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Central nervous system vasculitis

a Center for Vasculitis Care and Research and bRJ Fasenmyer Chair of Clinical Immunology, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio, USA

Rula A. Hajj-Alia and Leonard H. Calabreseb

Purpose of review In the past decade, primary and secondary central nervous system (CNS) vasculitides have been more commonly diagnosed and recognized than previously. With the increasing awareness of these disorders, it is crucial for the treating physician to differentiate between causes of CNS vasculitis and to recognize their marked clinical and pathophysiological heterogeneity. This review focuses on the major forms of primary CNS vasculitis, as well as secondary CNS vasculitis with emphasis on their clinical findings, diagnoses, and treatment. Recent findings The proposal of reversible cerebral vasoconstriction syndromes (RCVS) as a unifying concept for a group of disorders which are characterized by acute-onset severe recurrent headaches, with or without additional neurologic signs and symptoms, and prolonged but reversible vasoconstriction of the cerebral arteries, has been a major breakthrough in this field over the past decade. Recognition of this common mimic (i.e. RCVS) has allowed optimal management of a sizable group of patients previously confused with pathologically documented CNS vasculitis. Summary Sound treatment decisions are based on accurate diagnosis. It is essential for the clinicians involved in the evaluation of patients with CNS vasculitis to be aware of its mimics especially RCVS. This article provides a comprehensive review of CNS vasculitis and its differential diagnosis. Furthermore, it touches upon workup and treatment of CNS vasculitis. Keywords granulomatous angiitis of the central nervous system, primary angiitis of the central nervous system, reversible cerebral vasoconstriction syndromes

Curr Opin Rheumatol 21:10­18 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8711

Correspondence to Rula A. Hajj-Ali, Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA Tel: +1 216 444 9643; e-mail: [email protected] Current Opinion in Rheumatology 2009, 21:10­18

Introduction

Vasculitis that affects the central nervous system (CNS) is one of the most formidable diagnostic and therapeutic challenges for physicians. The ischemic symptoms and findings induced by CNS vasculitis may be identical to those produced by infection, occlusive vascular disease, or malignancy. Adding to the diagnostic challenge is the lack of an accurate and sensitive diagnostic test. The ability of the treating physician to tackle the diagnostic and therapeutic challenges is based on familiarity with the various clinical syndromes associated with CNS vasculitis, the understanding of the nature of the disease, and the knowledge of its mimics. Fortunately, over the past several years, multiple advances occurred in these areas. This review will summarize the clinical presentations, the differential diagnoses, and the diagnostic and therapeutic modalities of CNS vasculitis.

the CNS and secondary when associated with various other disorders. Initial reports of PACNS described it as a fatal and progressive granulomatous vasculitis and referred to it as granulomatous angiitis of the CNS (GACNS) [1]. Increasing interest in the disease emerged with the reports of successful treatment with cyclophosphamide and glucocorticoids. In 1988, Calabrese and Mallek [2] proposed the criteria for the diagnosis of PACNS. The presence of an acquired and otherwise unexplained neurologic deficit and with (a) the presence of either classic angiographic or histopathologic features of angiitis within the CNS, and (b) no evidence of systemic vasculitis or any condition that could elicit the angiographic or pathologic features. In the 1990s, it was recognized that PACNS is a heterogeneous disorder with clinical subsets that significantly differ in terms of prognosis and therapy. PACNS comprise different subsets including GACNS, and atypical

DOI:10.1097/BOR.0b013e32831cf5e6

Primary central nervous system vasculitis

Broadly, CNS vasculitis can be classified as primary angiitis of the CNS (PACNS) when it is confined to

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Central nervous system vasculitis Hajj-Ali and Calabrese 11

cases. Recently, the term reversible cerebral vasoconstriction syndrome (RCVS) was proposed to comprise a group of disorders characterized by acute onset of headaches, with or without neurologic deficit, and prolonged but reversible cerebral vasoconstriction. RCVS are confined to the CNS but has marked clinical and pathophysiological heterogeneity than GACNS. Being a major mimic of PACNS, RCVS will be discussed in the section of primary central nervous system vasculitis. However, it cannot be overemphasized that RCVS is not a form of true CNS vasculitis, but rather a group of vasoconstrictive syndromes.

