Primary angiitis of the CNS and ANCA-associated vasculitis: from pathology to treatment.

Vasculitis of the central nervous system can be a localized process, such as primary angiitis of the central nervous system (PACNS), or systemic vasculitis, such as ANCA-associated vasculitis (AAV). Since both conditions share neurological manifestations, the following review will discuss the neurological aspects of both. This review aims to provide a comprehensive comparison of the pathogenesis, clinical manifestation and assessment, diagnostic workup, and treatment protocol for both PACNS and AAV with central nervous system involvement. To provide a comprehensive comparison and update, a literature review was conducted using PubMed and Ovid databases (Embase and Medline). Then, the references were retrieved, screened, and selected according to the inclusion and exclusion criteria. PACNS and AAV share similarities in clinical presentation and neurological symptoms, especially in terms of headache, focal deficits, and cognitive impairment. Additionally, both conditions may exhibit similarities in laboratory and radiological findings, making brain biopsy the gold standard for differentiation between the two conditions. Moreover, the treatment protocols for PACNS and AAV are nearly identical. Comparing PACNS and AAV with CNS involvement highlights the similarities in clinical presentation, radiological findings, and treatment protocols between the two conditions. Further research should focus on establishing a practical diagnostic protocol.

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.

PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM - A DIAGNOSTIC CHALLENGE.

Primary angiitis of the central nervous system (PACNS) is a rare and severe disease confined to the central nervous system, i.e., the brain and spinal cord. The etiology, pathogenesis and immune mechanism of PACNS have not yet been completely elucidated. The diagnosis is challenging; it is based upon constellation of clinical picture, cerebrospinal fluid analysis, imaging methods or tissue biopsy as the gold standard. In differential diagnosis of PACNS, it is necessary to rule out infectious, malignant or systemic inflammatory diseases, as well as reversible cerebral vasoconstriction syndrome. Immunosuppressants are cornerstone therapy for PACNS, although evidence-based strategies for the management are lacking so far. PACNS is an entity with considerable morbidity and mortality. Awareness of this rare and heterogeneous disease is crucial for establishing early diagnosis and treatment initiation.

Diagnostic and therapeutic approach to adult central nervous system vasculitis.

The clinical manifestations of central nervous system (CNS) vasculitis are highly variable. In the absence of a positive CNS biopsy, CNS vasculitis is particularly suspected when markers of both vascular disease and inflammation are present. To facilitate the clinical and therapeutic approach to this rare condition, CNS vasculitis can be classified according to the size of the involved vessels. Vascular imaging is used to identify medium vessel disease. Small vessel disease can only be diagnosed with a CNS biopsy. Medium vessel vasculitis usually presents with focal neurological signs, while small vessel vasculitis more often leads to cognitive deficits, altered level of consciousness and seizures. Markers of CNS inflammation include cerebrospinal fluid pleocytosis or elevated protein levels, and vessel wall, parenchymal or leptomeningeal enhancement. The broad range of differential diagnoses of CNS vasculitis can be narrowed based on the disease subtype. Common mimickers of medium vessel vasculitis include intracranial atherosclerosis and reversible cerebral vasoconstriction syndrome. The diagnostic workup aims to answer two questions: is the neurological presentation secondary to a vasculitic process, and if so, is the vasculitis primary (i.e., primary angiitis of the CNS) or secondary (e.g., to a systemic vasculitis, connective tissue disorder, infection, malignancy or drug use)? In primary angiitis of the CNS, glucocorticoids and cyclophosphamide are most often used for induction therapy, but rituximab may be an alternative. Based on the available evidence, all patients should receive maintenance immunosuppression. A multidisciplinary approach is necessary to ensure an accurate and timely diagnosis and to improve outcomes for patients with this potentially devastating condition.

Outcomes among patients with primary angiitis of the CNS: A Nationwide United States analysis.

