7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Primary angiitis of the central nervous system in adults : Rula A Hajj-Ali, MD, Leonard H Calabrese, DO : Gene G Hunder, MD, Scott E Kasner, MD : Philip Seo, MD, MHS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 17, 2022. INTRODUCTION Central nervous system (CNS) vasculitis refers to a broad spectrum of diseases that result in inflammation and destruction of the blood vessels of the brain, spinal cord, and meninges. Angiitis, a synonym for vasculitis, refers generally to blood vessels on both the arterial and venous sides of the circulation. Primary angiitis of the CNS (PACNS) is the preferred name for vasculitis that is confined to the CNS. CNS vasculitis is considered secondary when it occurs in the context of a systemic inflammatory disease, such as a systemic vasculitis or systemic lupus erythematosus (SLE), or an infectious process such as varicella zoster virus. PACNS predominantly affects small- and medium-sized arteries of the brain parenchyma, spinal cord, and leptomeninges, resulting in symptoms and signs of CNS dysfunction. It is defined by inflammation of the cerebral vasculature without angiitis in other organs. The protean manifestations of PACNS, along with the nonspecificity of available investigational modalities, pose a challenge for accurate diagnosis. Clinicians caring for patients with suspected PACNS should be familiar with its mimics to avoid misdiagnosis. PACNS can be mimicked closely in both its clinical presentation and radiologic manifestations by a number of other disorders. The most frequent mimic of PACNS is a group of disorders known collectively as the reversible cerebral vasoconstriction syndromes (RCVS). (See "Reversible cerebral vasoconstriction syndrome".) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 1/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate The clinical characteristics, diagnosis, and treatment of PACNS will be reviewed here. PACNS in children is discussed separately. (See "Vasculitis in children: Incidence and classification", section on 'Primary angiitis of the central nervous system'.) EPIDEMIOLOGY Primary angiitis of the central nervous system (PACNS) is a rare disease. A retrospective analysis of 101 patients with PACNS reported an annual incidence rate of 2.4 cases per 1,000,000 person- years [1]. There is a 2:1 male predominance among reported cases [2]. The median age at diagnosis is 50 years, although it can occur at almost every age [1]. (See "Vasculitis in children: Incidence and classification", section on 'Primary angiitis of the central nervous system'.) ETIOPATHOGENESIS The cause of primary angiitis of the central nervous system (PACNS) is unknown. Several potential etiologic agents or mechanisms have been proposed, but understanding of the cause of PACNS remains highly speculative. Various infectious agents have been proposed as etiologic factors, such as varicella zoster virus, West Nile virus, Mycoplasma gallisepticum, and human immunodeficiency virus (HIV) [3-11]. Cerebral amyloid angiopathy and PACNS have been described together in some patients, and associations between amyloid deposition have also been proposed as a trigger [12-18]. (See "Cerebral amyloid angiopathy", section on 'Clinical and diagnostic features'.) Although the cause of PACNS is unknown, inflammation of the CNS causes the vessels to become narrowed, occluded, and thrombosed, resulting in tissue ischemia and necrosis of the territories of the involved vessels. PACNS is more likely to affect blood vessels in the cerebral cortex and leptomeninges than subcortical regions. Blood vessels supplying cranial nerves may also be involved. CLINICAL MANIFESTATIONS Primary angiitis of the central nervous system (PACNS) is characterized by a long prodromal period, with few patients presenting acutely [19,20]. The vasculitis can affect any part of the CNS, causing the clinical manifestations to be highly variable and nonspecific [2,21-23]. Headache is the most commonly reported symptom, occurring in about 60 percent of patients [1,2]. The headache typically varies in description, but is usually subacute and insidious, in https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 2/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate contrast to the sudden-onset thunderclap headache that is observed with reversible cerebral vasoconstriction syndromes (RCVS). Other symptoms include cognitive impairment, stroke, and transient ischemic attack, which are present in 30 to 50 percent of patients [1,2,19]. Patients with PACNS who develop strokes usually present with more than a single stroke in different anatomic territories. Other less common symptoms, including cranial neuropathies, ataxia, seizure, and coma, have been reported. Signs and symptoms suggestive of systemic vasculitis, such as peripheral neuropathy, fever, weight loss, or rash, are usually lacking. Spinal cord involvement occurs alone or coincides with parenchymal brain involvement [24]. Angiitis affecting the spinal cord usually presents as a myelopathy, with pain, motor weakness, and sensory findings. (See "Disorders affecting the spinal cord", section on 'Spinal cord infarction'.) Symptoms and signs of untreated PACNS progress over the course