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.

Differentiation between neurosarcoidosis and primary central nervous system vasculitis based on demographic, cerebrospinal and imaging features.

OBJECTIVES: Neurosarcoidosis (NS) and primary angiitis of central nervous system (PACNS) are inflammatory diseases affecting central nervous system, with overlapping clinical and pathological characteristics. Distinguishing these diseases is important given distinct therapeutic implications. In this study, we aimed to compare demographic, CSF and MRI characteristics between these two conditions. METHODS: All the clinical, CSF and laboratory characteristics at the time of presentation were retrieved from electronic medical records. Brain and/or spinal cord MRI performed near the time of presentation were blindly evaluated by two neuroradiologists. Data regarding involvement of pachy- and leptomeninges, basal meninges, cranial nerves, cerebral grey and white matter, and spinal cord were recorded for each patient. RESULTS: 78 patients with PACNS and 25 patients with NS were included in the study. Mean age of patients was 43.7 (±16.7) and 43.6 (±12.5) in PACNS and NS, respectively. African-American race was found to be associated with the diagnosis of NS rather than PACNS. Patients with PACNS had higher frequency of cerebral involvement, while patients with NS demonstrated more frequent spinal cord, basal meningeal and cranial nerve involvements. CONCLUSIONS: These findings suggest that MRI can be an efficient tool in distinguishing PACNS from NS. A follow-up study with a larger sample size would be required to validate our results.

Elevated cerebrospinal fluid levels of total protein in patients with secondary central nervous system vasculitis and giant cell arteritis.

Objectives: Secondary central nervous system vasculitis (SCNSV) is an extremely rare, refractory, and fatal disease in patients with giant cell arteritis (GCA). We compared the characteristics of GCA patients with and without SCNSV.Methods: This retrospective, single-center, observational cohort study included 35 patients with GCA admitted to Juntendo University Hospital from April 2009 to March 2019. The primary outcome was all-cause mortality.Results: We diagnosed four patients with GCA and SCNSV (SCNSV group) and 31 patients with GCA but no SCNSV (non-SCNSV group). The mortality rate of the SCNSV and non-SCNSV groups was 100% and 10%, respectively (p = .001). The SCNSV group had lower serum levels of C-reactive protein at the time of GCA diagnosis and higher cerebrospinal fluid (CSF) levels of total protein (102 mg/dL vs. 38 mg/dL, p = .008) and albumin (66 mg/dL vs. 21 mg/dL, p = .008) at the time of SCNSV diagnosis.Conclusion: At the time of SCNSV diagnosis, GCA patients had elevated CSF total protein and albumin levels. CSF examination in GCA patients suspected of having SCNSV may be useful for early diagnosis of SCNSV.

The diagnosis of primary central nervous system vasculitis.

The diagnosis of primary central nervous system (CNS) vasculitis is often difficult. There are neither specific clinical features nor a classical clinical course, and no blood or imaging investigations that can confirm the diagnosis. Contrast catheter cerebral angiography is neither specific nor sensitive, yet still underpins the diagnosis in many published studies. Here we describe an approach to its diagnosis, emphasising the importance of obtaining tissue, and present for discussion a new, binary set of diagnostic criteria, dividing cases into only 'definite' primary CNS vasculitis, where tissue proof is available, and 'possible,' where it is not. We hope that these criteria will be modified and improved by discussion among experts, and that these (improved) criteria may then be adopted and used as the basis for future prospective studies of the clinical features and diagnosis of this difficult and dangerous disorder, particularly for coordinated multicentre therapeutic trials.

Concordance of angiography and cerebral biopsy results for suspected primary central nervous system vasculitis: A multi-center retrospective review.

