Central nervous system (CNS) vasculitis is not a singular disease entity but rather a descriptive term for a group of conditions characterized by inflammation within the walls of CNS blood vessels. This inflammation leads to destructive changes, vessel occlusion, and ultimately, infarction. [1, 2] It is crucial to distinguish between ‘secondary’ CNS vasculitis, where the CNS involvement is part of a broader systemic vasculitic illness (such as microscopic polyangiitis or granulomatosis with polyangiitis), and ‘primary’ CNS vasculitis (PCNSV), also known as isolated angiitis of the CNS. In PCNSV, inflammation is largely confined to the CNS, with minimal or no overt systemic inflammation. Both primary and secondary forms of cerebral vasculitis are rare, serious, and potentially life-threatening conditions demanding accurate and timely Cns Vasculitis Diagnosis.
View this table:
Table 1 Conditions Associated with CNS Vasculitis
Diagnosing secondary CNS vasculitis can be more straightforward, particularly when clinical signs clearly point to concurrent or recent disease in organs outside the CNS, such as the lungs, kidneys, joints, or skin. However, challenges arise when neurological symptoms manifest in patients with a history of systemic vasculitis. In such cases, differentiating between secondary CNS involvement and opportunistic infections related to immunosuppressant treatments becomes a complex diagnostic puzzle.
The diagnosis of primary CNS vasculitis, however, presents a far greater challenge. Several factors contribute to this complexity. Its rarity limits the clinical experience within many neurology units. [3] Furthermore, there is no unique clinical presentation that definitively points to PCNSV. [4–10] Indirect diagnostic tests, including contrast angiography and digital subtraction angiography, are not foolproof. Accessing brain or spinal cord tissue for biopsy is invasive and carries potential risks.
Adding to these difficulties is the lack of universally accepted and firmly established criteria for clinically diagnosing primary CNS vasculitis. [9, 11] A consensus on defining PCNSV remains elusive. While angiography-based criteria (both formal contrast and magnetic resonance (MR)/CT angiography) are frequently used in studies and reports to diagnose PCNSV [9, 12–20], other experts advocate for relying on histological evidence. [10, 11, 20–23] This variability in diagnostic criteria complicates data interpretation and hinders progress in optimizing treatment strategies. To address this, it is beneficial to categorize patients into diagnostic groups based on the certainty of diagnosis. Building upon previous research on investigating suspected CNS vasculitis [6], this article proposes refined diagnostic criteria to delineate ‘definite’ and ‘possible’ primary CNS vasculitis. These draft criteria aim to serve as a foundation for future consensus, prospective analyses, and the design of more effective therapeutic trials for cns vasculitis diagnosis.
Clinical Presentation and Diagnostic Investigations
Primary CNS vasculitis lacks a pathognomonic clinical picture. The neurological manifestations are diverse, depending on the affected blood vessels within the CNS. The clinical course can vary, ranging from acute or subacute to chronically progressive, or relapsing and remitting patterns. [4, 5, 9, 21, 24, 25] Headache is a common symptom, along with non-specific features like encephalopathy, cognitive impairment, and generalized seizures. Focal neurological deficits are also frequently observed, including hemispheric, brainstem, or spinal cord dysfunction, movement disorders, and optic or other cranial neuropathies. Systemic inflammatory features, such as fever, night sweats, livedo reticularis, and oligoarthropathy, may be present but require specific investigation.
To aid in the initial clinical suspicion and recognition of primary CNS vasculitis amidst this clinical heterogeneity, three distinct presentation patterns have been previously described [6, 26]:
- Acute or subacute encephalopathy: Characterized by an acute confusional state that can progress to drowsiness and coma.
- ‘MS-plus’ or ‘pseudo-MS’ presentation: Resembles multiple sclerosis (MS) but with atypical features. This includes a relapsing-remitting course with optic neuropathy and brainstem episodes, but also features less typical of MS, such as seizures, persistent severe headaches, encephalopathic episodes, or stroke-like episodes affecting a hemisphere.
