Primary Angiitis of the CNS Workup

Patients in whom CNS angiitis is suspected should undergo a thorough workup to exclude systemic vasculitis and other diseases that can mimic primary angiitis of the central nervous system (PACNS).

CSF examination

Although it is nonspecific, CSF is abnormal in most patients with PACNS. Mild-to-moderate CSF pleocytosis, predominantly lymphocytes, is found in approximately 70-90% of cases. ^{[2, 14]} The vast majority of patients have elevated CSF protein, with a median protein concentration of 98 mg/dL (range 44-1034 mg/dL) in a recent report. ^[14] In some patients, oligoclonal bands can be detected in the CSF, reflecting an inflammatory process in the CNS. The glucose is usually normal. Cultures and cytology studies are important to exclude CNS infection and malignancies. In some patients, initial CSF examination results might be normal, but subsequent lumbar punctures show abnormalities as the disease evolves.

Other general lab studies

CBC, antinuclear antibodies (ANA), RF, SSA/SSB, p-ANCA, c-ANCA, cryoglobulin, complement levels, other tests for rheumatic diseases, and syphilis serology usually produce normal results but are helpful to rule out other conditions that can mimic PACNS.

ESR is usually normal or mildly elevated.

Head CT

Head CT in patients with primary angiitis of the central nervous system (PACNS) shows various combinations of nonspecific findings, including cerebral infarcts or hemorrhages with mass effect, hydrocephalus, or white matter hypodensity. CT may also be normal.

MRI of the brain

MRI of the brain is essential in the evaluation of patients with possible PACNS; it helps to exclude other diagnoses such as CNS tumors, demyelinating diseases, multiple small infarcts, and hydrocephalus.

MRI has also other benefits; it raises the suspicion of PACNS earlier by providing the clinician with evidence of a more extensive process than suspected on clinical grounds. It may also document the progression of the disease or response to therapy. MRI may also help in selecting a site for brain biopsy.

In PACNS, lesions on MRI are hyperintense on T2-weighted images and FLAIR sequences, and isointense or hypointense in T1-weighted images. Acute infarcts are represented by restricted diffusion on diffusion-weighted images (DWI). ^[18]

The MRI usually shows multiple lesions, predominantly in subcortical and deep white matter areas, with homogenous or patchy contrast enhancement. ^[19] MRIs showed prominent leptomeningeal enhancement in 8 of 49 patients with biopsy-proven PACNS in a recent series ^[9] , half of those 8 patients had vascular beta-amyloid deposits associated with granulomatous vascular inflammation.

The conventional resolution of magnetic resonance angiography (MRA) is insufficient to show the medium-sized and small vessels usually affected in PACNS.

Some of the publications that reported low sensitivity of MRI in PACNS described patients without pathological diagnosis who could have had benign angiopathy of the CNS or other diseases.

Patients in most of the recent reports of PACNS have had an abnormal brain MRI.

(a) T1-weighted left parasagittal MRI showing hypointense lesions in the cortical and subcortical white matter of the left superior temporal gyrus and frontal and frontoparietal operculum with sulcal obliteration. (b) The postgadolinium MRI at this level showing nodular parenchymal and linear pial enhancement.

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(a) T2-weighted axial MRI showing hyperintense lesions in the lentiform nuclei, head of the caudate nuclei and frontoparietal subcortical white matter. (b) On T1-weighted (postgadolinium) axial image, the lentiform nuclei and head of caudate nuclei are heterogeneously hypointense, while subcortical white matter lesions are isointense. Linear areas of pial enhancement are seen bilaterally.

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(a) T2-weighted axial MRI showing large, well-defined hyperintense lesions in the left frontal and parietal lobes. (b) Postgadolinium T1-weighted axial MRI showing nodular parenchymal and cortical-pial enhancement of the lesion. A follow up (after 3 mo) T2-weighted axial (c) and postgadolinium (d) T1-weighted axial MRIs showing significant reduction of the lesion size and nodular enhancing areas.

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Cerebral angiogram

When PACNS is suspected after routine laboratory studies, CSF exam, and MRI of the brain, a cerebral catheter angiogram should be performed. Classic findings are segmental changes of the contour and caliber beading of the contrast column, reflecting areas of narrowing and dilatation in the vessels. However, the angiography is neither sensitive nor specific for PACNS. Typical findings on angiography should not be relied on to make a diagnosis of PACNS or to justify the long-term steroid and immunosuppressant therapy. On the other hand, a negative angiography should be followed by a brain biopsy when clinical suspicion is high and long-term therapy is being considered. ^[20]

In 48 angiographies on 43 patients from different series, only 12 showed changes highly suggestive of vasculitis. ^[2]

In another recent retrospective study of 38 patients who underwent cerebral angiogram followed by brain biopsy for possible PACNS, typical angiographic findings of vasculitis were noted in 14 patients. On biopsy, none of these patients had PACNS and 6 of them had another specific pathological diagnosis, including infarctions, Alzheimer disease, and CADASIL. In the same study, 2 patients were diagnosed with PACNS on biopsy; neither of them had an angiogram read as typical for vasculitis. ^[21]

Many other conditions can give a similar angiographic picture of vasculitis, including atherosclerosis, benign angiopathy, reversible cerebral vasoconstriction syndromes, vasospasm after subarachnoid hemorrhage, hypertension, migraine, trauma, chronic meningitis, and oral contraceptives and sumatriptan use.