of months. In one series, the mean time from symptom onset to diagnosis was 170 days [2]. However, if left untreated, PACNS will progress; thus the diagnosis of PACNS will be less likely in patients presenting with stable symptoms and signs for many months without progression of any radiographic findings. This is an important contrast to the RCVS, which typically have a more acute onset and much shorter time to diagnosis. (See 'Alternative diagnoses' below and "Reversible cerebral vasoconstriction syndrome".) DIAGNOSTIC APPROACH The diagnosis of primary angiitis of the central nervous system (PACNS) is challenging as the symptoms are generally nonspecific and there is no specific diagnostic test. The workup for patients who may have PACNS must proceed simultaneously with the systematic evaluation and exclusion of other disorders. (See 'Alternative diagnoses' below.) When to suspect the diagnosis While there is no characteristic presentation of PACNS, there are some scenarios that are highly suspicious. PACNS should be suspected when strokes, more often recurrent, occur in young patients with no identifiable cardiovascular or hypercoagulable risk factors; in the development of cognitive dysfunction with or without headaches; and in recurrent or persistent focal neurologic symptoms, abnormal cerebrovascular imaging obtained in the setting of an unexplained neurological deficit, or unexplained spinal cord dysfunction not associated with systemic disease or any other process. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 3/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Alternative diagnoses The clinician must remember that when PACNS is suspected, the correct diagnosis is usually something else. As a result, careful exclusion of other disorders is essential. Because of the importance of eliminating a lengthy list of alternative diagnoses, the differential diagnosis of PACNS is discussed in detail below before making the diagnosis. The major categories of disease in the differential diagnosis of PACNS are presented below: Infection When considering a diagnosis of PACNS, it is most important to rule out infection since unwarranted immunosuppression can have devastating consequences. A number of bacterial, mycobacterial, viral, fungal, and rickettsial infections can mimic PACNS. Prompt culture of all potential sites of infection, including the cerebrospinal fluid (CSF), is therefore essential. The detection of pathogens associated with CNS vasculitis, especially in the setting of a chronic meningitis, may be enhanced via the use of a variety of serologies and targeted molecular studies (ie, polymerase chain reaction [PCR]). The application of next-generation sequencing has demonstrated some utility in detecting novel pathogens not clinically suspected and obviating the need for brain biopsy, but its place in the diagnostic algorithm remains to be established [25]. Organisms that cause subacute or chronic infections are the ones most likely to imitate PACNS. The major organisms of concern are: Treponema pallidum. (See "Neurosyphilis".) Borrelia burgdorferi. (See "Clinical manifestations of Lyme disease in adults".) Bartonella species. (See "Bartonella infections in people with HIV", section on 'Bacillary angiomatosis'.) Mycobacterium tuberculosis. (See "Central nervous system tuberculosis: An overview".) Herpesviruses such as varicella zoster virus and cytomegalovirus. Varicella zoster has been associated with a wide range of vascular disease ranging from granulomatous involvement of the aorta, to a syndrome resembling giant cell arteritis, granulomatous angiitis of the central nervous system, and stroke, and thus should be carefully searched for in virtually all settings [26] (see "Varicella zoster virus vasculopathy"). The clinical implications of identifying positive serology for varicella zoster virus in the absence of detectable virus remains controversial [27]. Hepatitis B and C viruses, which can be associated with polyarteritis nodosa and mixed cryoglobulinemia, respectively. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Overview of cryoglobulins and cryoglobulinemia".) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 4/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate HIV infection. (See "Approach to the patient with HIV and central nervous system lesions".) Fungi such as Aspergillus, Coccidioides, and Histoplasma species. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".) Cysticercosis can involve middle-size cerebral vessels of the subarachnoid space, often without clinical evidence of cerebral ischemia [28]. Cysticercosis is endemic in many regions of Central and South America, sub-Saharan Africa, India, and Asia. (See "Cysticercosis: Clinical manifestations and diagnosis".) Reversible cerebral vasoconstriction syndromes The RCVS are a group of disorders linked by prolonged but reversible vasoconstriction of the cerebral arteries [29]. The RCVS are typically associated with severe, acute-onset headaches that can recur intermittently for days to weeks, sometimes accompanied by neurologic symptoms and signs. The headaches associated with the RCVS are usually "thunderclap" in nature. Ischemic and/or hemorrhagic stroke may occur in the setting of RCVS. Thus, despite