Cerebral vasculitis, more accurately described as central nervous system (CNS) vasculitis, is not a singular disease but a descriptive term for inflammation within the walls of CNS blood vessels. This inflammation leads to destructive changes, vessel occlusion, and potentially infarction.1 2 CNS vasculitis is broadly categorized into two forms: secondary and primary. Secondary CNS vasculitis occurs when the CNS is involved as part of a systemic vasculitic illness, such as microscopic polyarteritis or granulomatosis with polyangiitis. Primary CNS vasculitis, also known as isolated CNS vasculitis, is characterized by inflammation largely confined to the CNS, with minimal or no systemic inflammation. Both forms of CNS vasculitis are rare, serious, and potentially life-threatening conditions.
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Table 1Conditions associated with CNS vasculitis
Diagnosing secondary CNS vasculitis can often be more straightforward, particularly when clinical signs point to concurrent or recent involvement of other organs like the lungs, kidneys, joints, or skin. However, challenges arise when CNS symptoms appear in patients with a history of systemic vasculitis, making it difficult to differentiate between secondary CNS vasculitis and opportunistic infections related to immunosuppressant treatments.
The diagnosis of primary CNS vasculitis presents a significantly greater challenge for several reasons. Its rarity limits the clinical experience within neurology units.3 The clinical presentation is not distinct, varying widely among patients.4–10 No single, definitive diagnostic test exists, including angiography.9 Furthermore, obtaining tissue samples from the brain or spinal cord for biopsy is invasive and carries potential risks.
Adding to these diagnostic complexities is the lack of universally accepted criteria for diagnosing primary CNS vasculitis.9 11 The very definition of the disease remains debated, with varying reliance on angiography (contrast, MR, or CT) versus histology for diagnosis across studies.9 12–20 While some advocate for angiography-based diagnosis, others emphasize the necessity of histological confirmation.10 11 20–23 This variability in diagnostic criteria makes it difficult to interpret research findings and hinders progress in treatment optimization. To address this, categorizing patients into ‘definite’ and ‘possible’ diagnostic groups based on diagnostic certainty is crucial. Building upon previous investigational approaches,6 refined diagnostic criteria are needed to differentiate between ‘definite’ and ‘possible’ primary CNS vasculitis. The aim is to foster consensus and future refinement of these criteria, enabling more robust prospective analyses and facilitating the development of effective therapeutic strategies.
Clinical Presentation and Diagnostic Investigations for CNS Vasculitis
Primary CNS vasculitis lacks a pathognomonic clinical presentation, manifesting with a wide array of neurological symptoms depending on the affected vasculature site. The clinical course can be acute, subacute, chronically progressive, or relapsing-remitting.4 5 9 21 24 25 Headache is a common complaint, along with non-specific features such as encephalopathy, cognitive impairment, and generalized seizures. Focal neurological deficits are also frequent, including hemispheric, brainstem, or spinal cord dysfunction, movement disorders, and optic and other cranial neuropathies. Systemic inflammatory features like fever, night sweats, livedo reticularis, and oligoarthropathy may be present but require specific inquiry to identify.
To improve initial clinical suspicion of primary CNS vasculitis amidst this diverse clinical landscape, three distinct presentation patterns have been previously described:6 26
- Acute or subacute encephalopathy: Characterized by an acute confusional state progressing to drowsiness and coma.
- ‘MS-plus’ or ‘pseudo-MS’ presentation: Mimicking multiple sclerosis (MS) with atypical features, including a relapsing-remitting course with optic neuritis and brainstem episodes, but also features less typical of MS, such as seizures, severe and persistent headaches, encephalopathic episodes, or stroke-like episodes.
- Intracranial mass lesions: Presenting with headache, drowsiness, focal neurological signs, and often elevated intracranial pressure.
It is important to recognize that these presentations are non-specific and can occur in various neurological disorders. However, in the absence of an obvious alternative diagnosis, these presentations should prompt consideration of primary CNS vasculitis in the differential diagnosis.
