The European Stroke Organisation (ESO) guideline on Primary Angiitis of the Central Nervous System (PACNS), developed according to ESO standard operating procedures (SOP) and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, was elaborated to assist clinicians in the diagnostic and treatment pathway of patients with PACNS in their decision making. A working group involving vascular neurologists, neuroradiologists, rheumatologists, a neuropathologist and a methodologist identified 17 relevant clinical questions; these were addressed according to the patient/population, intervention, comparison and outcomes (PICO) framework and systematic literature reviews were performed. Notably, each PICO was addressed with respect to large vessel (LV)-PACNS and small vessel (SV)-PACNS. Data to answer many questions were scarce or lacking and the quality of evidence was very low overall, so, for some PICOs, the recommendations reflect the ongoing uncertainty. When the absence of sufficient evidence precluded recommendations, Expert Consensus Statements were formulated. In some cases, this applied to interventions in the diagnosis and treatment of PACNS which are embedded widely in clinical practice, for example patterns of cerebrospinal fluid (CSF) and Magnetic Resonance Imaging (MRI) abnormalities. CSF analysis for hyperproteinorrachia and pleocytosis does not have evidence supporting their use as diagnostic tools. The working group recommended that caution is employed in the interpretation of non-invasive vascular imaging due to lack of validation and the different sensitivities in comparison with digital subtraction angiography (DSA) and histopathological analyses. Moreover, there is not a neuroimaging pattern specific for PACNS and neurovascular issues are largely underreported in PACNS patients. The group’s recommendations on induction and maintenance of treatment and for primary or secondary prevention of vascular events also reflect uncertainty due to lack of evidence. Being uncertain the role and practical usefulness of current diagnostic criteria and being not comparable the main treatment strategies, it is suggested to have a multidisciplinary team approach in an expert center during both work up and management of patients with suspected PACNS. Highlighting the limitations of the currently accepted diagnostic criteria, we hope to facilitate the design of multicenter, prospective clinical studies and trials. A standardization of neuroimaging techniques and reporting to improve the level of evidence underpinning interventions employed in the diagnosis and management of PACNS. We anticipate that this guideline, the first comprehensive European guideline on PACNS management using GRADE methodology, will assist clinicians to choose the most effective management strategy for PACNS.

Background and Objectives Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer disease (AD) immunotherapy with anti–β-amyloid (Aβ) monoclonal antibodies. ARIA-E can also occur spontaneously in cerebral amyloid angiopathy–related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased CSF levels of anti-Aβ autoantibodies. Although the pathophysiologic mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex vivo studies suggests that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated. Methods The spatial distribution and temporal variations of microglial activation associated with levels of anti-Aβ autoantibodies at (sub)acute presentation of ARIA-E and after corticosteroid therapy were evaluated in a longitudinal case series of patients with CAA-ri, the spontaneous variant of the iatrogenic ARIA-E reported in Aβ-lowering immunotherapy with monoclonal antibodies. Multimodal and multiparametric MRI was used for CAA and ARIA-E severity quantification, according to validated scoring system; CSF testing for anti-Aβ autoantibodies and AD biomarkers; ₁₁C-PK11195 PET for activated microglia. Results At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial colocalization with ARIA-E compared with chronic age-related white matter change imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation were greater in patients having AD and severe CAA concomitant disease compared with patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at posttreatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation. Discussion Our findings extend the current notion of ARIA-E by providing the first in vivo ¹¹C-PK11195 PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease. Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.

Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined. Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis. This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.

