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.

[Central nervous system vasculitis according to the 2012 revise international Chapel Hill consensus conference nomenclature of vasculitides].

Vasculitis can be primarily or secondarily to various underlying diseases. It frequently affects the nervous system, and neurological deficits may remain even after disease remission. Because the progression of vasculitides is usually acute to subacute, early initiation of treatment is important from the viewpoint of patients' functional status. However, early diagnosis may be difficult, particularly in patients with central nervous system vasculitis. Hence, it is important to understand the wide-ranging clinical manifestations of vasculitides. Here, we summarize the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides from the standpoint of central nervous system vasculitis.

Primary angiitis of the central nervous system in adults and children.

Primary angiitis of the central nervous system (PACNS) is a rare disease, although it is increasingly recognized both in adults and children. Little is known about pathogenesis, but efforts at classification into subtypes are being made, and the distinction of PACNS from reversible cerebral vasoconstriction syndrome has been a major advance. The prognosis for improvement, or at least stabilization, of neurologic function is good with prompt and aggressive treatment, but the diagnosis continues to be challenging. Refinement of treatment strategies is needed. Multicenter collaboration may be crucial to make additional progress via randomized trials.

Diagnosis and classification of central nervous system vasculitis.

Central nervous system vasculitis is one of the foremost diagnostic challenges in rheumatology. It results in inflammation and destruction of the vasculature within the CNS. When vasculitis is confined to brain, meninges or spinal cord, it is referred to as primary angiitis of the CNS. Secondary CNS vasculitis occurs in the setting of a systemic vasculitis, auto-inflammatory or infectious disease. Prompt and accurate diagnosis of CNS vasculitis is essential to prevent irreversible brain damage, and to secure precise treatment decisions. Progressive debilitating and unexplained neurological deficits, associated with abnormal cerebrospinal fluid is the typical picture of the disease. Biopsy of the brain remains the gold standard diagnostic test. The differential diagnosis of CNS vasculitis is highly diverse with a broad array of mimics at the clinical, radiographic and angiographic levels.

Comparative proteomic analysis of neutrophils from patients with microscopic polyangiitis and granulomatosis with polyangiitis.

Both microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) belong to ANCA-associated vasculitis (AAV), in which neutrophils play a key role in their pathology. In this study, in order to discriminate between MPA and GPA, protein profiles of peripheral blood polymorphonuclear cells (PMNs) of 11 MPA patients and 9 GPA patients and 10 healthy controls (HC) were analyzed by 2D-DIGE. In all the 864 spots detected, intensity of 55 spots was significantly different (p<0.05) among the three groups by ANOVA. 31 out of the 55 spots were identified by mass spectrometry. Orthogonal partial-least-squares-discriminate analysis revealed that the abundance profile of the protein spots discriminated the AAV group from the HC group, and the MPA group from the GPA group completely. 13 protein spots were considered as biomarker candidates to distinguish between MPA and GPA. In those, spots whose intensity was higher in MPA than in GPA included actin with various pI values, while a considerable part of spots whose intensity was higher in GPA were proteins related with the activity of neutrophils. Among the candidate proteins, ROC analysis showed that a combination of neutrophil gelatinase-associated lipocalin and a-kinase anchor protein 7 isoforms beta had a high diagnostic potential. BIOLOGICAL SIGNIFICANCE: In this study, protein profiles of polymorphonuclear cells (PMNs) of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) patients and healthy controls (HC) were investigated by 2D-DIGE, and MS analysis. As a result, we found that the protein profiles of PMNs were useful for distinguishing between patients (MPA and GPA) and HC, and between patients with MPA and patients with GPA. Especially, we found that the 13 protein spots that consisted of 10 proteins considerably contributed to the discrimination between MPA and GPA. This is the first to demonstrate that protein profiles of PMNs are different among MPA, GPA and healthy control. The 10 proteins we identified in this study would be new biomarkers for the diagnosis of the diseases, and may be reflect the pathology difference between MPA and GPA.

Neuropsychiatric systemic lupus erythematosus: lessons learned from magnetic resonance imaging.

