Adult Primary Central Nervous System Vasculitis

 Diagnosis and Diagnostic Criteria

Diagnostic criteria for PCNSV were proposed by Calabrese and Mallek^[17] in 1988 on the basis of their clinical experience and of published evidence (Table 1).^[17,18] These criteria included angiographic changes indicating a high probability of vasculitis, that is, areas of smooth vessel wall narrowing or occlusions alternating with dilated cerebral arteries affecting multiple cerebral arteries in the absence of proximal vessel atherosclerosis or other recognized abnormalities (Fig. 1a). A single abnormality in multiple arteries or multiple abnormalities in a single vessel were considered to be less consistent with PCNSV.^[1]

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Figure 1.

Imaging of patients with primary central nervous system vasculitis. (a) Cerebral angiogram showing alternating stenoses and dilatations consistent with primary central nervous system vasculitis (arrows). (b) Magnetic resonance angiography of the brain shows stenosis of the left posterior cerebral artery and the right middle cerebral artery (arrows).

Because of the more invasive nature of CNS biopsy, angiography has become the most used method of confirming the diagnosis in patients with suggestive clinical findings.

However, angiographic changes typical of vasculitis may be seen in nonvasculitic conditions such as vasospasm, CNS infections, lymphomas, cerebral arterial emboli, and also atherosclerosis.^[19,20] Furthermore, among pathologically documented cases, cerebral angiography may be normal, reflecting vascular involvement in small vessels below the resolution of angiography.^[9]

Overall, the sensitivity of angiography varies between 40 and 90%, whereas its specificity has shown to be as low as 30%.^[1,21–23]

Magnetic resonance angiography (MRA) is a reasonable initial approach to investigate patients with suspected PCNSV (Fig. 1b). However, MRA is less sensitive than conventional angiography in detecting lesions involving the posterior circulation and distal vessels.^[1,24] Therefore, if the clinical suspicion is high but MRA is normal, a standard cerebral angiography is warranted.

It is important to emphasize that the diagnosis of PCNSV should not be based on the findings of a positive angiography alone, and that angiography results should always be interpreted in conjunction with clinical, laboratory, and MRI findings.

Recently, to prevent misdiagnosis, particularly with the reversible cerebral vasoconstriction syndromes (RCVS), Birnbaum and Hellman^[18] have proposed new criteria based on the levels of certainty of the diagnosis (Table 1). These criteria may prevent patients with RCVS from being treated with cytotoxic therapy. However, they are not able to categorize patients with high-probability angiographic findings, but normal CSF analysis who may have either RCVS or PCNSV. The presence of precipitating factors, the type of onset and the neurological findings may be useful distinguishing features. Onset in the postpartum or following exposure to vasoactive substances would point to RCVS.^[25] RCVS has an acute onset followed by a monophasic course, usually without any new complications after 4 weeks, whereas in PCNSV, the onset is more insidious and the course is progressive with frequent appearance of cerebral infarcts. Headache is of the thunderclap type in RCVS, whereas it is subacute and progressive in PCNSV. MRI is often normal in RCVS, whereas PCNSV is extremely unlikely in the presence of a normal MRI. Several studies have indeed reported a sensitivity of MRI for PCNSV close to 100%.^[1,22] Abnormal findings on MRI are nonspecific and include cortical and subcortical infarction, parenchymal and leptomenigeal enhancement, intracranial hemorrhage, tumor-like mass lesions, and nonspecific areas of increased signal intensity on fluid-attenuated inversion recovery or T2-weighted images.

Advances in the neuroimaging techniques visualizing the wall of intracranial blood vessels could in the future improve the capacity to distinguish inflammatory from non-inflammatory lesions and, thus, the performance of the criteria.^[26·]

Vessel wall thickening and intramural contrast enhancement are quite specific findings in patients with active cerebral vasculitis affecting large arteries. Occasionally, enhancement may be marked and extend into the adjacent leptomeningeal tissue (peri-vascular enhancement).^[27,28] High-resolution, high-field contrast-enhanced MRI may be able to differentiate enhancement patterns of intracranial atherosclerotic plaques (eccentric), inflammation (concentric), and other wall pathologies. However, the sensitivity and specificity of MRI in this regard remain to be determined.^[29]