the reversibility of vasoconstriction, these disorders are not always characterized by benign prognoses. (See "Reversible cerebral vasoconstriction syndrome".) While there are some signs and symptoms common to both conditions, including headache, focal deficits, stroke, seizures, and angiographic irregularities, the nature of the headaches and imaging abnormalities are quite different and discussed separately. (See "Reversible cerebral vasoconstriction syndrome", section on 'Angiographic differential'.) Systemic vasculitis involving the brain Some forms of vasculitis can involve the CNS. The ones most likely to do so are the following: Beh et syndrome (see "Clinical manifestations and diagnosis of Beh et syndrome", section on 'Neurologic disease') Polyarteritis nodosa (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Neurologic disease') Vasculitides associated with antineutrophil cytoplasmic antibodies, including granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg- Strauss)") https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 5/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Cryoglobulinemic vasculitis (see "Overview of cryoglobulins and cryoglobulinemia") The diagnosis of CNS vasculitis secondary to a systemic form of vasculitis is usually inferred from biopsy or angiography of a non-CNS site. In most such patients, the systemic vasculitis is an established diagnosis before the CNS is involved. We assign high importance to performing a thorough evaluation to exclude an infectious etiology of the CNS process, given the immunosuppressive treatments that patients are usually receiving for their systemic vasculitis. Other systemic rheumatic diseases CNS manifestations due to other systemic rheumatic diseases may reflect vasculitis or other mechanisms and can occur with or without systemic symptoms. In this setting, diagnosis of the underlying diseases is frequently based upon vasculitic or non-vasculitic clinical features in organs outside the CNS, combined with selected laboratory results. The systemic rheumatic diseases most likely to involve the CNS and create confusion with the diagnosis of PACNS are: Systemic lupus erythematosus and related conditions Systemic lupus erythematosus (SLE), Sj gren's disease, mixed connective tissue disease, and dermatomyositis can all be associated with CNS involvement. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus" and "Clinical manifestations of Sj gren s disease: Extraglandular disease" and "Clinical manifestations and diagnosis of mixed connective tissue disease" and "Clinical manifestations of dermatomyositis and polymyositis in adults".) Neuropathologic abnormalities in lupus include multifocal microinfarcts, cortical atrophy, gross infarcts, hemorrhage, ischemic demyelination, and patchy, multiple sclerosis-like demyelination. The most common microscopic brain finding in SLE is microvasculopathy, described as "healed vasculitis" consistent with hyalinization, thickening, and thrombus formation [30-32]. Nonvasculitic autoimmune inflammatory meningoencephalitis Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM) is a syndrome characterized clinically by dementia that occurs in some patients with this disorder at a younger age of onset, rapid progression with significant cognitive and behavioral features, absence of family history, abnormal electroencephalography (EEG) findings, and elevated levels of inflammatory markers [33]. The CNS involvement that may be seen in Hashimoto thyroiditis is considered as a form of NAIM. The pathologic findings of NAIM are those of a panencephalitis without evidence of a vasculitis [33]. Patients with NAIM are usually https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 6/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate successfully treated with glucocorticoids. (See "Hashimoto encephalopathy", section on 'Nonvasculitic autoimmune inflammatory meningoencephalitis'.) Rheumatoid arthritis Rheumatoid vasculitis occasionally involves the CNS. However, the most common neurologic manifestation of rheumatoid vasculitis is vasculitic neuropathy. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".) Antiphospholipid syndrome The antiphospholipid syndrome can cause CNS dysfunction due to strokes caused by intracerebral clotting events, emboli associated with verrucous endocarditis, and white matter lesions suggestive of a vasculopathy. (See "Clinical manifestations of antiphospholipid syndrome".) Many but not all cases of the Sneddon syndrome, the combination of livedo reticularis and cerebrovascular lesions, are associated with antiphospholipid antibodies. However, the Sneddon syndrome is unlikely to be confused with PACNS if the livedo reticularis is appreciated. Atherosclerosis Atherosclerosis of intracranial vessels can mimic the angiographic findings of PACNS [2,34]. The patient with multiple atherosclerotic risk factors and CNS dysfunction such as evidence of a cerebrovascular accident is much more likely to have atherosclerosis than PACNS. Cerebral emboli Cerebral emboli can result in multifocal vascular occlusions that suggest the diagnosis of vasculitis. As many as 30 to 40 percent of ischemic strokes remain cryptogenic despite the availability of transesophageal echocardiography, carotid ultrasonography, and magnetic resonance angiography (MRA) to help identify embolic sources. