Primary angiitis of the central nervous system.

Primary angiitis of the central nervous system (CNS) is an uncommon inflammatory disorder, with highly variable clinical presentation. It needs to be differentiated from several mimickers, such as CNS involvement in systemic vasculitides, connective tissue disorders, infectious disease, and leukodystrophy as well as neoplastic diseases. The diagnosis requires a combination of clinical and laboratory investigations, multimodal imaging, and histopathological examination, which should be available for confirmation. In the present paper, the histopathological features of primary angiitis of the CNS are described and highlighted to help pathologists avoid misdiagnosis of a treatable acquired disease.

Headaches and Vasculitis.

Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability making this a disorder of paramount importance to all clinicians. Headache may be an important clue to vasculitic involvement of central nervous system (CNS) vessels. CNS vasculitis may be primary, in which only intracranial vessels are involved in the inflammatory process, or secondary to another known disorder with overlapping systemic involvement. Primary neurologic vasculitides can be diagnosed with assurance after intensive evaluation that incudes tissue confirmation whenever possible.

The role of susceptibility-weighted imaging & contrast-enhanced MRI in the diagnosis of primary CNS vasculitis: a large case series.

Primary CNS Vasculitis (PCNSV) is a rare, diverse, and polymorphic CNS blood vessel inflammatory condition. Due to its rarity, clinical variability, heterogeneous imaging results, and lack of definitive laboratory markers, PCNSV diagnosis is challenging. This retrospective cohort analysis identified patients with histological diagnosis of PCNSV. Demographic data, clinical presentation, neuroimaging studies, and histopathologic findings were recorded. We enrolled 56 patients with a positive biopsy of CNS vasculitis. Most patients had cerebral hemisphere or brainstem symptoms. Most brain MRI lesions were bilateral, diffuse discrete to confluent white matter lesions. Frontal lobe lesions predominated, followed by inferior cerebellar lesions. Susceptibility-weighted imaging (SWI) hemorrhages in 96.4% (54/56) of patients, either solitary microhemorrhages or a combination of micro and macrohemorrhages. Contrast-enhanced T1-WIs revealed parenchymal enhancement in 96.3% (52/54 patients). The most prevalent pattern of enhancement observed was dot-linear (87%), followed by nodular (61.1%), perivascular (25.9%), and patchy (16.7%). Venulitis was found in 19 of 20 individuals in cerebral DSA. Hemorrhages in SWI and dot-linear enhancement pattern should be incorporated as MINOR diagnostic criteria to diagnose PCNSV accurately within an appropriate clinical context. Microhemorrhages in SWI and venulitis in DSA, should be regarded as a potential marker for PCNSV.

Primary central nervous system vasculitis and headache: Ten themes.

PURPOSE OF REVIEW: The primary central nervous system (CNS) vasculitides refers to clinicopathologic disorders that share the histopathology of inflammation of cerebral or spinal blood vessels. Unrecognized and therefore untreated, vasculitis of the CNS results in irreversible injury and disability making these disorders of paramount importance to clinicians. RECENT FINDINGS: Headache is an important clue to vasculitic involvement of CNS vessels. CNS vasculitis can be primary, in which only intracranial or spinal vessels are involved in the inflammatory process, or secondary to another known disorder with overlapping systemic involvement. The suspicion of vasculitis based on the history, clinical examination, and laboratory studies warrants prompt evaluation and treatment to prevent cerebral ischemia or infarction. SUMMARY: Primary CNS vasculitides can be diagnosed with certainty after intensive evaluation that includes tissue confirmation whenever possible. As in its systemic counterparts, clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, tempered by anticipated medication adverse effects.

Unilateral Relapsing Primary CNS Vasculitis: Description of 3 Cases From a Single-Institutional Cohort of 216 Cases.

