Primary Angiitis of the Central Nervous System

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Primary Angiitis of the Central Nervous System Rula A. Hajj-Ali  •  Carol A. Langford KEY POINTS Primary angiitis of the central nervous system (PACNS) is defined as vasculitis that is confined only to the brain, meninges, or spinal cord. PACNS consists of subsets including granulomatous angiitis of the central nervous system (GACNS) and atypical PACNS that are differentiated by unique histologic and imaging characteristics. The diagnosis of PACNS is based on compatible clinical features together with evidence from spinal fluid, brain and vascular imaging, and often a brain biopsy. Ruling out mimics that have a similar clinical or angiographic appearance is central to the diagnosis of PACNS. Reversible cerebral vasoconstriction syndrome is among the most important mimics of PACNS, with treatment and outcome implications. The initial treatment of PACNS includes glucocorticoids either alone or in combination with cyclophosphamide based on the subset and severity of neurologic disease. The outcome of PACNS is variable, with the highest rate of disability and mortality seen in people with GACNS.

and more than 500 cases have now been described worldwide.8,9

EPIDEMIOLOGY Because of its rarity and our evolving understanding of this disease, the true incidence of PACNS is difficult to calculate.9 In the recent era, the estimated annual incidence rate of PACNS is 2.4 cases per 1 million person-years.9 Middleaged men are often affected by PACNS, with a median age at onset of approximately 50 years and a male-to-female ratio of approximately 2 : 1.5,6,9

GENETICS The pathogenesis of PACNS is not well understood. To date, no evidence has been found to suggest a genetic predisposition, although this possibility remains under active investigation.

CLINICAL FEATURES KEY POINTS

Vasculitis affecting the central nervous system (CNS) most commonly occurs as a manifestation of a primary systemic vasculitis or as a secondary vasculitis in settings such as connective tissue diseases or infections. When the disease is confined only to the CNS (the brain, meninges, and spinal cord), it is referred to as primary angiitis of the central nervous system (PACNS). PACNS is a rare disease that was first reported as a distinct clinical pathologic entity by Cravioto and Feigin in 1959.1 The disease initially was described as fatal “noninfectious granulomatous angiitis with a predilection for the nervous system.” Other reports of similar clinicopathologic phenotypes emerged in the literature, and “granulomatous angiitis of the central nervous system” was proposed to describe this entity.2,3 Different terms subsequently surfaced in the literature, such as isolated angiitis of the CNS to encompass cases that were characterized by nongranulomatous pathologic findings.4 Currently, PACNS is a wellaccepted term for this disease that emphasizes the sole involvement of the CNS.5,6 After the description of diagnostic criteria for PACNS proposed by Calabrese and Mallek in 19885 and the potential for effective treatment,7 published cases in the literature increased tremendously,

PACNS is divided into subsets that include granulomatous angiitis of the central nervous system (GACNS) and atypical PACNS. Mass-like lesions can occur in people with PACNS. Clinical features of GACNS typically include chronic insidious headaches along with diffuse and focal neurologic deficits.

Great progress has been made toward understanding the clinical features of PACNS despite the many challenges, which include the lack of highly specific diagnostic modalities, the sparse material for research, and the lack of controlled clinical trials. In the recent era, specific clinical and pathologic subsets of PACNS have been identified that have prognostic implications.10-13

Proposed Criteria for Primary Angiitis of the Central Nervous System In 1988, Calabrese and Mallek5 proposed diagnostic criteria for PACNS that emphasized the importance of ruling out mimics when diagnosing PACNS. These criteria include (1) the presence of an unexplained neurologic deficit after 1581

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thorough clinical and laboratory evaluation; (2) documentation by cerebral angiography and/or tissue examination of an arteritic process within the CNS; and (3) no evidence of a systemic vasculitides or any other condition to which the angiographic or pathologic features could be secondary. In 2009, Birnbaum and Hellmann12 proposed changes to the criteria described by Calabrese and colleagues, incorporating levels of diagnostic certainty in their assessment. They proposed use of the term definite diagnosis of PACNS when tissue biopsy findings provide confirmation of vasculitis and a probable diagnosis of PACNS when the diagnosis is based on high-probability findings on an angiogram in the absence of tissue confirmation but with consideration of cerebrospinal fluid (CSF) profiles and neurologic symptoms to discriminate between PACNS and its mimics. Although the original criteria by Calabrese and Mallek served as a platform of literature-based research, their interpretation has changed fundamentally as advancement of our diagnostic modalities has revealed many unexplained neurologic diseases. The importance of ruling out mimics of PACNS remains essential in the diagnostic approach of patients with suspected PACNS.