Cerebral and meningeal biopsy remains the gold standard for the diagnosis of PCNSV.^[6,19] The procedure in expert hands is well tolerated. Small intraparenchymal hematomas at the biopsy site are the most frequent complication (4.9%); however, permanent neurological sequelae are rare (only about 1% of cases).^[30,31] A positive biopsy confirms vasculitis, and excludes its mimickers. An optimal biopsy should include samples of dura, leptomeninges, cortex, and white matter. Diagnostic histopathological features include transmural vascular inflammation affecting small and medium-sized leptomeningeal and parenchymal arterial vessels. Vasculitis is characterized by skip and segmental vascular lesions. Therefore, because of sampling error, a negative biopsy does not entirely rule out the diagnosis of vasculitis. In fact, there is evidence that biopsy has a sensitivity of 53–63%in diagnosing PCNSV.^[6,22]

Biopsy of a radiographically abnormal area is preferable to random sampling of the nondominant frontal lobe or temporal tip. Miller et al.^[6] showed that 78% of the targeted biopsies were diagnostic, whereas none of the blind biopsies demonstrated vasculitis. Inclusion of leptomeninges may increase the diagnostic yield when PCNSV is suspected. Stereotactic guidance may be used for deeper lesions, but is usually unnecessary for more superficial lesions.

Histopathological Patterns

Three main histopathological patterns are seen in PCNSV.^[6] Granulomatous vasculitis is the most common pattern of vasculitis (58% of cases). It is characterized by vasculocentric mononuclear inflammation associated with well formed granulomas and multinucleated cells (Fig. 2a). β-4 amyloid deposition is present in almost 50% of these patients (Fig. 2b). Amyloid angiopathy is only associated with granulomatous vasculitis. The inflammatory response to vascular amyloid observed in a transgenic mouse model that develops prominent cerebral amyloid angiopathy (CAA) supports a role for amyloid deposition in triggering vascular inflammation.^[32]

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Figure 2.

Histopathologic patterns of primary central nervous system vasculitis. (a) Granulomatous pattern. Transmural inflammation involving an artery of the leptomeninges with prominent mononuclear and granulomatous (arrow) adventitial inflammation; focal fibrin thrombus formation is also present (arrow head; Hematoxylin and eosin X20). (b) Granulomatous pattern with β-A4 amyloid deposition. Left panel: two intraparenchimal arterioles showing transmural inflammation with vessel wall destruction (upper) and granulomas (lower; arrows; Hematoxylin and eosin, X20). Right panel: both vessels show amyloid deposition (arrows; immunoperoxidase staining for β-A4 amyloid, X20). (c) Lymphocytic pattern. Several leptomeningeal vessels show marked transmural lymphocytic inflammation, devoid of granulomas and histiocytes (Hematoxylin and eosin, X40). (d) Necrotizing pattern. Left panel: a segment of intraparenchymal muscular artery shows extensive mural necrosis with karyorrhetic debris and acute neutrophilic inflammation (arrows; Hematoxylin and eosin, X10). Right panel: the lumen is completely obliterated and clumped aggregates of fibrin are seen (Hematoxylin and eosin, X20).

Lymphocytic vasculitis is the second most predominant pattern (28% of cases). It is characterized by predominantly lymphocytic inflammation with occasional plasma cells extending through the vessel wall with features of vascular distortion and destruction (Fig. 2c).

Necrotizing vasculitis is the least frequently seen pattern (14% of cases). It is characterized by acute necrotizing vasculitis similar to polyarteritis nodosa with transmural fibrinoid necrosis (Fig. 2d). This process involves predominantly the small muscular arteries with disruption of the internal elastic lamina. Necrotizing vasculitis is significantly associated with intracranial hemorrhage.^[14] The destructive vasculitic process with fibrinoid necrosis may cause severe vessel wall weakening, thus, predisposing to blood vessels rupture and aneurysm formation. This mechanism may account for the association between necrotizing vasculitis and intracranial hemorrhage.

The three histologic patterns are associated with similar clinical manifestations, treatment response and outcomes. Furthermore, histological patterns, as observed in patients that underwent repeat biopsies, remain stable over time, suggesting that they are truly distinct patterns rather than different stages of the disease.

Special Subsets

Several subsets of PCNSV have been identified, which differ in terms of prognosis and optimal management (Table 2).

Spinal cord involvement has been documented in 5% of patients, but it is rarely the only manifestation.^[10] Most patients have concurrent or subsequent brain involvement during the disease course. The thoracic cord is predominantly affected. A careful medical evaluation must be performed to confirm the diagnosis of PCNSV and to exclude other conditions associated with acute or subacute transverse myelitis.

Angiography-negative PCNSV is characterized by normal angiograms but brain biopsies positive for vasculitis.^[9] These findings suggest that the vasculitis is limited to small vessels below the resolution of conventional angiography. Patients with angiography-negative PCNSV often present with cognitive dysfunction and have markedly elevated CSF protein, meningeal or parenchymal enhancing lesions on MRI, good response to therapy, and a favorable outcome.