Similar to clinical features, diagnostic investigations for primary CNS vasculitis lack specificity. Biochemical, immunological, serological, and imaging tests are not definitively diagnostic. Non-specific findings are common, such as normochromic anemia and elevated plasma viscosity. A comprehensive review of published cases indicated that brain MRI was abnormal in 93% of patients (suggesting it can be normal), and cerebrospinal fluid (CSF) analysis was abnormal in 74%. However, these abnormalities are also non-specific.27 Research continues into developing more specific MRI techniques, such as vessel wall imaging,28 to improve CNS vasculitis diagnosis, but these require rigorous correlation with neuropathological findings before clinical application.
Therefore, the primary role of blood tests, chest, abdominal, and pelvic CT scans, CSF examination, and MRI in suspected primary CNS vasculitis is to exclude alternative diagnoses—inflammatory, autoimmune, infectious, malignant, or other disorders. These investigations may also reveal clinically silent systemic involvement or identify accessible biopsy targets. Ocular examination, including slit-lamp ophthalmoscopy,29 and whole-body CT-positron emission tomography scanning can also contribute to excluding other conditions.
Given that CNS vasculitis affects blood vessels, imaging the cerebral vasculature seems a logical diagnostic approach. Cerebral catheter contrast angiography/digital subtraction angiography, along with CT and/or MR angiography, can reveal vascular abnormalities. These may include segmental narrowing (often multifocal) with localized dilations or beading. Single stenotic areas in multiple vessels are possibly more characteristic of primary CNS vasculitis than multiple stenotic areas within a single vessel. While contrast angiography remains a valuable tool, it carries a small but significant stroke risk. With advancements in MR resolution, the added diagnostic value of contrast angiography over MR/CT angiography is diminishing.
Despite its historical role in diagnosing primary CNS vasculitis, angiography has limitations. Since the early 1970s, it has been recognized that ‘vasculitic’ changes seen on angiography can also occur in atherosclerotic disease, post-subarachnoid hemorrhage, migraine, trauma, hypertension, infections, radiation vasculopathy, and illicit drug use.22 30 Histopathological studies have shown angiography’s sensitivity and specificity to be only around 25%–35%.9 25 27 31–34 CT and MR angiography appear even less sensitive, although less studied with histological confirmation.35–38 Thus, a normal angiogram does not rule out primary CNS vasculitis (figure 1), and many conditions can mimic primary CNS vasculitis angiographically. ‘Vasculitic’ changes on angiography indicate a potential vasculopathy but necessitate further diagnostic investigation. Reversible cerebral vasoconstriction syndrome is a particularly challenging differential diagnosis, although a detailed comparative study has highlighted key clinical and investigative differences.39 MRI-based vessel wall imaging may also offer diagnostic assistance.40
Figure 1
Figure 1: Brain MRI and angiogram of a 61-year-old man with CNS vasculitis, demonstrating non-specific MRI findings and a normal angiogram. The T2 MRI (A) shows diffuse high signal in the white matter, while the cerebral angiogram (B) appears normal, highlighting the limitations of angiography in diagnosing CNS vasculitis, which was confirmed by biopsy.
The Crucial Role of Cerebral Biopsy in CNS Vasculitis Diagnosis
Given the limitations of non-invasive diagnostic methods, cerebral biopsy emerges as an essential procedure for establishing a definitive diagnosis of primary CNS vasculitis (figure 2). While there is understandable reluctance to perform an invasive procedure like brain biopsy, especially in eloquent brain areas such as temporoparietal regions or the brainstem and spinal cord, the diagnostic benefits and safety profile warrant careful consideration. Concerns include procedural risks and the possibility of non-diagnostic biopsy results (‘non-specific change’ or ‘end-stage tissue damage’).
Figure 2Inflammatory infiltrate in central nervous system vasculitis with extension into the vessel wall (A) and the perivascular lymphocytic cuffing (B).
Figure 2: Histopathological features of CNS vasculitis. Microscopic images showing (A) inflammatory cell infiltration extending into the blood vessel wall and (B) perivascular lymphocytic cuffing, key histological findings in CNS vasculitis diagnosis obtained through brain biopsy.
Several factors, supported by accumulating research evidence, strongly favor biopsy in suspected primary CNS vasculitis.
