Uncommon Causes of Nontraumatic Intracerebral Hemorrhage.

Nontraumatic intracerebral hemorrhage is an important health issue. Although common causes such as hypertension and cerebral amyloid angiopathy predominantly affect the elderly, there exists a spectrum of uncommon etiologies that contribute to the overall incidence of intracerebral hemorrhage. The identification of these rare causes is essential for targeted clinical management, informed prognostication, and strategic secondary prevention where relevant. This topical review explores the uncommon intracerebral hemorrhage causes and provides practical clues for their clinical and imaging identification. By expanding the clinician's differential diagnosis, this review aims to bridge the gap between standard intracerebral hemorrhage classification systems and the nuanced reality of clinical practice.

Early remodeling and loss of light-induced dilation of retinal small arteries in CADASIL.

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1-2 µm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity.

Retinal vascular density in CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy).

Background and objective: Retinal vascular density (VD) measured using optical coherence tomography with angiography (OCTA) has been suggested as a potential marker of intracerebral vascular changes in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). We aimed to determine whether VD is related to the clinical and imaging manifestations of the disease. Methods: OCTA was performed in 104 CADASIL patients (parallel to their clinical and imaging assessment) and in 83 healthy individuals. Results: A significant reduction of VD related to age was detected in patients and controls in the superficial and deep vascular plexus of the whole foveal or parafoveal retinal area (p<0.0001). After adjustment for age, these parameters were found significantly lower in patients than in controls (p<0.03). Multivariable analysis did not show any association between retinal VD and history of stroke, modified Rankin Scale or Mini-Mental Status Examination scores. No significant association was found with MRI lesions either. Conclusion: In CADASIL, retinal VD is decreased early and progresses with ageing but does not appear related to the severity of clinical or imaging manifestations.

Neuroimaging standards for research into small vessel disease-advances since 2013.

Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2.

Segmentation of incident lacunes during the course of ischemic cerebral small vessel diseases.

Background: Lacunes represent key imaging markers of cerebral small vessel diseases (cSVDs). During their progression, incident lacunes are related to stroke manifestations and contribute to progressive cognitive and/or motor decline. Assessing new lesions has become crucial but remains time-consuming and error-prone, even for an expert. We, thus, sought to develop and validate an automatic segmentation method of incident lacunes in CADASIL caused by cysteine mutation in the EGFr domains of the NOTCH3 gene, a severe and progressive monogenic form of cSVD. Methods: Incident lacunes were identified based on difference maps of 3D T1-weighted MRIs obtained at the baseline and 2 years later. These maps were thresholded using clustering analysis and compared with results obtained by expert visual analysis, which is considered the gold standard approach. Results: The median number of lacunes at the baseline in 30 randomly selected patients was 7 (IQR = [2, 11]). The median number of incident lacunes was 2 (IQR = [0, 3]) using the automatic method (mean time-processing: 25 s/patient) and 0.5 (IQR = [0, 2]) using the standard visual approach (mean time-processing: 8 min/patient). The complementary analysis of segmentation results is enabled to quickly remove false positives detected in specific locations and to identify true incident lesions not previously detected by the standard analysis (2 min/case). A combined approach based on automatic segmentation of incident lacunes followed by quick corrections of false positives allowed to reach high individual sensitivity (median at 0.66, IQR = [0.21, 1.00]) and global specificity scores (0.80). Conclusion: The automatic segmentation of incident lacunes followed by quick corrections of false positives appears promising for properly and rapidly quantifying incident lacunes in large cohorts of cSVDs.

Early ischemic recurrence in acute spontaneous cervical artery dissection.

