Tel: þ1-319-356-4110, Fax: þ1-319-384-7199, E-mail: [email protected]

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Table 31.1 Differential diagnosis of cerebral vasculitis Intracranial atherosclerotic disease Central nervous system infections Multiple sclerosis and other demyelinating diseases Posterior reversible encephalopathy syndrome Reversible cerebral vasoconstrictive syndrome Drug-induced vasospasm Vasospasm after aneurysmal subarachnoid hemorrhage Peripartum vasculopathy Moyamoya syndrome Migraine

Table 31.2 Evaluation of patients with suspected vasculitis Brain imaging (CT, MRA) Electroencephalogram Vascular imaging (carotid duplex, CTA, MRA, arteriography) Other imaging Chest X-ray or CT Paranasal sinus X-rays Visceral arteriography Cerebrospinal fluid examination Urinalysis Blood and serologic studies Complete blood count Platelet count Prothrombin time and partial thromboplastin time Serum venereal disease research laboratory (VDRL) titer Erythrocyte sedimentation rate C-reactive protein Renal function tests Antinuclear antibodies Antibody to double-stranded DNA Extractible nuclear antigens Rheumatoid factor Anticardiolipin antibodies Neutrophil cytoplasmic antibodies (c-ANCA, p-ANCA) Hepatitis B surface antigen Cryoglobulins Brain and meningeal biopsy Renal, skin, muscle, peripheral nerve, temporal artery biopsy

not have a periventricular predilection. Small hemorrhages or larger areas of hemorrhage or infarction may also be found. Some patients may have enhancement of the meninges or small penetrating arteries. Diffuse or focal slow activity may be found on an electroencephalogram. The findings on examination of the cerebrospinal fluid (CSF) include lymphocytosis, increased protein, elevated inflammatory markers, and normal glucose. Serologic tests are usually abnormal among patients with cerebral

involvement of a multisystem vasculitis but usually normal among those with isolated vasculitis of the central nervous system (CNS.). The diagnosis of cerebral vasculitis is usually supported by the vascular imaging findings of segmental areas of stenosis or occlusion in multiple intracranial vessels, often described as “sausage-like” in appearance. The abnormalities are usually most prominent in pial arteries (Birnbaum and Hellmann, 2009). Rarely, peripheral microaneurysms or sluggish intravascular flow may be detected. Noninvasive vascular imaging (carotid duplex ultrasonography) may be helpful in assessment of larger artery vasculitis such as Takayasu disease, but it is not useful in isolated vasculitis of the CNS. Because most inflammatory vasculitides affect small to medium caliber arteries, the results of magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) of the brain are usually negative (Kuker, 2007b). Thus, arteriography is usually required to detect the arterial abnormalities (Moore and Cupps, 1983; Moore and Richardson, 1998). Extracranial MRA and CTA may be useful for assessment of patients with a vasculitis of larger arteries such as Takayasu disease. Arteriographic assessment, including CTA and MRA, of other vessels, such as the mesenteric, renal, or coronary arteries, may be indicated for evaluation of patients with multisystem vasculitis. Biopsy of skin, muscle, peripheral nerve, or temporal artery may be helpful in diagnosis of some multisystem vasculitides. The diagnosis of vasculitis restricted to the brain may require the performance of a brain and meningeal biopsy. The pathologic findings may be more easily found in meningeal arteries than in intracerebral vessels. Correlating the site of the biopsy with the findings on brain and vascular imaging is used to increase the yield of the biopsy. Management of most patients with noninfectious vasculitis involves the administration of immunosuppressive medications (Luqmani and Robinson, 2001). In some cases, patients are also treated with antithrombotic medications or local interventions including surgery or endovascular interventions.

CEREBRALVASCULITIS OF INFECTIOUS ORIGIN Bacterial, parasitic, fungal, rickettsial, spirochetal, or viral diseases may invade the meninges or blood vessel wall and lead to arterial thrombosis or rupture (Ye and Yang, 2008; Lidar et al., 2009; Kraemer and Berlit, 2010). Infections of the sinuses, throat, face, or ear may also lead to secondary arterial disease. Some infections that lead to cerebral vasculitis are opportunistic and are found among people with pre-existing illnesses such

CEREBRAL VASCULITIS as a malignancy, acquired immune deficiency syndrome, or a transplant that has caused an immune-compromised state. Other patients may have a history of an infection, ranging from syphilis to tonsillitis, or other evidence of an infection, such as cutaneous vesicles of herpes zoster. The usual course of an infectious vasculitis is acute to subacute. Patients have constitutional and clinical signs including fever and malaise. They often have signs of meningeal irritation, an encephalopathy and multifocal neurologic impairments. A few infections may lead to a major cerebral infarction with prominent focal neurologic signs; syphilis is a classic example. Some acutely ill patients have signs of increased intracranial pressure. Findings on brain imaging, which may include both ischemic and hemorrhagic lesions, vary by the infectious etiology. Examination of the CSF demonstrates signs of inflammation including leukocytosis, elevated inflammatory markers, and hypoglycorrachia. The diagnosis of an infectious cause of cerebral vasculitis often depends upon the results of blood and CSF cultures or titers. The focus of management of patients with infectious vasculitis of the brain is administration of antimicrobial agents. Some patients are also prescribed immunosuppressive agents to help limit the secondary inflammatory response. Detailed descriptions of individual infectious diseases that lead to cerebral vasculitis are included in other chapters and volumes of this series.

NONINFECTIOUS, INLAMMATORY, GIANT CELL, OR NECTROTIZING VASCULITIS Unlike the acute course of many infectious vasculitides, the clinical course of the noninfectious inflammatory vasculitides is usually subacute to indolent with gradual neurologic worsening. Patients may also have cranial nerve palsies, polyneuropathy, mononeuropathy multiplex, or myositis. Cerebral involvement is manifested by seizures, headache, behavioral or personality changes, dementia, or multifocal neurologic impairments, which may fluctuate. Some patients have prominent ocular symptoms or signs. The development of a major stroke syndrome due to an infarction or hemorrhage is uncommon. Patients with a multisystem vasculitis usually have dermatologic, renal, pulmonary, sinus, or orthopedic abnormalities that are clinically overt and relatively specific for the underlying vasculitis. The classification of these vasculitides (see Table 31.3) is primarily based on the multisystem pathologic hallmarks of the respective diseases. Some inflammatory or autoimmune diseases that cause neurologic disease are described in other chapters and volumes in this series.

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Table 31.3 Noninfectious inflammatory vasculitis Giant cell vasculitis Giant cell (temporal) arteritis Takayasu disease (aortitis) Necrotizing vasculitis Polyarteritis (periarteritis) nodosa Wegener disease Churg–Strauss angiitis Microscopic polyangiitis Collagen vascular diseases Systemic lupus erythematosus Rheumatoid arthritis Scleroderma Sj€ ogren syndrome Isolated vasculitis of the central nervous system Other vasculitis Buerger disease Amyloid-b-related angiitis

Giant cell vasculitis Takayasu disease and giant cell arteritis are vasculitides that are pathologically denoted by the presence of giant cells within the wall of affected arteries (Weyand and Goronzy, 2003a; Maksimowicz-McKinnon et al., 2009). In general, Takayasu disease affects the aorta and other large arteries while the affected arteries in giant cell arteritis are of medium caliber. Still, there are overlaps between the two diseases. For example, the aorta is involved in approximately 10% of persons with giant cell arteritis (Maksimowicz-McKinnon et al., 2009). Overlaps of clinical findings also occur. Still, the clinical presentations and epidemiologic aspects of Takayasu disease and giant cell arteritis are distinct, and thus, the two clinical disorders are described separately. While much about their evaluation and treatment is similar, physicians are best served by keeping these disorders as two different diseases.

