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Primary Angiitis of the Central Nervous System (PACNS)

Overview

PACNS is based upon the determination of unexplained neurological or psychiatric manifestations with demonstration of arteritis of the CNS by either angiography and/or pathological confirmation. Childhood PACNS is similar except for an age range of 1 month of age or older up to 18 years of age [1]. In many patients, the clinical presentation is one of the unexplained stroke-like features along with headache, cerebrospinal fluid (CSF) pleocytosis, and lack of systemic manifestations. In such a clinical setting, routine cerebral angiography remains indicated despite the attractiveness of magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) as less invasive alternative vascular imaging modalities. It has been proposed that the criteria for diagnosis be separated into definite and probable categories [2]. It has also been proposed that subcategorization into granulomatous angiitis of the central nervous system, benign angiopathy of the CNS, and atypical PACNS is also indicated [3].

In certain patients, there can be an insidious course with subtle manifestations predating a more definitive diagnosis by up to several years. This form of granulomatous angiitis is associated with small vessel infarction in different vascular territories along with a meningitic symptoms [4, 5]. There can also be spinal cord involvement [6]. Such small vessel involvement, especially in vessels smaller than 500 pm, limits the sensitivity of even routine angiography with a reported detection rate ranging from 40 to 90% [1]. One study reported a sensitivity of cerebral angiography as low as 27% when compared to documentation by tissue biopsy [7]. In such circumstances, leptomeningeal enhancement on MRI brain scan can be particularly pertinent in helping to raise concern about such a vasculitis process and guiding planned biopsy [8].

Diagnosis

It is expected that MRI brain scan will be of particular value in supporting or refuting CNS vasculitis. MRI brain scan abnormality, along with CSF pleocytosis, is found in greater than 90% of patients [2]. Conversely, a normal MRI brain scan and negative CSF exam are expected to have a high level of confidence in ruling out PACNS as an explanation for the symptoms. The helpful MRI clues to diagnosis are a characteristic vascular pattern in different distributions seen on either T2-weighted or fluid attenuation inversion recovery (FLAIR) images. This along with a lepto- meningeal enhancement pattern can be particularly pertinent. However, leptomen- ingeal enhancement is uncommonly reported to occur in roughly 8% of patients [9]. Enhancement of parenchymal lesions in PACNS is reported to occur in up to one- third of patients [4].

It is reported that the CSF is abnormal in up to 80-90% of patients with PACNS [2], but the findings can be quite subtle and nonspecific such as a modest elevation of the white blood cell count or the total protein. However, CSF analysis also serves to determine if there may be a systemic process such as infection, connective tissue disorder, or malignancy. A pronounced CSF white blood cell elevation, especially with polymorphonuclear leukocytes, rather than a relatively modest lymphocytic pleocytosis, should raise particular concern about alternative explanations. In such circumstances, gram stain and bacterial culture, along with viral culture and appropriate viral polymerase chain reaction (PCR), as well as a fresh, large CSF sample for cytology, will be indicated. White matter signal intensity changes in such a clinical setting should also lead to serious consideration of a multiple sclerosis panel.

PACNS remains a diagnostic challenge, and this is probably compounded by the fairly routine substitution of routine intra-arterial cerebral arteriography with less invasive modalities specifically MRA and CTA which have lower diagnostic yield. This mandates higher levels of suspicion for PACNS when features in Table 4.3 are present. The sensitivity of brain/leptomeningeal biopsy varies from 36 to 83% [2]. The supportive histologic findings include lymphocytic cellular infiltrates, granulomatous inflammation, and vessel wall fibrinoid necrosis [6]. In the Mayo Clinic cohort [10], of 163 patients diagnosed with PACNS, 105 were diagnosed on the basis of cerebral angiographic findings, while 58 were diagnosed by biopsy. The authors were able to identify some differentiations in their cohort with biopsy-proven subjects more likely to present with cognitive impairment as well as had higher CSF protein, less frequent cerebral infarction pattern, more frequent enhancing lesions on

Table 4.3 Features which can raise concern about primary angiitis of the central nervous system in a patient with stroke-like presentation

1. Unexplained ischemic stroke

4. Leptomeningeal enhancement

2. Multiple vascular territories involved

5. Cerebrospinal fluid pleocytosis

3. Accompanying headache

6. Suspicion of cerebral arterial narrowing, especially beading pattern, on angiography

MRI, as well as lesser mortality and morbidity. On the other hand, those identified by cerebral angiography had more frequent stroke-like presentations both clinically and by imaging along with greater mortality. It was theorized that this was attributable to larger vessel involvement in the angiogram-positive group.

Treatment

The importance of accurate diagnosis is underscored by the dilemma of an unrecognized and untreated serious disease process, with potentially devastating consequences, versus empiric therapy with potent immunosuppressive agents which can have serious long-term side effects. The treatment for PACNS remains empiric with no randomized clinical trials available to provide convincing guidance. Because of the inflammatory nature of the disease process, immunosuppression is considered the underpinning of effective management. This must factor in the risks versus potential benefits of such therapy especially with the absence of specific biomarkers for disease activity. This is in distinction to giant cell arteritis where both the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be of value in monitoring the course of the disease and response to therapy [11].

Birnbaum and Hellman [2] outlined a therapeutic approach for PACNS in 2008 based upon presently available information. They combined cyclophosphamide at 2 mg/kg/day with prednisone at 1 mg/kg/day. In severe acute presentations, they initiated methylprednisolone intravenously with 1000 mg daily for 3 days. This reflected some alteration of the recommendation of Salavarani et al. [4] in which corticosteroid therapy alone was felt to be adequate. In a recent review from 2013 [12], the combination of a corticosteroid and cyclophosphamide is felt to be the “gold standard.” However, in light of concerns about the longer-term side effects of daily oral cyclophosphamide, intravenous pulse therapy is reported to be less toxic and of equivalent efficacy [13].There is also increasing acceptance of limiting the course of oral cyclophosphamide therapy to no more than 3-6 months in light of these concerns over longer-term toxicity [14]. Over the longer term, it has been recommended that prednisone be tapered and discontinued over a 12-month period [2], and cyclophosphamide be replaced with lower-risk immunosuppressants such as azathioprine at 1-2 mg/kg/ day, methotrexate at 20-25 mg/week, or mycophenolate mofetil at 1-2 gram/day [15]. Most patients are felt to go into remission after a 12-18-month course of immunosuppression [16], but treatment for up to 2-3 years may be necessary [2].

 
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