Lateral right internal carotid angiogram shows beading of anterior cerebral arteries (arrowheads) and beading (straight arrows), segmental dilatation (curved arrow), and narrowing of middle cerebral arteries (open arrow).

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Brain biopsy

Brain biopsy is the only method able to establish a diagnosis of primary angiitis of the central nervous system (PACNS) and to rule out other diseases. Because vessels in leptomeninges are involved in most cases, the leptomeninges should always be sampled.

Lesions seen on MRI should be biopsied if accessible; otherwise, the nondominant frontal or temporal lobe can be sampled. Both open and stereotactic biopsies have been used with similar outcomes.

In a retrospective review, 61 patients underwent brain biopsy for suspected PACNS; 22 patients (36%) of them had pathological diagnosis of PACNS, 15 patients (25%) had no pathological diagnosis, and 24 patients (39%) had alternative diagnoses, including infections, primary CNS lymphoma, metastatic tumors, sarcoidosis, MS, and arteriovenous malformation. ^[22] This study, along with other reports, suggests a moderate sensitivity of less than 70% of brain biopsy in PACNS. False negative results have been reported, which is expected given the patchy distribution of the disease. However, specificity of brain biopsy in PACNS is considered to be high.

In a study of 79 patients, PACNS was confirmed in 11% of patients, and an alternative diagnosis was indentified in 30%. Cerebral amyloid angiopathy, encephalitis, demyelination, and CNS lymphoma were the most common alternative diagnoses. Post-surgical complications occured in 16% of patients, a quarter of which were serious. ^[23]

Small-vessel PACNS in children is a recently recognized subset in which cerebral angiogram is normal by definition. In a report of 11 cases, nonlesional biopsy was as good as lesional biopsy in confirming the diagnosis. Pathology showed intraluminal lymphocytic infiltrates without granulomatosis. ^[13]

Primary angiitis of the central nervous system (PACNS) affects arterioles and venules less than 300 microns in diameter with vessels of the leptomeninges almost always involved. ^[2] Concomitant involvement of larger vessels such as the arteries of the circle of Willis and its branches has been reported.

Typical histopathological features are chronic granulomatous inflammation and giant cells. ^[24] Detection of giant cells is not required to make the diagnosis. ^[2] Nongranulomatous inflammation and fibrinoid necrosis of vessel walls have been described.

Inflamed walls of the affected vessels are infiltrated with different subpopulations of leukocytes; including lymphocytes, monocytes, histiocytes, and plasma cells. In the few cases when immunophenotyping of leukocytes was done, the infiltrating cells were mainly CD4 T lymphocytes. ^[2]

Three histopathological patterns of vasculitis were observed in the Mayo Clinic review. ^[7] Granulomatous inflammation was the most common (58%) with nearly half of the cases associated with deposition of beta-A4 amyloid in the vessel wall. Pure lymphocytic infiltration was seen in 28% of cases, and necrotizing inflammation was seen in 14% of cases.

Several reports have described PACNS in association with beta-A amyloid deposition, usually in patients younger than expected for the more common sporadic cerebral amyloid angiopathy. This association is usually seen with granulomatous PACNS, and its etiology is unknown. It has been suggested that PACNS associated with amyloid is part of a spectrum of inflammatory responses evoked by these substances. ^{[7, 25, 26]}

Microscopic examination also reveals necrotic ischemic lesions, hemorrhages, and tract degeneration.

Low power view of inflamed vessel in the subarachnoid space shows fibrinoid necrosis (pink areas) superiorly.

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Higher power view of small inflamed vessel in the medulla, with fibrinoid necrosis in the wall and chronic transmural inflammation.

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Kolodny and colleagues proposed the following sequence for the development of vasculitic lesions: ^[24]

1. Intimal swelling and hyperplasia in arteries and adventitial lymphocyte infiltration in veins

2. Subintimal fibrinoid change and adventitial accumulation of histiocytes

3. Necrosis and fibrinoid change in media, fragmentation of internal elastic lamina, panmural infiltration of lymphocytes and histiocytes

4. Typical lesions: A granulomatous mass replaces all or part of vessel wall (lymphocytes, large mononuclear cells, fibroblasts, multinucleated giant cells, and variable numbers of plasma cells)

5. Possibly representing a late-stage, abundant fibrosis and relatively sparse lymphocytic infiltration, accompanied by large mononuclear and giant cells