A subset of patients with PCNSV demonstrate prominent leptomeningeal enhancement on MRI.^[11] These patients have typically an acute clinical onset, frequent cognitive dysfunction at presentation, and negative cerebral angiography and/or MRA. CNS biopsies show a granulomatous vascular inflammation, often associated with vascular amyloid angiopathy. Almost all patients have a good clinical response to corticosteroid therapy (alone or combined with immunosuppressive agents) with resolution of MRI enhancement and an overall favorable course.

Around a quarter of PCNSV biopsy-positive patients and half of those showing granulomatous vasculitis associate evidence of CAA.^[8] Brain biopsies show granulomatous vasculitis and vascular deposits of amyloid β peptide. Patients with PCNSV and CAA are older at presentation than those with PCNSV only, but younger than patients with CAA and no inflammation. They often present with cognitive dysfunction, whereas MRI shows enhancing meningeal lesions. These patients usually have a monophasic disease course and generally respond well to immunosuppressive treatment. The inflammatory reaction related to the presence of amyloid β-peptide varies from little or no inflammation, to perivascular infiltrates, and to frank granulomatous vasculitis. Patients with CAA-related perivascular inflammation have characteristics similar to those of patients associating CAA and granulomatous vasculitis.^[33]

Rapidly progressive PCNSV represents the worst end of the clinical spectrum of this vasculitis [12··]. These patients have a rapidly advancing course with often-fatal outcome. They are characterized by bilateral, multiple, large cerebral vessel lesions on angiograms, and multiple bilateral cerebral infarctions on MRI. The predominant histopathological pattern is of granulomatous and/or necrotizing vasculitis. These patients respond poorly to traditional immunosuppressive treatment.

Solitary tumor-like mass lesion is an underrecognized subset of PCNSV, which is found in approximately 4% of the patients.^[13] An association with CAA was observed in 29% of these patients. Excision of the lesion may be curative; however, in some patients aggressive immunosuppressive therapy has led to a favorable outcome obviating the need of surgery.

Intracranial hemorrhage is a not infrequent presentation of PCNSV, having been reported in 11–12.2% of patients.^[2,14] Intracerebral hemorrhage is the most common presentation, followed by subarachnoid hemorrhage. These patients have less frequently altered cognition, persistent neurologic deficit or stroke at presentation, as well as MRI evidence of cerebral infarctions. Necrotizing vasculitis is the predominant histopathologic pattern.

Treatment

There are no randomized clinical trials on drug therapy in PCNSV.

Treatment for PCNSV has been extrapolated from therapeutic strategies used in other vasculitides, or else derived from anecdotal reports and cohort studies. Earliest reports suggested a poor prognosis with fatal outcome in the majority of the cases, and transient or doubtful efficacy of glucocorticoids.^[19] Cupps et al.^[34] first found cyclophosphamide (CYC) in combination with corticosteroids to be effective also in PCNSV.

The most recent PCNSV cohort studies have described a more favorable course of PCNSV. In a cohort study^[1] of 101 patients, a favorable response to glucocorticoids alone or in combination with CYC was achieved in 81% of the cases. This therapy was also associated with a favorable outcome in that most patients with low disability at diagnosis continued to have low disability at follow-up, whereas most of the patients with severe disability at diagnosis had less disability at follow-up.

Glucocorticoid therapy should be initiated as soon as the diagnosis of PCNSV is established. We recommend an initial dose of prednisone (or its equivalent) of 1mg/kg/day as a single or divided dose. If patients do not respond promptly, CYC should be started. A short course of oral CYC of 3–6 months could be tried to induce remission, similarly to the regimen used in other vasculitides.^[35] Intravenous pulses of CYC are probably safer than daily oral therapy, whereas it is unclear whether the two regimes differ in terms of efficacy in PCNSV. Subsequently, patients should be switched to a lower-risk immunosuppressant such as azathioprine, methotrexate, or mycophenolate mofetil (MMF) for maintenance of remission. A treatment course of 12–18 months is adequate in the majority of cases.^[1]

Tumor necrosis factor-α blockers andMMF have successfully been used to treat patients with PCNSV resistant to glucocorticoids and immunosuppressants [36,37·].

Table 2 illustrates the treatment modalities and outcomes in different PCNSV subsets.

Serial MRI and MRA (4–6 weeks after the onset of treatment, then every 3–4months during the first year of treatment, or in case of a new neurological deficit), as well repeat careful neurological examinations are useful to monitor the disease course. In patients with stable imaging but worsening clinical symptoms, repeat CSF examination and repeat angiography may be indicated.