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)" and "Overview of the evaluation of stroke", section on 'Embolic stroke'.) Various types of embolic events can create confusion with PACNS. These include paradoxical emboli in patients with patent foramen ovale as well as emboli in patients with atrial fibrillation, atrial myxoma, and nonbacterial thrombotic endocarditis. (See "Nonbacterial thrombotic endocarditis" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Prevention of thromboembolism' and "Patent foramen ovale", section on 'Cryptogenic stroke'.) Atheroemboli are another cause of embolic stroke that may be confused with PACNS. Atheroemboli are often released from vessels other than the carotid arteries (especially the aorta), with a predilection for the middle cerebral artery [35]. Systemic signs of atheroembolism (eg, livedo reticularis, acute renal failure), if present, would exclude https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 7/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate PACNS. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".) Intravascular lymphoma Intravascular lymphoma that leads to widespread occlusion of small vessels is an occasional mimicker of PACNS [36-38]. Appropriate immunohistochemistry staining as well as B- and T-cell markers should be performed on biopsy specimens even with the pathologic finding of angiitis, since the presence of vasculitic changes does not exclude an underlying lymphoproliferative condition. Lymph node, bone marrow, and CSF involvement may not be evident at presentation, as delays of up to five years have been reported before the emergence of extracranial disease [3]. (See "Intravascular large cell lymphoma".) Miscellaneous A number of other diseases that can mimic PACNS include: Cerebral artery dissection Cervical internal carotid artery dissection occasionally presents with headache and scintillating scotomata in the ipsilateral visual field. Many patients with carotid or vertebral artery dissections progress to cerebral ischemia. The combination of headache followed by stroke mimics PACNS. (See "Migraine-associated stroke: risk factors, diagnosis, and prevention".) Sarcoidosis Approximately 5 percent of patients with sarcoidosis develop clinically evident neurological involvement. In a manner similar to PACNS, sarcoidosis can be associated with granulomatous brain masses, encephalopathy, and/or meningeal disease. (See "Neurologic sarcoidosis".) Paraneoplastic and autoimmune encephalitis These are inflammatory conditions of the brain with many etiologies. Some are related to cancer and others are associated with antibodies against neuronal cell surface and synaptic protein. (See "Paraneoplastic and autoimmune encephalitis".) Susac syndrome Susac syndrome is a rare, poorly characterized disorder associated with the clinical triad of visual loss caused by branch retinal artery occlusions, sensorineural hearing loss, and subacute encephalopathy [39,40]. The presence of hyperintense lesions in the corpus callosum on T2-weighted MR images may be a clue to the diagnosis [41,42]. CADASIL CADASIL is the acronym for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. This disorder is a heritable, noninflammatory vasculopathy resulting from mutations in the gene for the protein Notch 3. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 8/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate The simplest way of diagnosing CADASIL and distinguishing it from PACNS is via a skin biopsy of clinically normal skin. The demonstration of granular osmiophilic material within the vascular basal lamina of arteries, arterioles, and precapillaries is diagnostic of CADASIL. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".) Mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome (MELAS) 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 [43]. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS'.) Cerebroretinal vasculopathy syndrome is an autosomal dominant retinal vasculopathy with cerebral leukodystrophy, leading to stroke and dementias with middle-age onset [44]. Moyamoya disease Moyamoya disease is a cerebrovascular disease of unknown cause characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches. It generally affects adults in the third to fourth decade of life, and in adults it can cause strokes, recurrent transient ischemic attacks, sensorimotor paralysis, seizures, and/or migraine-like headaches. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Other conditions include amyloid angiopathy and inflammatory bowel disease- associated cerebral vasculitis. (See "Cerebral amyloid angiopathy".) Evaluation As part of the diagnostic evaluation, all patients should undergo routine laboratory testing and serological evaluations to rule out systemic disease, whether infectious or inflammatory. Obtaining cerebrospinal fluid is an essential step in the evaluation and should only be omitted if there are contraindications to perform a lumbar puncture. The evaluation also includes cerebrovascular imaging and/or obtaining tissue biopsy of the leptomeninges and brain for either ruling out other etiologies or confirming suspected PACNS. Initial neuroimaging should include MR imaging (MRI), since a normal MRI is very unlikely in PACNS. The selection of additional neuroimaging studies depends upon the initial MRI findings and individual patient characteristics. The results of the various tests must be interpreted in conjunction with each other in order to determine whether to treat the patient with immunosuppressive therapy, even in the setting of a negative brain biopsy. Laboratory testing to exclude alternative diagnoses The purpose of laboratory testing is primarily to exclude an underlying systemic disease or alternative diagnoses. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 9/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate We perform the following basic laboratory tests in patients suspected of having PACNS: Complete blood count with differential Serum urea nitrogen and creatinine Serum aspartate and alanine aminotransferases Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) Urinalysis Acute phase reactants such as the ESR and CRP are usually normal in PACNS. An elevated ESR and CRP should raise suspicion of systemic involvement by either an infectious or inflammatory process. We also perform the following serologic assays to exclude other underlying systemic rheumatic diseases: Antinuclear antibodies (ANA) Antibodies to the Ro/SSA, La/SSB, Sm, and RNP antigens Antibodies to double-stranded deoxyribonucleic acid (DNA) Antiphospholipid antibodies (lupus anticoagulant [LA], IgG, and IgM anticardiolipin [aCL] antibodies; and IgG and IgM anti-beta2-glycoprotein [GP] I) Antineutrophil cytoplasmic antibodies (ANCA) Serum C3 and C4 Serum cryoglobulins Serum and urine protein electrophoresis with immune electrophoresis Quantitative immunoglobulin levels (IgG, IgM, IgA) Testing for infections appropriate to the clinical circumstances is critical, as the treatment for infectious causes of CNS dysfunction differs radically from the therapy for immune-mediated disorders. A thorough history for any risk factors for immunodeficiency as well as travel history is important in the assessment for any exposure or an immunodeficiency state. In addition to cultures of the blood, CSF, and other body fluids, diagnostic tests for infection may include assays for the following organisms: Treponema pallidum Borrelia burgdorferi Bartonella species Mycobacterium tuberculosis Herpesviruses (varicella zoster virus, cytomegalovirus, others) Hepatitis B and C viruses HIV https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 10/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Cysticercosis Lumbar puncture Analysis of the CSF is a crucial part of the evaluation of patients with potential PACNS and should be performed in all patients unless there are contraindications. The importance of CSF analysis in excluding any infectious or malignant process and the performance of adequate stains and cultures of the CSF cannot be overemphasized. (See "Molecular diagnosis of central nervous system infections" and "Lumbar puncture: Technique, indications, contraindications, and complications in adults" and "Cerebrospinal fluid: Physiology and utility of an examination in disease states".) The CSF is abnormal in 80 to 90 percent of patients with pathologically documented disease. Normal CSF findings can occur with localized disease and in patients presenting with mass-like lesions. There are no specific abnormalities of the CSF in PACNS; however, the CSF findings in the majority of patients show an aseptic meningitis pattern with modest lymphocytic pleocytosis, normal glucose levels, elevated protein level, and occasionally the presence of oligoclonal bands and elevated IgG synthesis [19]. By contrast, in the RCVS, the most common mimic of PACNS, the CSF analysis is usually normal or reflects findings of subarachnoid hemorrhage if this is present [45]. Neuroimaging Various neuroimaging modalities can be used to assess for both parenchymal and vascular abnormalities in the evaluation of possible PACNS. MRI should be performed in all patients with PACNS. The selection of additional neuroimaging modalities depends on the initial MRI findings and individual patient characteristics. Some clinicians may choose to order an MRA at the same time as the initial MRI out of convenience because the patient is in the scanner, though it lacks both sensitivity and specificity for PACNS. Computed tomography angiography (CTA) may be more sensitive for detecting vascular irregularities than MRA, but is far less sensitive than catheter-based angiography. (See 'MRI' below and 'MR angiography and CT angiography' below.) Conventional angiography remains an important part of the diagnostic testing for suspected PACNS, and our authors obtain angiography in patients who have MRI findings of multiple cortical and subcortical infarcts that are otherwise unexplained. Angiography can detect segmental narrowing in multiple vessels that are typical of, though not pathognomonic for, PACNS, and help further rule out alternative diagnoses such as atherosclerosis, moyamoya, and dissection. These tests may also be helpful in selecting a location for brain biopsy if needed. (See 'Conventional angiography' below.) MRI MRI is sensitive in detecting abnormalities in PACNS