Takayasu disease Takayasu disease (aortitis, arteritis) is most commonly diagnosed in eastern Asia and Mexico. In North America, the incidence of Takayasu disease is estimated as 2.6 per million (Weyand and Goronzy, 2003a). The pattern of Takayasu disease in Mexico appears to be similar to that reported in Asia (Soto et al., 2008). Studies from Europe also have reported cases of Takayasu disease in several different ethnic groups (Karageorgaki et al., 2009; Watts et al., 2009; Arnaud et al., 2010). In most parts of the world, women under the age of 40 constitute the majority of affected persons. In Japan, the ratio of affected women to men is approximately 11:1.

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Takayasu disease may also be diagnosed in children or infants. (Al Abrawi et al., 2008; Gedalia and Cuchacovich, 2009; Tullus and Marks, 2009). The etiology of Takayasu disease is not established. Because of the geographic and ethnic patterns of the disease, there is a presumed genetic predisposition to Takayasu disease. For example, a polymorphism in the I-k B-like protein may increase susceptibility to Takayasu disease (Seko, 2007). The vasculitis may also be associated with elevations of lipoproteins that are associated with an increased risk of cardiovascular complications (de Carvalho et al., 2009). A potential association between Takayasu disease and ulcerative colitis is also reported. (Balamtekin et al., 2009). Patients appear to have increased production of interleukin-6, which in the presence of g-interferon activates macrophages (Weyand and Goronzy, 2003a). Secondary granulomatous changes in all layers of the arterial wall, including the appearance of giant cells in the media and adventitia, are present. The walls of the affected arteries are thickened and as a result, the vascular lumens are narrowed. In some instances, secondary formation of aneurysms occurs. The disease may extend anywhere from the aortic root down the aorta to below the bifurcation of the iliac arteries (Guillevin and Lhote, 1997; Chung et al., 2007). The proximal portions of the brachiocephalic (innominate) artery, left common carotid artery, and left subclavian artery are commonly involved. Some patients also have involvement of the renal or mesenteric arteries. In most cases, the areas of aortic involvement are contiguous, but skip lesions and mixed areas of active and inactive disease may be found (Chung et al., 2007). Moriwaki et al. (1997) developed a classification that defines the extent of the arterial lesions, which is useful in differentiating the patterns of the disease (Table 31.4). Based on a series of 108 patients, Park et al. (2005) reported that the type I pattern was the most common with types V and IV being the next most frequent. The pattern of affected arteries is correlated with the clinical presentations. Systemic symptoms include low-grade fever, malaise, weight loss, generalized aching, and muscle pain (Hall et al., 1985; Hunder, 1996) (Table 31.5). Some patients have new-onset hypertension. Aortic regurgitation, pulmonary hypertension, carotidynia, headache, and pain with chewing (jaw claudication) may also occur (Weyand and Goronzy, 2003b; Weyn et al., 2009). Involvement of the mesenteric arteries may cause abdominal pain (Wu and Virdis, 2009). Ischemic symptoms in the upper extremities include limb claudication (pain with exercise) or a cold sensation in the arms. Symptoms of subclavian steal syndrome are also reported (Luqmani and Robinson, 2001). Stroke, which is a leading cause of death or disability among persons

Table 31.4 Classification of the extent of Takayasu disease 1* 2a* 2b* 3*

4* 5*

Involvement of only the major branches off aortic arch Involvement of ascending aorta with/without major branches Involvement of descending aorta with/without ascending aorta and branches Involvement of descending aorta, abdominal aorta, and renal arteries but without involvement of arch and major branches Involvement of only abdominal aorta and renal arteries Generalized arterial involvement

*May involve coronary and pulmonary arteries (Adapted from Moriwaki et al., 1997.)

Table 31.5 Clinical features of Takayasu disease General: Fever and chills Malaise Weight loss Carotidynia or neck pain Pain with chewing (jaw claudication) Limb claudication, most commonly the arm Abdominal pain Chest pain Decreased pulses in the arms Asymmetric blood pressures in the arms; may be less than in the legs Ocular: Amaurosis fugax Progressive ischemic oculopathy Neurologic: Cerebral infarction Transient ischemic attack Seizures Vascular dementia

with Takayasu disease, is usually ischemic in origin. Recurrent transient ischemic attacks (TIA) may also be a presentation. Rarely, stroke among persons with Takayasu disease is attributed to concomitant atherosclerosis (Park et al., 2008). Subarachnoid or intracerebral hemorrhage is a potential complication. In a French study, Arnaud et al. (2010) reported that stroke was more common in patients of North African ancestry than among whites. Patients may also have seizures or evidence of a posterior reversible encephalopathy syndrome (Fujita et al., 2008). Ocular findings include amaurosis fugax, anterior ischemic optic neuropathy,

CEREBRAL VASCULITIS or progressive ocular ischemia. (The initial report of this disease by Takayasu was to an ophthalmologic meeting.) On examination, pulses and blood pressures are diminished in one or both upper extremities (Maksimowicz-McKinnon et al., 2009). Blood pressure levels in the arms are less than those recorded in the legs. Bruits may be auscultated in the neck and supraclavicular regions. Atrophy of the facial musculature may be detected. Neurologic abnormalities reflect focal brain ischemia or hemorrhage. Rarely, a peripheral neuropathy may occur (Finsterer, 2009). The differential diagnosis of Takayasu disease includes advanced atherosclerosis, congential arterial abnormalities, coarctation of the aorta, aortic dissection, collagen vascular diseases, Buerger disease, and Behc¸et disease. The diagnosis of Takayasu disease is made on the basis of the clinical findings, the results of serologic studies, and the findings on vascular imaging. Affected patients often have anemia, an elevated erythrocyte sedimentation rate (ESR,) and an elevated C-reactive protein (CRP). A low ESR at diagnosis or at subsequent epochs is associated with quiescence of the vascular lesions (Park et al., 2005). Arteriography, CTA, or MRA demonstrates severe stenosis, occlusion, or aneurysms of the aorta and its major branches. Chest CT examination may show calcification and thickening of the wall of the aorta and great vessels as well as mural thrombi (Khandelwal et al., 2011). A relatively specific CT finding is the double ring pattern in the aorta, which reflects the inflammatory changes in the affected vessel (Mohan and Kerr, 2001). Delayed gadolinium-enhanced MRI may show enhancement of the aortic wall (Seko, 2007). Duplex ultrasonography of the carotid arteries may show a homogenous increase in thickness of the arterial wall (macaroni sign) (Mohan and Kerr, 2001; Nicoletti et al., 2009). Biopsy of affected arteries is usually not performed. However, if surgical reconstruction is performed, specimens should be forwarded for pathologic examination. The 5 year survival for those with Takayasu disease is approximately 70–90% (Park et al., 2005; Phillip and Luqmani, 2008). Recently, a French study reported that affected North African patients had a poorer prognosis (Arnaud et al., 2010). The prognosis of patients with Takayasu disease generally is influenced by the presence of major cardiovascular or cerebrovascular complications (Weyand and Goronzy, 2003a). Patients with severe stroke, congestive heart failure, hypertension, aortic regurgitation, or a secondary cardiomyopathy have a poor prognosis. Besides leading to death, most survivors will have some chronic disability from the arteritis or its ischemic complications (Maksimowicz-McKinnon and Hoffman, 2007; Maksimowicz-McKinnon et al., 2007). Takayasu disease also has a major negative impact on