CLINICAL SUBSETS The original pathologic reports of PACNS as a granulomatous angiitis imposed a histologic-based nomenclature on the disease that led to the original name granulomatous angiitis of the CNS (GACNS). Until the 1980s, PACNS was largely considered a homogeneous entity with a uniform clinical picture and a grave prognosis. This paradigm was challenged with the introduction of direct vascular imaging as a diagnostic tool and the recognition that nongranulomatous pathologic findings occur in PACNS. Initial attempts at subclassification of PACNS described three broad subsets: GACNS, benign angiopathy of the CNS (BACNS), and “atypical” PACNS.14 It has since become recognized that BACNS is part of the reversible cerebral vasoconstriction syndrome (RCVS),11 with the other PACNS subsets now being defined by pathologic or radiographic features.

Granulomatous Angiitis of the Central Nervous System GACNS is a subset of PACNS that is described as a clinicopathologic entity characterized by granulomatous angiitis confined to the brain. GACNS is a rare subset of PACNS, in which patients clinically present with chronic insidious headaches along with diffuse and focal neurologic deficits. Because the disease is confined to the brain, meninges, or spinal cord, signs and symptoms of systemic inflammatory diseases are usually lacking. The diagnosis of this subset is confirmed by the pathologic findings of granulomatous angiitis (Figure 92-1). Typically the CSF findings include those of an aseptic meningitis picture with negative staining for microorganisms. GACNS predominantly affects middleaged men. The most common findings on neuroimaging include infarcts, most often bilateral, as well as highintensity T2-weighted fluid attenuation inversion recovery (FLAIR) lesions on magnetic resonance imaging (MRI) in

Figure 92-1  Histopathologic findings of patients with granulomatous angiitis of the central nervous system vasculitis.

the subcortical white matter and deep gray matter. A cerebral angiogram is not the diagnostic modality of choice given its poor spatial resolution in the detection of small vessel vasculitis, which mainly occurs in GACNS.

Atypical Central Nervous System Vasculitis Atypical CNS vasculitis, a subset of PACNS, comprises multiple manifestations of PACNS that are clinically, radiologically, or pathologically distinct from GACNS. Atypical PACNS is the most frequent and heterogeneous subset of PACNS. Included in this subset are patients with specific presentations such as lesions or patients with pathologic findings of lymphocytic infiltration rather than granulomatous angiitis. Mass-like Presentation

Mass-like (ML) presentation is a rare manifestation of PACNS that occurs in less than 5% of cases. This presentation has gained attention after the recent report of a series of 38 patients with histologically confirmed PACNS who presented with a solitary cerebral mass.15 Typically the diagnosis is unanticipated and is confirmed after pathologic examination with either biopsy samples or surgical excision of the mass. Unfortunately, no specific features on clinical assessment, neuroimaging, cerebral angiography, or CSF examination can reliably distinguish ML-PACNS from other more common causes of a solitary cerebral mass. Use of appropriate stains and cultures to rule out mycobacterial, fungal, or other infections and immunohistochemistry/gene rearrangement studies to exclude lymphoproliferative disease are essential to secure the diagnosis and exclude concomitant infectious or malignant processes. Cerebral Amyloid Angiitis

Amyloid protein, in particular amyloid-β peptide, a fragment of the amyloid precursor peptide, can deposit in the brain, causing disease ranging from Alzheimer’s disease to



CHAPTER 92    Primary Angiitis of the Central Nervous System

cerebral amyloid angiopathy (CAA). CAA-related inflammation and angiocentric inflammatory reaction in CAA is referred to as amyloid-β–related angiitis (ABRA).16 Patients with ABRA tend to be older and more prone to hallucinations and mental status changes than are other patients with PACNS. MRI cannot distinguish between ABRA and other forms of PACNS, although ABRA has a higher incidence of cerebral hemorrhage. ABRA carries a poor outcome, which could be related to older age and comorbidities. Angiographically Defined Central Nervous System Vasculitis

The poor specificity of the cerebral angiogram poses a major challenge in the diagnosis of PACNS. When the diagnosis of PACNS is based on angiographic findings, a thorough evaluation should be performed to rule out mimics, especially RCVS.17,18 Spinal Cord Presentation

Spinal cord presentation of PACNS is a rare subset in which disease is present only in the spinal cord. The diagnosis is usually made by biopsy.19 Nongranulomatous PACNS

Pathologic findings of lymphocytic infiltration rather than granulomatous findings can occur in PACNS. In this category, ruling out secondary causes of CNS vasculitis, such as infectious or lymphoproliferative diseases, should be emphasized. Adequate staining and immunophenotyping should always be carefully carried out in this category.