OBJECTIVES: To define the frequency and characteristics of patients with unilateral relapsing involvement in a cohort of patients with adult primary CNS vasculitis (PCNSV). METHODS: We retrospectively studied a cohort of 216 patients with PCNSV seen at the Mayo Clinic, Rochester, MN from 1983 to 2022. Twenty-five patients (19.8%) had at least 2 flares. Three of them (1.4%) had unilateral relapsing vasculitis. We described these 3 patients and compared them with the entire cohort of 216 patients. RESULTS: All 3 patients had angiography-negative and biopsy-positive PCNSV with granulomatous-necrotizing and lymphocytic vasculitides and amyloid beta-related angiitis. The main manifestation at diagnosis and during flares was seizures. Unilateral lesions with gadolinium enhancement were the main MRI finding. Spinal fluid examination at diagnosis was normal in 2 patients. All had multiple flares (from 4 to 10) and were treated with long-term high-dose prednisone and numerous traditional immunodepressive drugs, and one received rituximab for steroid resistance. All 3 patients had slight disability with mild cognitive impairment at last follow-up. DISCUSSION: Unilateral relapsing involvement represents a rare subset of PCNSV with peculiar characteristics and can be observed in all neuropathologic patterns.

Intracranial vessel wall magnetic resonance imaging features of infectious vasculitis.

Vasculitis is a complication of several infectious diseases affecting the central nervous system, which may result in ischemic and/or hemorrhagic stroke, transient ischemic attack, and aneurysm formation. The infectious agent may directly infect the endothelium, causing vasculitis, or indirectly affect the vessel wall through an immunological mechanism. The clinical manifestations of these complications usually overlap with those of non-infectious vascular diseases, making diagnosis challenging. Intracranial vessel wall magnetic resonance imaging (VWI) enables the evaluation of the vessel wall and the diseases that affect it, providing diagnostic data beyond luminal changes and enabling the identification of inflammatory changes in cerebral vasculitis. This technique demonstrates concentric vessel wall thickening and gadolinium enhancement, associated or not with adjacent brain parenchymal enhancement, in patients with vasculitis of any origin. It permits the detection of early alterations, even before a stenosis occurs. In this article, we review the intracranial vessel wall imaging features of infectious vasculitis of bacterial, viral, and fungal etiologies.

A 53-year-old woman with a rapidly progressive, non-enhancing left frontotemporal lesion.

Fifty-three-year-old woman presented with chronic, episodic headache.

Predictors of improvement for patients with CNS vasculitis stenoses: A high-resolution vessel wall MRI follow-up study.

PURPOSE: To investigate the predictors of the improvement for patients with isolated intracranial vasculitis stenoses using high-resolution vessel wall magnetic resonance imaging (HR VW-MRI). METHODS: We retrospectively reviewed data from consecutive patients with confirmed intracranial vasculitis under the same conventional conservative treatment based on a prospectively established HR VW-MRI database between December 2016 and December 2020. According to the changes between the degree of stenosis at baseline compared to follow-up MR angiography, the patients were divided into an improvement group and a non-improvement group. A multivariate analysis was performed to identify the predictive factors associated with the improvement of stenoses secondary to intracranial vasculitis. RESULTS: Overall, 41 patients (mean age 32.0 ± 10.1 years, 16 females) with isolated intracranial vasculitis stenoses were included (41.5 % [17/41] in the improvement group, and 58.5 % [24/41] were in the non-improvement group). The degree of wall enhancement on follow-up imaging was significantly reduced compared with that on the baseline imaging in the improvement group (P = 0.004). The multivariate analysis showed that the degree of enhancement (OR, 0.219, 95 % CI, 0.054 to 0.881; P = 0.033) at baseline was an independent predictive factor associated with the improvement in the intracranial vasculitis stenoses. CONCLUSIONS: In patients with isolated intracranial vasculitis stenoses, the less enhancement the vessel wall was, the more likely the degree of stenosis would be reduced by conventional conservative therapy.

Childhood Small-Vessel Primary Angiitis of the Central Nervous System: Overlap With MOG-Associated Disease.