- Intracranial mass lesions: Presenting with headache, drowsiness, focal neurological signs, and often elevated intracranial pressure.
It is important to note that these presentations are not specific to PCNSV and can occur in various neurological disorders. However, in the absence of an obvious alternative explanation, these clinical scenarios should prompt consideration of primary CNS vasculitis in the differential diagnosis and necessitate further investigation for accurate cns vasculitis diagnosis.
Similar to the clinical features, investigations for primary CNS vasculitis lack diagnostic specificity. Biochemical, immunological, serological, and imaging tests typically reveal non-specific abnormalities. For instance, normochromic anemia and elevated plasma viscosity are common findings. A comprehensive systematic review of published cases revealed that brain MRI scans were abnormal in 93% of patients, and cerebrospinal fluid (CSF) analysis was abnormal in 74%. [27] However, these abnormalities are again non-specific. Ongoing research focuses on developing more specific MRI-based techniques, such as vessel wall imaging [28], to improve the diagnosis of cerebral vasculitis. However, these methods require rigorous correlation with neuropathological findings before they can be reliably used in clinical practice for cns vasculitis diagnosis.
Therefore, blood tests, chest, abdominal, and pelvic CT scans, CSF examination, and MR imaging primarily serve to exclude alternative diagnoses, including inflammatory, autoimmune, infectious, malignant, and other conditions. These investigations can also identify clinically silent systemic involvement and accessible sites for tissue biopsy, aiding in differential diagnosis and confirming or ruling out secondary causes of vasculitis. Ocular examination, including slit-lamp ophthalmoscopy [29], and whole-body CT-positron emission tomography scanning can play a similarly crucial role in identifying systemic involvement and guiding diagnostic strategies for cns vasculitis diagnosis.
Given that vasculitis affects blood vessels, imaging the cerebral vasculature seems like a direct diagnostic approach. Cerebral catheter contrast angiography/digital subtraction angiography, as well as CT and/or MR angiography, can indeed reveal vascular abnormalities. These may include segmental narrowing (often multifocal) with localized dilatations or beading. Single stenotic areas in multiple vessels are more frequently observed in primary CNS vasculitis compared to multiple stenotic areas along a single vessel. However, formal contrast/digital subtraction angiography carries a small but significant risk of stroke. With advancements in MR resolution, formal contrast/digital subtraction angiography is becoming less essential as MR/CT angiography can often provide comparable diagnostic information for cns vasculitis diagnosis.
Figure 1: 61-year-old male presenting with headache, cognitive decline, neuropsychiatric symptoms, and episodic disequilibrium. (A) T2 MRI of the brain reveals diffuse high signal abnormalities, predominantly in the white matter of the anterior frontal, parietal, and temporal lobes. (B) Cerebral angiogram appears normal. However, cerebral biopsy confirmed the diagnosis of cerebral vasculitis. T2W: T2 weighted; TSE: turbo spin echo.