BACKGROUND AND PURPOSE: Early ischemic recurrence (EIR) following the diagnosis of acute spontaneous cervical artery dissection (CeAD) has been little investigated. We aimed to determine the prevalence and determinants on admission of EIR in a large single-center retrospective cohort study of patients with CeAD. METHODS: EIR was defined as any ipsilateral clinical or radiological cerebral ischemia or intracranial artery occlusion, not present on admission and occurring within 2 weeks. CeAD location, degree of stenosis, circle of Willis support, presence of intraluminal thrombus, intracranial extension, and intracranial embolism were analyzed on initial imaging by 2 independent observers. Uni- and multivariate logistic regression was used to determine their association with EIR. RESULTS: Two hundred thirty-three consecutive patients with 286 CeAD were included. EIR was observed in 21 patients (9%,95%CI=5-13%) with a median time from diagnosis of 1.5 days (range:0.1-14.0 days). No EIR was observed in CeAD without ischemic presentation or with less than 70% stenosis. In the remaining cases, poor circle of Willis (OR=8.5, CI95%=2.0-35.4, p = 0.003), CeAD extending to other intracranial arteries than just V4 (OR=6.8, CI95%=1.4-32.6, p = 0.017), cervical artery occlusion (OR=9.5, CI95%=1.2- 39.0, p = 0.031), and cervical intraluminal thrombus (OR=17.5, CI95%=3.0-101.7, p = 0.001) were independently associated with EIR. CONCLUSIONS: Our results suggests that EIR is more frequent than previously reported, and that its risk might be stratified on admission with a standard workup. In particular, the presence of a poor circle of Willis, intracranial extension (other than just V4), cervical occlusion, or cervical intraluminal thrombus are associated with high risk of EIR, for which specific management should be further evaluated.

White Matter Hyperintensities of the Corpus Callosum Are Associated With Clinical Severity in CADASIL.

BACKGROUND: In CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), clinical severity is not related to the total burden of white matter hyperintensities (WMHs), presumably because of heterogeneous underlying tissue alterations. We aimed to investigate whether WMHs in the corpus callosum (WMHCC) are due to secondary degeneration and related to clinical severity. METHODS: We evaluated data from 228 CADASIL patients included in an ongoing prospective cohort with available 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging sequences. We analyzed in a blind manner WMHCC and lacunes in presumably connected areas to determine whether WMHCC are related to secondary degeneration. We evaluated the links between WMHCC and the Mattis dementia rating scale and the modified Rankin Scale-widely used measures of global cognitive performances and disability, respectively. Linear regression models were adjusted for age, sex, level of education, brain volume, number of lacunes, and volume of WMH. RESULTS: Among 228 patients, only 105 (46%) had WMHCC while all had WMH in the rest of the white matter. In 74% of cases, WMHCC crossed a presumably connected nearby lacune, which was significantly higher than the expected value if the spatial distributions of WMHCC and nearby lacunes were unrelated (11%; P<0.001). Patients with WMHCC had worse Mattis dementia rating scale (median [P25-P75], 138 [122-142] versus 143 [140-143]; P<0.001) and worse modified Rankin Scale (2 [1-3] versus 1 [0-1]; P<0.001). In adjusted models, Mattis dementia rating scale was significantly associated with WMHCC (estimate, -6.2 [95% CI, -11.8 to -0.1]). CONCLUSIONS: In CADASIL, WMHCC are likely related to secondary degeneration and are independently related to clinical severity, in contrast to the total burden of WMH.

Stroke Risk and Antithrombotic Treatment During Follow-up of Patients With Ischemic Stroke and Cortical Superficial Siderosis.