BACKGROUND: Primary angiitis of the central nervous system (PACNS) is a relapsing-remitting disease with a heterogeneous course. Case series have delineated the long-term disease course but not acute outcomes or their determinants. The national United States hospital burden of PACNS has not been quantified. METHODS: Analysis of the United States Nationwide Readmissions Database (2016-2018) to characterize the frequency of PACNS hospitalizations, demographic features, inpatient mortality, and discharge outcomes. RESULTS: During the 3-year study period, unweighted 1843 (weighted 3409) patients with PACNS were admitted to the 1078 Healthcare Cost and Utilization Project HCUP participating hospitals; with weighting, this value indicates that 1136 patients were admitted each year to US hospitals, representing yearly 0.01 cases per 100 000 national hospitalizations. The majority of patients were hospitalized in metropolitan teaching hospitals (81.6%). The median age at admission was 54.9 (IQR: 44.0-66.5) years and 59.4% were women. Neurologic manifestations included ischemic stroke in 38.2%, transient ischemic attack in 20.2%, seizure disorder in 22.8%, and intracranial hemorrhage in 13.0%. Overall, 60.0% of patients were discharged home, 35.0% discharged to a rehabilitation facility or nursing home and 5.0% died before discharge. Patient features independently associated with the discharge to another facility or death included older age (odds ratio [OR], 1.03 [95% CI, [1.03-1.04]]), male sex (OR, 1.22 [1.04-1.43]), intraparenchymal hemorrhage (OR, 1.41 [1.08-1.84]), ischemic stroke (OR, 2.79 [2.38-3.28]), and seizure disorder (OR, 1.57 [1.31-1.89]). CONCLUSION: Our study showed PACNS is still a rare inflammatory disorder of the blood vessels of the central nervous system suggesting an annual hospitalization of 5.1 cases per 1,000,000 person-years in the more diverse and contemporary US population. Overall, 4 in 10 had unfavorable discharge outcome, being unable to be discharged home, and 1 in 20 died before discharge.

[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.

[Primary central nervous system vasculitis: a differential diagnosis of longitudinally extensive spinal cord lesion].

A 63-year-old man was admitted to our hospital with a 2-month history of anxiety. He presented with cognitive impairment and muscle weakness. On MRI, T2-weighted images showed longitudinally extensive spinal cord lesion (LESCL) from C2 to T6 and gadolinium-enhanced T1-weighted images showed fan-shaped multiple linear enhancements converging to the lateral ventricles. He was diagnosed as primary central nervous system vasculitis (PCNSV) by brain biopsy. After using high dose corticosteroids, cognitive impairment and muscle weakness were dramatically improved. In patients with cognitive impairment, PCNSV should be included in the differential diagnosis of LESCL.

Retrospective Analysis of 28 Cases Confirmed for Primary Angiitis of the Central Nervous System by Biopsy.

OBJECTIVE: The present study aimed to summarize the clinical characteristics, therapeutic effects, and long-term prognosis of cases confirmed with primary angiitis of the central nervous system (PACNS) by biopsy, analyze the risk factors, and provide clinical guidance for the diagnosis and treatment of the disease. METHODS: Retrospective analysis was performed on 28 cases of PACNS confirmed by biopsy, and the age, gender, pathological results, course of the disease, imaging manifestations, treatment, and prognosis of the patients were analyzed and summarized. RESULTS: The cohort (age 16-60 years) comprised of 16 males. The average time from the visit to diagnosis was 6 months. The first symptom was chronic headache in 18 patients. The pathological results were accompanied by demyelination in 10 cases and glial hyperplasia in 6 cases. A total of 27 patients received treatments including glucocorticoid+cyclophosphamide; of these, 3 cases of craniotomy were improved. Among the 28 patients, 15 patients improved after the treatment, 12 patients had no significant improvement, and 1 patient was deceased. Patients with a long course of the disease before diagnosis, a Karnofsky performance status (KPS) score <60 at the time of diagnosis, a behavioral, cognitive abnormality before treatment, and a short-term relapse (0.3-1 month) have a poor outcome. CONCLUSIONS: PACNS patients are prone to misdiagnosis and mistreatment, with unknown etiology and poor prognosis due to delayed treatment. Therefore, early biopsy, pathological diagnosis, and timely treatment with glucocorticoid shock are recommended, and patients with obvious mass effect should be treated by surgical resection.