Despite its historical use in many studies for diagnostic confirmation (or exclusion) of primary CNS vasculitis, catheter angiography has limitations. As early as the 1970s, it was recognized that similar ‘vasculitic’ changes can occur in atherosclerotic disease, as a reaction to subarachnoid hemorrhage, in migraine, trauma, hypertension, infections, radiation vasculopathy, and illicit drug use. [22, 30] Later histopathological studies demonstrated that catheter angiography has a sensitivity and specificity of only around 25%–35%. [9, 25, 27, 31–34] CT-based or MR angiography, while less studied with histopathological confirmation, appear even less sensitive. [35–38] Therefore, a normal angiogram does not exclude primary CNS vasculitis (Figure 1), and numerous alternative inflammatory, metabolic, malignant, or other vasculopathies can mimic PCNSV on angiography. ‘Vasculitic’ changes seen on angiography, in fact, indicate a potential vasculopathy that requires further investigation for definitive cns vasculitis diagnosis. Reversible cerebral vasoconstriction syndrome (RCVS) presents a particularly challenging diagnostic alternative. However, a detailed comparative study has highlighted key clinical and investigational differences between RCVS and PCNSV. [39] MRI-based vessel wall imaging may also offer diagnostic assistance in differentiating these conditions. [40]
The Pivotal Role of Cerebral Biopsy
Given the limitations of non-invasive diagnostic methods, cerebral tissue biopsy emerges as a crucial step in achieving a secure cns vasculitis diagnosis for primary CNS vasculitis (Figure 2). While there is understandable reluctance to perform such an invasive procedure, particularly when eloquent brain regions like dominant temporoparietal areas or the brainstem and spinal cord are involved, the benefits of biopsy often outweigh the risks. Concerns include potential procedural risks and the possibility of imperfect sensitivity, where neuropathological examination reveals only ‘non-specific changes’ or ‘end-stage tissue damage infarction/gliosis’.
Figure 2: Histopathological hallmarks of inflammatory infiltrate in central nervous system vasculitis, showing (A) extension into the vessel wall and (B) perivascular lymphocytic cuffing.
However, several factors, supported by a growing body of observational research, strongly advocate for biopsy in suspected PCNSV cases.
Firstly, multiple studies have demonstrated the relative safety of brain biopsy. The term ‘relative’ is important when considering the life-threatening nature of PCNSV, potential alternative diagnoses, and the risks associated with treatments if CNS vasculitis is indeed present. A retrospective study of 61 patients who underwent biopsy for suspected CNS vasculitis reported no mortalities and no permanent adverse effects from the procedure. [31] Another study examining 56 brain biopsies for cryptogenic neurological disease also reported no deaths or permanent deficits. [41] A larger series assessing over 7000 stereotactic brain biopsies revealed a mortality rate of less than 1% and a morbidity rate of 3.5%, with permanent disability being rare. [42] Interestingly, evidence suggests that the risks associated with biopsies for suspected malignancy may be higher than those for cryptogenic neurological disease. A meta-analysis of 831 cryptogenic neurological disease biopsies reported a procedure-related mortality of zero. [43] Furthermore, even brainstem and spinal cord biopsies are now recognized as less hazardous than previously perceived. [44] Several authorities have presented data indicating that the risks of immunosuppressive treatments often used for presumed PCNSV are greater than the risks associated with brain biopsy. [13, 45]
Secondly, our understanding of the diagnostic yield and clinical utility of biopsy has improved. The sensitivity of brain biopsy for diagnosing PCNSV is estimated to be in the range of 50%–70%. [9, 25, 31, 41] Crucially, a definitive diagnosis – either of vasculitis or another specific pathology – is achieved in approximately 75% of patients undergoing biopsy. [31, 41, 45] Notably, alternative diagnoses revealed by biopsy are frequently infectious – as seen in 10 out of 61 biopsies in one series [31] – highlighting the critical importance of histological confirmation before initiating immunosuppressant therapy for presumed vasculitis. A recent meta-analysis found no significant difference in diagnostic yield, morbidity, or mortality between frame-based and frameless biopsy techniques. [46]
Finally, as previously mentioned, cerebral vasculitis is a descriptive term encompassing a spectrum of specific disorders. The concept of ‘primary CNS vasculitis’ has long been anticipated to include various distinct entities, and these are now being gradually identified and characterized. [47–49] Aβ-related angiitis (ABRA) is one such disorder, likely a subtype of cerebral amyloid angiopathy (CAA). In ABRA, intramural amyloid deposits trigger an anti-amyloid inflammatory response, leading to vasculitic changes. Biopsy is essential to differentiate ABRA from other forms of primary CNS vasculitis and from CAA-related inflammation (where perivascular inflammation occurs in the context of CAA, potentially also triggered by amyloid deposition, but without true vasculitis). Similarly, biopsy is necessary to identify other recognized subtypes of PCNSV. [47–49] Beyond individual patient diagnosis, tissue examination is vital for discovering and defining further specific entities within the spectrum of CNS vasculitides, advancing our understanding and refining cns vasculitis diagnosis.