Moyamoya angiopathy (MMA) is a peculiar cerebrovascular condition characterized by progressive steno-occlusion of the terminal part of the internal carotid arteries (ICAs) and their proximal branches, associated with the development of a network of fragile collateral vessels at the base of the brain. The diagnosis is essentially made by radiological angiographic techniques. MMA is often idiopathic (moyamoya disease-MMD); conversely, it can be associated with acquired or hereditary conditions (moyamoya Syndrome-MMS); however, the pathophysiology underlying either MMD or MMS has not been fully elucidated to date, and this poor knowledge reflects uncertainties and heterogeneity in patient management. MMD and MMS also have similar clinical expressions, including, above all, ischemic and hemorrhagic strokes, then headaches, seizures, cognitive impairment, and movement disorders. The available treatment strategies are currently shared between idiopathic MMD and MMS, including pharmacological and surgical stroke prevention treatments and symptomatic drugs. No pharmacological treatment able to reverse the progressive disappearance of the ICAs has been found to date in both idiopathic and syndromic cases. Antithrombotic agents are usually prescribed in ischemic MMA, although the coexisting hemorrhagic risk should be considered. Surgical revascularization techniques, which are currently the best available treatment in symptomatic MMA, are associated with good long-term outcomes and reduced ischemic and hemorrhagic risks. Given the lack of dedicated randomized clinical trials, current treatment is mainly based on observational studies and physicians’ and surgeons’ expertise.

A few cases of parkinsonism linked to COVID-19 infection have been reported so far, raising the possibility of a post-viral parkinsonian syndrome. The objective of this review is to summarize the clinical, biological, and neuroimaging features of published cases describing COVID-19-related parkinsonism and to discuss the possible pathophysiological mechanisms. A comprehensive literature search was performed using NCBI’s PubMed database and standardized search terms. Thirteen cases of COVID-19-related parkinsonism were included (7 males; mean age: 51 years ± 14.51, range 31–73). Patients were classified based on the possible mechanisms of post-COVID-19 parkinsonism: extensive inflammation or hypoxic brain injury within the context of encephalopathy (n = 5); unmasking of underlying still non-symptomatic Parkinson’s Disease (PD) (n = 5), and structural and functional basal ganglia damage (n = 3). The various clinical scenarios show different outcomes and responses to dopaminergic treatment. Different mechanisms may play a role, including vascular damage, neuroinflammation, SARS-CoV-2 neuroinvasive potential, and the impact of SARS-CoV-2 on α-synuclein. Our results confirm that the appearance of parkinsonism during or immediately after COVID-19 infection represents a very rare event. Future long-term observational studies are needed to evaluate the possible role of SARS-CoV-2 infection as a trigger for the development of PD in the long term.

Objective: Epidemiological data to characterize the individual risk profile of patients with spontaneous cervical artery dissection (sCeAD) are rather inconsistent.Methods and Results: In the setting of the Italian Project on Stroke in Young Adults Cervical Artery Dissection (IPSYS CeAD), we compared the characteristics of 1,468 patients with sCeAD (mean age = 47.3 ± 11.3 years, men = 56.7%) prospectively recruited at 39 Italian centers with those of 2 control groups, composed of (1) patients whose ischemic stroke was caused by mechanisms other than dissection (non‐CeAD IS) selected from the prospective IPSYS registry and Brescia Stroke Registry and (2) stroke‐free individuals selected from the staff members of participating hospitals, matched 1:1:1 by sex, age, and race. Compared to stroke‐free subjects, patients with sCeAD were more likely to be hypertensive (odds ratio [OR] = 1.65, 95% confidence interval [CI] = 1.37–1.98), to have personal history of migraine with aura (OR = 2.45, 95% CI = 1.74–3.34), without aura (OR = 2.67, 95% CI = 2.15–3.32), and family history of vascular disease in first‐degree relatives (OR = 1.69, 95% CI = 1.39–2.05), and less likely to be diabetic (OR = 0.65, 95% CI = 0.47–0.91), hypercholesterolemic (OR = 0.75, 95% CI = 0.62–0.91), and obese (OR = 0.41, 95% CI = 0.31–0.54). Migraine without aura was also associated with sCeAD (OR = 1.81, 95% CI = 1.47–2.22) in comparison with patients with non‐CeAD IS. In the subgroup of patients with migraine, patients with sCeAD had higher frequency of migraine attacks and were less likely to take anti‐migraine preventive medications, especially beta‐blockers, compared with the other groups.Interpretation: The risk of sCeAD is influenced by migraine, especially migraine without aura, more than by other factors, increases with increasing frequency of attacks, and seems to be reduced by migraine preventive medications, namely beta‐blockers. ANN NEUROL 2023;94:585–595