Granulomatous angiitis of the central nervous system

Reversible cerebral vasoconstriction syndromes

GACNS represents about 20% of all patients with PACNS. It appears to be male-predominant and occurs at any age. It is characterized by a long prodromal period, with few patients presenting acutely. Signs and symptoms of systemic vasculitis such as peripheral neuropathy, fever, weight loss, or rash are usually lacking. Because the vasculitis may affect any area of the CNS, its presentation may vary widely, and no set of clinical signs is specific for the diagnosis. Signs and symptoms of GACNS are summarized below: (1) Chronic headaches. (2) Encephalopathy. (3) Strokes/transient ischemic attack (more common recurrent). (4) Seizures. (5) Behavioral and cognitive changes. (6) Focal motor/sensory abnormalities. (7) Ataxia. (8) Myelopathy. GACNS may be suspected in the setting of chronic meningitis, recurrent focal neurologic symptoms, unexplained diffuse neurologic dysfunction, or unexplained spinal cord dysfunction not associated with systemic disease or any other process. The characteristic pathologic findings include classic granulomatous angiitis affecting the small and medium leptomeningeal and cortical arteries with Langhans or foreign body giant cells, necrotizing vasculitis, or a lymphocytic vasculitis. The inflamed vessels become narrowed, occluded, and thrombosed, causing tissue ischemia and necrosis of the territories of the involved vessels. The primary event that elicits the inflammatory process in GACNS remains unknown. It is possible that altered host defense mechanisms tilt the balance of the immune system and allow a viral illness to escape the immune system, which sets off the vasculitic process [3­8].

Benign angiopathy of the CNS (BACNS) was initially proposed as a term to characterize a distinct subset of patients with isolated neurologic events, characterized by female predominance, acute presentation, reversible angiographic abnormalities, normal results on spinal fluid examination, and monophasic course [9]. The term `angiopathy' was used because of uncertainty regarding the nature of the pathologic process affecting the vessel wall and the lack of evidence of blood vessel inflammation. In 2002, Hajj-Ali et al. [10] described dramatic resolution of angiographic abnormalities in series of 16 patients within 4­12 weeks without intensive immunosuppressive therapy. With these data, it became apparent that the underlying pathophysiologic disorder in BACNS patients was reversible vasoconstriction rather than vasculitis. Further on, the term BACNS evolved into a new terminology referred to as reversible cerebral vasoconstriction syndromes. The evolvement in the terminology to RCVS occurred with the recognition that RCVS comprise a group of diverse conditions, all characterized by reversible multifocal narrowing of the cerebral arteries heralded by sudden, severe (thunderclap) headaches with or without associated neurologic deficits and most importantly by reversible angiographic findings. RCVS include BACNS, Call­Fleming syndrome, postpartum angiopathy, migrainous vasospasm, and drug-induced `arteritis' [11]. Calabrese et al. [11] proposed critical elements for the diagnosis of RCVS which are summarized below. (1) Transfemoral angiography or indirect computed tomography angiography (CTA) or magnetic resonance angiography (MRA) documenting multifocal segmental cerebral artery vasoconstriction. (2) No evidence for aneurysmal subarachnoid hemorrhage. (3) Normal or near-normal cerebrospinal fluid analysis (protein level <80 mg%, leukocytes <10 mm3, normal glucose level). (4) Severe, acute headaches, with or without additional neurologic signs or symptoms. (5) Reversibility of angiographic abnormalities within 12 weeks after onset. If death occurs before the follow-up studies are completed, autopsy rules out such conditions as vasculitis, intracranial atherosclerosis, and aneurysmal subarachnoid hemorrhage, which can also manifest with headache and stroke. It is essential to differentiate between RCVS and GACNS given the different therapeutic and prognostic implications. The signs and symptoms of the two subsets are sharply different (Table 1). Ducros et al. [12] recently described their experience of 67 patients with RCVS. The clinical and radiographic findings of this series are summarized in Table 2. The disturbance in