Treatment Strategies for Primary CNS Vasculitis
The treatment of primary CNS vasculitis lacks a strong evidence base from direct clinical trials. Treatment recommendations have remained largely unchanged for decades. Cyclophosphamide and corticosteroids remain the cornerstone of therapy. [6, 10, 22, 50] Cyclophosphamide is typically used for an induction period of 10–12 weeks and then transitioned to less toxic immunosuppressants like azathioprine or methotrexate for maintenance therapy. [51] This approach is primarily based on evidence from trials in renal and rheumatological vasculitides, where diagnosis can be more readily confirmed serologically or through tissue biopsy. Mycophenolate mofetil, in systemic vasculitis, appears less effective than azathioprine or methotrexate in maintaining remission. [52] While reports suggest potential efficacy of rituximab [53], these are often based on cases without histopathological confirmation, raising questions about their generalizability and applicability in confirmed PCNSV. Further research, particularly randomized controlled trials, are needed to establish evidence-based treatment protocols for primary CNS vasculitis and optimize outcomes following cns vasculitis diagnosis.
Proposed Diagnostic Criteria for Primary CNS Vasculitis
Despite advances in other rare diseases, our understanding of the causes, diagnosis, and treatment of primary CNS vasculitis has not significantly progressed in recent decades, except for the recognition of distinct pathological subtypes. We still lack randomized controlled trials to guide treatment, and the recommendation of cyclophosphamide for definite disease, dating back over 30 years, remains the standard of care, largely based on evidence from vasculitis studies in other organs. Primary CNS vasculitis, though uncommon, has seen less progress compared to other rare disorders, partly due to the significant variability in diagnostic approaches.
A major contributing factor to this stagnation is the widespread variation in diagnostic approaches. Approximately 75% of published cases lack histopathological confirmation. [54] Given (a) the consistent range of alternative diagnoses revealed in biopsy-based studies of suspected cerebral vasculitis, and (b) the low yield of vasculitis in biopsy series (as exemplified by a study at a major US academic hospital where none of the 14 patients with clinical and angiographic features suggestive of PCNSV had vasculitis on biopsy [55]), combined with (c) the extensive list of non-vasculitic conditions that can mimic the angiographic changes of ‘vasculitis’, the current practice of labeling cases without biopsy proof as definite primary CNS vasculitis in publications is difficult to justify.
Therefore, we propose simple, easily applicable binary diagnostic criteria (Box 1): ‘possible’ or ‘definite’ primary CNS vasculitis. While these criteria can be further refined and improved by experts, we hope they will promote the principle of histopathological proof for a definite cns vasculitis diagnosis.
Box 1: Proposed Criteria for the Diagnosis of Central Nervous System (CNS) Vasculitis
Definite Primary CNS Vasculitis
- Clinical presentation suggestive of CNS vasculitis with exclusion of alternative possible diagnoses and of primary systemic vasculitic syndrome.
- Plus the presence of positive CNS histology, i.e., biopsy or autopsy showing CNS angiitis (granulomatous, lymphocytic, or necrotizing), including evidence of vessel wall damage.
Possible Primary CNS Vasculitis
- Clinical presentation compatible with CNS vasculitis with exclusion of alternative possible diagnoses and of primary systemic vasculitic syndrome.
- Plus laboratory and imaging support for CNS inflammation (elevated cerebrospinal fluid protein and/or cells, and/or oligoclonal bands, and/or MR scan evidence compatible with CNS vasculitis), with angiographic exclusion of other specific entities.