OBJECTIVE: Primary CNS Vasculitis (PCNSV) is a rare disease that is often challenging to diagnose. Cerebral angiography and biopsy have been utilized in the diagnostic workup for several decades but limited literature reports on the concordance of findings of angiography and biopsy. The primary objective of this work was to examine how cerebral angiography corresponded with biopsy findings in patients with suspected PCNSV. PATIENTS AND METHODS: A total of 128 patients who underwent workup for PCNSV between years 2005-2016 were identified by query of existing neurological surgery and angiography databases at University Hospitals Cleveland Medical Center (UHCMC) and the Cleveland Clinic Foundation (CCF). The primary outcome was to examine the concordance of results between angiography and cerebral biopsy. Secondary outcomes included examining concordance between results of biopsy and other commonly performed tests for diagnosis of PCNSV including Magnetic Resonance Imaging (MRI), cerebrospinal fluid white blood cell count (CSF WBC), Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP). RESULTS: 128 patients underwent cerebral biopsy for diagnosis of suspected PCNSV. 93 (73%) of these patients also underwent angiography. Of the 34 patients with positive biopsy findings, only 5 also had positive angiography. Positive angiography was not found to be correlated with positive biopsy in our analysis. The only test that was significantly associated with biopsy proven vasculitis was increased CSF WBC count (P = 0.0114). CONCLUSIONS: PCNSV is a rare disease and often requires multiple tests or procedures to obtain definitive diagnosis. These results suggest that cerebral angiography findings are not associated with biopsy findings and should be used cautiously in the diagnostic work-up of PCNSV.

Exploratory proteomic analysis implicates the alternative complement cascade in primary CNS vasculitis.

OBJECTIVE: To identify molecular correlates of primary angiitis of the CNS (PACNS) through proteomic analysis of CSF from a biopsy-proven patient cohort. METHODS: Using mass spectrometry, we quantitatively compared the CSF proteome of patients with biopsy-proven PACNS (n = 8) to CSF from individuals with noninflammatory conditions (n = 11). Significantly enriched molecular pathways were identified with a gene ontology workflow, and high confidence hits within enriched pathways (fold change >1.5 and concordant Benjamini-Hochberg-adjusted p < 0.05 on DeSeq and t test) were identified as differentially regulated proteins. RESULTS: Compared to noninflammatory controls, 283 proteins were differentially expressed in the CSF of patients with PACNS, with significant enrichment of the complement cascade pathway (C4-binding protein, CD55, CD59, properdin, complement C5, complement C8, and complement C9) and neural cell adhesion molecules. A subset of clinically relevant findings were validated by Western blot and commercial ELISA. CONCLUSIONS: In this exploratory study, we found evidence of deregulation of the alternative complement cascade in CSF from biopsy-proven PACNS compared to noninflammatory controls. More specifically, several regulators of the C3 and C5 convertases and components of the terminal cascade were significantly altered. These preliminary findings shed light on a previously unappreciated similarity between PACNS and systemic vasculitides, especially anti-neutrophil cytoplasmic antibody-associated vasculitis. The therapeutic implications of this common biology and the diagnostic and therapeutic utility of individual proteomic findings warrant validation in larger cohorts.

Long-term outcomes of patients with primary angiitis of the central nervous system.

OBJECTIVES: Primary angiitis of the central nervous system (PACNS) is a vasculitis confined to the brain and spinal cord, which often presents with severe cognitive and functional deficits. Despite progress in diagnosis, little is still known about long-term outcomes. Our aim was to evaluate long-term functional capabilities, quality of life, and depression, and to determine the effect of treatment duration on patient outcomes. METHODS: We identified patients by ICD-9 codes for cerebral angiitis, and included them if they met two of the three following criteria: inflammatory cerebrospinal fluid (CSF), cerebral angiogram typical of vasculitis, or findings of vasculitis on pathologic examination of brain tissue. Disability was assessed by the Barthel Index, quality of life was assessed by EuroQol, and depression was assessed with Patient Health Questionnaire. RESULTS: Seventy-eight patients met the inclusion criteria, of which 27 responded to the questionnaire (34.6%). Mean follow-up of those who responded was 5.5 years (± 4.7). Nineteen of 27 patients (70.4%) had mild disability; meanwhile, 5 (18.5%) had severe disability. Fourteen of 27 patients (51.9%) had no mobility problem, 18 (66.7%) had no problems with self-care, 15 (55.6%) had no problems with usual activities, 14 (51.9%) had no pain, and 8 (29.6%) had no anxiety. Approximately 70% of patients had minimal or no depression. CONCLUSIONS: This is the longest reported follow-up of patients with PACNS described in the literature to date. Most patients had mild long-term disability and minimal to no depression, which may be reflective of treatment advances.

Atypical presentation of fulminant primary central nervous system angiitis.

