Annals of Indian Academy of Neurology
: 2022  |  Volume : 25  |  Issue : 6  |  Page : 989--990

Primary angiitis of the central nervous system: A great mimicker

Tanish Modi1, Manish Modi2,  
1 MBBS Intern, Department of Internal Medicine, Government Medical College and Hospital, Chandigarh, India
2 Department of Neurology, PGIMER, Chandigarh, India

Correspondence Address:
Manish Modi
Department of Neurology, PGIMER, Chandigarh

How to cite this article:
Modi T, Modi M. Primary angiitis of the central nervous system: A great mimicker.Ann Indian Acad Neurol 2022;25:989-990

How to cite this URL:
Modi T, Modi M. Primary angiitis of the central nervous system: A great mimicker. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 27 ];25:989-990
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Primary angiitis of the central nervous system (PACNS) refers to vasculitis limited to the brain, spinal cord, and meninges without any secondary etiology. It is a rare disease, with one study estimating the average annual incidence rate of PACNS to be 2.4 cases per 1,000,000 person-years.[1] The disease can affect people of any age but usually occurs in the fourth or fifth decades of life.[2]

The review article by Sundaram & Sylaja.[3] (published in this issue) succinctly summarizes the practical aspects and the challenges in establishing the diagnosis, as well as provides updates on emerging therapeutic protocols.

The cause is unclear; however, there have been various mechanisms proposed, including molecular mimicry due to infections such as Varicella zoster virus (VZV), Human Immunodeficiency virus (HIV), Cytomegalovirus (CMV), and Mycoplasma.[1] Inflammation of the vessels leads them to become stenosed, occluded, and thrombosed, leading to ischemic infarcts of the supplied territories as well as hemorrhages resulting from the weakened vessels.

The clinical presentation can be highly variable but tends to be insidious rather than acute. The most common reported symptom is headache, which is subacute and insidious, contrasting with the thunderclap headache seen in Reversible cerebral vasoconstriction syndrome (RCVS), an important differential and angiographic mimic.[2]

The disease should be considered in a young patient without significant hypercoagulable or atherosclerotic risk factors presenting with recurrent strokes/TIAs.

Systemic manifestations such as fever, weight loss, anorexia, and arthralgias should prompt consideration of alternative etiologies, particularly secondary vasculitis due to systemic rheumatological disease. Notably, recurrent strokes in a high-risk individual with co-morbidities are more likely to be atheroemboli rather than PACNS, which may be originating from a cryptogenic source such as the aorta.[4]

Ruling out the differential diagnoses is of paramount importance in diagnosing this condition, especially considering the risks of long-term immunosuppressive therapy, which may be related to the therapy itself or due to reactivation of the underlying infection, which in fact was the primary etiology.

The importance of performing a lumbar puncture cannot be overstated. Cerebrospinal fluid (CSF) shows some abnormality in up to 80–90% of patients with PACNS, although it is usually non-specific. Testing CSF for infectious etiologies with modalities such as Polymerase Chain Reaction (PCR) for viruses and bacteria is also warranted.

Magnetic resonance imaging (MRI) is abnormal in almost all cases. The individual findings in MRI are variable, but majorities have evidence of subacute and chronic infarcts. A cluster of findings including infarcts, hemorrhages, and parenchymal and leptomeningeal enhancement strongly suggest PACNS.

The next step is to document vessel changes, typically with the means of conventional angiography (CA) because non-invasive modalities such as Magnetic Resonance Angiography (MRA) and Computerized Tomography Angiography (CTA) are not usually sensitive enough to detect abnormalities in the smaller vessels, more preferentially affected in PACNS. The diagnostic yield of CA ranges from 70–88%.[5],[6] CA has a specificity and positive predictive value of less than 30% for diagnosing PACNS as many conditions can mimic similar angiographic appearance.

Biopsy remains the gold standard for diagnosing PACNS and should be carried out in the majority of patients. A targeted biopsy from a radiologically abnormal area provides better sensitivity; however, in the absence of a suitable site, the tip of the non-dominant temporal lobe is the usual site, albeit in compromise for sensitivity. A meta-analysis revealed a diagnostic yield of 74.7% (95% confidence interval [CI] 64.0–84.1%) for suspected PACNS.[7] A lower sensitivity may be a result of the segmental nature of inflammation (skip lesions) or involvement of medium-sized vessels.

Notably, imaging-based PACNS affects predominantly medium-sized vessels and may have false-negative biopsy results as larger vessels may not be included in the sampled tissue. Conversely, biopsy-proven PACNS primarily involves small-sized vessels beyond the resolution of vascular imaging and may be initially reported as angiographically negative.[5],[6]

Establishing the diagnosis is a challenging task, and the lack of specificity of most of the currently available diagnostic methods necessitates the need to explore novel modalities and biomarkers. The article has discussed the role of up-and-coming techniques such as high-resolution MR vessel wall imaging (HRVWI) to differentiate between angiographically similar vasculopathies. A study reported abnormality in 20 (95.2%) out of 21 patients on HRVWI with a confirmed diagnosis of PACNS according to the Calabrese and Mallek criteria.[7] The presence of vessel wall enhancement can help exclude RCVS.[8]

Novel biomarkers are emerging as tools to suggest the diagnosis. IL-17 in the CSF as a marker for inflammation and its established role in Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, CSF amyloid-beta A4 protein (APP) as a marker for nervous system damage, and circulating endothelial cells in venous blood as a surrogate for endothelial damage may serve as indicators to suggest PACNS.[9]

Despite well-laden diagnostic criteria, the unfamiliarity of the disease and the non-specific nature of most of the diagnostic tests delay the median time to reach the diagnosis of PACNS to 15 weeks and even longer for biopsy-proven cases.[5]

The mainstay of treatment is induction of remission and maintenance therapy with immunosuppressants. As highlighted above, the infection must be confidently ruled out before starting immunosuppressive therapy. Glucocorticoids may be started in the interim, pending full diagnostic workup after ruling out infections on initial investigations. The authors propose starting pulse intravenous methylprednisolone 1 g/day for 3–5 days before switching to oral prednisolone. Some experts suggest avoiding IV pulse steroids, because steroid-induced mental status changes may cause diagnostic difficulty, and suggest beginning prednisone at 1 mg/kg/day until the diagnostic evaluation is complete.[5],[6] Induction therapy is commonly initiated with a combination of glucocorticoids and cyclophosphamide. Failure to respond to these drugs should warrant a search for an alternative etiology before switching to a different immunosuppressant. As highlighted in the article, azathioprine, mycophenolate mofetil, and methotrexate are used as maintenance therapy. Biological agents such as rituximab and anti-tumor necrosis factor alpha inhibitors (infliximab and etanercept) may be used in refractory cases.

To assess response to treatment, periodic clinical evaluation including symptomatic improvement (e.g., resolution of headaches) and quantification of residual disability (e.g., using the mRS scale) must be clubbed with neuroimaging to look for evidence of new lesions, which could indicate relapse. A lack of new lesions on MRI is a reliable way to assess the progression of the disease.


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