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quality of life (Abularrage et al., 2008; Akar et al., 2008). Like other long-term multisystem diseases, scores for physical and mental health are severely impaired; patients have difficulty in performing activities of daily living (Maksimowicz-McKinnon et al., 2007). Treatment emphasizes immunosuppressive therapy with steroids (Ogino et al., 2008; Borg and Dasgupta, 2009; Mukhtyar et al., 2009). Initial doses are high with subsequent tapering. Relapses and reactivation of the arteritis also occur (Maksimowicz-McKinnon and Hoffman, 2007). Relapses of the disease may accompany reductions in the dose of steroids (MaksimowiczMcKinnon et al., 2007). On occasion, steroids are complemented by treatment with methotrexate or cyclophosphamide (Hunder, 1996; Chan and Luqmani, 2009). Mycophenolate mofetil or antitumor necrosis factor-a agents, including infliximab, are also being used (Shinjo et al., 2007; Filocamo et al., 2008; Langford, 2008; Molloy et al., 2008; Maffei et al., 2009). In particular, these agents have been prescribed for children (Buonuomo et al., 2011). The interleukin-6 receptor has also been blocked using tocilizumab (Mima and Nishimoto, 2009). Antiplatelet agents are usually administered to prevent thromboembolism. Surgical reconstruction procedures, such as aortoaxillary bypass, or endovascular interventions are also performed in some patients with severe disease (Ogino et al., 2008; Tracci and Cherry, 2009; Zhang et al., 2009a). Lee et al. (2009) report that endovascular therapy may provide sustained benefit in maintaining arterial patency, particularly among patients with chronic, inactive Takayasu disease. Because a majority of affected patients are young women, issues related to management of pregnancy are considerable. The best management of this situation has not yet been established (Seo, 2007).

Giant cell arteritis Giant cell (temporal) arteritis is a leading cause of acute visual loss in the elderly (Hunder, 1996). If the vasculitis is promptly identified and treated, visual loss may be averted. Giant cell arteritis (GCA) ia also an uncommon cause of stroke or vascular dementia (Solans-Laque et al., 2008). GCA is marked by segmental granulomatous inflammation of medium-caliber arteries. It preferentially affects arteries of the head; the most commonly involved are the superficial temporal, ophthalmic, and posterior ciliary arteries. Occasionally, the disease will affect extracranial vessels including the vertebral artery and less commonly, the carotid artery. Histopathologic changes include inflammatory changes along the internal elastic lamina, which is disrupted, and the presence of intramural giant cells, which are the pathologic hallmark of the disease. GCA is characterized by an

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increased production of interleukin-6, which suggests that it is a T cell-associated disease (Brack et al., 1999; Martinez-Taboada et al., 2008b). Lawrence et al. (2008) estimate that approximately 225 000 Americans have GCA. It is the most common vasculitis among people over 50 years of age (Lee et al., 2008). GCA is relatively uncommon in younger people (Nesher et al., 2009). The symptoms suggestive of temporal arteritis in younger persons are often secondary to other autoimmune disease, such as polyarteritis nodosa, Churg–Strauss angiitis, and Buerger disease (Nesher et al., 2009). GCA is most commonly found among women of northern European ancestry (Ferro, 1998; Weyand and Goronzy, 2003b). The disease is relatively rare among persons of Hispanic, African, or Asian descent (Lee et al., 2008). Liozon et al. (2009) report familial aggregations of GCA and polymyalgia rheumatica. Affected patients have fatigue, low-grade fever, and weight loss (Table 31.6). GCA is a potential cause of a fever of unknown origin (Zenone, 2007). Patients also complain of pain and stiffness in the neck and proximal muscles of the upper and lower extremities (polymyalgia rheumatica) (Weyand and Goronzy, 2003b). The symptoms of shoulder and hip pain are particularly prominent in the morning. While there is a strong relationship between polymyalgia rheumatica and GCA, not all patients with polymyalgia rheumatica develop the arterial disease. Approximately 750 000 Americans have polymyalgia rheumatica (Lawrence et al., 2008). Involvement of the mesenteric arteries may produce abdominal pain. Limb claudication or Raynaud’s phenomenon may also be found when the femoral or subclavian arteries are affected (Warrington et al., 2009). Painful chewing (jaw claudication) is a classic symptom Table 31.6 Clinical features of giant cell arteritis General: Fever, fatigue, malaise Weight loss Polymyalgia rheumatica; soreness and stiffness in shoulders and hips Jaw claudication Temporal headache (usually unilateral and severe) Palpably enlarged, tortuous, and tender artery Myocardial infarction, chest pain Ocular: Amaurosis fugax Monocular or binocular blindness Neurologic: Cerebral infarction Transient ischemic attack

(Luqmani and Robinson, 2001). Chewing presumably increases metabolic demands in the muscles of mastication, which are perfused by extracranial arteries affected by the arteritis, and thus perfusion is inadequate. Scalp necrosis and tongue infarction are other potential complications (Brodmann et al 2009; Grunewald et al., 2009; Tsianakas et al., 2009). Headache, usually unilateral, persistent, and severe, is the most common symptom. It is throbbing in quality. Because of the nature of the headache, patients usually seek medical attention within a relatively short time from onset. The development of new-onset headache in a person older than 60, particularly if it is in a temporal location, should lead to consideration of GCA. The index of suspicion should be low. Patients may have transient visual loss. More ominous is the sudden onset of monocular or binocular blindness, which is often irreversible and which is secondary to occlusion of the posterior ciliary artery. Occasionally, patients have symptoms of oculomotor nerve, abducens nerve, or lingual nerve dysfunction. Rarely, a patient may have a myelopathy or peripheral neuropathy (Finsterer, 2009). Stroke or TIA is an uncommon complication but it may be the initial symptom. GCA should be considered if an elderly patient has a stroke along with an elevated ESR or CRP. Ischemic cerebrovascular events most commonly affect the brainstem, cerebellum, and posterior portions of the cerebral hemispheres, reflecting involvement of the extracranial segment of the vertebral artery (Caselli et al., 1988; Reich et al., 1990). Cortical blindness is a potential complication. Gonzalez-Gay et al. (2004) reported that during a follow-up period of up to 27 years, strokes occurred in 8 of 287 patients with GCA. The risk of ischemic stroke is highest among those patients who have hypertension or a history of ischemic heart disease (Salvarani et al., 2009). Rarely, GCA may lead to vascular dementia (Solans-Laque et al., 2008). On examination, the superficial temporal artery is usually tender, tortuous, and palpably enlarged (Luqmani and Robinson, 2001). A cervical bruit may be auscultated. Pulses in the neck and superficial temporal artery may be diminished. Neurologic abnormalities reflect the location of stroke. Ophthalmologic findings include anterior ischemic optic neuropathy: blindness, an afferent pupillary defect, and optic pallor. Patients may also have shoulder and hip muscle tenderness on palpation. Most patients have a markedly elevated ESR and CRP. However, the ESR may be normal in approximately 20% of cases. Elevations of the CRP are more sensitive than increases in the ESR. The presence of normal levels of CRP and ESR generally excludes the diagnosis of giant cell arteritis. Still, isolated cases of GCA without abnormal levels of CRP or ESR are reported