BACKGROUND: Primary Angiitis of the Central Nervous System (PACNS) is a rare cause of CNS vasculitis that should be included as part complete differential diagnosis, especially in cases with suggestive imaging findings and an absence of secondary causes for CNS vasculitis. CASE PRESENTATION: We describe a case of a 47-year-old previously healthy Caucasian male presenting with rapid progression of encephalopathy and fevers. Extensive infectious, autoimmune, and imaging workups were unrevealing. A diagnosis of PACNS was made posthumously on histopathology. CONCLUSIONS: PACNS is a challenging diagnosis owing to frequent discrepancies between radiologic and histopathologic findings. Tissue biopsy is key to diagnosing PACNS.

A Pilot Study Evaluating Cerebral Vasculitis in Kawasaki's Disease.

Cerebral vasculitis is thought to be a possible underlying mechanism of severe neurological complications of Kawasaki's disease (KD), such as cerebral infarct or aneurysm rupture. To evaluate the intracranial inflammatory response in patients with acute-stage KD, we measured the levels of cytokines (interleukin [IL]-6 and tumor necrosis factor [TNF]-α) and pentraxin-3 (PTX3) in the cerebrospinal fluid of patients with KD (n = 7) and compared the levels to those of the age- and sex-matched febrile control patients (bacterial meningitis [n = 5], enteroviral meningitis [n = 10], nonspecific viral illness without central nervous system involvement [n = 10]). PTX3 and TNF-α were rarely detected and only in trace concentration in KD, and the levels of IL-6 were not different from those of nonspecific viral illnesses. These mediators are not established biomarkers for cerebral vasculitis but might reflect vascular inflammation in various diseases including KD. Therefore, intracranial inflammation including vasculitis seems to be insignificant in our patients with KD. However, our results might be attributed to the fact that these patients lacked any clinical signs of cerebral or coronary vessel involvement. None of them underwent brain imaging. To clarify this issue, further studies involving patients with neurologic symptoms and proven involvement of cerebral vessels are needed.

Primary central nervous system vasculitis associated with lymphoma.

OBJECTIVES: To record the clinical findings, response to therapy, and course of patients with primary CNS vasculitis (PCNSV) associated with lymphoma. PATIENTS AND METHODS: We reviewed the histories of 936 patients with a diagnosis of any type of vasculitis and lymphoma who were seen at the Mayo Clinic over a 32-year period. Ten patients with both PCNSV and lymphoma were identified. We compared the findings in these 10 patients with those from 158 patients with PCNSV without lymphoma seen over 29 years. RESULTS: Ten of a total of 168 (5.9%) patients with PCNSV also had a history of lymphoma: 6 with Hodgkin lymphoma (HL) and 4 with non-HL (NHL). A granulomatous vasculitis was found in all 8 patients with cerebral biopsies, accompanied by vascular deposits of ß-amyloid peptide in 2. In 7 patients, medical diagnostic workup for PCNSV revealed the lymphoma. Compared to the 158 patients with PCNSV without lymphoma, patients with lymphoma were more frequently male (p = 0.04), had increased gadolinium leptomeningeal enhancement (p = 0.03) at presentation, and had more neurologic disability at last follow-up (p = 0.01). No significant differences in treatment response were observed in the 2 groups (p = 0.202). Considering all 168 patients, increased disability at last follow-up was associated with increasing age at diagnosis (odds ratio [OR] 1.4), lymphoma (OR 5.9), and cerebral infarction (OR 3.2), while reduced disability was associated with gadolinium-enhanced lesions (OR 0.43) and amyloid angiopathy (OR O.23). CONCLUSIONS: Lymphoma may be diagnosed simultaneously with PCNSV, suggesting an immunologic paraneoplastic mechanism.

A Closer Look at Angiitis of the central nervous system.

Angiitis of the central nervous system (ACNS) is a rather new disease entity that is defined as vascular inflammation limited to the central nervous system and was formally nominated in 1959. Etiologically, it can be divided into primary and secondary ACNS. However, the potential pathogenesis of ACNS remains unclear. The clinical presentation is variable, and there is no consensus concerning its diagnosis and management. Although the incidence is relatively low, ACNS is still a life-threatening condition. It is essential to get a comprehensive and updated understanding of the disease. In this paper, we reviewed the history, definition, classification, pathogenesis, and clinical manifestations of ACNS. In addition, we focused on the latest investigations and viewpoints regarding the diagnosis and treatment of ACNS.

Subtypes of primary angiitis of the CNS identified by MRI patterns reflect the size of affected vessels.