and should be performed in all patients suspected to have PACNS. MRI of the brain commonly shows multiple infarcts in https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 11/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate multiple vascular territories, and often in areas of the brain not affected by more common causes of stroke (such as the corpus callosum). However, these findings are not specific for PACNS and the interpretation of MRI findings should be performed by an expert neuroradiologist who is familiar with the findings of CNS vasculitis and its radiologic mimics. In addition, there may rarely be tumor-like lesions [46-48]. Conversely, a negative MRI carries a high negative predictive value for the diagnosis of PACNS [1]. MR angiography and CT angiography In most cases of PACNS, the medium and small intracranial arteries are affected rather than the large proximal arteries. MRA and CTA are most reliable for the assessment of the large proximal arteries and therefore are inadequate for the demonstration of more distal vasculopathy. Notably, the finding of narrowing of multiple large proximal intracranial arteries as detected by MRA or CTA should suggest an alternative diagnosis, such as atherosclerosis, dissection, moyamoya disease, or reversible cerebral vasoconstriction in the appropriate clinical setting. The resolution of conventional angiogram remains superior to MRA and CTA in detecting abnormalities in smaller vessels. Conventional angiography Visualization of the cerebral vasculature with conventional angiography is a common part of the investigation when PACNS is suspected based on the clinical presentation and MRI findings described above. (See 'MRI' above and "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'.) Classic cerebral angiography studies in PACNS reveal findings of segmental narrowing referred to as "beading," usually in the medium and small arteries. Involvement of several sites of the cerebral circulation is typical of PACNS ( picture 1). Other findings include circumferential or eccentric vessel irregularities. While the findings are characteristic of cerebral arteritis, these findings are not specific, and may be encountered in non-vasculitic disorders such as atherosclerosis and vasospasm [43]. PACNS has a host of potential mimickers of its angiographic features (see 'Alternative diagnoses' above). In addition, angiographic findings interpreted as "consistent with vasculitis" greatly outnumber true cases of PACNS. Thus, a positive angiogram does not make the diagnosis of PACNS. In a study of 38 patients with suspected PACNS, 14 patients had typical angiographic findings of vasculitis [49]. None were found to have vasculitic changes at brain biopsy. This study reflects the poor specificity of the angiographic findings and/or the limited sensitivity of brain biopsy. The sensitivity of angiography is also limited, and in two series of patients PACNS, the sensitivity of angiography in biopsy-proven PACNS cases was only 60 percent [50,51]. PACNS may be limited to the small vessels that are below the resolution of conventional angiography, which is particularly common when the pattern of infarction is predominantly subcortical, and thus a negative angiogram cannot be used to exclude the diagnosis of PACNS. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 12/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate In unusual cases of PACNS, the disease presents radiologically as a CNS mass lesion, manifested on angiography by the presence of an avascular mass effect. Proper interpretation of CNS angiograms requires insight into the clinical context of the specific patient, experience in reading abnormal angiograms, and thorough appreciation of the range of normal findings within the circulation of the internal carotid artery and its intracerebral branches ( image 1). Although it is not common to perform serial angiograms as a way of following response to treatment, repeat angiography is sometimes useful if the diagnosis remains unclear days to weeks after the performance of an initial study. A rapid change in angiographic appearance (eg, evolution from a flagrantly abnormal study to one that is essentially normal within days or weeks) argues compellingly for an RCVS rather than PACNS ( image 2) [29]. (See "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'.) Brain and leptomeningeal biopsy Selecting patients for brain biopsy The gold standard for the diagnosis of PACNS is histopathology. A brain biopsy should be performed in most patients with suspected PACNS. A biopsy will help histologically identify PACNS as well as exclude other lesions or vasculitis mimics, particularly infection or malignancy. Sampling of the leptomeninges as well as the underlying cortex increases the diagnostic yield; however, the test characteristics of the brain biopsy are far from optimal. The sensitivity of brain biopsy for PACNS is approximately 75 percent, thus leaving the clinician with a false negative rate of 25 percent [50]. A meta-analysis revealed a diagnostic yield of 74.7 percent (95% CI 64.0-84.1 percent) for suspected PACNS [52]. Biopsies may also identify a cause other than PACNS in up to 39 to 50 percent of patients [53,54]. In other words, a brain biopsy