BACKGROUND: Childhood (c) primary angiitis of the central nervous system (PACNS) is a rare condition that most often affects small vessels (SV), is nearly exclusively lymphocytic, and devoid of vessel necrosis. Diagnosis of cSV-PACNS is challenging. We noted possible histological overlap of cSV-PACNS with myelin oligodendrocyte glycoprotein disease (MOGAD) on biopsy, prompting a 10-year retrospective review of our experience. MATERIALS AND METHODS: Database-search for brain biopsy cases, age <18 years, performed for an acquired neurological deficit with suspicion of vasculitis, with histological evidence of lymphocytic small-vessel inflammation. RESULTS: We identified 7 patients; 2/7 were serum-positive for anti-MOG antibodies and 1/7 for anti-NMDA antibodies. The remaining 4/7 proved to be idiopathic lymphocytic vasculitis/cSV-PACNS. All 7 showed overlapping features of lymphocytes permeating parenchymal SV walls, vessel wall distortion without fibrinoid necrosis, and absence of microglial clusters or intravascular thrombi. Tissue infarction was confined to a single case of idiopathic lymphocytic vasculitis. Although demyelination was diligently sought, only subtle demyelination was identified in the 2 MOGAD cases and absent in the remainder. CONCLUSION: There is considerable histological overlap between cSV-PACNS and at least some cases of MOGAD or anti-NMDA-encephalitis; at diagnosis, the differential should include cSV-PACNS but correct classification requires post-biopsy serological testing.

[Primary CNS Vasculitis - An Overview]. / Primäre ZNS-Vaskulitis.

Primary CNS Vasculitis - An Overview Abstract. Cerebral vasculitis, especially the primary vasculitis of the central nervous systems (primary CNS vasculitis), are rare inflammatory diseases of the small- and medium-sized vessels of the CNS. The pathogenesis of primary CNS vasculitis is unclear. Infectious triggers are hypothesized to induce an activation of the immune system with resulting inflammation of the blood vessels within the CNS. Clinically, primary CNS vasculitis presents heterogeneously with leading symptoms such as headache, memory impairment and other neurological deficits. A broad diagnostic work-up prior to treatment initiation is crucial. Treatment consists of immunotherapy (pulse and maintenance therapy) and requires long-term neurological treatment and follow-up due to the increased risk of recurrence of the disease.

Focal status epilepticus may trigger relapse of primary angiitis of the CNS.

The role of neuroinflammation in epileptogenesis is extensively investigated, but short-term effects of seizures on established CNS pathologies are less studied and less predictable. We describe the case of a woman with previous recurrent episodes of focal cerebral haemorrhage of unknown cause who developed a pseudo-tumoural oedema triggered by provoked focal status epilepticus. A brain biopsy revealed that the underlying condition was primary angiitis of the CNS. Ictal-induced blood-brain barrier dysfunction allows the entry of water and inflammatory molecules that, in the context of CNS inflammatory diseases, may trigger a self-reinforcing process. Caution should be observed when tapering antiepileptic drugs in patients with such conditions.

Primary Angiitis of the CNS: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: To facilitate and improve the diagnostic and therapeutic process by systematically reviewing studies on patients with primary angiitis of the CNS (PACNS). METHODS: We searched PubMed, looking at the period between 1988 and February 2020. Studies with adult patients with PACNS were included. We extracted and pooled proportions using fixed-effects models. Main outcomes were proportions of patients with certain clinical, imaging, and laboratory characteristics and neurologic outcomes. RESULTS: We identified 46 cohort studies including a total of 911 patients (41% biopsy confirmed, 43% angiogram confirmed, and 16% without clear assignment to the diagnostic procedure). The most frequent onset symptoms were focal neurologic signs (63%), headache (51%), and cognitive impairment (41%). Biopsy- compared with angiogram-confirmed cases had higher occurrences of cognitive impairment (55% vs 39%) and seizures (36% vs 16%), whereas focal neurologic signs occurred less often (56% vs 95%). CSF abnormalities were present in 75% vs 65% and MRI abnormalities in 97% vs 98% of patients. Digital subtraction angiography was positive in 33% of biopsy confirmed, and biopsy was positive in 8% of angiogram-confirmed cases. In 2 large cohorts, mortality was 23% and 8%, and the relapse rate was 30% and 34%, during a median follow-up of 19 and 57 months, respectively. There are no randomized trials on the treatment of PACNS. The initial treatment usually includes glucocorticoids and cyclophosphamide. DISCUSSION: PACNS is associated with disabling symptoms, frequent relapses, and significant mortality. Differences in symptoms and neuroimaging results and low overlap between biopsy and angiogram suggest that biopsy- and angiogram-confirmed cases represent different histopathologic types of PACNS. The optimal treatment is unknown.