OBJECTIVE: To describe patterns of diagnostic findings, and identify subgroups of primary angiitis of the central nervous system (PACNS). METHODS: We retrospectively analysed 31 patients with PACNS. Cases were selected by predetermined diagnostic criteria and stratified into biopsy-proven and imaging-based PACNS. We compared clinical characteristics, cerebrospinal fluid (CSF) findings and imaging results including high-resolution vessel wall MRI between groups. RESULTS: There were 31 cases of PACNS (mean age 45.6 years, 58.1% female), of whom 17 (55%) were biopsy-proven, 14 (45%) were based on imaging findings. Patients with a positive biopsy had fewer infarcts (29.4% vs 85.7%, p=0.003), were more likely to have meningeal and parenchymal contrast enhancement (76.5% vs 28.6%, p=0.012), were less likely to have abnormal MR angiography (11.8% vs 100%, p<0.001) and did not show vessel wall enhancement at the time of diagnosis (0% vs 76.9%, p<0.001). In contrast, patients with imaging-based diagnosis showed more frequently multiple infarcts and vessel abnormalities, with vessel wall enhancement in most of the cases. Clinical characteristics and CSF analysis did not reveal marked differences between groups. INTERPRETATION: Multi-parametric MRI distinguishes two subtypes of PACNS that most likely differ concerning the affected vessel size. Biopsy-proven PACNS primarily involves smaller vessels beyond the resolution of vascular imaging, while imaging-based PACNS affects predominantly medium-sized vessels leading to false-negative biopsy results. Using distinct MRI patterns may be helpful for selecting patients for appropriate invasive diagnostic modalities.

Ten year clinical experience with stroke and cerebral vasculitis.

Angiitis of the central nervous system (CNS) is difficult to diagnose but potentially fatal. When stroke occurs in a younger individual or is associated with multiple infarcts on imaging, clinicians must decide how far to pursue a possible diagnosis of vasculitis. The aim of this study is to establish the prevalence of primary and secondary cerebral angiitis among patients presenting with stroke. Hospital attendances over a 10year period were surveyed by searching for diagnostic codes and key words specific for cerebral vasculitis/angiitis. Case notes were reviewed by the authors using two sets of criteria for angiitis of the CNS. Thirty-two patients were initially considered likely to have cerebral angiitis by treating physicians. Thirteen had been admitted to hospital with stroke. During this period, there were 7475 admissions for ischaemic and haemorrhagic stroke. Six patients had a final diagnosis of vasculitic stroke but only one had definite CNS angiitis with a first presentation as ischaemic stroke (0.02%). Most patients who did have cerebral vasculitis developed multifocal or subacute neurological deficits, or already had an immunological disorder known to be associated with secondary CNS angiitis. Of 19 patients given an alternative final diagnosis, the most common were atherosclerotic/embolic cerebrovascular disease (n=9) and reversible cerebral vasoconstriction syndrome (n=7). Stroke is rarely the first manifestation of cerebral vasculitis. Our findings suggest that routine screening for angiitis in stroke patients may not be warranted.

[Central nervous system Vasculitis due to infectious diseases].

Varicella zoster virus may cause vasculitis or vasculopathy, and positive polymerase chain reactions for varicella zoster virus deoxyribonucleic acid in the cerebrospinal fluid and/or the intrathecal synthesis of antibodies to the varicella zoster virus suggest these diagnoses. Meningovascular syphilis may involve the middle cerebral artery and basilar artery and may cause a stroke. Aspergillus is vasoinvasive and may cause hemorrhagic infarction by forming an intravascular thrombus.

[Treatment for central nervous system vasculitis].

Central nervous system (CNS) vasculitis is classified into two categories based on whether it is primary or secondary. Primary CNS vasculitis is rare disorder of unknown cause that is restricted to the brain and spinal cord. Currently, there are no randomized clinical trials for treatment of primary CNS vasculitis. Therefore, treatment regimens for primary CNS vasculitis have been derived from therapeutic strategies used in other kinds of vasculitis. Early detection is important because corticosteroid treatment with or without cyclophosphamide can often prevent serious outcomes and may result in a favorable response. However, because some patients are intolerant or respond poorly to combination therapy, development of novel treatment options is eagerly awaited. Several immunosuppressive agents such as mycophenolate mofetil, tumor necrosis factor-α blockers, and rituximab could be options for refractory patients.

Central nervous system angiitis: a series of 31 patients.

