Primary central nervous system vasculitis, referred to as primary angiitis of the central nervous system (PACNS), is a rare cause for encephalopathy-related signs and symptoms associated with recurrent episodes of ischemia or hemorrhage. A recent review published in Journal of the Neurological Sciences provided an update on diagnosis, differential diagnosis and treatment for PACNS.1

Although considered a rare condition, PACNS is the most common vasculitis involving the central nervous system and can affect all age groups.2 The diagnosis of PACNS is often challenging, as there are no specific features or clinical course. Additionally, no blood nor imaging studies are available to confirm diagnosis.3

The recurrent episodes of ischemia or hemorrhage associated with PACNS can lead to multiple signs and symptoms, including cognitive and affective abnormalities, headaches, and seizures.1 While the disorder is restricted to the brain and spinal cord, spinal cord involvement has been documented in 5% of patients. This is rarely the only manifestation and brain involvement is typically present in most patients.4


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The autoimmune, inflammatory disease is limited to small and medium-sized vessels of the central nervous system, with histological evidence for granulomatous inflammation of the vessel wall, necrotizing or lymphocytic vasculitis.5 Accordingly, there are 2 subtypes of PACNS based on the size of the affected vessels: small-vessel variant or medium-vessel variant.1

Diagnosis

More than 3 decades ago, Calabrese and Mallek proposed diagnostic criteria for PACNS, including a history or clinical findings of an unexplained acquired neurologic deficit, angiographic or histopathologic features of vasculitis within the central nervous system, and exclusion of systemic vasculitis or other associated conditions.6

Birnbaum and Hellman proposed modified diagnostic criteria in 2009, with a definite diagnosis based on a tissue biopsy and a probable diagnosis considered in the absence of tissue confirmation, in the presence of high probability findings of vasculitis on an angiogram, abnormal findings on imaging, and characteristic cerebrospinal fluid profile.7

When clinical history and examination are suggestive of PACNS and imaging and cerebrospinal fluid analysis support the diagnosis, angiography is recommended in cases of suspected involvement of middle vessels. A biopsy should be completed for definitive diagnosis in patients with suspected involvement of small vessels.1

In the presence of normal magnetic resonance imaging, the diagnosis of PACNS is extremely unlikely, and potential findings on imaging include cortical and subcortical infarction, parenchymal and leptomeningeal enhancement, intracranial hemorrhage, tumor-like mass lesions, and nonspecific areas of increased signal intensity on fluid attenuated inversion recovery or T2-weighted images.2 The pattern of contrast enhancing may aid in distinguishing PACNS and neurosarcoidosis.1

As brain biopsy is an invasive procedure, angiography has become the most common method for confirming the diagnosis of PACNS. Findings, however, are not specific and in some cases of pathologically-confirmed PACNS involving small vessels, cerebral angiography may be normal.8 Digital subtraction angiography is recommended in patients with suspected PACNS, with prior data suggesting a sensitivity between 40% and 90%, and a specificity of less than 30%.2  

In 90% of patients, cerebrospinal fluid analysis frequently reveals lymphocytic pleocytosis or elevated protein levels. Oligoclonal banding may also be present. Strunk and colleagues determined the immune cell profiling in the cerebrospinal fluid of patients with PACNS and reported highly diverse spinal fluid immune-cell repertoire. They suggested this may reflect the heterogeneity of the vasculitis subtypes.9 

For the diagnosis of PACNS it is essential to rule out other conditions in the differential diagnosis. Various conditions may mimic PACNS, including noninflammatory vasculopathies, infectious vasculopathies, demyelinating syndromes, metabolic diseases, systemic vasculitis, malignant diseases, autoimmune and rheumatic diseases.1

The gold standard for the diagnosis of PACNS is cerebral and meningeal biopsy showing vasculitis. While incorrect interpretation or sampling of nonrepresentative tissue may result in false biopsy results, brain biopsy helps to prevent unnecessary immunosuppressive treatments in alternative diagnoses.1

The proposed diagnostic criteria proposed by Birnbaum and Hellman aimed at preventing misdiagnosis, particularly regarding reversible cerebral vasoconstriction syndromes (RCVS), a vasospastic disorder associated with severe headaches. This requires different management.1