COVID-19 leukoencephalopathy with subacute magnetic resonance imaging findings of vasculitis and demyelination.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) commonly results in a respiratory illness in symptomatic patients; however, those critically ill can develop a leukoencephalopathy. We describe two patients who had novel subacute MRI findings in the context of coronavirus disease 2019 (COVID-19) leukoencephalopathy, which we hypothesize could implicate a potent small-vessel vasculitis, ischemic demyelination and the presence of prolonged ischemia. Recent evidence of the direct neuroinvasiness of SARS-CoV-2 leading to ischemia and vascular damage supports this hypothesis.

Moyamoya syndrome in a child with Legius syndrome: Introducing a cerebral vasculopathy to the SPRED1 phenotype?

Legius syndrome is a disorder of the RAS and mitogen-activated protein kinase (MAPK) pathway first described in 2007 by Eric Legius, et al., that has been considered a milder phenotype than reported in the RASopathy neurofibromatosis type 1 (NF1). However, with approximately 200 cases reported in the literature, the Legius syndrome phenotype remains to be fully characterized. We report a child who presented with moyamoya syndrome and who has Legius syndrome due to a pathogenic variant in SPRED1. Vascular complications such as moyamoya syndrome have been reported in NF1. However, this association has not been reported in Legius syndrome. This child's case may represent an expansion of the clinical phenotype of Legius syndrome, and further study is needed. We emphasize the importance of obtaining neuroimaging studies in patients with Legius syndrome who present with new neurologic deficits.

Spontaneously changing MRI findings of primary central nervous system vasculitis: A case report.

Spontaneously disappearing lesions on magnetic resonance imaging (MRI) has been described in primary central nervous system lymphoma. In this case, we report our experience of spontaneously changing MRI findings of primary central nervous system vasculitis (PCNSV) confirmed histopathologically. A 69-year-old man presented with sudden unsteady gait. Fluid-attenuated inversion recovery (FLAIR) images showed high-intensity areas in the right deep white matter. Contrast-enhanced T1-weighted MRI demonstrated a nodular lesion in the white matter of the left occipitoparietal lobe. On repeat MRI 7 days later, FLAIR hyperintense lesions had spontaneously disappeared and contrast-enhanced lesions had progressed, with new contrast lesions in the right corpus callosum. Repeat MRI 14 days after admission demonstrated contrast-enhancing lesions either increased or decreased in intensity in both occipitoparietal lobes. Contrast-enhancing lesions were therefore biopsied. Histopathological examination revealed vasculitis with fibrinoid necrosis. PCNSV was diagnosed without any signs of inflammation in blood vessels other than cerebral blood vessels. Spontaneously changing MRI findings may play an important role in diagnosing PCNSV.

Intracerebral endotheliitis and microbleeds are neuropathological features of COVID-19.

Coronavirus disease 19 (COVID-19) is a rapidly evolving pandemic caused by the coronavirus Sars-CoV-2. Clinically manifest central nervous system symptoms have been described in COVID-19 patients and could be the consequence of commonly associated vascular pathology, but the detailed neuropathological sequelae remain largely unknown. A total of six cases, all positive for Sars-CoV-2, showed evidence of cerebral petechial hemorrhages and microthrombi at autopsy. Two out of six patients showed an elevated risk for disseminated intravascular coagulopathy according to current criteria and were excluded from further analysis. In the remaining four patients, the hemorrhages were most prominent at the grey and white matter junction of the neocortex, but were also found in the brainstem, deep grey matter structures and cerebellum. Two patients showed vascular intramural inflammatory infiltrates, consistent with Sars-CoV-2-associated endotheliitis, which was associated by elevated levels of the Sars-CoV-2 receptor ACE2 in the brain vasculature. Distribution and morphology of patchy brain microbleeds was clearly distinct from hypertension-related hemorrhage, critical illness-associated microbleeds and cerebral amyloid angiopathy, which was ruled out by immunohistochemistry. Cerebral microhemorrhages in COVID-19 patients could be a consequence of Sars- CoV-2-induced endotheliitis and more general vasculopathic changes and may correlate with an increased risk of vascular encephalopathy.