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke (IS) or transient ischemic attack (TIA) and cortical superficial siderosis (cSS), there are few data regarding the risk of future cerebrovascular events and also about the benefits and safety of antithrombotic drugs for secondary prevention. We investigated the associations of cSS and stroke risk in patients with recent IS or TIA. METHODS: We retrospectively analyzed the Microbleeds International Collaborative Network (MICON) database. We selected patients with IS or TIA from cohorts who had MRI-assessed cSS, available data on antithrombotic treatments, recurrent cerebrovascular events (intracranial hemorrhage [ICrH], IS, or any stroke [ICrH or IS]), and mortality. We calculated incidence rates (IRs) and performed univariable and multivariable Cox regression analyses. RESULTS: Of 12,669 patients (mean age 70.4 ± 12.3 years, 57.3% men), cSS was detected in 273 (2.2%) patients. During a mean follow-up of 24 ± 17 months, IS was more frequent than ICrH in both cSS (IR 57.1 vs 14.6 per 1,000 patient-years) and non-cSS (33.7 vs 6.3 per 1,000 patient-years) groups. Compared with the non-cSS group, cSS was associated with any stroke on multivariable analysis {IR 83 vs 42 per 1,000 patient-years, adjusted hazard ratio [HR] for cSS 1.62 (95% CI: 1.14-2.28; p = 0.006)}. This association was not significant in subgroups of patients treated with antiplatelet drugs (n = 6,554) or with anticoagulants (n = 4,044). Patients with cSS who were treated with both antiplatelet drugs and anticoagulants (n = 1,569) had a higher incidence of ICrH (IR 107.5 vs 4.9 per 1,000 patient-years, adjusted HR 13.26; 95% CI: 2.90-60.63; p = 0.001) and of any stroke (IR 198.8 vs 34.7 per 1,000 patient-years, adjusted HR 5.03; 95% CI: 2.03-12.44; p < 0.001) compared with the non-cSS group. DISCUSSION: Patients with IS or TIA with cSS are at increased risk of stroke (ICrH or IS) during follow-up; the risk of IS exceeds that of ICrH for patients receiving antiplatelet or anticoagulant treatment alone, but the risk of ICrH exceeds that of IS in patients receiving both treatments. The findings suggest that either antiplatelet or anticoagulant treatment alone should not be avoided in patients with cSS, but combined antithrombotic therapy might be hazardous. Our findings need to be confirmed by randomized clinical trials.

Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors.

The recent discovery that the prevalence of cysteine mutations in the NOTCH3 gene responsible for CADASIL was more than 100 times higher in the general population than that estimated in patients highlighted that the mutation location in EGFr-like-domains of the NOTCH3 receptor could have a major effect on the phenotype of the disease. The exact impact of such mutations locations on the multiple facets of the disease has not been fully evaluated. We aimed to describe the phenotypic spectrum of a large population of CADASIL patients and to investigate how this mutation location influenced various clinical and imaging features of the disease. Both a supervised and a non-supervised approach were used for analysis. The results confirmed that the mutation location is strongly related to clinical severity and showed that this effect is mainly driven by a different development of the most damaging ischemic tissue lesions at cerebral level. These effects were detected in addition to those of aging, male sex, hypertension and hypercholesterolemia. The exact mechanisms relating the location of mutations along the NOTCH3 receptor, the amount or properties of the resulting NOTCH3 products accumulating in the vessel wall, and their final consequences at cerebral level remain to be determined.

Elderly CADASIL patients with intact neurological status.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most devastating cerebral small vessel diseases. However, despite its progression with aging, some patients remain neurologically intact (Nint) even when they get older. Their main characteristics are poorly known. We aimed to delineate their clinical, imaging, and molecular features. METHODS: Individuals aged over 65 years were selected from a cohort of 472 CADASIL patients. Subjects who had no focal deficit, cognitive impairment, or disability were considered Nint. Their demographic, genetic, clinical, and imaging features were compared to those with permanent neurological symptoms (Nps). RESULTS: Among 129 patients, 23 (17.8%) individuals were considered Nint. The frequency of vascular risk factors and NOTCH3 cysteine mutations in epidermal growth factor-like repeat (EGFr) domains 7-34 did not differ between Nint and Nps patients but Nint patients had less stroke events and were more likely to have migraine with aura. The number of lacunes and microbleeds and degree of brain atrophy were lower in the Nint group, but the volume of white matter hyperintensities did not differ between the two groups. CONCLUSIONS: Nearly one in five CADASIL patients can remain Nint after the age of 65 years. Their clinical and imaging profile differed from that of other age-matched CADASIL patients. The location of NOTCH3 mutation inside or outside EGFr domains 1-6 cannot fully explain this discrepancy. The factors involved in their relative preservation of brain tissue from severe damage despite aging remain to be determined.