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12 Vasculitis syndromes Table 1 Comparison of clinical and diagnostic characteristics of reversible cerebral vasoconstriction syndromes and granulomatous angiitis of the central nervous system RCVS Patients Headaches CSF findings Angiography Female predominant Acute Normal to near-normal Diffuse areas of multiple stenoses and dilatation involving intracranial cerebral arteries, which are reversible within 6­12 weeks No vasculitic changes GACNS Male predominant Chronic, insidious Abnormal Frequently normal; otherwise, findings range from single or multiple arterial cut-off areas, to luminal irregularities in single or multiple arteries, to diffuse abnormalities that are occasionally indistinguishable from RCVS. These abnormalities are frequently irreversible Granulomatous angiitis

CNS biopsy

CNS, central nervous system; CSF, cerebrospinal fluid; GACNS, granulomatous angiitis of the central nervous system; RCVS, reversible cerebral vasoconstriction syndrome. Adapted with modification from [11] with permission.

the control of cerebral vascular tone seems to be the critical element in the pathophysiology of RCVS [10,13]. In support of this hypothesis is the dearth of inflammatory changes in CNS pathology of patients with RCVS. Our recent report [13] of the largest series of RCVS to date included 120 patients, 21 of whom underwent brain biopsies. None of these biopsies revealed any vasculitic changes. In addition, 98% of the follow-up vascular imaging in this series revealed partial or full reversibility of the initial vascular abnormalities. The alteration in vascular tone in RCVS may be spontaneous or evoked by various exogenous or endogenous factors. Exogeneous factors include sympathomimetic or serotonergic drugs [14­20], and direct or neurosurgical trauma [21­23]. Endogenous factors include serotonergic tumors and uncontrolled hypertension [24].

Primary angiitis of the central nervous system: atypical cases

group are patients with abnormal cerebrospinal fluid (CSF) findings that preclude a diagnosis of RCVS or those with GACNS-like presentation but without granulomatous features on CNS biopsies. In addition, patients presenting with PACNS at unusual anatomic sites such as the spinal cord or those presenting with mass lesions are included in this category.

Secondary central nervous system vasculitis

Secondary CNS vasculitis has been described in association with multiple conditions including systemic vasculitides, connective tissue disease (CTD), sarcoidosis, infections, and lymphoproliferative diseases. CNS involvement in these setting is frequently a presumed diagnosis, on the basis of radiographic rather than pathologic modalities.

Infectious causes of central nervous system vasculitis

Most PACNS patients present atypically. This subset does not fit the diagnostic features for either GACNS or RCVS, yet these patients demonstrate angiographic or histopathologic evidence of PACNS. Included in this

Table 2 Clinical and radiographic data in 67 patients with reversible cerebral vasoconstriction syndrome Age Female/male Precipitating factor None Postpartum Vasoactive substance Headaches Recurrent thunderclap Single thunderclap Recurrent severe Focal neurological deficits Seizures Abnormal brain MRI cSAH Silent infarct RPLS 42.5 (range 19­70) 43/24 25 5 37 67 63 3 1 14 2 19 15 1 6 (37%) (8%) (55%) (100%) (94%) (4.5%) (1.5%) (21%) (3%) (28%) (22%) (1%) (9%)

Infections affecting the CNS are great mimickers of PACNS. The infection may be occult and a high degree of suspicion coupled with the epidemiologic features and the individual risk factors are important features in the workup of patients with possible PACNS. In the workup of patients for possible PACNS, it is imperative to search for an infectious process through CSF or pathologic examination, even when a vasculitic process is established by pathologic basis. The possibility of infections with human immunodeficiency virus (HIV), Varicella zoster (VZV), or syphilis should be actively identified. VZV-associated cerebral angiitis affects older age groups [25] and the disease tends to be more localized than PACNS as well as less severe. The known antecedent infection with herpes zoster suggests the underlying cause. Cerebral angiographic findings of segmental, unilateral involvement of the vessels in the distribution of the middle cerebral artery and, occasionally, the internal carotid artery are characteristic findings in VZV angiitis. The diagnosis is confirmed by the presence of higher antibodies levels of VZV in the CSF than in the serum or by a positive VZV PCR in the CSF [26].

cSAH, cortical subarachnoid hemorrhage; RPLS, reversible posterior leukoencephalopathy. Adapted with permission from [12].