not only establishes a diagnosis in the setting of suspected PACNS in roughly 70 percent of cases but also may provide an alternative diagnosis in a fair number of patients [55]. There are two settings of particular concern where obtaining tissue is paramount: The presence of a focal lesion on MR with characteristics that suggest an inflammatory or infectious process, but noninvasive approaches to diagnosis have failed. The presence of a mass lesion in the brain for which the principal concern is usually malignancy or abscess. PACNS is occasionally a surprise finding. In such cases, the finding of vasculitis on pathologic exam does not exclude the diagnosis of infection or malignancy, and appropriate stains and markers should be pursued for accurate diagnosis. Biopsy of a radiologically abnormal area heightens the sensitivity of brain/leptomeningeal biopsies. In the absence of a focal lesion within the brain parenchyma, the temporal tip of the https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 13/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate nondominant hemisphere is the preferred biopsy site [56]. Histopathology Histopathologic findings in the brain in patients with PACNS may include the presence of Langerhans or foreign body giant cells, necrotizing vasculitis, or lymphocytic vasculitis. PACNS is referred to as granulomatous angiitis of the CNS (GACNS) if the pathologic findings are those of granulomatous angiitis affecting the small and medium leptomeningeal and cortical arteries ( image 3) [23,57]. However, the classic finding of granulomatous segmental vasculitis with Langerhans or foreign body giant cells is present in less than 50 percent of the biopsies [58]. The biopsy is not granulomatous in most such cases, and only reveals lymphocytic vasculitis. Appropriate stains, viral studies, and cultures should be performed on the biopsies, since the finding of vasculitis does not preclude the diagnosis of an associated infection or a lymphoproliferative process that is causing the vasculitis. Because of the focal and segmental distribution of CNS vasculitis, a positive biopsy is diagnostic, but a single isolated negative biopsy does not exclude primary or secondary CNS vasculitis [58]. Establishing the diagnosis The diagnosis of PACNS is based upon a constellation of symptoms and signs in the setting of supportive studies, and the exclusion of alternative diagnoses. (See 'Alternative diagnoses' above.) The diagnosis of PACNS can usually be made when all of the following are present: An acquired, otherwise unexplained neurological deficit Evidence of either classic angiographic or histopathologic features of angiitis within the CNS No evidence of systemic vasculitis or any other condition that could elicit the angiographic or pathologic findings These clinical findings are consistent with the diagnostic criteria that were proposed in 1988 [34]. There are patients in whom the diagnosis of PACNS is made without meeting all the criteria described above. In such scenarios, the term "atypical/possible PACNS" has been used to describe the uncertainty about the diagnosis or the variation from the typical pathologic findings. This usually includes lymphocytic PACNS, angiographically defined PACNS, and a mass lesion presentation. Lymphocytic PACNS This group of patients is distinguished by lymphocytic infiltration rather than granulomatous findings on the pathologic examination. When the pathologic https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 14/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate findings are predominantly lymphocytic, careful pathologic examination and immunophenotyping should be performed to rule out a lymphomatous CNS process. Angiographically defined PACNS This group is diagnosed by an abnormal cerebrovascular study and CSF examination, but with a normal CNS biopsy. The culprit vessel size involvement is usually medium-sized vessels rather than the small vessel typically seen in PACNS. In this subset, a diligent workup should be performed to rule out other vasculopathies, given the poor specificity of the cerebrovascular imaging study in the diagnosis of PACNS. Moreover, signs of inflammatory brain changes should be present, such as an abnormal CSF finding or enhancement of arterial vessel walls (in the absence of other causes of arterial enhancement). The RCVS, in particular, should be ruled out since this is a major mimic of this category. Mass lesion presentation These patients present with a solitary cerebral mass lesion. The diagnosis is usually a surprise after pathologic findings of a vasculitic process are observed as part of the pathologic evaluation. A complete analysis of the biopsy is mandatory to exclude alternative diagnoses, especially infection and malignancy even with the finding of vasculitis. TREATMENT Immunosuppressive therapy has been associated with success in central nervous system (CNS) vasculitis [1]. However, no prospective studies of any of the therapies described below have been conducted in patients with primary angiitis of the CNS (PACNS). Thus, our suggestions for treatment are influenced by anecdotal evidence related to PACNS and extrapolation of therapeutic strategies from other forms of vasculitis and retrospectively