OBJECTIVE: The clinical manifestations of nervous system involvement in systemic lupus erythematosus (neuropsychiatric SLE [NPSLE]) are highly diverse, and their etiology is incompletely understood. The aim of this study was to provide an inventory of abnormalities on conventional brain magnetic resonance imaging (MRI) in NPSLE and to interpret the findings in relation to possible underlying pathogenetic mechanisms. METHODS: MR images of the first episode of active NPSLE in 74 patients were retrospectively reviewed. All patients fulfilled the American College of Rheumatology (ACR) 1982 revised criteria for the classification of SLE and were classified according to the 1999 ACR case definitions for NPSLE syndromes. We excluded patients with a history of brain disease and patients in whom other mechanisms unrelated to SLE caused the neuropsychiatric symptoms. RESULTS: The principal findings were: 1) focal hyperintensities in white matter (WM) (49% of all patients) or both WM and gray matter (GM) (5% of all patients), suggestive of vasculopathy or vasculitis; 2) more widespread, confluent hyperintensities in the WM, suggestive of chronic hypoperfusion due to the same mechanisms; 3) diffuse cortical GM lesions (12% of all patients), compatible with an immune response to neuronal components or postseizure changes; and 4) absence of MRI abnormalities, despite signs and symptoms of active disease (42% of all patients). CONCLUSION: Several distinct brain MRI patterns were observed in patients with active NPSLE, suggestive of different pathogenetic mechanisms. To advance our understanding of the various processes leading to NPSLE, the radiographic manifestations may be a good starting point and useful for categorization of patients in further research.

Small-vessel disease relates to poor poststroke survival in a 12-year follow-up.

OBJECTIVE: We sought to compare ultra-long-term poststroke survival in small-vessel disease (SVD) vs non-SVD subtype of stroke. METHODS: We followed patients hospitalized with acute ischemic stroke (age 55-85) for 12 years. The diagnosis of SVD was based on the criteria of Trial of Org 10172 in Acute Stroke Treatment. A detailed medical history regarding the relevant risk factors was obtained. Stroke severity was assessed with the modified Rankin Scale (mRS) at 3 months. Influence of the SVD subtype of stroke was analyzed using Kaplan-Meier log-rank analysis with endpoint all-cause death, and Cox regression proportional hazards model was constructed for multivariate analysis. The association between SVD and causes of death (cardiac, brain-related, all other) was analyzed using Kaplan-Meier log-rank analysis. RESULTS: Of the 486 patients, stroke etiology was SVD in 63 patients (13.0%). Median survival was 4.3 years for SVD and 7.9 years for non-SVD (p ≤ 0.001). In the stepwise Cox regression analysis adjusted for relevant confounders, independent predictors of death were SVD (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.06-2.41), advanced age (HR 1.07, 95% CI 1.05-1.09), stroke severity (mRS 3-5 vs 1-2; HR 2.02, 95% CI 1.58-2.58), smoking (HR 1.44, 95% CI 1.10-1.88), and cardiac failure (HR 1.53, 95% CI 1.14-2.06). SVD was associated with cardiac cause of death (p = 0.021). CONCLUSIONS: In this well-characterized ischemic stroke cohort of patients aged 55-85 years with a 12-year follow-up, acute index stroke attributable to SVD was associated with poorer long-term survival and higher risk for cardiac death than other stroke subtypes.

Cerebral vasculitis: imaging signs revisited.

Inflammatory stenoses of cerebral blood vessels, although rare in general, are an important cause of cerebral ischemia in younger patients. The diagnosis is often difficult. The first step in the diagnostic process is the identification of brain lesions consistent with cerebral vasculitis. Brain lesions are frequently found in this patient group, especially if modern imaging tools such as diffusion and perfusion-weighted imaging are employed. Although no specific pattern for this entity exists, multiple infarcts of various ages in more than one vascular territory should raise this suspicion. The next step in the imaging of patients with suspected vasculitis is the demonstration of the underlying vascular pathology. MR angiography is the mainstay of investigating patients for intracranial vascular stenoses. However, at 1.5 T it is only diagnostic for stenoses of large brain arteries. Hence, conventional angiography is still required to investigate stenoses of medium and small-sized brain arteries. Recent work suggests that MRI can directly demonstrate mural thickening and contrast enhancement in basal brain arteries, rendering biopsy obsolete in this patient group. A classification for cerebral vasculitis is proposed according to the size of the affected brain vessels, analogous to the pertinent nomenclature of primary systemic vasculitis.

Nosology of primary vasculitis.

PURPOSE OF REVIEW: Recent developments in the nosology of primary systemic vasculitis are placed in the context of an historical overview. The ongoing attempts to develop criteria for classification and diagnosis are discussed. RECENT FINDINGS: Giant cell arteritis has supplanted temporal arteritis as the preferred term for chronic granulomatous arteritis in older adults. A new classification system for childhood vasculitis has been proposed by a European collaborative group. A study of idiopathic polyarteritis nodosa demonstrates greater similarity to microscopic polyangiitis in relapse rate than previously reported. Controversy has arisen over the eponym Wegener's granulomatosis because of alleged involvement of Friedrich Wegener in the Nazi regime during World War II. Diagnostic criteria for Kawasaki disease are problematic because many patients with coronary artery involvement do not fulfill current criteria at the time of presentation. Classification of antineutrophil cytoplasm autoantibody-associated small vessel vasculitis based on antineutrophil cytoplasm autoantibody specificity has been complicated by the finding that different ethnic groups may have very different clinical features relative to antigen specificity; for example, most patients with Wegener's granulomatosis in China have myeloperoxidase-antineutrophil cytoplasm autoantibodies rather than proteinase 3-antineutrophil cytoplasm autoantibodies. SUMMARY: Within the past year, new classification systems for primary vasculitis have been proposed, new classification criteria have been developed, and the appropriateness of a longstanding eponym has been challenged.