Firstly, brain biopsy has been demonstrated to be relatively safe. It is crucial to emphasize ‘relative’ safety, considering the severity of the disease and its diagnostic alternatives, as well as the potential risks of treatments if CNS vasculitis is confirmed. A retrospective study of 61 patients who underwent biopsy for suspected CNS vasculitis reported no mortalities or permanent adverse effects from the procedure.31 A study of 56 brain biopsies for cryptogenic neurological disease similarly reported no deaths or permanent deficits.41 A larger series assessing over 7000 stereotactic biopsies showed a mortality rate below 1% and a morbidity rate of 3.5%, with few cases of permanent disability.42 Indeed, some data suggests that biopsy for suspected malignancy carries higher risks than for cryptogenic neurological disease; a meta-analysis of 831 cryptogenic neurological disease biopsies reported zero procedure-related mortality.43 Furthermore, biopsies of the brainstem and spinal cord are now recognized as less risky than previously perceived.44 Evidence suggests that the risks associated with immunosuppressive treatments for presumed CNS vasculitis may outweigh the risks of biopsy itself.13 45
Secondly, the diagnostic yield and clinical utility of brain biopsy are significant. Sensitivity is estimated to be between 50% and 70%.9 25 31 41 Importantly, biopsy leads to a definitive diagnosis—vasculitis or another specific pathology—in approximately 75% of patients.31 41 45 Infectious diagnoses are not uncommon findings from biopsies performed for suspected vasculitis—occurring in 10 out of 61 biopsies in one series31—underscoring the importance of histological confirmation to avoid presumptive immunosuppressant treatment. A recent meta-analysis found no significant difference in diagnostic yield, morbidity, or mortality between frame-based and frameless biopsy techniques.46
Finally, it’s crucial to remember that cerebral vasculitis is a descriptive term, not a single disease entity. ‘Primary CNS vasculitis’ likely encompasses a spectrum of distinct disorders, which are gradually being identified and characterized.47–49 Aβ-related angiitis (ABRA), possibly a subtype of cerebral amyloid angiopathy (CAA), is one such disorder where amyloid deposits trigger an inflammatory vasculitic reaction. Biopsy is essential to distinguish ABRA from other primary CNS vasculitis forms and from CAA-related inflammation without vasculitis. Similarly, biopsy is necessary to identify other recognized subtypes of primary CNS vasculitis.47–49 Beyond individual patient diagnosis, tissue examination is essential for further characterizing and classifying specific entities within the spectrum of primary CNS vasculitis.
Treatment Strategies for CNS Vasculitis
Treatment for primary CNS vasculitis lacks robust clinical trial evidence, and established recommendations have remained largely unchanged for decades. Cyclophosphamide and corticosteroids remain the mainstay of treatment,6 10 22 50 with cyclophosphamide often transitioned to less toxic immunosuppressants like azathioprine or methotrexate after an induction period of 10–12 weeks.51 This approach is primarily based on evidence from trials in renal and rheumatological vasculitis, where diagnosis is often serologically or histologically confirmed. Mycophenolate mofetil appears less effective than azathioprine or methotrexate in maintaining remission in systemic vasculitis.52 While reports suggest potential efficacy of rituximab,53 these are often based on cases without histological verification and thus require cautious interpretation.
Proposed Diagnostic Criteria for Primary CNS Vasculitis: Towards Improved CNS Diagnosis
Despite advances in other rare diseases, understanding, diagnosing, and treating primary CNS vasculitis has seen limited progress in recent decades, except for the recognition of pathological subtypes. Evidence-based treatment remains lacking, with cyclophosphamide, recommended over 30 years ago for definite disease, still the primary treatment choice, largely extrapolated from systemic vasculitis studies. A significant barrier to progress is the considerable variability in diagnostic approaches; approximately 75% of published cases lack histological confirmation.54 Given the range of disorders mimicking cerebral vasculitis revealed in biopsy-based studies, the low yield of vasculitis in biopsies performed for suspected CNS vasculitis even with suggestive clinical and angiographic features,55 and the angiographic overlap with non-vasculitic conditions, relying on angiography alone for a ‘definite’ diagnosis in research and clinical practice is difficult to justify.
Therefore, simple, binary diagnostic criteria are proposed (box 1): ‘possible’ or ‘definite’ primary CNS vasculitis. These criteria are intended as a starting point, open to refinement by experts in the field, with the ultimate goal of broadly accepting histological proof as essential for a definite diagnosis.
