Nicola Rifino

BACKGROUND: Surgical revascularization is the cornerstone of treatment for moyamoya angiopathy (MMA), yet postoperative contralateral progression and the timing of surgery after acute ischemia remain controversial. While current guidelines recommend delaying bypass after a recent ischemic event, rapidly progressive symptoms may necessitate urgent intervention. OBSERVATIONS: A 26-year-old woman with unilateral MMA underwent a left superficial temporal artery–middle cerebral artery (STA-MCA) bypass for recurrent ischemic events and impaired cerebrovascular reserve. Despite initial improvement and confirmed bypass patency, she developed contralateral ischemic symptoms 3 weeks later, with new right internal carotid artery–MCA stenosis and vessel wall enhancement. CSF analysis revealed herpes simplex virus 2 positivity, and a heterozygous factor V Leiden mutation was identified. Despite antiviral and corticosteroid therapy, ischemic deficits worsened. An emergency right STA-MCA bypass was performed under dual antiplatelet therapy (DAPT), resulting in immediate symptom resolution and sustained graft patency. LESSONS: MMA may rapidly progress from unilateral to bilateral involvement. When medical therapy fails, urgent revascularization—even under DAPT—can be safe and effective. Vigilant postoperative surveillance and readiness for contralateral bypass are crucial in atypical, rapidly evolving cases. https://thejns.org/doi/10.3171/CASE25903

Introduction: Cerebrovascular diseases are a major cause of morbidity/mortality worldwide, yet more than 30% of strokes remain of undetermined origin. Rare cerebrovascular diseases (rCVDs) contribute to this burden but are often underdiagnosed due to limited awareness, clinical heterogeneity, and fragmented diagnostic access. The ALIGNED project was established to address these gaps through a nationwide multidisciplinary network. Methods: ALIGNED was aimed to improve clinical/molecular characterization of rCVDs through standardized data collection, assess level of care of rCVDs by an online/on-site survey and reduce the geographical gap across Italy, by a virtual model of rCVDs care. In the first phase we conducted a survey to evaluate the availability of diagnostic/therapeutic pathways. Preliminary molecular profiling (i.e., transcriptomic/proteomic analyses) has been carried out on middle-cerebral artery and plasma samples from Moyamoya angiopathy (MMA) patients. Results: Fourty-nine centers adhered to the project. Initially, we collected a cohort of 308 subjects with rCVDs: CADASIL (162), COL4A1/A2-related disease (9), Sneddon syndrome (25), Fabry disease (32), and MMA (80). Web-based survey and site visits provided a representative overview of national capabilities in rCVD diagnosis and care. Transcriptomic analysis showed a peculiar expression profile of angiogenesis growth factors/inhibitors in MMA cerebral vessels. Plasma proteomic profiles of MMA patients highlighted circulating proteins expressed in dysfunctional angiogenesis. Discussion: Preliminary data suggested a substantial variability in the quality of rCVDs management and in the availability of diagnostic tools across Italy. Thus, mapping Italian expertise and facilities emerged as a crucial target for pinpointing gaps, improving resource allocation, standardizing rCVD care to guarantee equitable access for patients.

Background and ObjectivesIatrogenic cerebral amyloid angiopathy (iCAA) is a rare form of CAA believed to result from β-amyloid (Aβ) transmission during neurosurgical procedures. We aimed to compare...

Background: The pathophysiological mechanisms of Moyamoya angiopathy (MA) are still largely unknown, although a dysfunctional vasculogenesis has been hypothesized to contribute to it. The association between this rare cerebrovascular condition and variants of Ring Finger Protein 213 (RNF213) strengthens the role of genetic factors in MA pathogenesis. Methods: To investigate the molecular mechanisms of MA, we carried out RNA interference (RNAi) targeting RNF213 in human endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). The combined effect of RNAi and/or hypoxia on expression of key angiogenic factors was analyzed through qRT-PCR and Western blot. Functional assays were performed to characterize the impact of RNAi on vasculogenesis. Gene-expression arrays were performed on vessel walls of MA patients and controls. Results: RNF213-RNAi impaired angiogenic capability in ECs, whereas the simultaneous silencing of RNF213 and its phosphatase PTP1B restored angiogenesis function in ECs but worsened it in VSMCs. Angiogenic factor expression appeared to be modulated in ECs by the combined effects of RNAi and/or hypoxia, and in pathological vessels of MA patients as compared with controls. Conclusions: Our findings contribute to associating the relevance of RNF213 in MA cellular models and highlight the importance of EC-VSMC crosstalk for vascular integrity. Additionally, the study could lay the foundations for improving experimental models of MA pathophysiology.