Imaging of cerebral vasculitis.

BACKGROUND: In young patients, vasculitic stenoses of cerebral blood vessels are an important cause of cerebral ischaemia. Diagnosis may prove very difficult. SUMMARY OF REVIEW: The diagnostic process is usually initiated by the detection of brain lesions consistent with cerebral vasculitis. Multiple infarcts of various ages in more than one vascular territory are thought to be suggestive of a vascular inflammatory disease. The next step in the imaging of patients with suspected vasculitis is the search for an underlying vascular stenosis. Today, magnetic resonance angiography is the principal modality for the investigation of patients thought to have intracranial stenoses. At 1.5 T, only large brain arteries can be imaged with a high diagnostic accuracy. Intraarterial DSA remains an indispensable tool for the investigation of medium and small brain artery stenoses. CONCLUSIONS: However, contrast-enhanced magnetic resonance imaging may be able to demonstrate wall thickening and contrast uptake in large cerebral arteries, obviating biopsy in patients with basal vasculitis.

Pediatric granulomatous arthritis: an international registry.

OBJECTIVE: Blau syndrome and its sporadic counterpart, early-onset sarcoidosis, share an identical phenotype featuring the classic triad of arthritis, dermatitis, and uveitis and are associated with mutations of CARD15 in 50-90% of cases. We chose the term "pediatric granulomatous arthritis" to refer to both. An international registry was established in the spring of 2005 to define the phenotype spectrum and establish the mutation frequency and variants. METHODS: Histologically confirmed granuloma and arthritis were required for inclusion. Probands and relatives were genotyped for CARD15. Deidentified clinical information was collected. RESULTS: One year after the inception of the registry, 61 individuals from 22 pedigrees had been entered. Seven pedigrees with 19 individuals (8 affected, 11 unaffected) had clinical disease that was atypical, and none of the individuals in those pedigrees showed mutations. There were 9 classic simplex pediatric granulomatous arthritis pedigrees including 19 individuals (9 affected, 10 unaffected) and 6 classic multiplex pedigrees with 22 individuals (17 affected, 5 unaffected). Cutaneous presentation was the most common. Arthritis was polyarticular in 96% of patients. Isolated eye disease was never the presenting symptom, but significant/severe visual impairment was observed in 41% of patients. Eye disease was bilateral in 21 of 22 patients and was complicated by glaucoma in 6 of 22 patients and by cataracts in 50% of patients. Skin biopsy was the best diagnostic approach (because of accuracy and low invasiveness). CONCLUSION: In this series, the first combining familial and sporadic pedigrees and, to our knowledge, the largest, we further defined the phenotype and showed that all affected classic (and no nonclassic) pedigrees carry a mutation and that there is no asymptomatic carriage. If these data are confirmed, mutation analysis rather than tissue sampling may prove to be the most efficient diagnostic procedure.

[Cerebral vasculitis]. / Zerebrale Vaskulitis.

Cerebral vasculitides are infrequent in neurological practice but important for the differential diagnosis of multifocal CNS symptoms. The clinical presentation is typically a combination of chronic headache, multiple strokes and encephalopathy. In systemic vasculitis, a combination of CNS symptoms with inflammatory signs and with peripheral nervous system symptoms (painful multiplex polyneuropathy) or other organ manifestations (skin, joints, kidney, heart, lungs, eye) are frequent. In isolated CNS angiitis, CSF examinations are of particular value. Besides MRI, angiography, CSF and serum examinations, the verification of the diagnosis by biopsy is mandatory.

Central nervous system vasculitis.

Vasculitis is an inflammation of the vessel wall. It may be either primary or secondary. Primary vasculitis includes systemic vasculitis (large, medium, and small-vessel vasculitis) and localized vasculitis (isolated angiitis of the central nervous system and non-systemic vasculitic neuropathy). Secondary vasculitis may be present in connective tissue disorders or may be caused by infections, neoplasms, and substance abuse. Patients presenting with symptoms suggestive of vasculitis require brain neuroimaging, lumbar puncture, and angiography, but only biopsy allows a definite diagnosis.