DIAGNOSIS AND DIAGNOSTIC TESTS KEY POINTS Spinal fluid, brain and vascular imaging, and brain biopsy are central to the diagnosis of PACNS and the process of ruling out other diseases. Abnormal spinal fluid is found in 80% to 90% of patients with PACNS. Abnormalities on a cerebral angiogram are not specific for PACNS and can be seen in a wide range of other settings. Reversible cerebral vasoconstriction syndrome is an important mimic of PACNS that is characterized by thunderclap headaches, normal CSF, and abnormal findings of a cerebral angiogram in which the changes resolve within 12 weeks. Other important entities in the differential diagnosis of PACNS include infection, lymphoproliferative disease, primary systemic vasculitis, connective tissue disease, and thromboembolic disease.

The diagnosis of PACNS is challenging because of the nonspecific clinical presentation, the lack of highly specific laboratory and radiologic tests, and the difficulty of obtaining pathologic material.

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Diagnostic Tests Laboratory Findings Elevation of acute-phase reactants, anemia, and thrombocytosis are not typical of PACNS, and if present, they should raise the possibility of a primary systemic vasculitis or another underlying disease. Laboratory testing to rule out connective tissue diseases and thromboembolic abnormalities should be performed. Infectious workup with appropriate cultures, serologies, and polymerase chain reaction testing should be directed by clinical and diagnostic findings and host risk factors. Cerebrospinal Fluid Analysis CSF is an important tool in the evaluation of PACNS. Although CSF findings are nonspecific in PACNS, their value lies in ruling out other entities. Obtaining appropriate CSF cultures, microbiologic stains, cytology, and flow cytometry is crucial in ruling out infectious and neoplastic disease. Elevated protein levels, modest lymphocytic pleocytosis, and occasionally oligoclonal bands and elevated IgG synthesis characterize the CSF in 80% to 90% of patients with pathologically documented PACNS.5,20,21 The median CSF white blood cell count is approximately 20 cells/µL, and the median CSF protein level is approximately 120 mg/dL.5,9 Radiologic Evaluation MRI is a sensitive modality for the diagnosis of PACNS, reaching 90% to 100%.9,22 Abnormalities include infarcts in 50% of patients, commonly affecting the cortex and the subcortex bilaterally.9,23 Affected areas include subcortical white matter, followed by deep gray matter, deep white matter, and the cerebral cortex.24 Hyperintense lesions on T2-weighted sequences are common but not specific for PACNS.25 Other abnormalities include mass lesions in 5% of patients,15 leptomeningeal enhancement in 8% of cases,9 and gadolinium-enhanced intracranial lesions in about onethird of patients.9 Cerebral vasculature imaging by catheter-directed dye angiogram or through magnetic resonance angiography (MRA) is an important modality in the diagnosis of PACNS. Alternating areas of dilatation and stenosis characterize the angiographic findings in PACNS and typically involve the vasculature on both sides but sometimes can involve single vessels.26 Other angiographic features include smooth tapering of one or multiple vessels. Although cerebral angiograms may visualize abnormalities in medium-sized vessels, they have limited sensitivity to detect abnormalities in small vessels that are less than 500 µm in diameter. Although cerebral angiography is valuable, its specificity for the diagnosis of PACNS can be as low as 25%.27 The reported “typical” angiographic findings for vasculitis are not specific to PACNS and can be encountered in atherosclerosis, radiation vasculopathy, or vascular spasm.26,27 Moreover, a cerebral angiogram carries a poor positive predictive value in the diagnosis of PACNS in that the angiographic findings seen in RCVS can be consistent with those found in PACNS.28 Vascular studies thus should be interpreted with caution and should not be considered the diagnostic

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“gold standard” in PACNS. Ongoing research using highresolution contrast-enhanced MRI to look at the vessel wall characteristics of wall thickening and wall enhancement is under way.29 This promising technique may enable us to characterize and differentiate between CNS vasculitis, RVCS, and intracranial atherosclerosis. Recent reports indicate that vessel wall enhancement occurs at a much higher rate in PACNS compared with RCVS. Larger studies are needed to validate these interesting findings. Brain Biopsy Brain biopsy is thought to carry a low morbidity and mortality in patients with PACNS14 and is an important part of the evaluation to confirm the diagnosis and rule out mimics. When a brain biopsy is performed, an alternative diagnosis is identified in 30% to 40% of cases.30 The interpretation of the brain biopsy results should take into consideration the potential for false-negative results because of the patchy degree of involvement and the small amount of tissue that often is able to be obtained. The finding of vasculitis on pathologic examination does not exclude the diagnosis of infection or malignancy, and appropriate stains and markers should be pursued for accurate diagnosis.

DIFFERENTIAL DIAGNOSIS The differential diagnosis algorithm of PACNS is large because of the lack of highly specific clinical features or laboratory or imaging findings (Table 92-1). Excluding other entities that can have similar findings is critical in confirming a diagnosis of PACNS. Certain disease categories in particular should be considered and warrant further detailed discussion.