Box 1
Proposed Criteria for the Diagnosis of Central Nervous System (CNS) Vasculitis
Definite
- Clinical presentation suggestive of CNS vasculitis, after excluding alternative diagnoses and primary systemic vasculitic syndromes.
- Plus, positive CNS histology: biopsy or autopsy showing CNS angiitis (granulomatous, lymphocytic, or necrotizing), including evidence of vessel wall damage.
Possible
- Clinical presentation compatible with CNS vasculitis, after excluding alternative diagnoses and primary systemic vasculitic syndromes.
- Plus, laboratory and imaging evidence supporting CNS inflammation (elevated CSF protein and/or cells, and/or oligoclonal bands, and/or MRI findings compatible with CNS vasculitis), with angiographic exclusion of other specific entities.
- But lacking histological proof of vasculitis.
CNS vasculitis was first comprehensively described 60 years ago by Cravioto and Feigin, who detailed its classical histopathological features as a ‘diffuse disorder of the central nervous system with some focal accentuation’.2 Calabrese and Mallek’s landmark study three decades later provided a lasting account of clinical features, summarized angiographic changes, and recommended high-dose corticosteroids and cyclophosphamide therapy.9 They defined primary angiitis of the CNS as ‘an acquired clinical disease characterized by CNS dysfunction unexplained after thorough investigations, unassociated with systemic illness, and with angiographic or biopsy evidence of CNS-confined vasculitis.’ Their proposed diagnostic criteria included: (1) unexplained acquired neurological deficit; (2) either classic angiographic or histopathological features of angiitis; and (3) absence of systemic vasculitis or other conditions explaining angiographic or pathological findings.9 Subsequent studies have often used these criteria or variations, allowing diagnosis based on angiography without biopsy.12 13
However, studies in the following two decades revealed that angiographic changes considered typical of vasculitis are non-specific (table 2). Furthermore, many confirmed primary CNS vasculitis cases had normal angiograms. Calabrese himself later confirmed that the diagnostic specificity and positive predictive value of angiography in this context are below 30%.34 This low specificity means patients with ‘typical’ angiographic changes are statistically more likely to have an alternative diagnosis than primary CNS vasculitis.11 27 45 55 Consequently, many authors have emphasized the necessity of biopsy for diagnostic confirmation, and proposals for diagnostic criteria requiring biopsy for a definite diagnosis have emerged.4 6 11 20 56 Powers,11 for example, argued against including cases without histological confirmation in publications.
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Table 2Conditions that may show ‘vasculitic’ changes on contrast angiography
Despite these arguments, universal acceptance of biopsy-based diagnosis is lacking. A 2017 systematic study of diagnostic tests in primary CNS vasculitis27 reviewed 701 published cases, with biopsy confirmation in only 35.4%. Notably, 99 biopsy-confirmed cases had normal angiograms. The study also observed an increasing reliance on angiography and decreased histopathological testing over the past two decades, reiterating the recommendation for a ‘definite’ diagnostic category restricted to tissue-proven cases. Despite these recommendations, ongoing studies, including prospective nationwide surveys, continue to include patients without histological confirmation.13
The proposed draft criteria also mandate tissue proof for a ‘definite’ diagnosis, representing a more stringent approach than most published studies. This rigor is justified by the extensive differential diagnoses for primary CNS vasculitis, particularly angiographically. The ‘probable’ diagnostic category is omitted due to the low specificity of angiography. Instead, cases lacking histological proof should be classified as ‘possible’, with angiography’s role limited to excluding other specific vascular disorders (e.g., moyamoya disease, fibromuscular dysplasia). These refined criteria can serve as a foundation for retrospective literature analyses and, importantly, for future prospective studies on the clinical features, diagnosis, and treatment of this challenging and serious condition.
Key Points in CNS Vasculitis Diagnosis
- Cerebral angiography without histological confirmation is not diagnostic for primary CNS vasculitis.
- CNS biopsy is a diagnostically crucial and relatively safe procedure.
- Binary diagnostic criteria, categorizing cases as ‘definite’ or ‘possible’, are proposed to replace less specific categories like ‘probable’.
Acknowledgments
We extend our gratitude to Dr. Shelley Renowden and Professor Seth Love for their assistance with providing the images used in figures 1 and 2.
