Central nervous system vasculitis

Central nervous system vasculitisRula A. Hajj-Ali a and Leonard H. Calabrese ba Center for Vasculitis Care and Research and b RJFasenmyer Chair of Clinical Immunology, Departmentof Rheumatic and Immunologic Diseases, ClevelandClinic, Cleveland, Ohio, USACorrespondence to Rula A. Hajj-Ali, Center forVasculitis Care and Research, Department ofRheumatic and Immunologic Diseases, ClevelandClinic, 9500 Euclid Avenue, Cleveland, OH 44195,USATel: +1 216 444 9643; e-mail: hajjalr@ccf.orgCurrent Opinion in Rheumatology 2009,21:10–18Purpose of reviewIn the past decade, primary and secondary central nervous system (CNS) vasculitideshave been more commonly diagnosed and recognized than previously. With theincreasing awareness of these disorders, it is crucial for the treating physician todifferentiate between causes of CNS vasculitis and to recognize their marked clinicaland pathophysiological heterogeneity. This review focuses on the major forms of primaryCNS vasculitis, as well as secondary CNS vasculitis with emphasis on their clinicalfindings, diagnoses, and treatment.Recent findingsThe proposal of reversible cerebral vasoconstriction syndromes (RCVS) as a unifyingconcept for a group of disorders which are characterized by acute-onset severerecurrent headaches, with or without additional neurologic signs and symptoms, andprolonged but reversible vasoconstriction of the cerebral arteries, has been a majorbreakthrough 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 previouslyconfused with pathologically documented CNS vasculitis.SummarySound treatment decisions are based on accurate diagnosis. It is essential for theclinicians involved in the evaluation of patients with CNS vasculitis to be aware of itsmimics especially RCVS. This article provides a comprehensive review of CNSvasculitis and its differential diagnosis. Furthermore, it touches upon workup andtreatment of CNS vasculitis.Keywordsgranulomatous angiitis of the central nervous system, primary angiitis of the centralnervous system, reversible cerebral vasoconstriction syndromesCurr Opin Rheumatol 21:10–18ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins1040-8711IntroductionVasculitis that affects the central nervous system (CNS) isone of the most formidable diagnostic and therapeuticchallenges for physicians. The ischemic symptoms andfindings induced by CNS vasculitis may be identical tothose produced by infection, occlusive vascular disease,or malignancy. Adding to the diagnostic challenge is thelack of an accurate and sensitive diagnostic test. Theability of the treating physician to tackle the diagnosticand therapeutic challenges is based on familiarity withthe various clinical syndromes associated with CNS vasculitis,the understanding of the nature of the disease, andthe knowledge of its mimics. Fortunately, over the pastseveral years, multiple advances occurred in these areas.This review will summarize the clinical presentations,the differential diagnoses, and the diagnostic and therapeuticmodalities of CNS vasculitis.Primary central nervous system vasculitisBroadly, CNS vasculitis can be classified as primaryangiitis of the CNS (PACNS) when it is confined tothe CNS and secondary when associated with variousother disorders. Initial reports of PACNS described itas a fatal and progressive granulomatous vasculitis andreferred to it as granulomatous angiitis of the CNS(GACNS) [1]. Increasing interest in the disease emergedwith the reports of successful treatment with cyclophosphamideand glucocorticoids. In 1988, Calabrese andMallek [2] proposed the criteria for the diagnosis ofPACNS.The presence of an acquired and otherwise unexplainedneurologic deficit and with(a) the presence of either classic angiographic or histopathologicfeatures of angiitis within the CNS, and(b) no evidence of systemic vasculitis or any conditionthat could elicit the angiographic or pathologicfeatures.In the 1990s, it was recognized that PACNS is a heterogeneousdisorder with clinical subsets that significantlydiffer in terms of prognosis and therapy. PACNS comprisedifferent subsets including GACNS, and atypical1040-8711 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/BOR.0b013e32831cf5e6Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Central nervous system vasculitis Hajj-Ali and Calabrese 11cases. Recently, the term reversible cerebral vasoconstrictionsyndrome (RCVS) was proposed to comprise agroup of disorders characterized by acute onset of headaches,with or without neurologic deficit, and prolongedbut reversible cerebral vasoconstriction. RCVS are confinedto the CNS but has marked clinical and pathophysiologicalheterogeneity than GACNS. Being a majormimic of PACNS, RCVS will be discussed in the sectionof primary central nervous system vasculitis. However, itcannot be overemphasized that RCVS is not a form oftrue CNS vasculitis, but rather a group of vasoconstrictivesyndromes.Granulomatous angiitis of the central nervous systemGACNS represents about 20% of all patients withPACNS. It appears to be male-predominant and occursat any age. It is characterized by a long prodromal period,with few patients presenting acutely. Signs and symptomsof systemic vasculitis such as peripheral neuropathy,fever, weight loss, or rash are usually lacking. Because thevasculitis may affect any area of the CNS, its presentationmay vary widely, and no set of clinical signs is specificfor the diagnosis. Signs and symptoms of GACNS aresummarized below:(1) Chronic headaches.