Reversible Cerebral Vasoconstriction Syndromes Distinguishing RCVS, the leading mimic of PACNS, is important because it has different implications for treatment and outcome (Table 92-2). RCVS consists of a group of disorders characterized by acute-onset headaches and reversible cerebrovasoconstriction.11 These disorders include Call-Fleming syndrome, drug-induced angiopathy, migraine angiitis, BACNS, postpartum angiopathy, and drug-induced vasospasm. The clinical features of RCVS include acute onset of severe headaches, with or without neurologic deficit, with evidence of cerebral vasoconstriction that is reversible. The headaches are usually recurrent thunderclap headaches and can be precipitated by straining and coughing. RCVS can be associated with strokes (39%), generalized tonic-clonic seizures (17%), convexity subarachnoid hemorrhage (34%), lobar hemorrhage (20%), and brain edema (38%).18 RCVS occurs more frequently in women than men. In contrast to PACNS, findings of CSF analysis are generally normal in people with RCVS except when a concomitant disorder or subarachnoid bleeding is present. The diagnosis of RCVS is usually considered when cerebral vascular imaging reveals multiple areas of smooth or tapered arterial narrowing followed by segments of normal-caliber or distended arteries. Typically, arterial narrowing involves multiple intracerebral arteries and their branches in both

TABLE 92-1  Differential Diagnosis of Primary Angiitis of the Central Nervous System Secondary Cerebral Vasculitis Primary Systemic Vasculitides Granulomatosis with polyangiitis Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis Polyarteritis nodosa Behçet’s disease Systemic Autoimmune Disease Systemic lupus erythematosus Sjögren’s syndrome Inflammatory myositis Rheumatoid arthritis Mixed connective tissue disease Other Multisystem Inflammatory Disorders Sarcoidosis Susac’s syndrome Infection Bacterial Mycobacterial Fungal Viral Protozoal Malignancy Central nervous system lymphoma Glioma Angiocentric lymphoma Lymphomatoid granulomatosis Metastatic malignancy Vasospastic Disorders Reversible cerebral vasoconstrictive syndrome Drug exposures Other Arterial Disease Atherosclerosis Fibromuscular dysplasia Moyamoya disease Dissection Hypercoagulable States Anti-phospholipid antibody syndrome Thrombotic thrombocytopenic purpura Strokelike Syndromes CADASIL Mitochondrial diseases Sickle cell disease Fabry’s disease Sneddon’s syndrome Leukoencephalopathies Progressive multifocal leukoencephalopathy Reversible posterior leukoencephalopathy syndrome Cerebral Hemorrhage Hypertensive Aneurysmal Amyloid angiopathy Arteriovenous malformation Embolic Disease Thrombus Cholesterol emboli Myxoma Endocarditis Air emboli CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.



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TABLE 92-2  Differentiating Clinical and Radiologic Features between Reversible Cerebral Vasoconstrictive Syndrome and Primary Angiitis of the Central Nervous System

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finding in PACNS.38 True CNS vasculitis rarely occurs in Behçet’s disease.39

Feature

RCVS

PACNS

Systemic Autoimmune Diseases

Gender

Female predominant

Male predominant

Cerebrospinal fluid

Normal

Abnormal

Normal magnetic resonance image

10%-15%

Very rare

Abnormal angiogram

100%

40%-50%

Headache pattern

Recurrent thunderclap

Insidious, chronic

Infarct pattern

Watershed

Small, scattered

Lobar hemorrhage

Common

Extremely rare

Convexity subarachnoid hemorrhage

Common

Very rare

The brain is a common target in connective tissue diseases. In systemic lupus erythematosus (SLE), CNS involvement occurs in 14% to 80% of adults and in 22% to 95% of children.40 Multifocal microinfarcts, cortical atrophy, gross infarcts, hemorrhage, ischemic demyelination, and patchy multiple-sclerosis–like demyelination are typical findings in neuropsychiatric lupus. The most common microscopic brain finding in SLE is microvasculopathy, described as “healed vasculitis” consistent with hyalinization, thickening, and thrombus formation.41,42 Rheumatoid arthritis, Sjögren’s syndrome, and mixed connective tissue disease rarely affect the CNS in a vasculitic pattern.43 CNS vasculitis is typically a late occurrence in these diseases.

PACNS, Primary angiitis of the central nervous system; RCVS, reversible cerebral vasoconstrictive syndrome.

Infections hemispheres, resulting in severe arterial narrowing. The diagnosis of RCVS is secured when repeat vascular imaging reveals reversibility of the cerebral vascular abnormalities, often occurring in about 6 to 12 weeks, which is in contrast to the fixed angiographic abnormalities encountered in PACNS. Controlled trials to direct treatment of RCVS are lacking. Calcium channel blockers are used for symptomatic treatment of the headaches, although no evidence exists that they alter the clinical outcome. Some experts prescribe glucocorticoid therapy, although no evidence exists that it improves the outcome.