- But without histological proof of vasculitis.
Vasculitis confined to the CNS was first thoroughly described 60 years ago by Cravioto and Feigin, who detailed the classic histopathological features, defining it as a ‘diffuse disorder of the central nervous system with some focal accentuation’. [2] However, Calabrese and Mallek’s landmark study three decades later provided a lasting account of the clinical features, summarized angiographic findings, and emphasized treatment with high-dose corticosteroids and cyclophosphamide. [9] They defined PCNSV as ‘an acquired clinical disease characterized by CNS dysfunction unexplained after thorough investigations, unassociated with systemic illness, and yielding evidence of vasculitis confined to the CNS by cerebral angiography or CNS tissue biopsy.’ Their proposed diagnostic criteria for primary angiitis of the CNS included: (1) unexplained acquired neurological deficit after thorough initial evaluation; (2) either classic angiographical or histopathological features of angiitis within the CNS; and (3) no evidence of systemic vasculitis or other conditions causing secondary angiographic or pathological features. [9] Ongoing studies continue to use these criteria or variations, allowing diagnosis based on angiography without biopsy. [12, 13]
However, subsequent research over the next two decades confirmed that angiographic changes considered typical of vasculitis were not specific to PCNSV (Table 2). Furthermore, many confirmed PCNSV cases had normal cerebral angiograms. Calabrese himself later confirmed that the diagnostic specificity and positive predictive value of cerebral angiography in this context were less than 30%. [34] This low specificity means that patients with ‘typical’ vasculitic changes are statistically more likely to have an alternative disorder than primary CNS vasculitis. [11, 27, 45, 55] Consequently, many authors have emphasized the importance of tissue biopsy to confirm the diagnosis, and proposals for diagnostic criteria requiring biopsy proof for a definite diagnosis have emerged. [4, 6, 11, 20, 56] Powers [11], for instance, asserted that ‘patients without histological confirmation should not be included in case reports, case series, or reviews’ related to cns vasculitis diagnosis.
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Table 2 Conditions That May Mimic Vasculitic Changes on Contrast Angiography
Despite these recommendations, such proposals have not been universally accepted. A 2017 systematic study of diagnostic test results in primary CNS vasculitis [27] identified 701 published cases. Biopsy confirmed the diagnosis in only 248 (35.4%). In 99 biopsy-proven vasculitis cases, cerebral angiography was normal. The study also noted an increasing reliance on angiography and decreasing histopathological testing over the past two decades. They also advocated for a definite diagnostic category limited to cases with tissue proof. Despite these recommendations, current studies and prospective surveys still include patients without histological confirmation [13], hindering progress in refining cns vasculitis diagnosis.
Our proposed draft criteria also require tissue proof for a ‘definite’ classification. They are more stringent than criteria used in most published studies, but this rigor is justified by the wide range of disorders mimicking primary CNS vasculitis, particularly angiographically. We propose no ‘probable’ category due to the low specificity of contrast angiography. Instead, all suspected cases lacking histological proof should be classified as ‘possible,’ implicitly limiting angiography’s role to excluding other specific disorders like moyamoya disease and fibromuscular dysplasia. These new criteria can serve as a basis for retrospective literature-based studies and, more importantly, for future prospective studies focusing on the clinical features, diagnosis, and treatment of this challenging and serious disorder to improve cns vasculitis diagnosis and patient outcomes.
Key Points
- In primary central nervous system (CNS) vasculitis, cerebral angiography without histology is not diagnostic.
- CNS biopsy is diagnostically crucial and relatively safe.
- We propose binary diagnostic criteria, categorizing cases as ‘definite’ or ‘possible’, and eliminating the ‘probable’ category for enhanced diagnostic clarity in cns vasculitis diagnosis.
Acknowledgments
We extend our gratitude to Dr. Shelley Renowden and Professor Seth Love for their assistance with providing the images for figures 1 and 2.
References