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Central nervous system vasculitis Hajj-Ali and Calabrese 13 Figure 1 Cerebral angiogram of a patient with meningovascular syphilis

(a) Magnetic resonance angiography showing basilar artery narrowing with irregularity (long arrow) and abrupt cut off of the right vertebral artery (short arrow). (b) Angiogram showing narrowed left internal carotid artery. Reprinted with permission from [29].

Cerebrovascular disease in HIV is very complex and challenging. Although a significant number (35%) of pathologic findings of AIDS-associated CNS disease demonstrate encephalitis, leptomeningitis, and/or vasculitis, opportunistic infections account for the majority of the brain disorder [27]. This demonstrates the complexity of CNS disease in AIDS and the high degree of scrutiny needed in establishing an accurate diagnosis. Treponema pallidum can invade any vessel in the subarachnoid space and results in thrombosis, ischemia and infarction. In the current era, neurosyphilis is most common in patients with HIV infections [28]. Meningitis and meningovascular disease are the usual manifestation. This will manifest as an ischemic stroke in a young person and can be easily mistaken as PACNS (Fig. 1) [29]. Of a special interest is the increasing report of CNS vasculitis associated with hepatitis C virus (HCV) without underlying cryoglobulinemia [30]. The detection of HCV genetic sequences in postmortem brain tissue has suggested a biologic mechanism that underlies the cognitive findings in patients with HCV infection [31]. Other organisms of interest that can affect the CNS include Borrelia burgdorferi [32], Bartonella [33], and Mycobacterium tuberculosis [34] causing mainly meningitis-like pictures. Interestingly, cysticercosis can involve middle-size cerebral vessels in subarachnoid cysticercosis

even in patients without clinical evidence of cerebral ischemia [35].

Systemic vasculitides

Most systemic vasculitides involve the CNS, but are most commonly reported in polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Behcet's disease, Wegener's ¸ granulomatosis [36], and Churg­Strauss syndrome [37]. Ascertaining the cause of neurologic dysfunction in systemic vasculitides is a multifaceted challenge. A diligent workup should be sought in these patients to exclude any opportunistic infections, metabolic dysfunction, and drug toxicity. The CNS may be involved in around 2­8% of Wegener's granulomatosis patients [36]. Stroke, seizures headaches, confusion, and transient neurologic events such as paresthesia, blackouts, or visual loss are common manifestations [38]. Radiographically confirmed vasculitis of the CNS in Wegener's granulomatosis is rare, because the small vessels (50­300 mm in diameter) are typically below the sensitivity of routine angiography [36]. The CNS may be affected in 10­49% of patients with Behcet's disease resulting either from primary inflam¸ mation of CNS tissue or from vasculitis with a venous predominance leading to ischemic stroke [39,40].

Connective tissue diseases

CNS involvement in CTDs in not uncommon, especially in patients with systemic lupus erythematosus (SLE)

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14 Vasculitis syndromes

[41]. Other CTDs that can involve the CNS include ¨ Sjogren's syndrome, rheumatoid arthritis, mixed CTDs, and dermatomyositis. An important consideration in the diagnostic approach to a patient with neurologic dysfunction in the setting of CTDs is whether the particular clinical syndrome is due to CTD-mediated organ dysfunction, a secondary phenomenon related to infection, medication side-effects, or metabolic abnormalities (e.g. uremia), or is due to an unrelated condition. The most common disorder affecting the CNS in SLE is a bland vasculopathy consistent with small-vessel hyalinization, thickening and thrombus formation [42], ¨ and microinfarcts [43]. Sjogren's syndrome, like Behcet ¸ disease, may mimic multiple sclerosis and present as a relapsing-remitting or primary progressive neurologic dysfunction [44]. Rheumatoid vasculitis affecting the CNS is rare and may present with seizures, dementia, hemiparesis, cranial nerve palsy, blindness, hemispheric dysfunction, cerebellar ataxia, or dysphasia [45,46].