CNS vasculopathies: Challenging mimickers of primary angiitis of the central nervous system.

Primary angiitis of the central nervous system (CNS) is an inflammatory vasculopathy affecting the brain and spinal cord. It is a difficult diagnosis to make because of its insidious nonspecific course and its multiple mimics. This review identifies and discusses some noninfectious mimickers of primary CNS angiitis, including: reversible cerebral vasoconstriction syndrome, Sneddon's Syndrome, amyloid-beta-related angiopathy, Susac Syndrome, and neurosarcoidosis. Each condition will be reviewed in terms of epidemiology, pathology, clinical presentation, diagnostic approach, and treatment. Distinguishing these mimics from the primary angiitis of the CNS is important for proper treatment and prognosis.

IVIG in childhood primary angiitis of the central nervous system: A case report.

Aggressive immunosuppressive therapies have been proposed to treat primary angiitis of the central nervous system (PACNS). Here, we report the first successfully stabilized case of childhood, small-vessel PACNS with intravenous immunoglobulin (IVIG) therapy. A 12-year-old boy was admitted to our hospital complaining of recurrent headaches and upper-left homonymous quadrantanopia, since the age of 11 years. Brain computed tomography scans revealed fine calcification in the right temporal and occipital lobes. Brain magnetic resonance imaging scans revealed white matter lesions, with gadolinium enhancement, which waxed, waned, and migrated for 1 year, without immunomodulatory therapies. A cerebrospinal fluid study showed pleocytosis (12 cells per µl). No clinical or serological findings suggested systemic inflammation or vasculitis. Brain angiography was unremarkable. Brain biopsy revealed thickened and hyalinized small vessels, with intramural infiltration of inflammatory cells, which confirmed the diagnosis of small-vessel PACNS. Because the patient developed surgical site infection following biopsy, the administration of monthly IVIG (2 g/kg) was prescribed, instead of immunosuppressive agents. After IVIG therapy, the patient remained stable, except for a single episode of mild radiological exacerbation at 16 months, which occurred when the IVIG interval was expanded. Oral prednisone was added and gradually tapered. At 50 months, his intellectual abilities and motor functions were normal, although he showed residual upper-left homonymous quadrantanopia and post-exercise headache. A temporary headache, associated with the immunoglobulin infusion, was resolved by slowing the infusion rate. PACNS should be treated aggressively to improve prognosis. However, when immunosuppressants are contraindicated, IVIG may be an alternative therapeutic option.

[Primary central nervous system vasculitis]. / Pervichnyi vaskulit tsentral'noi nervnoi sistemy.

Primary vasculitis (angiitis) of the central nervous system (PACNS) is a rare disease targeting the vessels of the brain, spinal cord and leptomeninges without systemic involvement. The etiology is not clear enough. The authors review clinical, laboratory and radiological features of PACNS. Clinical manifestations are variable and depend on the caliber of affected vessels. The main clinical manifestations of small sized vessel vasculitis include encephalopathy (cognitive disorders, epileptic seizures), headache and transient cerebral ischemia. The main clinical presentation of vasculitis of medium/large cerebral arteries is ischemic strokes, which usually develop in different vascular territories. CSF findings in the majority of patients show modest lymphocytic pleocytosis, elevated protein level and occasionally the presence of oligoclonal bands. MRI data are not specific and include infarcts, hyperintensity (FLAIR) and sometimes tumor-like lesions. The gold standard for the verification of PACNS affected small-sized arteries is brain and leptomeningeal biopsy. Cerebral angiography allows the verification of vasculitis of medium and large cerebral arteries revealing segmental narrowings (beading). High resolution black blood MRI before and after contrast injection may visualize intracranial vessel wall contrast enhancement - the sign of inflammation in intracranial arteries. Treatment of PACNS includes corticosteroids and cyclophosphamide. In the case of patient intolerance, rituximab and blockers of tumor necrosis factor may be used.