Primary Systemic Vasculitides Primary systemic vasculitides such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome), polyarteritis nodosa, or Behçet’s disease can affect the CNS, leading to inflammation and vasculitis. In GPA, CNS disease occurs in 7% to 11% of patients and presents in three ways: direct invasion of granuloma from extracranial sites, remote intracranial granuloma, and, rarely, as a result of CNS vasculitis.31 The diagnosis of CNS vasculitis is often made on the basis of radiologic findings and by exclusion of other causes of the neurologic deficits, especially infection.32 As in GPA, the diagnosis of CNS vasculitis in EGPA is often presumed without histologic confirmation when other mimics are excluded. Neuroophthalmologic manifestations including amaurosis fugax, superior oblique palsy, ischemic optic neuropathy, fourth cranial palsy, and scattered areas of retinal infarction are common presentations of CNS vasculitis in people with EGPA.33,34 In Behçet’s disease, CNS involvement occurs in 14% of cases, manifesting as meningoencephalitis involving the brain stem and rarely as a consequence of thrombosis and inflammation of the dural venous sinuses.35-37 Pathologic evaluation in neuro-Behçet’s disease typically shows a mononuclear infiltration around the small vessels of the brain, including the venous system, which is not a typical

Infections are one of the most important entities that should be ruled out when considering PACNS. Vasculitis can occur in the setting of HIV, often presenting as multifocal cerebral ischemia with pathologic findings of angiocentric lymphoproliferative lesions.44 In addition, HIV can result in granulomatous arteritis45 or can affect the brain as a result of co-infections such as syphilis. Treponema pallidum infection can affect vessels in the subarachnoid space and result in thrombosis, ischemia, and infarction that can mimic PACNS.46 Other infectious agents that have predilection to the brain include varicella-zoster virus (VZV). VZV affects the brain either by involvement of large cerebral vessels, often affecting the proximal segments of the anterior and middle cerebral arteries in immunocompetent people, or small vessel disease in immunocompromised patients.47 A history of VZV rash is usually although not always elicited before the CNS involvement. The diagnosis of VZV angiitis is confirmed by finding VZV DNA in CSF or by the presence of reduced serum/CSF ratios of VZV IgG.48 Tuberculosis affecting the CNS is an important cause of CNS vasculitis in endemic areas, and care must be taken to exclude it. Hepatitis C,49 West Nile virus,50 parvovirus B19,51 and rarely herpes simplex virus52 can cause CNS vasculitis. Cytomegalovirus can cause CNS vasculitis as an opportunistic infection in immunocompromised people.53 Rarely, cysticercosis can involve middle-sized cerebral arteries.54 A travel history and history of exposures are important features of the workup of patients with suspected PACNS.

Lymphoproliferative Diseases Lymphoproliferative disease with predilection to the vascular wall, such as lymphomatoid granulomatosis (LG), can cause CNS vasculitis, leading to multiple small cortical infarcts and pathologic findings of multifocal angiocentric, angiodestructive lymphoma.55 Concomitant HIV infection is common with LG and should be ruled out.56 Rarely, LG is associated with other systemic autoimmune diseases such as Sjögren’s syndrome.57 Other lymphoproliferative diseases such as CNS lymphoma and intravascular lymphoma can mimic PACNS.

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Miscellaneous Atherosclerotic involvement of the intracerebral arteries is common and is often a consideration in the workup of PACNS. The poor specificity of the cerebral angiogram poses a major limitation in differentiating inflammatory causes from other vasculopathies. However, the lack of inflammatory changes of the CSF and the presence of multiple atherosclerotic risk factors should raise suspicion for atherosclerotic disease. Other entities such as antiphospholipid antibody syndrome, hypercoagulable states, and thromboembolic causes should be carefully ruled out. The workup of PACNS should include a transesophageal echocardiogram and a hypercoagulable profile to rule out thromboembolic causes, especially in patients presenting with recurrent strokes. Other rare diseases that mimic the angiographic findings of PACNS include Moyamoya disease, small vessel arterial dissection, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), radiation vasculopathy, and thromboangiitis obliterans.58

TREATMENT

subsets in which cyclophosphamide is considered at the outset of the treatment. Use of TNF inhibitors or rituximab in patients with PACNS that is resistant to glucocorticoids and other immunosuppressive agents has thus far been confined to case reports, which provide insufficient evidence from which to draw conclusions regarding efficacy.60-62 Failure to respond to cyclophosphamide should prompt evaluation for an alternative diagnosis before additional treatment with an alternative immunosuppressive agent is instituted. Assessing disease status and defining remission are crucial steps in the course of treatment of PACNS. Permanent deficits occurring after the initial event in PACNS should not erroneously be considered to be lack of remission. Disease is considered in remission when stability or improvement of the clinical and radiologic features is achieved. Serial MRI should be obtained to help in the assessment of disease activity. Adjunctive therapy for osteoporosis prevention and prophylaxis for opportunistic infections should be incorporated into the treatment plan.