CEREBRAL VASCULITIS (Yoeruek et al., 2008). Elevations of interleukin-6 and cytokines are also found. In addition, many patients have a mild normocytic, normochromic anemia and leukocytosis. Although it is not widely performed, ultrasound may detect thickening of the wall of the temporal artery (halo sign) (Salvarani et al., 2002). Fat-saturated, contrast enhanced, T1-weighted MRI has been used to screen the temporal artery for disease. In studies that compared the results to biopsy, the sensitivity and specificity of MRI were 27% to 81% and 89% to 97% respectively (Ghinoi et al., 2008; Khoury et al., 2008). Because of the importance of an accurate diagnosis, at present, MRI is not an alternative to biopsy. Temporal artery biopsy is the most definitive diagnostic study and should be recommended in cases of suspected GCA. Because the arteritis is multifocal and associated with skip lesions with segments of normal arterial histology, a long segment (2–4 cm) of artery is removed for pathologic examination (Breuer et al., 2009). Even with this precaution, a biopsy may be falsely negative. If the first arterial biopsy is negative and concern about the diagnosis remains high, the contralateral temporal artery also should be biopsied. In some instances, the diagnosis of giant cell arteritis is retained even when the biopsies are negative. In summary, at least three of the following five features should be present for a diagnosis of GCA: (1) age of onset greater than 50; (2) new-onset headache or localized head pain; (3) temporal artery tenderness to palpation or reduced temporal artery pulse; (4) ESR greater than 50 mm/h; (5) abnormal temporal artery biopsy. Imaging of the aorta may detect involvement by GCA; the findings may be detected by CT at the time of initial diagnosis (Agard et al., 2008). Thickening of the aortic wall, ectasia, or aneurysm formation is found. Marie et al. (2009) evaluated 66 patients with nonatherosclerotic aortic lesions; GCA was diagnosed in 48. In most cases, the aortic involvement was asymptomatic. Aortic regurgitation may also be present (Marchal and Sprynger, 2008). Aortic involvement may be more common among older people (Nesi et al., 2009). In addition, the presence of hypertension, a history of polymyalgia rheumatica, and marked elevations of inflammatory markers are predictors of aortic involvement of GCA (Gonzalez-Gay et al., 2004). Nevertheless, evidence of aortitis may be detected among patients who do not have other symptoms of GCA or polymyalgia rheumatica (Liang et al., 2009). The aortic disease may be of sufficient severity that surgical repair is needed (Mennander et al., 2008). The impact of aortic disease on the course of GCA is yet to be defined. The usual course of GCA is 2–3 years. Patients with a marked inflammatory response (markedly elevated ESR, fever, leukocytosis, thrombocytopenia, or anemia)

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appear to have a more prolonged course with a higher risk of recurrent flares (Nesher et al., 2008). Corticosteroids are the mainstay of treatment (Fraser et al., 2008; Pipitone and Salvarani, 2008; Borg and Dasgupta, 2009; Chan and Luqmani, 2009). The usual initial dose of prednisone is 60–80 mg/day. An alternate day regimen is recommended. Because the feared complication of visual loss may occur without warning, steroids are started while awaiting the results of the biopsy. Intravenous steroids may be used to initiate treatment. Clinical responses are often quite dramatic. Within 24 hours, the headache and the symptoms of polymyalgia rheumatica may resolve. Maintenance high-dose steroid treatment is required for at least 2–3 weeks. Subsequently, the dose of steroids is tapered gradually while the patient’s clinical status and ESR and CRP are monitored. A recurrence of symptoms or an increase in either ESR or CRP may require an increase in steroid dose. Because many patients are elderly women with a high risk of osteoporosis, measures to preserve bone mass with calcium and vitamin D supplementation and bisphosphonate medication are prescribed. Patients should also be monitored for other side-effects of long-term administration of corticosteroids including cataracts, myopathy, gastritis, hypertension, or aseptic necrosis of the femoral head. Methotrexate, azathioprine, or tumor necrosis factor-a inhibitors may be prescribed to patients with persistent and resistant GCA (Martinez-Taboada et al., 2008a; Pipitone and Salvarani, 2008). Patients are often treated with antiplatelet agents with an attempt to prevent both ischemic stroke and visual loss (Pipitone and Salvarani, 2008). However, the results of small studies are inconclusive (Nesher et al., 2004; Lee et al., 2006; Narvaez et al., 2008). A trial of administration of statins as an antiinflammatory therapy also has been negative (Narvaez et al., 2007).

Necrotizing vasculitis The necrotizing vasculitides include polyarteritis nodosa, Cogan syndrome, necrotizing polyangiitis, Wegener disease, and Churg–Strauss angiitis. In addition, Buerger disease is also a vasculitis that has a necrotizing component found in arteries. These disroders share common pathologic features that involve small to medium caliber arteries. Besides evidence of inflammatory changes and fibrinoid necrosis of the vascular wall, granulomatous changes may also be found. Some vasculitides have the presence of antineutrophil cytoplasmic antibodies (ANCA) as a serologic hallmark. While all these disorders may affect the peripheral nervous system or central nervous system, the clinical presentations of these disorders are relatively distinct. Besides leading to arterial

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occlusion and ischemia, hemorrhages secondary to vascular rupture is a potential complication.

Polyarteritis nodosa Polyarteritis (periarteritis) nodosa (PAN) is a rare necrotizing vasculitis that affects small to medium caliber arterioles, capillaries, and venules (Dillon et al., 2010). The incidence of PAN is estimated as 0.9 per million (Mohammad et al., 2009). The disease is diagnosed among people from all ethnic groups and it appears to be more common among men than women (Hunder, 1996). Peak ages for the disease are between 40 and 60 years (Sigal, 1987; Ferro, 1998). Children may also be affected (Cakar et al., 2008; Dillon et al., 2010). Approximately, 10% of cases of PAN are associated with hepatitis B virus infections (Hunder, 1996). PAN has also been found in association with malignancies (Fain et al., 2007). PAN primarily involves the renal, mesenteric, and coronary arteries. A retinal vasculitis may also be found. The cerebral vasculature is infrequently affected but it is most commonly found among younger patients. The leading causes of death associated with PAN are renal failure and neurologic disease. Affected patients are usually acutely ill with fever, fatigue, joint pain, skin eruptions, anorexia, and weight loss (Table 31.7) (Pagnoux et al., 2010). Dermatologic changes include purpura, livedo, skin nodules, urticaria, skin necrosis, mucosal ulcers, and hemorrhages, or genital ulcers (Kluger et al., 2008; Rashtak and Pittelkow, 2008). Gastrointestinal involvement that occurs in approximately 15–65% of cases causes abdominal pain, nausea, vomiting, diarrhea, and melena (Ebert et al., 2008; Ahn et al., 2009). Testicular pain or tenderness may occur (Meeuwissen et al., 2008). Patients may have mucosal ulcers or hemorrhages. Renal involvement may lead to renal failure or hypertension (Dillon et al., 2010). Involvement of the coronary arteries may cause myocardial infarction or congestive heart failure. Venous thromboembolism is a rare complication (Allenbach et al., 2009). Retinal vasculitis produces ocular ischemia or hemorrhages. Approximately 80% of patients have neurologic findings; the most common is a mononeuropathy multiplex (Finsterer, 2009; Pagnoux et al., 2010). Approximately 50% of cases have involvement of the central nervous system; headaches, seizures, spinal cord infarction, and encephalopathy are the most common symptoms. Intracerebral hemorrhages are more common than ischemic stroke (Morelli et al., 1998). The hemorrhages are usually lobar in location and may be the initial presentation. The development of a lobar hemorrhage in a young man who also has prominent constitutional symptoms should lead to consideration of PAN.

