Diffuse inflammation of small- and medium-sized blood vessels confined exclusively to the brain, meninges, or spinal cord is called primary angiitis of the central nervous system (PACNS). In the last few years, there have been significant advances in the understanding of this disorder due to the identification of pathological and clinical subsets, along with advances in the imaging modality of vessel wall abnormalities. A considerable gap still exists, however, particularly with respect to its pathophysiological mechanisms. Although various laboratory and neuroimaging findings may support the diagnosis of primary CNS angiitis, they are not highly specific, and neurologists often face a substantial challenge when diagnosing this disorder because they need to rule out a vast array of nonvasculitic conditions and secondary causes of central nervous system vasculitis. Therefore, a correct and timely diagnosis of primary CNS angiitis requires a high degree of suspicion coupled with knowledge of other diseases that can masquerade as primary CNS vasculitis. In this article, the authors focus on the clinical and pathological findings, diagnostic work-up, differential diagnosis, and current therapeutic options of this still enigmatic and complex entity.
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• Primary angiitis of the CNS is an uncommon disease with protean clinical manifestations that often make diagnosis and treatment very challenging.
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• The current diagnostic approach is characterized by a low sensibility and specificity; hence, diagnosis relies on a high degree of clinical awareness and thorough investigation aimed at ruling out a broad list of alternative diagnoses and mimickers.
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• Brain biopsy is currently the gold standard for definite diagnosis of primary angiitis of the CNS (PACNS).
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• Reversible cerebral vasoconstriction syndrome is the most common mimic of primary CNS angiitis.
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• Immunosuppressive therapy with glucocorticoids alone or in combination with cyclophosphamide is the first line of treatment, despite lack of evidence based on controlled clinical trials.
Historical note and terminology
Vasculitis or angiitis is defined as an inflammatory disease of arteries, veins, or both that results in histologically demonstrable structural injuries to the vessel wall, often accompanied by thrombosis and evidence of ischemic damage to the tissues served by the affected blood vessels. A vasculitis is considered primary when it occurs without an identifiable cause or when it is unassociated with an underlying disease and secondary when it occurs as a manifestation of a diverse group of underlying diseases.
The central nervous system vasculature can be affected secondarily by numerous forms of vasculitis such as generalized autoimmune diseases (systemic lupus erythematosus, Sjögren syndrome) or systemic vasculitis (Wegener granulomatosis, polyarteritis nodosa) as well as by drugs (amphetamines, cocaine), infections (bacterial, fungal, protozoal, mycoplasmal, rickettsial, viral), malignancy (Hodgkin lymphoma, non-Hodgkin lymphoma, leukemia, lung cancer), Behçet disease, Cogan syndrome, and sarcoidosis (93).
Primary CNS vasculitis was first described by Harbitz in 1922, but it was not until 1959 that Cravioto and Feigin introduced the concept of vasculitis with a unique predilection for the CNS and coined the term "noninfectious granulomatous angiitis with a predilection for the nervous system” (61; 29). In their classical description, they explained 2 cases from their own series and also gave a literature review of suspected cases including 1 case from Harbitz (61), 2 cases from Newman and Wolf (97), and 2 from McCormick and Neubuerger (86). They questioned the diagnosis of Churg-Strauss syndrome in Newman and Wolf's cases and also temporal arteritis in McCormick and Neuberger's cases. They suggested that along with their own 2 cases, these 6 cases should be grouped together as delineating a distinct clinical and pathological entity. They also suggested the possible utility of biopsy in establishing the diagnosis and cortisone/ACTH in therapy. Another case was added in the literature in 1966 by Hughes and Brownell (66).
By the 1970s, this disease was considered a severe, uniformly fatal disorder and unresponsive to therapy with few notable exceptions like the case reported by Snyder and McClelland in 1978 (133). In all published case reports until that time, the entity had been recognized at postmortem examinations. Cupps and colleagues described the efficacy of cyclophosphamide and high-dose glucocorticoids, with the idea driven by the successful use of these agents in systemic angiitic syndromes (31). Sigal in 1987 wrote an excellent review paper shedding light on the neurologic manifestations of vasculitic and rheumatological syndromes (131). Fauci and colleagues in 1979 and then Calabrese and Mallek in 1988 proposed the diagnostic criteria that relied equally on histopathology or, alternatively, cerebral angiography in the appropriate clinical setting (44; 22). These criteria include:
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(1) An unexplained neurologic deficit despite aggressive diagnostic evaluation.