OUTCOME KEY POINTS

KEY POINTS

PACNS has an estimated mortality rate of 10% to 17%.

No standardized trials relating to the treatment of PACNS have been conducted.

Moderate to severe disability occurs in up to 20% of patients with PACNS.

Typically, GACNS is initially treated with glucocorticoids and cyclophosphamide. The treatment of PACNS subsets besides GACNS is based on the diagnostic subset and severity of neurologic impairment.

The treatment of PACNS is guided by expert opinion and reports of case series, as well as by extrapolation from controlled trials relating to primary systemic vasculitis. To date, no controlled trials have been conducted to investigate the treatment of PACNS. Thus it is not possible to determine a specific treatment algorithm, and therapy is based on the subtype and neurologic severity. The report of successful treatment of GACNS with a combination of cyclophosphamide and glucocorticoids led to the regular use of this regimen.7 Generally, patients are treated with a combination of cyclophosphamide and highdose glucocorticoids for 3 to 6 months until remission is achieved. Cyclophosphamide is then stopped and use of a maintenance agent is initiated, following the same principles used in small-vessel vasculitis.59 Maintenance therapy usually consists of either azathioprine or mycophenolate mofetil and rarely methotrexate given its low CNS penetration. The duration of maintenance therapy in PACNS is not well defined. The treatment of atypical PACNS varies highly. Multiple factors affect the treatment regimen in atypical PACNS, and the treatment is usually individualized, taking into consideration the degree of the neurologic deficit and the features of the diagnosis. All atypical PACNS cases are treated with high dose of glucocorticoids initially, and the decision to add other immunosuppressive agents is based on each individual case. ABRA and ML-PACNS are two PACNS

Originally, PACNS was described as a fatal disease by Cravioto,1 but an improved outlook became possible after the description of treatment with glucocorticoids and cyclophosphamide. According to recent reports, the estimated mortality rate of PACNS varies between 10% and 17%,9,63 with one study finding that survival correlated with the initial findings of infarcts and gadolinium-enhanced lesions on MRI.9 Salvarani and colleagues9 and Hajj-Ali and colleagues63 reported that 20% of patients with PACNS had moderate to severe disability as assessed by the modified Rankin disability scores and the Barthel index, respectively. Salvarani and colleagues9 reported an improvement in disability scores over time.

CONCLUSION Considerable progress has been made in our understanding of PACNS. Our ability to recognize disease mimics has substantially increased our accuracy in diagnosing PACNS. The identification of RCVS in particular has clarified many of the cases that had been erroneously diagnosed as PACNS. Effective diagnosis and management of PACNS requires a multidisciplinary team to evaluate the clinical features, obtain and interpret diagnostic tests, and determine the most effective regimen that will treat the underlying disease and minimize therapeutic toxicity. A great need exists for controlled trials to further guide treatment for patients with PACNS in their initial and maintenance phases. Prospective evaluation of long-term cohorts is necessary to better determine the rates of disability and long-term outcome of PACNS.



CHAPTER 92    Primary Angiitis of the Central Nervous System

The references for this chapter can also be found on ExpertConsult.com.