Table 31.7 Clinical features of polyarteritis nodosa General Fever Fatigue Skin eruptions and ulcers Mucosal ulcers and hemorrhages Abdominal pain Anorexia, nausea, and vomiting Diarrhea and melena Testicular pain Hypertension Myocardial infarction Ocular Anterior ischemic optic neuropathy Posterior ischemic optic neuropathy Central retinal artery occlusion Branch retinal artery occlusion Choroidal ischemia Diplopia Ptosis Tonic pupil Internuclear ophthalmoplegia Nystagmus Neurologic Mononeuropathy multiplex Headache Seizures Encephalopathy Intracranial hemorrhage Spinal cord infarction

Leukocytosis or eosinophilia is found on the complete blood count. Rarely, a pancytopenia may be present (Harrold and Liu, 2008). The ESR often is elevated. Red blood cells and elevated protein levels are found on urinalysis. Serologic studies for hepatitis B antigen may be positive and antiphospholipid antibodies may be present. Arteriography of the mesenteric and renal arteries reveals stenosis and dilation of vessels and microaneurysms (Hunder, 1996; Ozaki et al., 2009). Cerebral arteriography is performed rarely unless the initial presentation of the disease is a cerebrovascular event. Findings are similar to those noted on arteriography of other organs. The diagnosis of PAN is usually confirmed by biopsy. The most common sites for biopsy are the kidney, skin, muscle, or a peripheral (sural) nerve. The French Vasculitis Study evaluated the specificity of clinical and laboratory features in predicting the diagnosis of PAN (Henegar et al., 2008). The three most potent, positive predictors are: (1) the presence of hepatitis B DNA or antigen in serum, (2) arteriographic abnormalities, and (3) clinical findings of mononeuropathy or polyneuropathy. Factors that point against the

CEREBRAL VASCULITIS diagnosis are the presence of: (1) asthma, (2) renal dysfunction, (3) clinical evidence of ear or nose changes, (4) cryoglobulinemia, or (5) an elevated ANCA. Most of these features suggest other types of necrotizing vasculitis. The 5 year survival rate is approximately 60% (Mohammad et al., 2009; Pagnoux et al., 2010). Age greater than 65, secondary hypertension, and gastrointestinal disease that requires surgery are poor prognostic signs (Pagnoux et al., 2010). Those patients with nonhepatitis B-associated PAN or major cutaneous manifestations have the highest risk for relapses (Pagnoux et al., 2010). Cyclophosphamide and steroids are the primary treatment (Ebert et al., 2008; Chan and Luqmani, 2009). Cyclophosphamide, which is prescribed to patients with severe disease, may be given in a daily dose or through a pulse intravenous regimen. Adequate hydration and the concomitant administration of mesna is used to lower the risk of hemorrhagic cystitis and secondary bladder malignancy. Other potential side-effects of cyclophosphamide include gonadal dysfunction, alopecia, bone marrow suppression, and other malignancies. Corticosteroids may be given in combination with the cyclophosphamide. Interferon-a-2 is also given to persons with hepatitis-B-associated PAN (Hunder, 1996). Plasma exchange, intravenous immunoglobulins, and biotherapies are potential therapies (Guillevin and Pagnoux, 2007). Vascular surgical procedures including coronary artery bypass operations or abdominal surgery are done (Yanagawa et al., 2010).

Cogan syndrome The pathologic findings of the vasculitis of Cogan syndrome are similar to those found with PAN. This vasculitis is most commonly diagnosed in young men (Bicknell and Holland, 1978; Gluth et al., 2006). Orsoni et al. (2004) reported cases of Cogan syndrome in children. The primary clinical features are bilateral hearing loss, uveitis, interstitial keratitis, eye pain, prominent lacrimation, conjunctivitis, and ocular ischemia (Table 31.8) (Orsoni et al., 2002). The vestibular and auditory signs are usually bilateral and include vertigo, tinnitus, and sensorineural hearing loss (Cundiff et al., 2006). In addition, patients have fever, headache, weight loss, joint pain, or a meningoencephalitis (Gluth et al., 2006; Pysden et al., 2009). Cerebral involvement may also cause personality changes or cognitive impairments. Cardiac involvement may lead to aortic insufficiency. The diagnosis is largely made on the pattern of the clinical findings. In addition, thrombocytopenia may be found. Cerebrospinal fluid abnormalities include a mild to moderate lymphocytosis and an elevated protein. Corticosteroids are the primary method of treatment (Pysden et al., 2009).

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Table 31.8 Clinical features of Cogan syndrome General Fever Weight loss Joint pain Aortic insufficiency Otologic Bilateral hearing loss Vertigo Tinnitus Ocular Uveitis Interstitial keratitis Lacrimation Eye pain Visual loss Neurologic Meningoencephalitis Personality changes Encephalopathy

Blockers of tissue necrosis factor-a have also been used. The hearing loss may be permanent; some patients have had cochlear implants in an effort to restore hearing (Gluth et al., 2006).

Wegener disease Wegener disease (granulomatosis) is a fulminating necrotizing vasculitis that produces granulomas of the sinuses and airways (Fuchs and Tanner, 2009). The vasculitis may also affect small to medium caliber arteries of the brain. The illness may be mimicked by microscopic polyangiitis. Wegener disease may be secondary to antibodies to complementary proteinase-3 that cross-react with plasminogen and that induce development of anti-c-neutrophil cytoplasmic antibodies (c-ANCA) (Chen and Kallenberg, 2009). T cells are responsible for the granuloma formation. The incidence is approximately 10 per million (Mohammad et al., 2009; Watts et al., 2009). The peak age incidence for Wegener disease is in the fourth and fifth decades and it is slightly more common among men than women (Hunder, 1996; Luqmani and Robinson, 2001; Watts et al., 2009). Wegener disease also occurs in childhood (Cabral et al., 2009). There is a potential association with systemic malignancy (Fain et al., 2007). The frequency of Wegener disease has not changed in the last two decades. Besides the prominent sinus and pulmonary involvement, the disease is complicated by a necrotizing glomerulonephritis and ocular or neurologic symptoms. If untreated, Wegener disease has a rapidly fatal course.