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(2) A high probability angiogram for arteritis or histopathological evidence of arteritis confined to the CNS.
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(3) Exclusion of all those disorders capable of mimicking the angiographic findings or associated with vascular inflammation of the CNS.
Over time it became increasingly common for patients to be diagnosed with primary angiitis of the CNS solely on angiographic grounds without supporting histopathology. As a result, patients, diagnosed solely on the basis of abnormal angiogram, were treated with prolonged and intensive immunosuppressive regimens based on the supposition that cases diagnosed by angiographic findings were clinically equivalent to biopsy-proven cases (145).
The achievements of 1980s proved to be lessons of the 1990s. First, enthusiasm for the empiric treatment of cerebral vasculitis waned because of recognition of the unreliability of cerebral angiography in its diagnosis. A second factor that lessened interest in empiric therapy with cyclophosphamide for CNS vasculitis was the recognition of permanent side effects in up to 40% of patients treated with oral cyclophosphamide for Wegener granulomatosis. Calabrese and colleagues described so-called benign angiopathy of the CNS among young women with the prior diagnosis of primary angiitis of the CNS (21). They differed in the onset with a focal cerebral deficit, normal CSF, lack of progression, and spontaneous resolution. They proposed primary angiitis of the CNS as a heterogeneous disease with granulomatous angiitis of the CNS and benign angiopathy of the CNS, and with atypical forms as clinical subsets. Hajj-Ali and coworkers provided evidence that the pathologic process in benign angiopathy of the CNS is vasoconstriction rather than vasculitis, thus indicating that benign angiopathy of the CNS should not be included in the spectrum of primary angiitis of the CNS (56). Reversible cerebral vasoconstriction is the term now used to describe entities such as postpartum angiopathy, Call-Fleming syndrome (23), benign angiopathy of the CNS, and others. In 2005, MacLaren and colleagues explained that the clinical course of patients with primary angiitis of the CNS differed markedly depending on the size of the vessel involved (84). They proposed 2 subsets of primary angiitis of the CNS: small-vessel disease and medium-vessel disease.
But the debate still continues as these classifications continue to evolve. Calabrese rightly noted: "A penumbra is a space of partial illumination, such as in eclipse, between perfect shadow and full light. Despite significant progress, primary angiitis of the CNS remains foursquare in the penumbra awaiting full illumination" (17). The knowledge about this intriguing disease continues to expand, and excellent reviews were done in the last decades (149; 147; 146; 58).
Vasculitis predominantly affecting the CNS has been given several diagnostic labels in the past 90 years. Harbitz first described it as "unknown forms of arteritis" (61). The same condition was later described as, "non infectious granulomatous angiitis involving the central nervous system" (97), as "giant cell arteritis involving small meningeal and intracerebral vessels" (86), as " noninfectious granulomatous angiitis with a predilection for the nervous system" (29), as" granulomatous angiitis of the nervous system" (14) or simply "granulomatous angiitis" (15), and as "isolated angiitis of CNS" (31; 92). The nomenclature of this unique disease entity continues to evolve, and terms such as granulomatous angiitis of the CNS and isolated angiitis of the CNS fall out of use as neither is appropriate because the histology can be granulomatous or lymphocytic and subclinical involvement of extracranial arteries (eg, pulmonary and abdominal visceral angiitis) have been reported. Granulomatous pathology in cerebral vessels is highly nonspecific as it had been shown to be associated with various disease entities like temporal giant-cell arteritis (69), herpes zoster (108; 64), lymphoproliferative tumors (104; 70), sarcoidosis (24), amyloidal angiopathy (48), and systemic lupus erythematosus (124). The final diagnostic label of "primary angiitis of the central nervous system" proposed by Calabrese and Mallek in 1988 and endorsed by Lie in 1991 and 1992 is the most appropriate and correct one according to our current understanding of this unique disease (22; 80; 81).