REFERENCES 1. Cravioto H, Feigin I: Noninfectious granulomatous angiitis with predilection for the nervous system. Neurology 9:599–609, 1959. 2. McCormick HM, Neubuerger KT: Giant-cell arteritis involving small meningeal and intracerebral vessels. J Neuropathol Exp Neurol 17:471– 478, 1958. 3. Budzilovich GN, Feigin I, Siegel H: Granulomatous angiitis of the nervous system. Arch Pathol 76:250–256, 1963. 4. Moore PM: Diagnosis and management of isolated angiitis of the central nervous system. Neurology 39:167–173, 1989. 5. Calabrese LH, Mallek JA: Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 67:20–39, 1988. 6. Lie JT: Primary (granulomatous) angiitis of the central nervous system: a clinicopathologic analysis of 15 new cases and a review of the literature. Hum Pathol 23:164–171, 1992. 7. Cupps TR, Moore PM, Fauci AS: Isolated angiitis of the central nervous system. Prospective diagnostic and therapeutic experience. Am J Med 74:97–105, 1983. 8. Molloy ES, Hajj-Ali RA: Primary angiitis of the central nervous system. Curr Treat Options Neurol 9:169–175, 2007. 9. Salvarani C, Brown RD, Jr, Calamia KT, et al: Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 62:442–451, 2007. 10. Neel A, Paganoux C: Primary angiitis of the central nervous system. Clin Exp Rheumatol 27:S95–S107, 2009. 11. Calabrese LH, Dodick DW, Schwedt TJ, et al: Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med 146:34–44, 2007. 12. Birnbaum J, Hellmann DB: Primary angiitis of the central nervous system. Arch Neurol 66:704–709, 2009. 13. Calabrese LH: Vasculitis of the central nervous system. Rheum Dis Clin North Am 21:1059–1076, 1995. 14. Calabrese LH, Duna GF, Lie JT: Vasculitis in the central nervous system. Arthritis Rheum 40:1189–1201, 1997. 15. Molloy ES, Singhal AB, Calabrese LH: Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system. Ann Rheum Dis 67:1732–1735, 2008. 16. Eng JA, Frosch MP, Choi K, et al: Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 55:250–256, 2004. 17. Ducros A, Boukobza M, Porcher R, et al: The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain 130:3091–3101, 2007. 18. Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al: Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol 68: 1005–1012, 2011. 19. Salvarani C, Brown RD, Jr, Calamia KT, et al: Primary CNS vasculitis with spinal cord involvement. Neurology 70:2394–2400, 2008. 20. Pou Serradell A, Maso E, Roquer J, et al: Isolated angiitis of the central nervous system. Clinical and neuropathological study of 2 cases. Rev Neurol (Paris) 151:258–266, 1995. 21. Stone JH, Pomper MG, Roubenoff R, et al: Sensitivities of noninvasive tests for central nervous system vasculitis: a comparison of lumbar puncture, computed tomography, and magnetic resonance imaging. J Rheumatol 21:1277–1282, 1994. 22. Calabrese LH: Therapy of systemic vasculitis. Neurol Clin 15:973–991, 1997. 23. Hurst RW, Grossman RI: Neuroradiology of central nervous system vasculitis. Semin Neurol 14:320–340, 1994. 24. Pomper MG, Miller TJ, Stone JH, et al: CNS vasculitis in autoimmune disease: MR imaging findings and correlation with angiography. AJNR Am J Neuroradiol 20:75–85, 1999. 25. Bekiesinska-Figatowska M: T2-hyperintense foci on brain MR imaging. Med Sci Monit 10(Suppl 3):80–87, 2004. 26. Alhalabi M, Moore PM: Serial angiography in isolated angiitis of the central nervous system. Neurology 44:1221–1226, 1994. 27. Duna GF, Calabrese LH: Limitations of invasive modalities in the diagnosis of primary angiitis of the central nervous system. J Rheumatol 22:662–667, 1995.