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Table 31.9 Clinical features of Wegener disease General Cough Weight loss Hematuria Arthritis Venous thromboembolism Diabetes insipidus Rhinolaryngologic Sinus pain Sinus destruction and mass Nasal discharge Nasal ulcers Ocular Uveitis Corneal ulcers Orbital mass Retinal infarction or hemorrhage Neurologic Isolated cranial neuropathy Mononeuropathy multiplex Peripheral neuropathy Meningoencephalitis Cerebral hemorrhage Cerebral infarction

Findings include sinus pain, orbital inflammatory masses, a nasal discharge, subglottic stenosis, cough, weight loss, hematuria, and arthritis (Table 31.9) (Ahn et al., 2009; Hernandez-Rodriguez et al., 2010). Venous thromboembolic events may occur (Allenbach et al., 2009). Neurologic symptoms, which occur in approximately 50% of cases, are most commonly an isolated cranial or peripheral neuropathy ( Seror et al., 2006; Finsterer, 2009; Nowack et al., 2009; Zhang et al., 2009b). Mononeuropathy multiplex or myopathy, which may be painless, is also found (Cattaneo et al., 2007). Patients may also have evidence of CNS involvement including a hypertrophic pachymeningitis, diabetes insipidus, intracerebral or subarachnoid hemorrhage, or cerebral arterial or venous thrombosis (Sharma et al., 2010). In addition, Wegener disease may produce an encephalopathy or myelopathy. On examination, nasal ulcers may be detected. Ocular findings include uveitis, corneal ulcers, orbital myositis, orbital pseudotumor, or retinal infarctions or hemorrhages (Fauci et al., 1983; Nishino et al., 1993a, b; Seror et al., 2006). Most patients have an elevated ESR and eosinophilia. Elevated titers of c-ANCA are found in approximately 90% of affected persons (Mohan and Kerr, 2001). A positive result from this serologic test is highly specific for the diagnosis of Wegener disease. CT examination of the chest may show nodular or cavitary lesions in the airways

and lungs. CT of the head (sinuses/orbits) reveals bony destruction, opacification of the sinuses. or mass lesions. In most instances, vascular imaging is not done. The 5 year survival rate is approximately 75% (Phillip and Luqmani, 2008). Severe renal dysfunction and relapses are predictors of an unfavorable outcome (Eriksson et al., 2009). The quality of life among persons with ANCA-associated vasculitis including Wegener disease is reduced (Carpenter et al., 2009). Patients with Wegener disease, including those with presumed cerebral vasculitis, are usually treated with a combination of steroids and cyclophosphamide (Chan and Luqmani, 2009). The latter may be given daily by an oral route or in a pulse intravenous regimen. The daily oral regimen of cyclophosphamide may be more effective (Hunder, 1996). Remission is achieved in up to 90% of patients. The side-effects of cyclophosphamide and measures to limit them are the same as for those patients receiving the medication to treat PAN. Methotrexate, mycophenolate mofetil, azathioprine, or rituximab are alternatives (Iatrou et al., 2009; Oristrell et al., 2009; Pallan et al., 2009; Sharma et al., 2010). Pagnoux et al. (2008) concluded that treatment with methotrexate was superior to management with azathioprine. Surgical management to resect local granulomatous disease also is carried out (Hernandez-Rodriguez et al., 2010).

Churg–Strauss angiitis Churg–Strauss angiitis is a relatively rare necrotizing vasculitis of small to medium arteries. The incidence of Churg–Strauss angiitis is estimated to be 2–6/ 100 000 with a higher frequency among persons with a history of asthma (Mohammad et al., 2009; Vinit et al., 2011). Churg–Strauss angiitis is more common in women than men; the peak age group is 40–60 years. Rarely, it may be diagnosed in children (Gedalia and Cuchacovich, 2009). The course of the illness ranges from subacute to fulminant with most deaths due to complicating heart disease. Its pathologic hallmark is the development of eosinophilic-rich granulomatas. The disorder appears to be, in part, associated with abnormal responses by regulatory T cells and their responses to the presence of eosinophilia (Saito et al., 2008; Zwerina et al., 2009). Increased expression of interleukin-10 is also seen. The eosinophils may also release tissue factors that may activate the coagulation cascade and platelet activity that results in thrombin and clot formation (Ames et al., 2010). The elevated titers of ANCA may shift endothelial function that also promotes thrombosis (Ames et al., 2010). Subtyping of cases of Churg–Strauss angiitis based on the presence or absence of ANCA is being proposed (Grau, 2008).

CEREBRAL VASCULITIS Churg–Strauss angiitis may follow the use of leukotriene receptor antagonists for treatment of asthma (Harrold et al., 2007). Prolonged use of one of these agents, montelukast, has been associated with 4.5-fold higher risk of Churg–Strauss angiitis (Hauser et al., 2008). However, it is not clear if the medications are a cause or trigger of the disease, or merely a factor that unmasks the underling vasculitis (McDanel and Muller, 2005; Harrold et al., 2007; Keogh, 2007). Grau (2008) pointed out that the use of leukotriene receptor antagonists to treat asthma may lower the requirement for steroids, which, in turn, unmasks the angiitis. Most patients have a history of asthma, sinusitis, bronchitis, pneumonia, and hyperallergic skin reactions (Table 31.10) (Noth et al., 2003). Subcutaneous nodules and palpable purpuric lesions may be found. Fever and weight loss are often present. Other systemic findings include pulmonary disease, congestive heart failure, pericarditis, myocarditis, and abdominal pain (Noth et al., 2003; Kim et al., 2007; Ahn et al., 2009). Venous thromboembolism is diagnosed in approximately 8% of cases (Allenbach et al., 2009). The most common neurologic complications, which occur in approximately 20% of cases, are cranial nerve palsies, mononeuropathy including the phrenic nerve, mononeuropathy multiplex, or polyneuropathy (Wolf et al., 2009; Zhagn et al., 2009). The course of the polyneuropathy may be acute and mimic Guillain–Barre´ syndrome (Djukic et al., 2008). Neuropathic involvement may be more commonly detected among patients with prominent skin involvement (Chao et al., 2007). The areas of affected skin Table 31.10 Clinical features of Churg–Strauss angiitis General Asthma Sinusitis Bronchitis and pneumonia Skin nodules Palpable skin purpuric lesions Venous thromboembolism Myocarditis Pericarditis Abdominal pain Ocular Anterior ischemic optic neuropathy Retinal ischemia Neurologic Mononeuropathy multiplex Polyneuropathy Cranial nerve palsies Cerebral hemorrhage Cerebral infarction