Central nervous system vasculitis from Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorder in children: A case report.

BACKGROUND: Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders (EBV-T/NK-LPD) is a group of rare disorders resulting from EBV-infected T/NK-cells. It manifests as a broad spectrum of clinical symptoms according to immunologic status and viral load of an infected patient. Here, we report a boy who developed central nervous system (CNS) vasculitis and myelopathy as possible neurologic manifestations of EBV-T/NK-LPD. CASE REPORT: A 16-year-old boy came to our hospital with a necrotic skin lesion on his right shoulder. He suffered from local skin reactions with high fevers after mosquito bites since he was 10 years old. During the evaluation of his skin lesion, he suddenly developed left facial palsy. Brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) showed acute infarctions of the pons and middle cerebellar peduncle and irregularities of both anterior inferior cerebellar arteries. Serologic testing showed an elevation of total Ig E levels, anti-VCA IgG levels, and anti-EA IgG titers. EBV DNA copy numbers of the whole blood and cerebrospinal fluid (CSF) were elevated. Biopsy of the right shoulder skin showed extranodal NK/T-cell lymphoma. According to clinical features and laboratory findings, he was diagnosed with EBV-T/NK-LPD. He was treated with chemotherapy and hematopoietic stem cell transplantation but developed recurrent infarctions during treatment. CONCLUSION: This case showed the diagnostic challenge of neurologic manifestations of EBV-T/NK-LPD. EBV-T/NK-LPD-associated CNS vasculitis needs to be considered as a differential diagnosis of CNS vasculitis, when it is accompanied by the typical clinical spectrum of EBV-T/NK-LPD such as severe mosquito bite allergy, extranodal NK/T-cell lymphoma.

Treatment of Vasculitis of the Nervous System.

The diagnosis of primary central and peripheral nerve vasculitides should be established with certainty if suspected before commencing potent immunosuppressive therapy. The aim of induction therapy is to rapidly control the underlying inflammatory response and stabilize the blood-brain and blood-nerve barriers, followed by maintenance immunosuppression tailored to the likeliest humoral and cell-mediated autoimmune inflammatory vasculitic processes.

High-resolution Intracranial Vessel Wall Imaging in Monitoring Treatment Response in Primary CNS Angiitis.

INTRODUCTION: High-resolution vessel wall imaging (HR-VWI) is emerging as a tool of notable utility in the diagnosis of intracranial vessel pathology. Its role in monitoring vessel wall disease response to treatment, however, is less well-established. CASE REPORT: We report the case of a 45-year-old man with left middle and anterior cerebral artery infarcts and an National Institute of Health Stroke Scale (NIHSS) score of 2. Time-of-flight magnetic resonance angiography and digital subtraction angiography showed multifocal intracranial vessel pathology without extracranial vessel involvement. Comprehensive investigation with echocardiography and 24 hours Holter electrocardiography was unrevealing and the coagulation and routine autoimmune panel results were within normal limits. Cerebrospinal fluid showed mildly elevated protein and a diagnosis of probable primary central nervous system (PCNS) angiitis was made. The diagnosis was corroborated by intracranial HR-VWI, which showed homogenous, concentric enhancement of the left supraclinoid internal carotid artery (ICA) wall. The patient received high-dose IV methylprednisolone and cyclophosphamide. Repeat brain magnetic resonance imaging with HR-VWI at 3 and 9 months showed reduction and final resolution of vessel wall enhancement without recurrent infarcts. He has since remained clinically stable with an NIHSS score of 0 on low-dose oral glucocorticoids. CONCLUSIONS: Our report illustrates the utility of HR-VWI in diagnosing a case of PCNS angiitis through the demonstration of a vasculitic pattern of mural enhancement. Furthermore, it has provided evidence of disease response to treatment, assisting us in modifying treatment accordingly. Tracking disease activity and response to treatment in cases of central nervous system vasculitis can be another important use of HR-VWI in clinical practice besides assisting in establishing the diagnosis.