While PACNS is characterized by insidious, chronic headaches, RCVS is associated with recurrent thunderclap headaches. Lobar hemorrhage, sulcal subarachnoid hemorrhage, and reversible edema are common among patients with RCVS but are rare in PACNS. Characteristic angiography findings among patients with RCVS include “sausage on a string” sign and positive nimodipine test during angiography. Among those with PACNS, angiography findings include irregular, notched, ectasia and a negative nimodipine test.1  

Treatment

As the data on treatment of PACNS are limited, the treatment options for PACNS have been similar to those used for systemic vasculitides. Intravenous and oral corticosteroids are used for acute flares, and cyclophosphamide can be used in an attempt to induce remission. The majority of patients with PACNS have a favorable response to prednisone with or without cyclophosphamide.10

Rituximab, a CD20 depleting monoclonal antibody, may be used as a safe and effective alternative to cyclophosphamide in patients with refractory PACNS and may also be used as primary treatment following corticosteroid treatment.1 Additional studies are required to determine the role of tocilizumab against PACNS.

The optimal duration of induction and maintenance treatment is unclear. Methotrexte, mycophenolate mofetil and azathoprine may be used after remission is achieved. The duration of maintenance therapy will be determined according to clinical, biochemical and radiological findings.1  

While earlier reports suggested a poor prognosis with fatal outcomes in most cases, more recent studies have shown a more favorable course of PACNS.2 Schuster and colleagues reported remission rates of 68%, with favorable outcomes evident in 80% of patients after 2 years.11  

Conclusion

As PACNS presentation and findings within the diagnostic work-up lack specificity, it is critical to exclude differential diagnoses prior to starting immunosuppressive therapy. Using a step by step approach, clinicians can immensely improve their ability to do this. “PACNS is an important but rare differential diagnosis in daily neurological practice. The strict adherence to diagnostic criteria and the avoidance of inappropriate therapies in [noninflammatory] vasculopathies and infectious diseases are essential, “concluded study researchers.

References

1. Kraemer M, Berlit P. Primary central nervous system vasculitis – An update on diagnosis, differential diagnosis and treatment. J Neurol Sci. 2021;117422. doi:10.1016/j.jns.2021.117422

2. Salvarani C, Brown RD Jr, Hunder GG. Adult primary central nervous system vasculitis. Lancet. 2012;380(9843):767-77. doi:10.1016/S0140-6736(12)60069-5

3. Rice CM, Scolding NJ. The diagnosis of primary central nervous system vasculitis. Pract Neurol. 2020;20(2):109-114. doi:10.1136/practneurol-2018-002002

4. Salvarani C, Brown RD Jr, Calamia KT, et al. Primary CNS vasculitis with spinal cord involvement. Neurology. 2008;70(24 Pt 2):2394-400. doi:10.1212/01.wnl.0000314687.69681.24

5. Giannini C, Salvarani C, Hunder G, Brown RD. Primary central nervous system vasculitis: pathology and mechanisms. Acta Neuropathol. 2012;123(6):759-72. doi:10.1007/s00401-012-0973-9

6. 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). 1988;67(1):20-39. doi:10.1097/00005792-198801000-00002

7. Birnbaum J, Hellmann DB. Primary angiitis of the central nervous system. Arch Neurol. 2009;66(6):704-9. doi:10.1001/archneurol.2009.76

8. Salvarani C, Brown RD Jr, Calamia KT, Christianson TJH, Huston J 3rd, Meschia JF, Giannini C, Miller DV, Hunder GG. Angiography-negative primary central nervous system vasculitis: a syndrome involving small cerebral vessels. Medicine (Baltimore). 2008;87(5):264-271. doi:10.1097/MD.0b013e31818896e1

9. Strunk D, Schulte-Mecklenbeck A, Golombeck KS, et al. Immune cell profiling in the cerebrospinal fluid of patients with primary angiitis of the central nervous system reflects the heterogeneity of the disease. J Neuroimmunol. 2018;321:109-116. doi:10.1016/j.jneuroim.2018.06.004

10. Salvarani C, Brown RD Jr, Christianson TJ, et al. Adult primary central nervous system vasculitis treatment and course: analysis of one hundred sixty-three patients. Arthritis Rheumatol. 2015;67(6):1637-45. doi:10.1002/art.39068

11. Schuster S, Ozga AK, Stellmann JP, et al. Relapse rates and long-term outcome in primary angiitis of the central nervous system. J Neurol. 2019;266(6):1481-1489. doi:10.1007/s00415-019-09285-1

This article originally appeared on Neurology Advisor