(2) Encephalopathy.(3) Strokes/transient ischemic attack (more commonrecurrent).(4) Seizures.(5) Behavioral and cognitive changes.(6) Focal motor/sensory abnormalities.(7) Ataxia.(8) Myelopathy.GACNS may be suspected in the setting of chronicmeningitis, recurrent focal neurologic symptoms, unexplaineddiffuse neurologic dysfunction, or unexplainedspinal cord dysfunction not associated with systemicdisease or any other process.The characteristic pathologic findings include classicgranulomatous angiitis affecting the small and mediumleptomeningeal and cortical arteries with Langhansor foreign body giant cells, necrotizing vasculitis, or alymphocytic vasculitis. The inflamed vessels becomenarrowed, occluded, and thrombosed, causing tissueischemia and necrosis of the territories of the involvedvessels.The primary event that elicits the inflammatoryprocess in GACNS remains unknown. It is possible thataltered host defense mechanisms tilt the balance ofthe immune system and allow a viral illness to escapethe immune system, which sets off the vasculitic process[3–8].Reversible cerebral vasoconstriction syndromesBenign angiopathy of the CNS (BACNS) was initiallyproposed as a term to characterize a distinct subset ofpatients with isolated neurologic events, characterized byfemale predominance, acute presentation, reversibleangiographic abnormalities, normal results on spinal fluidexamination, and monophasic course [9]. The term‘angiopathy’ was used because of uncertainty regardingthe nature of the pathologic process affecting the vesselwall and the lack of evidence of blood vessel inflammation.In 2002, Hajj-Ali et al. [10] described dramaticresolution of angiographic abnormalities in series of 16patients within 4–12 weeks without intensive immunosuppressivetherapy. With these data, it became apparentthat the underlying pathophysiologic disorder in BACNSpatients was reversible vasoconstriction rather than vasculitis.Further on, the term BACNS evolved into a newterminology referred to as reversible cerebral vasoconstrictionsyndromes. The evolvement in the terminologyto RCVS occurred with the recognition that RCVS comprisea group of diverse conditions, all characterized byreversible multifocal narrowing of the cerebral arteriesheralded by sudden, severe (thunderclap) headacheswith or without associated neurologic deficits and mostimportantly by reversible angiographic findings. RCVSinclude BACNS, Call–Fleming syndrome, postpartumangiopathy, migrainous vasospasm, and drug-induced‘arteritis’ [11 ]. Calabrese et al. [11 ] proposed criticalelements for the diagnosis of RCVS which are summarizedbelow.(1) Transfemoral angiography or indirect computed tomographyangiography (CTA) or magnetic resonanceangiography (MRA) documenting multifocal segmentalcerebral artery vasoconstriction.(2) No evidence for aneurysmal subarachnoid hemorrhage.(3) Normal or near-normal cerebrospinal fluid analysis(protein level

12 Vasculitis syndromesTable 1 Comparison of clinical and diagnostic characteristics of reversible cerebral vasoconstriction syndromes and granulomatousangiitis of the central nervous systemRCVSGACNSPatients Female predominant Male predominantHeadaches Acute Chronic, insidiousCSF findings Normal to near-normal AbnormalAngiographyDiffuse areas of multiple stenoses and dilatationinvolving intracranial cerebral arteries, whichare reversible within 6–12 weeksCNS biopsy No vasculitic changes Granulomatous angiitisFrequently normal; otherwise, findings range from singleor multiple arterial cut-off areas, to luminal irregularitiesin single or multiple arteries, to diffuse abnormalities thatare occasionally indistinguishable from RCVS. Theseabnormalities are frequently irreversibleCNS, central nervous system; CSF, cerebrospinal fluid; GACNS, granulomatous angiitis of the central nervous system; RCVS, reversible cerebralvasoconstriction syndrome. Adapted with modification from [11 ] with permission.the control of cerebral vascular tone seems to be thecritical element in the pathophysiology of RCVS[10,13 ]. In support of this hypothesis is the dearth ofinflammatory changes in CNS pathology of patients withRCVS. Our recent report [13 ] of the largest series ofRCVS to date included 120 patients, 21 of whom underwentbrain biopsies. None of these biopsies revealed anyvasculitic changes. In addition, 98% of the follow-upvascular imaging in this series revealed partial or fullreversibility of the initial vascular abnormalities.The alteration in vascular tone in RCVS may be spontaneousor evoked by various exogenous or endogenousfactors. Exogeneous factors include sympathomimetic orserotonergic drugs [14–20], and direct or neurosurgicaltrauma [21–23]. Endogenous factors include serotonergictumors and uncontrolled hypertension [24].Primary angiitis of the central nervous system:atypical casesMost PACNS patients present atypically. This subsetdoes not fit the diagnostic features for either GACNS orRCVS, yet these patients demonstrate angiographic orhistopathologic evidence of PACNS. Included in thisTable 2 Clinical and radiographic data in 67 patients withreversible cerebral vasoconstriction syndromeAge 42.5 (range 19–70)Female/male 43/24Precipitating factorNone 25 (37%)Postpartum 5 (8%)Vasoactive substance 37 (55%)Headaches 67 (100%)Recurrent thunderclap 63 (94%)Single thunderclap 3 (4.5%)Recurrent severe 1 (1.5%)Focal neurological deficits 14 (21%)Seizures 2 (3%)Abnormal brain MRI 19 (28%)cSAH 15 (22%)Silent infarct 1 (1%)RPLS 6 (9%)cSAH, cortical subarachnoid hemorrhage; RPLS, reversible posteriorleukoencephalopathy. Adapted with permission from [12 ].group are patients with abnormal cerebrospinal fluid(CSF) findings that preclude a diagnosis of RCVSor those with GACNS-like presentation but withoutgranulomatous features on CNS biopsies. In addition,patients presenting with PACNS at unusual anatomicsites such as the spinal cord or those presenting with masslesions are included in this category.Secondary central nervous system vasculitisSecondary CNS vasculitis has been described in associationwith multiple conditions including systemic vasculitides,connective tissue disease (CTD), sarcoidosis,infections, and lymphoproliferative diseases. CNS involvementin these setting is frequently a presumed diagnosis,on the basis of radiographic rather than pathologicmodalities.Infectious causes of central nervous system vasculitisInfections affecting the CNS are great mimickers ofPACNS. The infection may be occult and a high degreeof suspicion coupled with the epidemiologic features andthe individual risk factors are important features in theworkup of patients with possible PACNS. In the workupof patients for possible PACNS, it is imperative to searchfor an infectious process through CSF or pathologicexamination, even when a vasculitic process is establishedby pathologic basis. The possibility of infectionswith human immunodeficiency virus (HIV), Varicellazoster (VZV), or syphilis should be actively identified.VZV-associated cerebral angiitis affects older age groups[25] and the disease tends to be more localized thanPACNS as well as less severe. The known antecedentinfection with herpes zoster suggests the underlyingcause. Cerebral angiographic findings of segmental, unilateralinvolvement of the vessels in the distribution ofthe middle cerebral artery and, occasionally, the internalcarotid artery are characteristic findings in VZV angiitis.The diagnosis is confirmed by the presence of higherantibodies levels of VZV in the CSF than in the serum orby a positive VZV PCR in the CSF [26].Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Central nervous system vasculitis Hajj-Ali and Calabrese 13Figure 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 (shortarrow). (b) Angiogram showing narrowed left internal carotid artery. Reprinted with permission from [29].Cerebrovascular disease in HIV is very complex andchallenging. Although a significant number (35%) ofpathologic findings of AIDS-associated CNS diseasedemonstrate encephalitis, leptomeningitis, and/or vasculitis,opportunistic infections account for the majority ofthe brain disorder [27]. This demonstrates the complexityof CNS disease in AIDS and the high degree ofscrutiny needed in establishing an accurate diagnosis.Treponema pallidum can invade any vessel in the subarachnoidspace and results in thrombosis, ischemia andinfarction. In the current era, neurosyphilis is most commonin patients with HIV infections [28]. Meningitis andmeningovascular disease are the usual manifestation.This will manifest as an ischemic stroke in a youngperson and can be easily mistaken as PACNS (Fig. 1)[29].Of a special interest is the increasing report of CNSvasculitis associated with hepatitis C virus (HCV) withoutunderlying cryoglobulinemia [30]. The detection ofHCV genetic sequences in postmortem brain tissuehas suggested a biologic mechanism that underlies thecognitive findings in patients with HCV infection [31].Other organisms of interest that can affect the CNSinclude