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28. Kadkhodayan Y, Alreshaid A, Moran CJ, et al: Primary angiitis of the central nervous system at conventional angiography. Radiology 233: 878–882, 2004. 29. Obusez EC, Hui F, Hajj-Ali RA, et al: High-resolution MRI vessel wall imaging: spatial and temporal patterns of reversible cerebral vasoconstriction syndrome and central nervous system vasculitis. AJNR Am J Neuroradiol 35:1527–1532, 2014. 30. Alrawi A, Trobe JD, Blaivas M, et al: Brain biopsy in primary angiitis of the central nervous system. Neurology 53:858–860, 1999. 31. Nishino H, Rubino FA, Parisi JE: The spectrum of neurologic involvement in Wegener’s granulomatosis. Neurology 43:1334–1337, 1993. 32. Seror R, Mahr A, Ramanoelina J, et al: Central nervous system involvement in Wegener granulomatosis. Medicine (Baltimore) 85:54– 65, 2006. 33. Weinstein JM, Chui H, Lane S, et al: Churg-Strauss syndrome (allergic granulomatous angiitis). Neuro-ophthalmologic manifestations. Arch Ophthalmol 101:1217–1220, 1983. 34. Vitali C, Genovesi-Ebert F, Romani A, et al: Ophthalmological and neuro-ophthalmological involvement in Churg-Strauss syndrome: a case report. Graefes Arch Clin Exp Ophthalmol 234:404–408, 1996. 35. Al-Araji A, Sharquie K, Al-Rawi Z: Prevalence and patterns of neurological involvement in Behçet’s disease: a prospective study from Iraq. J Neurol Neurosurg Psychiatry 74:608–613, 2003. 36. Al-Araji A, Kidd DP: Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol 8:192–204, 2009. 37. Akman-Demir G, Serdaroglu P, Tasci B: Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. The Neuro-Behcet Study Group. Brain 122(Pt 11):2171–2182, 1999. 38. Hirohata S: Histopathology of central nervous system lesions in Behçet’s disease. J Neurol Sci 267:41–47, 2008. 39. Zouboulis CC, Kurz K, Bratzke B, et al: Adamantiades-Behçet disease: necrotizing systemic vasculitis with a fatal outcome. Hautarzt 42:451– 454, 1991. 40. Brey RL: Neuropsychiatric lupus: clinical and imaging aspects. Bull NYU Hosp Jt Dis 65:194–199, 2007. 41. Ellis SG, Verity MA: Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955–1977. Semin Arthritis Rheum 8:212–221, 1979. 42. Hanly JG, Walsh NM, Sangalang V: Brain pathology in systemic lupus erythematosus. J Rheumatol 19:732–741, 1992. 43. Neamtu L, Belmont M, Miller DC, et al: Rheumatoid disease of the CNS with meningeal vasculitis presenting with a seizure. Neurology 56:814–815, 2001. 44. Montilla P, Dronda F, Moreno S, et al: Lymphomatoid granulomatosis and the acquired immunodeficiency syndrome. Ann Intern Med 106: 166–167, 1987. 45. Yankner BA, Skolnik PR, Shoukimas GM, et al: Cerebral granulomatous angiitis associated with isolation of human T-lymphotropic virus type III from the central nervous system. Ann Neurol 20:362–364, 1986. 46. Kakumani PL, Hajj-Ali RA: A forgotten cause of central nervous system vasculitis. J Rheumatol 36:655, 2009. 47. Pierot L, Chiras J, Debussche-Depriester C, et al: Intracerebral stenosing arteriopathies. Contribution of three radiological techniques to the diagnosis. J Neuroradiol 18:32–48, 1991. 48. Gilden DH: Varicella zoster virus vasculopathy and disseminated encephalomyelitis. J Neurol Sci 195:99–101, 2002. 49. Dawson TM, Starkebaum G: Isolated central nervous system vasculitis associated with hepatitis C infection. J Rheumatol 26:2273–2276, 1999. 50. Alexander JJ, Lasky AS, Graf WD: Stroke associated with central nervous system vasculitis after West Nile virus infection. J Child Neurol 21:623–625, 2006. 51. Bilge I, Sadikoglu B, Emre S, et al: Central nervous system vasculitis secondary to parvovirus B19 infection in a pediatric renal transplant patient. Pediatr Nephrol 20:529–533, 2005. 52. Schmitt JA, Dietzmann K, Muller U, et al: Granulomatous vasculitis— an uncommon manifestation of herpes simplex infection of the central nervous system. Zentralbl Pathol 138:298–302, 1992. 53. Koeppen AH, Lansing LS, Peng SK, et al: Central nervous system vasculitis in cytomegalovirus infection. J Neurol Sci 51:395–410, 1981. 54. Barinagarrementeria F, Cantu C: Frequency of cerebral arteritis in subarachnoid cysticercosis: an angiographic study. Stroke 29:123–125, 1998.

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55. Kleinschmidt-DeMasters BK, Filley CM, Bitter MA: Central nervous system angiocentric, angiodestructive T-cell lymphoma (lymphomatoid granulomatosis). Surg Neurol 37:130–137, 1992. 56. Katsetos CD, Fincke JE, Legido A, et al: Angiocentric CD3(+) T-cell infiltrates in human immunodeficiency virus type 1-associated central nervous system disease in children. Clin Diagn Lab Immunol 6:105–114, 1999. 57. Khanna D, Vinters HV, Brahn E: Angiocentric T cell lymphoma of the central nervous system in a patient with Sjögren’s syndrome. J Rheumatol 29:1548–1550, 2002. 58. No YJ, Lee EM, Lee DH, et al: Cerebral angiographic findings in thromboangiitis obliterans. Neuroradiology 47:912–915, 2005. 59. Molloy ES, Langford CA: Advances in the treatment of small vessel vasculitis. Rheum Dis Clin North Am 32:157–172, 2006.

60. Salvarani C, Brown RD, Jr, Calamia KT, et al: Efficacy of tumor necrosis factor alpha blockade in primary central nervous system vasculitis resistant to immunosuppressive treatment. Arthritis Rheum 59:291– 296, 2008. 61. De Boysson H, Arquizan C, Guillevin L, et al: Rituximab for primary angiitis of the central nervous system: report of 2 patients from the French COVAC cohort and review of the literature. J Rheumatol 40:2102, 2013. 62. Salvarani C, Brown RD, Jr, Huston J, 3rd, et al: Treatment of primary CNS vasculitis with rituximab: case report. Neurology 82:1287–1288, 2014. 63. Hajj-Ali R, Villa-Forte AL, Abou-Chebel A, et al: Long term outcome of patients with primary angiitis of the central nervous system (PACNS). Arthritis Rheum 43:S162, 2000.