Miscellaneous disorders

Other miscellaneous conditions include amyloid angiopathy and inflammatory bowel diseases.

Diagnosis

The first task of the clinician is to accurately catalogue areas of disease involvement by careful history and physical examination. The evolution of the differential diagnosis and test selection depends on the expected prevalence of an illness in the population and the physician's prior experience. The presence of systemic features, symptoms outside the CNS, and clues from past medical history deviate the hierarchy of the differential diagnosis to either systemic vasculitides, infectious or vaso-oclusive diseases. There are no laboratory tests that are diagnostic for CNS vasculitis. Acute-phase reactants, such as sedimentation rate and C-reactive protein, are usually normal in patients with PACNS. If serum markers of inflammation are elevated, secondary forms of CNS vasculitis should be evaluated. If the history and physical examination point to a systemic vasculitis, testing should proceed accordingly. Testing for a variety of infectious organisms, such as mycobacteria, fungi, syphilis, and HIV, is warranted in patients presenting with chronic meningitis. Other serologic tests are indicated if there is a history of exposure, such as tick bites in Lyme disease. Evaluation for hypercoagulable states, emboli, and investigation of drug exposure, including over-the-counter medications, are essential in patients who present with acute focal or multifocal disease. CSF analysis is an essential tool in the diagnostic evaluation; CSF analysis is of great value in ruling out infectious mimics. CSF findings are abnormal in 80­90% of pathologically documented cases of PACNS. Findings usually reflect aseptic meningitis, with modest pleocytosis, normal glucose, elevated protein levels, and occasionally the presence of oligoclonal bands and elevated IgG synthesis. The importance of obtaining appropriate stains, cultures, and serology evaluations to exclude any infectious causes cannot be overstressed, especially in patients presenting with chronic meningitis. Patients with RCVS typically have a normal or near-normal CSF analysis. Neuroimaging studies, such as computed tomography (CT) and magnetic resonance imaging (MRI)2, are not specific or sufficient for diagnosis of CNS vasculitis. MRI is a more sensitive diagnostic imaging technique than CT, except when cerebral hemorrhage is suspected. The sensitivity of MRI in biopsy-proven cases approaches 100% [50,53]. MRI findings include multiple and often bilateral infarcts in cortex, deep white matter, or leptomeninges, with or without contrast enhancement [54­ 56]. Normal MRI of the brain is not infrequent in RCVS. The most common findings in RCVS include infarction,

Antiphospholipid syndrome (APS) is one of the syndromes that are highly encountered in the differential diagnosis of CNS vasculitis [47,48]. Thrombotic-related events are the most common APS neurologic manifestation. Seizures, cognitive dysfunction, or psychosis may be the target of antibody-mediated endothelial damage in APS [49]. Antiplatelet or anticoagulant therapies are currently indicated for APS-related ischemic strokes, but they remain controversial for nonthrombotic neurologic manifestations. Vasculitis of the CNS has been reported in association with Hodgkin's and non-Hodgkin's lymphoma and angioimmunolymphoproliferative lesions [50]. The anatomic lesions of the lymphoproliferative disease could be within or outside the CNS. Mass lesions, lymphocytic disease, and spinal cord involvement raise the suspicion of lymphoproliferative disease. Appropriate immunohistochemistry staining as well as B-cells and T-cells markers should be performed even with the pathologic finding of angiitis because the presence of vasculitic changes does not exclude an underlying lymphoproliferative condition. Other miscellaneous disorders include mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome (MELAS), which is a mitochondrial genetic disorder caused by a point mutation at nucleotide 3243 (A3243G) leading to stroke-like episodes before age 40, seizures, dementia, and ragged-red fibers in muscle [51]. Another is the cerebroretinal vasculopathy syndrome, which is an autosomal-dominant retinal vasculopathy with cerebral leukodystrophy leading to stroke and dementias with middle-age onset [52].