Borrelia burgdorferi [32], Bartonella [33], andMycobacterium tuberculosis [34] causing mainly meningitis-likepictures. Interestingly, cysticercosis can involvemiddle-size cerebral vessels in subarachnoid cysticercosiseven in patients without clinical evidence of cerebralischemia [35].Systemic vasculitidesMost systemic vasculitides involve the CNS, but are mostcommonly reported in polyarteritis nodosa (PAN), microscopicpolyangiitis (MPA), Behçet’s disease, Wegener’sgranulomatosis [36], and Churg–Strauss syndrome [37].Ascertaining the cause of neurologic dysfunction insystemic vasculitides is a multifaceted challenge. Adiligent workup should be sought in these patients toexclude any opportunistic infections, metabolic dysfunction,and drug toxicity. The CNS may be involvedin around 2–8% of Wegener’s granulomatosis patients[36]. Stroke, seizures headaches, confusion, and transientneurologic events such as paresthesia, blackouts, or visualloss are common manifestations [38]. Radiographicallyconfirmed vasculitis of the CNS in Wegener’s granulomatosisis rare, because the small vessels (50–300 mm indiameter) are typically below the sensitivity of routineangiography [36].The CNS may be affected in 10–49% of patients withBehçet’s disease resulting either from primary inflammationof CNS tissue or from vasculitis with a venouspredominance leading to ischemic stroke [39,40].Connective tissue diseasesCNS involvement in CTDs in not uncommon, especiallyin patients with systemic lupus erythematosus (SLE)Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

14 Vasculitis syndromes[41 ]. Other CTDs that can involve the CNS includeSjögren’s syndrome, rheumatoid arthritis, mixed CTDs,and dermatomyositis. An important consideration in thediagnostic approach to a patient with neurologic dysfunctionin the setting of CTDs is whether the particularclinical 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 SLEis a bland vasculopathy consistent with small-vesselhyalinization, thickening and thrombus formation [42],and microinfarcts [43]. Sjögren’s syndrome, like Behçetdisease, may mimic multiple sclerosis and present as arelapsing-remitting or primary progressive neurologicdysfunction [44]. Rheumatoid vasculitis affecting theCNS is rare and may present with seizures, dementia,hemiparesis, cranial nerve palsy, blindness, hemisphericdysfunction, cerebellar ataxia, or dysphasia [45,46].Miscellaneous disordersAntiphospholipid syndrome (APS) is one of the syndromesthat are highly encountered in the differentialdiagnosis of CNS vasculitis [47,48 ]. Thrombotic-relatedevents are the most common APS neurologic manifestation.Seizures, cognitive dysfunction, or psychosis maybe the target of antibody-mediated endothelial damage inAPS [49]. Antiplatelet or anticoagulant therapies arecurrently indicated for APS-related ischemic strokes,but they remain controversial for nonthrombotic neurologicmanifestations.Vasculitis of the CNS has been reported in associationwith Hodgkin’s and non-Hodgkin’s lymphoma andangioimmunolymphoproliferative lesions [50]. The anatomiclesions of the lymphoproliferative disease could bewithin or outside the CNS. Mass lesions, lymphocyticdisease, and spinal cord involvement raise the suspicion oflymphoproliferative disease. Appropriate immunohistochemistrystaining as well as B-cells and T-cellsmarkers should be performed even with the pathologicfinding of angiitis because the presence of vasculiticchanges does not exclude an underlying lymphoproliferativecondition.Other miscellaneous disorders include mitochondrialencephalomyopathy, lactic acidosis, and stroke syndrome(MELAS), which is a mitochondrial geneticdisorder caused by a point mutation at nucleotide3243 (A3243G) leading to stroke-like episodes beforeage 40, seizures, dementia, and ragged-red fibers inmuscle [51]. Another is the cerebroretinal vasculopathysyndrome, which is an autosomal-dominant retinal vasculopathywith cerebral leukodystrophy leading tostroke and dementias with middle-age onset [52 ].Other miscellaneous conditions include amyloid angiopathyand inflammatory bowel diseases.DiagnosisThe first task of the clinician is to accurately catalogueareas of disease involvement by careful history andphysical examination. The evolution of the differentialdiagnosis and test selection depends on the expectedprevalence of an illness in the population and the physician’sprior experience. The presence of systemic features,symptoms outside the CNS, and clues from pastmedical history deviate the hierarchy of the differentialdiagnosis to either systemic vasculitides, infectious orvaso-oclusive diseases. There are no laboratory tests thatare diagnostic for CNS vasculitis. Acute-phase reactants,such as sedimentation rate and C-reactive protein, areusually normal in patients with PACNS. If serum markersof inflammation are