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may be denervated. Anterior ischemic optic neuropathy or retinal vasculitis leading to visual loss may also occur (Kattah et al., 1994; Koenig et al., 2008; De Salvo et al., 2009). Because the vasculitis may involve the choroid plexus, primary intraventricular or subarachnoid hemorrhage is a potential complication. While cerebral infarction occurs, other signs of central nervous system involvement are rare (Wolf et al., 2009; Ghaeni et al., 2010). The presence of eosinophilia, which is marked, is a diagnostic hallmark. However, a minority of patients with eosinophilia will have Churg–Strauss syndrome (Sade et al., 2007). Alternative explanations for hypereosinophilia include helminthic infections, allergic reactions, and malignancies. The level of serum eosinophil cationic protein is a marker of the activity of Churg– Strauss angiitis (Guilpain et al., 2007). In addition, most patients will have elevated titers of perinuclear (p-) ANCA (Noth et al., 2003). Patients with the presence of p-ANCA usually have renal disease, parenchymal pulmonary disease, constitutional symptoms, and peripheral and central nervous system involvement (Grau, 2008). Patients with p-ANCA-negative Churg–Strauss angiitis have a higher risk of cardiac disease (Grau, 2008). Antimyeloperoxidase activity may also be elevated (Vinit et al., 2011). A chest X-ray usually shows areas of consolidation in the lungs. Cardiac MRI may demonstrate inflammatory changes within the myocardium or a pericardial effusion (Wassmuth et al., 2008; Bhagirath et al., 2009; Marmursztejn et al., 2009). Echocardiography may reveal abnormalities in approximately two-thirds of the patients who have abnormalities detected by MRI (Dennert et al., 2010). Electromyography and nerve conduction velocities most commonly exhibit findings consistent with peripheral neuropathy. Vascular imaging is rarely done. Brain imaging shows blood in those patients with hemorrhage secondary to choroid plexus involvement. The 5 year survival rate for people with Churg– Strauss angiitis is estimated to be 66–100% (Phillip and Luqmani, 2008). However, the morbidity is considerable when assessed by health-related quality of life measures (Carpenter et al., 2009). Treatment usually involves corticosteroids and cyclophosphamide (Bosch et al., 2007; Ribi et al., 2008; Chan and Luqmani, 2009; Nakamura et al., 2009). Ancillary management is similar to that prescribed to patients with PAN or Wegener disease who are receiving the medications. Patients who do not respond to this regimen or who have side-effects from the initial interventions may receive azathioprine, intravenous immune globulin, interferon-a, mycophenolate mofetil, ciclosporin, rituximab, and antitumor necrosis factor-a agents (Ribi et al., 2008; Iatrou et al., 2009; Saech et al., 2010; Donvik and Omdal,

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2011). Metzler et al. (2008) successfully treated seven patients with refractory Churg–Strauss angiitis with interferon-a; however, one patient did develop imaging evidence of a leukoencephalopathy. Omalizumab, an anti-IgE therapy, has also been used (Bargagli et al., 2008). Plasma exchange has also been administered to critically ill patients with multiorgan involvement (Bosch et al., 2007). The efficacy of the alternative therapies is not established.

Microscopic polyangiitis Microscopic polyangiitis is a rare necrotizing vasculitis that is differentiated from PAN because it primarily affects arterioles, capillaries, and venules, and that may overlap with Wegener’s disease (Guillevin and Lhote, 1997; Mahr, 2009; Nagai et al., 2009). The most common manifestation of the disease is a necrotizing glomerulonephritis that causes hematuria, proteinuria, and renal failure (Table 31.11). Less commonly, the lungs are implicated and pulmonary hemorrhages may result (Oh et al., 2009). Venous thromboembolism may also occur (Allenbach et al., 2009). Other findings are livedo racemosum, purpura, weight loss, fever, and a mononeuropathy multiplex (Cattaneo et al., 2007; Nagai et al., 2009; Zhang et al., 2009b). Kluger et al. (2008) report that the appearance of the skin lesions is associated with the development of the mononeuropathy multiplex. While the vasculitis may affect small intracranial arteries, secondary infarction and cerebral symptoms are uncommon (Tang et al., 2009). Most patients have an elevated p-ANCA titer (Oh et al., 2009). The 5 year survival rate among people with microscopic polyangiitis is estimated to be 45–75% (Phillip and Luqmani, 2008). Severe renal disease and relapses are predictors of a poor outcome (Eriksson et al., 2009). A leading cause of death is pulmonary hemorrhage. Patients are treated with the combination of corticosteroids and cyclophosphamide (Chan and Luqmani, 2009; Oh Table 31.11 Clinical features of microscopic polyangiitis General Glomerulonephritis and renal failure Pulmonary hemorrhage Purpura Weight loss Fever Venous thromboembolism Neurologic Mononeuropathy Cerebral infarction Cerebral hemorrhage

et al., 2009). Other medical therapies include methotrexate, mycophenolate mofetil, and azathioprine (Pagnoux et al., 2008; Iatrou et al., 2009). Refractory cases may benefit from treatment with rituximab or tumor necrosis factor-a antagonists.

Primary angiitis of the central nervous system Primary (isolated) angiitis (vasculitis) of the central nervous system (CNS) (granulomatous angiitis) is a rare necrotizing segmental arteriopathy of small to medium caliber intracranial arteries that is restricted to the CNS (Sigal, 1987; Moore, 1989; Lie, 1997; Ferro, 1998; Fieschi et al., 1998; Salvarani et al., 2007; Birnbaum and Hellmann, 2009; Kraemer and Berlit, 2011). The most common histopathologic findings include granulomatous formation with infiltration and areas of fibrinoid necrosis (Birnbaum and Hellmann, 2009). Involvement of venules with secondary hemorrhage may also be seen (Panda et al., 2000). The mean age of affected persons is 50 and the ratio of men to women is estimated as being 2:1 (Birnbaum and Hellmann, 2009). While the disease is most commonly detected in adults, primary angiitis of the CNS may also be diagnosed in children (Benseler, 2006). MacLaren et al. (2005) have proposed dividing the presentations of primary angiitis of the CNS into two subtypes based on the caliber of the arteries affected by the condition. Clinical manifestations, which may be nonspecific, usually evolve over days and weeks (Neel and Pagnoux, 2009). Common symptoms are headache of variable severity and quality, seizures, mental status changes, or an encephalopathy (Table 31.12). The headaches are generally not as severe as those seen with subarachnoid hemorrhage but they are often relentlessly progressive (Birnbaum and Hellmann, 2009). Approximately 20% of patients will develop stroke or focal neurologic symptoms (Birnbaum and Hellmann, 2009). While stroke is usually not the presenting finding, all types of cerebrovascular events have been described. When focal motor, sensory or visual impairments representing stroke are found, they are often superimposed Table 31.12 Clinical features of primary angiitis of the central nervous system Headache Seizures Encephalopathy Cerebral hemorrhage Cerebral infarction Myelopathy Cauda equina syndrome