Clinical and imaging features distinguishing Susac syndrome from primary angiitis of the central nervous system.

INTRODUCTION: To assess clinical and/or imaging features useful to distinguish between Susac syndrome (SuS) and primary angiitis of central nervous system (PACNS). METHODS: Multicenter retrospective analysis of two cohorts of Argentine patients diagnosed with SuS and PACNS. RESULTS: 13 patients diagnosed with SuS (6 women and 7 men, mean age 35 ±â€¯10 years) and 15 with PACNS (10 women and 5 men, mean age 44 ±â€¯18 years) were analyzed. Cognitive impairment (11 out of 13 patients vs. 5 out of 15, p = .006), ataxia (7 out of 13 vs. 2 out of 15, p = .042) and auditory disturbances (7 out of 13 vs. 0 out of 15, p = .003) were more frequent in SuS patients; whereas seizures were more frequent in PACNS patients (8 out of 15 vs. 1 out of 13, p = .035). On MRI, corpus callosum (CC) involvement was observed more often in SuS, with abnormalities in CC genu, in 13 out of 13 SuS patients vs. only 2 out of 15 PACNS patients (p < .001); in CC body these were present in 13 out of 13 SuS patients vs. 1 out of 15 PACNS patients, (p < .001); and in CC splenium in 12 out of 13 Sus patients vs. 1 of 15 PACNS, p < .001). Cortical lesions were more frequent in PACNS patients (10 out of 15 vs. 3 out of 13 SuS patients, p = .02), as were hemorrhages (5 out of 15 vs. 0 out of 13 SuS, p = .04) and multiple basal ganglia infarcts (7 out of 15 vs. 1 out of 13 Sus, p = .037). CONCLUSION: Specific clinical and/or MRI findings may help distinguish SuS from PACNS with potential therapeutic implications.

Cerebral vasculitis and lateral rectus palsy - two rare central nervous system complications of dengue fever: two case reports and review of the literature.

BACKGROUND: Dengue fever is a common mosquito-borne viral illness with a clinical spectrum ranging from a simple febrile illness to potentially life-threatening complications such as dengue hemorrhagic fever and dengue shock syndrome. Dengue infection can affect many organs, including the central nervous system. The neurological manifestations reported in dengue infections are meningitis, encephalitis, stroke, acute disseminated encephalomyelitis, and Guillain-Barré syndrome. CASE PRESENTATION: We report the cases of two interesting patients with confirmed dengue infection who presented with complications of possible central nervous system vasculitis and cranial nerve palsy. The first patient was a 53-year-old previously healthy Singhalese woman who developed acute-onset slurring of speech and ataxia with altered sensorium 1 day after recovery from a critical period of dengue hemorrhagic fever. Subsequent investigations revealed evidence of encephalopathy with brainstem ischemic infarctions. Her clinical picture was compatible with central nervous system vasculitis. She was treated successfully with intravenous steroids and had a full functional recovery. The second patient was a middle-aged Singhalese woman who had otherwise uncomplicated dengue infection. She developed binocular diplopia on day 4 of fever. An ocular examination revealed a convergent squint in the left eye with lateral rectus palsy but no other neurological manifestation. CONCLUSIONS: Central nervous system vasculitis due to dengue infection is a very rare phenomenon, and to the best of our knowledge, only one case of central nervous system vasculitis has been reported to date, in a patient of pediatric age. Cranial nerve palsy related to dengue infection is also rare, and only a few cases of isolated abducens nerve palsy have been reported to date. The two cases described in this report illustrate the rare but important central nervous system manifestations of dengue fever and support the fact that the central nervous system is one of the important systems that can be affected in patients with dengue infection.

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.