elevated, secondary forms of CNSvasculitis should be evaluated. If the history and physicalexamination point to a systemic vasculitis, testing shouldproceed accordingly. Testing for a variety of infectiousorganisms, such as mycobacteria, fungi, syphilis, andHIV, is warranted in patients presenting with chronicmeningitis. Other serologic tests are indicated if there is ahistory of exposure, such as tick bites in Lyme disease.Evaluation for hypercoagulable states, emboli, and investigationof drug exposure, including over-the-countermedications, are essential in patients who present withacute focal or multifocal disease.CSF analysis is an essential tool in the diagnostic evaluation;CSF analysis is of great value in ruling out infectiousmimics. CSF findings are abnormal in 80–90% ofpathologically documented cases of PACNS. Findingsusually reflect aseptic meningitis, with modest pleocytosis,normal glucose, elevated protein levels, andoccasionally the presence of oligoclonal bands andelevated IgG synthesis. The importance of obtainingappropriate stains, cultures, and serology evaluations toexclude any infectious causes cannot be overstressed,especially in patients presenting with chronic meningitis.Patients with RCVS typically have a normal or near-normalCSF analysis.Neuroimaging studies, such as computed tomography(CT) and magnetic resonance imaging (MRI)2, are notspecific or sufficient for diagnosis of CNS vasculitis. MRIis a more sensitive diagnostic imaging technique thanCT, except when cerebral hemorrhage is suspected. Thesensitivity of MRI in biopsy-proven cases approaches100% [50,53]. MRI findings include multiple and oftenbilateral 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,Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Central nervous system vasculitis Hajj-Ali and Calabrese 15Figure 2 Cerebral angiography of a patient with reversible cerebral vasoconstriction syndrome at diagnosis (left) and after 1 month ofcalcium-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 withpermission from [10].particularly in arterial ‘watershed’ and ‘borderzone’regions, parenchymal hemorrhages and small nonaneurysmalsubarachnoid hemorrhages overlying the corticalsurface [21]. In RCVS, brain infarction results from severehypoperfusion distal to severe vasoconstriction, andhemorrhage presumably results from reperfusion injury.Posterior reversible leukoencephalopathy has also beenreported in RCVS [57].Cerebral angiography is a critical modality in evaluatingpatients with CNS vasculitis. However, a treating physicianshould be aware of its limited specificity and lack ofquantitative and qualitative codification. The sensitivityof cerebral angiography decreases with the calibre of thevessel, being most sensitive for disease of larger vessels.Moreover, the angiographic findings should be interpretedcautiously, given its poor specificity [58]. Thefindings of alternating areas of vascular constriction andectasia or beading are not specific for vasculitis, and thesefindings should be interpreted along with clinical featuresand CSF findings [58,59]. These findings can be encounteredin vasospastic, infectious, embolic, atheroscleroticdiseases, and hypercoagulable states. In pathologicallyproven cases, such as GACNS, the sensitivity of cerebralangiography findings is as low as 10–20% [60]. Cerebralangiogram is not considered the procedure of choice inascertaining the diagnosis of GACNS. However, involvementof multiple vessels in multiple vascular beds (highprobabilityangiogram) raises the possibility of RCVS.These angiographic findings are characteristic of RCVS.More important is the, documentation of reversibility ofthe angiographic abnormalities, along the course of thedisease, which is essential to secure the diagnosis ofRCVS (Fig. 2) [10].Pathologic evaluation of the CNS is usually entertainedin patients with a chronic meningitis-like picture andwhether there is any suspicion for infectious or neoplasticprocess [61]. The procedure of choice is open-wedgebiopsy of the tip of the nondominant temporal lobe withsampling of the overlying leptomeninges and underlyingcortex [50]. Alternatively, directing the biopsy to an areaof leptomeningeal enhancement, when present, mayincrease the sensitivity. Brain biopsy is limited by itslow sensitivity. False negative biopsies can be as high as25% of autopsy-documented cases [62]. Finally, thepresence of vasculitis in the biopsy specimen shouldnot preclude performing special stains and cultures foroccult infections that may produce secondary vascularinflammation.TreatmentThe therapeutic guidelines of CNS vasculitis are basedlargely on extrapolation from other systemic vasculitidesand from experts’ consensus opinion. There are noCopyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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