Recent randomised trials have questioned the benefit of endovascular therapy (EVT) for MeVO stroke, but data from clinical practice are limited. This study aimed to assess the effectiveness and safety of EVT, with or without intravenous thrombolysis (IVT), vs IVT alone in MeVO stroke using registry-based real-world data. This retrospective multicentre study included patients from 82 Italian centres in the Safe Implementation of Treatments in Stroke (SITS) registry (January 2020–December 2023). Adults with acute ischaemic stroke due to MeVO (ACA A1/A2, MCA M2/M3 or more distal or PCA P1/P2), treated with IVT or EVT ± IVT, and with available 90-day mRS scores were included. Patients with tandem occlusions were excluded. Propensity score matching (1:1) was used to balance baseline variables. Primary outcome was functional independence (mRS 0–2) at 90 days. Secondary outcomes included in-hospital mortality, intracranial haemorrhage incidence and recanalisation status. Among 1375 total patients, 780 were included and matched (390 per group) by propensity score. Baseline characteristics were balanced. Functional independence at 90 days was achieved in 60.6% of EVT ± IVT patients vs 60.9% in the IVT-only group (odds ratio [OR] 0.99; 95% CI, 0.73–1.34; P = .939). When restricted to patients with baseline mRS < 2, functional independence rates remained comparable between groups, confirming the primary findings. In-hospital mortality was non-significantly lower in the EVT ± IVT group (5.4% vs 8.7%, P = .069). Symptomatic intracranial haemorrhage rates were comparable between groups, although overall haemorrhagic complications were higher with EVT (18.4% vs 11.2%, P < .0001). Stratified analyses by stroke severity and treatment timing showed consistent lack of benefit across all subgroups (all interaction P-values > .05). The absence of functional benefit from EVT observed in this real-world cohort is consistent with the results of the ESCAPE-MeVO and DISTAL randomized trials. Notably, the higher rate of any intracranial haemorrhage in the EVT group (18.4% vs 11.2%), driven primarily by minor haemorrhagic events, represents a clinically meaningful safety concern that must be weighed against the lack of demonstrated efficacy. A hypothesis-generating signal was observed in patients treated within 180 minutes (OR 2.16, 95% CI 1.06–4.38), warranting prospective investigation. The retrospective design and the limitations inherent to registry-based data, including incomplete procedural data and anatomical heterogeneity in MeVO classification, should be considered when interpreting these findings. Endovascular therapy did not improve long-term functional outcomes compared to IVT alone in MeVO stroke but was associated with higher haemorrhagic risk. These findings support a cautious approach to EVT in this setting, in line with recent trial evidence.

Background: Moyamoya angiopathy (MMA) is a rare, progressive cerebrovascular disorder characterized by stenosis or occlusion of the terminal internal carotid arteries, leading to the development of fragile collateral vessels. Headache is a common but understudied symptom of MMA, reported in up to 75% of patients. The headache phenotype often mimics migraine or tension‐type headache, although cluster headache‐like episodes have also been described. Aims to summarize current evidence on the clinical characteristics, underlying mechanisms, and treatment strategies for headache in MMA. Materials and Methods: A narrative review of the literature was conducted, focusing on the prevalence, phenotype, pathophysiological mechanisms, and therapeutic options for headache in MMA. Results: The pathogenesis of headache in MMA remains unclear but is likely multifactorial, involving impaired cerebrovascular autoregulation, microvascular ischemia, and collateral vessel development. No standardized treatment exists for MMA‐related headache. Antiplatelet therapy, particularly aspirin, may offer some benefit, whereas NSAIDs and triptans require caution due to cerebrovascular risks. Emerging therapies such as calcitonin gene‐related peptide (CGRP) inhibitors and Lasmiditan show potential but lack specific data in MMA patients. Surgical revascularization, mainly through direct or combined bypass, is an established intervention for stroke prevention and may also reduce headache burden. However, postoperative outcomes are heterogeneous, with reports of both headache improvement and new‐onset headache. Discussion and Conclusion: Headache is a frequent and clinically relevant manifestation of MMA that significantly impacts quality of life. Evidence on optimal management remains scarce, and current strategies are largely empirical. Further studies are needed to clarify pathogenic mechanisms, refine patient selection for surgical interventions, and evaluate pharmacological treatments, including novel agents, to improve clinical outcomes.

Monoallelic cysteine-altering NOTCH3 (NOTCH3^cys) variants cause the adult-onset small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and biallelic NOTCH3 loss-of-function (NOTCH3^lof) variants cause a rare, childhood-onset small vessel disease. Whether monoallelic NOTCH3^lof variants also cause a small vessel disease is subject of debate. The aim of this study was to delineate the small vessel disease phenotype of individuals with a monoallelic NOTCH3^lof variant and to compare it with CADASIL. In this observational study, monoallelic NOTCH3^lof cases were ascertained in Genome Aggregation Database (gnomAD); UK Biobank; 6 clinical centers from Europe, Asia, and the United States; and literature. In gnomAD, NOTCH3^lof allele frequency was determined. In UK Biobank, normalized white matter hyperintensity volume (nWMHv), peak width of skeletonized mean diffusivity (PSMD), lacune count, and stroke were compared among NOTCH3^lof cases, NOTCH3^cys cases, and controls. In clinical NOTCH3^lof cases, white matter hyperintensities, lacune count, and stroke incidence were assessed, and skin vessel wall pathology was analyzed using immunohistochemistry and electron microscopy. In gnomAD, 306 NOTCH3^lof variants were identified (allele frequency 0.6/1,000). In UK Biobank, 102 NOTCH3^lof cases were ascertained (median age 58 years, range 40-69, 55% female). NOTCH3^lof cases had an increased nWMHv (Δ0.44 mm³, p < 0.001) and PSMD (Δ0.19 × 10^-4, p = 0.017) compared with controls. nWMHv and PSMD in NOTCH3^lof cases were comparable to NOTCH3^cys cases; however, in contrast to NOTCH3^cys cases, NOTCH3^lof cases did not have an increased stroke risk compared with controls. Clinically ascertained NOTCH3^lof cases (n = 69, median age 50 years, range 20-94, 54% female) often had white matter hyperintensities (28/32, 88%) while lacunes (12/32, 38%) and stroke (11/69, 15%) were predominantly seen in cases with cardiovascular risk factors and at advanced age. Skin vessels of NOTCH3^lof cases more frequently showed abundant vessel wall collagen deposition compared with NOTCH3^cys cases and controls (37% vs 10% [p = 0.016] and 5% [p < 0.001] of vessels). We conclude that monoallelic NOTCH3^lof variants cause a small vessel disease that (1) remains subclinical in most cases but may be exacerbated by cardiovascular risk factors and aging, and (2) is distinct from CADASIL regarding vessel pathology and disease severity. These findings will guide counseling and management of individuals in whom a NOTCH3^lof variant is found.