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Central nervous system vasculitis Hajj-Ali and Calabrese 15 Figure 2 Cerebral angiography of a patient with reversible cerebral vasoconstriction syndrome at diagnosis (left) and after 1 month of calcium-channel blocker therapy (right)

Note the multiple areas of stenosis (white arrows) and dilatation in multiple vessels (black arrows) and their resolution after treatment. Reprinted with permission from [10].

particularly in arterial `watershed' and `borderzone' regions, parenchymal hemorrhages and small nonaneurysmal subarachnoid hemorrhages overlying the cortical surface [21]. In RCVS, brain infarction results from severe hypoperfusion distal to severe vasoconstriction, and hemorrhage presumably results from reperfusion injury. Posterior reversible leukoencephalopathy has also been reported in RCVS [57]. Cerebral angiography is a critical modality in evaluating patients with CNS vasculitis. However, a treating physician should be aware of its limited specificity and lack of quantitative and qualitative codification. The sensitivity of cerebral angiography decreases with the calibre of the vessel, being most sensitive for disease of larger vessels. Moreover, the angiographic findings should be interpreted cautiously, given its poor specificity [58]. The findings of alternating areas of vascular constriction and ectasia or beading are not specific for vasculitis, and these findings should be interpreted along with clinical features and CSF findings [58,59]. These findings can be encountered in vasospastic, infectious, embolic, atherosclerotic diseases, and hypercoagulable states. In pathologically proven cases, such as GACNS, the sensitivity of cerebral angiography findings is as low as 10­20% [60]. Cerebral angiogram is not considered the procedure of choice in ascertaining the diagnosis of GACNS. However, involvement of multiple vessels in multiple vascular beds (high-

probability angiogram) raises the possibility of RCVS. These angiographic findings are characteristic of RCVS. More important is the, documentation of reversibility of the angiographic abnormalities, along the course of the disease, which is essential to secure the diagnosis of RCVS (Fig. 2) [10]. Pathologic evaluation of the CNS is usually entertained in patients with a chronic meningitis-like picture and whether there is any suspicion for infectious or neoplastic process [61]. The procedure of choice is open-wedge biopsy of the tip of the nondominant temporal lobe with sampling of the overlying leptomeninges and underlying cortex [50]. Alternatively, directing the biopsy to an area of leptomeningeal enhancement, when present, may increase the sensitivity. Brain biopsy is limited by its low sensitivity. False negative biopsies can be as high as 25% of autopsy-documented cases [62]. Finally, the presence of vasculitis in the biopsy specimen should not preclude performing special stains and cultures for occult infections that may produce secondary vascular inflammation.

Treatment

The therapeutic guidelines of CNS vasculitis are based largely on extrapolation from other systemic vasculitides and from experts' consensus opinion. There are no