Central nervous system (CNS) angiitis is a rare inflammatory disorder. To date, clinical data are lacking and treatment remains a matter of debate. The aim of this study is to analyse the main characteristics, response to therapy and outcome of 32 patients with CNS angiitis. Single-centre retrospective study in a tertiary centre was made. Diagnosis of CNS angiitis was made by cerebral angiography and/or magnetic resonance angiography and/or CNS biopsy. The main features and outcomes of primary and secondary CNS angiitis were compared and predictive factors of a favourable outcome were searched. Thirty-one patients (median age 45 Q1-Q3 37-54) sex ratio F/M 2.1) were included. Main clinical features were hemiparesis (35.5 %) and headache (29 %). The median CSF protein level was 0.64(0.52-0.81) g/L and was superior to 1 g/L in six cases. CNS magnetic resonance (MR) imaging findings were most frequently ischemic (96.8 %), bilateral (83.9 %), multiple (87.1 %) and supratentorial (96.8 %). The MR angiography was abnormal in all cases. Among the 31 patients in the study, 19 (61.3 %) were diagnosed with primary CNS angiitis. Systemic lupus erythematosus (n = 6) and vasculitis (n = 4) were the most frequent aetiologies of secondary CNS angiitis. No difference was evidenced between primary and secondary CNS angiitis. Steroids were administered in 79.2 % of treated patients and combined with immunosuppressants in 79.2 % of cases. Eight cases of CNS angiitis relapse were noted. CNS angiitis remains a severe illness. Treatment often associated steroids and immunosuppressants, and diagnosis delay is significantly associated with a poorer prognosis.

[Diagnosis of isolated angiitis of the central nervous system].

We have analyzed clinical presentations, neuroimaging data, blood and cerebrospinal fluid diagnostic tests in isolated angiitis of the central nervous system on the basis of data of recent publications and 22 our own cases. Due to the insufficient diagnostic value of invasive methods including biopsy of leptomeningeal and intracerebral vessels, we considered practical approaches to the diagnosis of cerebral vasculitis and ways of its optimization. We suggested the stratification of clinical, neuroimaging and laboratory criteria for the evaluation of their sensitivity and specificity and for the development of diagnostic algorithms.

[Syphilitic cerebral vasculitis: diagnostic possibilities].

We studied 1387 patients with different forms of syphilis for neurological deficiency. Thirty patients had vascular neurosyphilis. Two cases are described in detail. A 40-year-old man had recurring episodes of acute disturbance of the cerebral blood flow and progressive cognitive disorders. A 32-year-old patient presented with progressive dementia, hallucinatory symptoms and minor multifocal neurological changes. The diagnosis of neurosyphilis was verified by CSF-test results. The diagnosis of cerebral vasculitis was proved by the data of magnetic resonance imaging (MRI), magnetic resonance (MR) angiography, ophthalmological methods, and duplex scanning of brachiocephalic arteries, transcranial duplex scanning. Diagnostic criteria of syphilitic cerebral vasculitis were defined and presented.

CD4(+) T cells predominate in cerebrospinal fluid and leptomeningeal and parenchymal infiltrates in cerebral amyloid ß-related angiitis.

BACKGROUND: In amyloid (Aß)-related angiitis (ABRA)of the central nervous system (CNS), cerebral amyloid angiopathy occurs in association with primary vasculitis of small- and medium-sized leptomeningeal and cortical arteries. It has been suggested that ABRA is triggered by vascular deposition of A followed by an Aß-directed (auto)immune response. OBJECTIVE: To provide a detailed description of the cellular composition of the inflammatory infiltrates in the cerebrospinal fluid (CSF) and CNS and their response to immunotherapy in a typical case of ABRA. DESIGN: Report of a single case. SETTING: Neurologic referral center. PATIENT: 67-year-old white woman. MAIN OUTCOME MEASURES: Neurologic examination,magnetic resonance imaging, lumbar puncture, flow cytometry,leptomeningeal biopsy, and histopathologic analysis. RESULTS: In a typical case of ABRA, we demonstrate for the first time the presence of a vast majority of partially activated CD4(+) T cells in CSF and leptomeningeal and parenchymal (peri)vascular infiltrates, which were frequently found in close proximity to major histocompatibility complex (MHC) class II-expressing microglia, epithelioid macrophages, and multinucleated giant cells containing intracellular deposits of Aß. CONCLUSION: Our findings support the notion of adaptive Aß-directed autoimmunity as the underlying pathogenic mechanism in ABRA.