CEREBRAL VASCULITIS on the findings of an encephalopathy. Rarely, signs reflecting spinal cord injury or a cauda equina syndrome may happen (Paisansinsup et al., 2004; Salvarani et al., 2008). Funduscopic examination may show perivascular inflammatory lesions. Uveitis may also be detected (Rosenbaum et al., 1998). The differential diagnosis includes multisystem vasculitis, encephalitis, and other central nervous system infections, neoplasms or paraneoplastic syndromes, reversible cerebral vasoconstrictive syndrome, and arterial dissections (Calabrese et al., 1992; Birnbaum and Hellmann, 2009; Hajj-Ali and Calabrese, 2009; Neel and Pagnoux, 2009) (Table 31.13). Blood serologic studies are usually normal. Examination of the cerebrospinal fluid often shows increased pressure, a moderate lymphocytosis (usually < 100–250 cells), normal glucose, elevated proteins, and elevated immune globulins (Birnbaum and Hellmann, 2009). The findings on CT or MRI are nonspecific, and in approximately 10% of cases, the studies are normal (Singh et al., 2003; Birnbaum and Hellmann, 2009). More commonly, focal or multifocal small ischemic lesions or cortical or white matter hemorrhages also are seen. Rarely a lesion that mimics a mass will be detected. Fluid-attenuated inversion recovery (FLAIR) sequences on MRI may reveal hyperintense vessels. Contrast-enhanced MRI may also show enhancement of the penetrating vessels and the leptomeninges. Because the vasculitis affects small to moderate arteries, the yield of CTA and MRA is relatively low and an arteriogram is required for diagnosis. In approximately 50–90% of cases, a cerebral arteriogram will be abnormal (Birnbaum and Hellmann, 2009). Abnormalities include segmental narrowing and dilation in multiple medium caliber pial Table 31.13 Differential diagnosis of primary angiitis of the central nervous system* Reversible vasoconstrictive syndrome Peripartum vasculopathy Disseminated intracranial atherosclerosis Fibromuscular dysplasia Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes Susac syndrome Basilar meningitis Acute disseminated encephalomyelitis Demyelinating diseases Sarcoidosis Multisystem vasculitis Primary central nervous system lymphoma Lymphomatoid granulomatosis Carcinomatous meningitis Gliomatosis cerebri *(Adapted from Birnbaum and Hellmann, 2009.)

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arteries. Occasionally arterial occlusion, sluggish flow, or peripheral aneurysms are detected. Brain and meningeal biopsy is the standard way to diagnose isolated vasculitis of the CNS. The biopsy should include both brain and meningeal tissue (Neel and Pagnoux, 2009). Unfortunately, a biopsy may be falsely negative in approximately 50% of cases. The low yield is due to the segmental involvement of vessels and the need to limit the extent of the biopsy as much as possible. Inclusion of meningeal tissue increases the yield of the biopsy. Efforts to coordinate the site of the biopsy with the findings of vascular and brain imaging may increase the likelihood of a positive pathologic finding. The following features are usually necessary for the diagnosis of primary angiitis of the central nervous system: (1) neurologic deficits that are unexplained after an extensive diagnostic evaluation; (2) evidence of vasculitis as detected by arteriography or biopsy; (3) no evidence of systemic vasculitis to which the imaging or pathologic findings can be ascribed (Calabrese et al., 1992). Birnbaum and Hellmann (2009) concluded that a definite diagnosis of primary angiitis of the central nervous system could be made only if there was tissue confirmation. Other cases, including those with changes on arteriography, would be considered as probable. Patients with primary involvement of smaller caliber arteries appear to have relapses leading to severe brain injury while those with primary involvement of mediumcaliber arteries are more likely to have an isolated severe event (MacLaren et al., 2005). The former group appears to respond well to immunosuppressive therapy but they have a high risk for neurologic worsening when medications are stopped. The prognosis of patients with isolated angiitis of the CNS also depends upon their clinical status at the time of diagnosis. Without treatment, the course is progressive and usually results in death. Most patients are treated with a course of high-dose corticosteroids alone or in combination with cyclophosphamide (Birnbaum and Hellmann, 2009; Neel and Pagnoux, 2009). Experience with other immunosuppressive agents is limited (Chenevier et al., 2009).

Amyloid-b-related angiitis A few cases of granulomatous angiitis associated with sporadic, amyloid-b peptide-related cerebral amyloid angiopathy (CAA) have been described (Scolding et al., 2005; Amick et al., 2008). Pathologic findings include destructive changes in the blood vessels with granuloma formation. The mean age of patients with amyloid-b-related angiitis (ABRA) generally are older than those with primary angiitis of the CNS but younger than most patients with CAA. Clinical features include headache, changes in cognition, hallucinations, seizures,

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and focal neurologic signs (Scolding et al., 2005). Recurrent TIA also has been described (Amick et al., 2008). A mild inflammatory reaction is found in the cerebrospinal fluid. MRI changes in the cerebral white matter may be found and are similar to those found with primary angiitis of the CNS. Presumably management will be similar to that given to patients with primary angiitis of the CNS, although experience is limited.

Buerger disease Buerger disease (thromboangiitis obliterans) is a nonatherosclerotic segmental inflammatory disease that affects small and medium caliber arteries. It induces secondary thrombotic occlusion. The presumed etiology is a cell-mediated immune response to arterial antigens. While exposure to tobacco appears to be crucial to the development and course of the disease, endothelial dysfunction is also present (Cooper et al., 2006; Lazarides et al., 2006; Olin and Shih, 2006). The disease may also be related to hyperhomocysteinemia or diabetes mellitus (Malecki et al., 2009). Elevations of antiendothelial cell antibodies are present (Olin et al., 1990). In the brain, the primarily affected vessels are the distal (pial) branches of the anterior cerebral, middle cerebral, and posterior cerebral arteries. While Buerger disease is rare, it is much more common among men than women; the ratio is estimated at 3–14:1. However, recent reports suggest that the frequency of the disease is increasing in women (Malecki et al., 2009). The stereotypical patient is a young man that smokes. The disease is most commonly described in Eastern Europe, the Middle East, and Asia. The criteria for the diagnosis of Buerger disease are: (1) smoking history, (2) onset of symptoms under the age of 50, (3) severe infrapopliteal arterial disease, (4) upper limb phlebitis migrans, and (5) absence of risk factors, other than smoking, for accelerated atherosclerosis (Lazarides et al., 2006). Approximately 2% of cases will have neurologic involvement (stroke). Given the low incidence of Buerger disease and the low frequency of neurologic complications, the cause and effect relationship between the arteriopathy and stroke is not established. The most common complaints of Buerger disease involve progressive ischemia of the arms and legs (Table 31.14). Patients have involvement of multiple limbs. Limb symptoms usually start distally and move proximally. Findings include pain with exercise (claudication) or at rest, Raynaud phenomenon, superficial phlebitis, and digital and limb ulcers (Hoeft et al., 2004). In advanced cases, gangrene that leads to limb amputations may occur (Olin and Shih, 2006). While neurologic symptoms are uncommon, they are usually

Table 31.14 Clinical features of Buerger disease General Progressive limb ischemia Intermittent limb claudication Raynaud phenomenon Superficial phlebitis Digital or limb ulcers Limb gangrene Neurologic Polyneuropathy Cerebral infarction

are secondary to ischemic stroke (Rai et al., 2004). Peripheral neuropathy also may occur (Finsterer, 2009). The findings of small arterial changes (corkscrew or tree root pattern) are found on arteriography (No et al., 2005; Lazarides et al., 2006). Treatment focuses on smoking cessation (Hoeft et al., 2004). Stopping smoking slows progression of the disease and lessens the risk of amputations (Jimenez-Ruiz et al., 2006). Substitution of smokeless tobacco for smoking is not effective. Medications such as corticosteroids, calcium channel blockers, antiplatelet agents, and oral anticoagulants seem not to be effective. Iloprost, a stable prostacyclin analog, has been found to be effective in lessening the risk of limb pain and amputation among patients (Bozkurt et al., 2004). Bone marrow transplantation and hyperbaric oxygen have also been used to treat patients with Buerger disease (Saito et al., 2007). Surgical procedures include amputation, bypass operations, and sympathectomy (Bozkurt et al., 2004; Lazarides et al., 2006).

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