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16 Vasculitis syndromes

controlled trials that direct the treatment. On the basis of the grave historical prognosis of GACNS, and the original reports of the successful treatment with use of cyclophosphamide, GACNS patients are treated with a combination regimen of cyclophosphamide and glucocorticoids. Upon securing remission for 3­6 months, cyclophosphamide is switched to an alternative immunosuppressant agent such as azathioprine, methotrexate, or mycophenolate mofetil. This therapeutic paradigm is extrapolated from the recent studies in Wegener's granulomatosis [63]. Serial MRI examinations at 3­4-month intervals to search for silent progression during tapering of therapy and evaluation and documentation of clearance of CSF abnormalities are important measures in following these patients. Adjunctive therapies, such as prophylaxis for pneumocystis carinii infection and adequate prophylaxis for osteoporosis, should be implemented to avoid treatment-related toxicities. In RCVS, successful treatment has been reported with calcium channel blockers, short-term glucocorticoids and magnesium sulfate [11]. Spontaneous remission has also been encountered in the literature. Nimodipine or verapamil should be considered as first-line therapy. Alternatively, short-term high-dose glucocorticoids have been reported to be effective. The rationale for this approach is based on the efficacy of high-dose glucocorticoids to reverse experimentally induced vasoconstriction [64]. Documentation of dynamic angiographic changes within 6­12 weeks after therapy is essential in securing the diagnosis. Most cases of PACNS in the atypical category can be initially treated with glucocorticoids alone, with tailoring of treatment according to severity and/or progression of the disease. For those patients with a RCVS-like presentation, the addition of a calcium channel blocker is warranted. The addition of cyclophosphamide may be needed in patients with a severe presentation. Treatment of CNS disease in systemic vasculitis is directed by the underlying systemic vasculitis. In general, high-dose glucocorticoids are essential in all patients in addition to other immunomodulating agents. Cyclophosphamide is favored in extraarticular disease manifestations in RA [65]; however, tumor necrosis factor inhibitors such as infliximab may be successful in treatmentresistant rheumatoid vasculitis [66]. Rituximab use in neuropsychiatric systemic lupus erythematosis (NPSLE) therapy is promising. Rapid improvement of CNS-related manifestations, particularly acute confusional state was described in a recent report [67]. These results warrant further analysis of rituximab as treatment of NPSLE. The prognosis of infection-associated CNS vasculitis is highly variable. In addition to the appropriate anti-

microbial drugs, adjunctive immunosuppressive therapy may be required in patients who do not respond to antimicrobial therapy, though there are no supportive data for this recommendation.

Conclusion

Considerable progress has been made over the past decade in our understanding of CNS vasculitis. The recognition of RCVS as different syndromes from GACNS has been a major breakthrough in this field. It is crucial to be aware of RCVS, giving its different therapeutic and prognostic implications. When faced by a patient with suspected CNS vasculitis, a diligent workup should be performed to exclude any mimics. Hypercoagulable state, systemic vasculitides, and infections are important disorders to be ruled out. There are no specific laboratory tests for CNS vasculitis. Brain imaging is nonspecific for the diagnosis of CNS vasculitis including cerebral angiography. CSF examination is a fundamental tool, especially to rule out infectious process. Careful clinical, radiological, and laboratory correlation is essential for the right diagnosis. There are no controlled therapeutic trials for the treatment of CNS vasculitis. Glucocorticoids and cyclophosphamide remain the treatment core of GACNS. Calcium channel blockers and intravenous magnesium sulfate appear to be effective in RCVS. There is a need for controlled trials in the treatment of CNS vasculitis. Future research should be directed to better delineate the therapeutic modalities.

References and recommended reading

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18 Vasculitis syndromes

61 Parisi JE, Moore PM. The role of biopsy in vasculitis of the central nervous system. Semin Neurol 1994; 14:341­348. 62 Cupps TR, Moore PM, Fauci AS. Isolated angiitis of the central nervous system: prospective diagnostic and therapeutic experience. Am J Med 1983; 74:97­105. 63 Molloy ES, Langford CA. Advances in the treatment of small vessel vasculitis. Rheum Dis Clin North Am 2006; 32:157­172. 64 Chen D, Nishizawa S, Yokota N, et al. High-dose methylprednisolone prevents vasospasm after subarachnoid hemorrhage through inhibition of protein kinase C activation. Neurol Res 2002; 24:215­222. 65 Turesson C, Matteson EL. Management of extra-articular disease manifestations in rheumatoid arthritis. Curr Opin Rheumatol 2004; 16:206­ 211. 66 Unger L, Kayser M, Nusslein HG. Successful treatment of severe rheumatoid vasculitis by infliximab. Ann Rheum Dis 2003; 62:587­588. 67 Tokunaga M, Saito K, Kawabata D, et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis 2007; 66:470­475. This report describes the clinical and laboratory tests of 10 patients with NPSLE before and after rituximab treatment.

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