Trajectory Pattern of Cognitive Decline in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

BACKGROUND AND OBJECTIVE: The course and pattern of cognitive decline in ischemic cerebral small vessel disease (cSVD) remains poorly characterized. We analysed the trajectory pattern of cognitive decline from age 25 to 75 years in CADASIL. METHODS: We applied latent process mixed models to data obtained from CADASIL patients who were repeatedly scored during follow-up using 16 selected clinical scales or cognitive tests. RESULTS: The modelled evolutions of these scores obtained from 1243 observations in 265 patients recruited at the French National Referral Centre (50.1 years on average and 45.3% males) showed wide and heterogeneous variations in amplitude along the age-related progression of the disease. While the Backward Digit Span remained essentially stable, a linear deterioration of scores obtained using the Symbol Digit Numbers or Number of Errors of Trail Making Test B was detected from 25 to 75 years. In contrast, the largest score changes were observed at midlife using the Digit Cancellation Task. All other tests related to executive functions, memory performances, or global cognitive efficiency showed a rate of change accelerating especially at the advanced stage of the disease. Male gender, the presence of gait disorders or of some disability at baseline were found to predict earlier or large changes of 4 scores (Index of Sensitivity to Cueing, Delayed Total Recall, Initiation/Perseveration and Barthel Index) in a subgroup of individuals distinct form the rest of the sample. DISCUSSION: Cognitive alterations develop heterogeneously during the progression of CADASIL and vary largely according to the stage of the disease. These results suggest that not only the target population, study duration but also the stage of disease progression should be considered in preparing future clinical trials aimed at reducing cognitive decline in any such condition.

Susac syndrome: A scoping review.

Susac syndrome is a rare disease characterized by an inflammatory microangiopathy limited to the brain, eye, and ear vessels. It mainly affects young women. Although the pathophysiology is not fully elucidated, recent advances favour a primitive vasculitis affecting the cerebral, retinal and cochlear small vessels. Diagnosis relies on the recognition of the triad including: 1/subacute encephalopathy with unusual headache and pseudo-psychiatric features associated with multifocal ischemic white matter, grey matter nuclei and specifically corpus callosum lesions along with leptomeningeal enhancement on brain MRI, 2/ophthalmological involvement that may be pauci-symptomatic, with bilateral occlusions of the branches of the central artery of the retina at fundoscopy and arterial wall hyperfluorescence on fluorescein angiography, 3/cochleo-vestibular damage with neurosensorial hearing loss predominating on low frequencies. The full triad may not be present at diagnosis but should be sought repeatedly. Relapses are frequent during an active period lasting approximately 2 years. Eventually, the disease resolves but isolated retinal arterial wall hyperfluorescence without new occlusions may recur, which should not result in treatment intensification. First-line treatment mostly consists of high dose corticosteroids. In refractory patients or in case of relapse, immunomodulatory molecules such as intravenous immunoglobulins or immunosuppressive drugs such as mycophenolate mofetil, cyclophosphamide or rituximab should be started. Sequelae -mostly hearing loss and cognitive impairment- are usually mild but remain frequent in these young patients.

Cerebral Small-Vessel Diseases: A Look Back from 1991 to Today.

BACKGROUND: Cerebral small-vessel diseases (cSVDs) encompass a number of causes involving, but not limited to, alterations in the intracranial microvasculature, leading to the accumulation of brain tissue damage and the development of various degrees of cognitive impairment, behavioral alterations, gait instability, and localization signs, often associated with the occurrence of ischemic or hemorrhagic strokes. SUMMARY: In 2021, although key questions remain unanswered, there is general agreement on the construct, its main pathophysiological bases, and the terms used to describe its main clinical and radiological features. However, this has not always been the case, and the 30th anniversary of Cerebrovascular Diseases is an opportunity to look back from 1991 to the present to understand how a number of features, sometimes considered independent, have been progressively brought together by successive scientific breakthroughs, gradually leading to the definition of the now widely accepted concept of cSVDs. KEY MESSAGES: In the course of this journey, we will detail with particular attention the role of what we consider 2 crucial events: the advent of cerebral MRI and the building of large cohorts with monogenic forms of small-vessel disease of the brain.

Brain magnetic resonance imaging lesion load at diagnosis, severity at onset and outcomes in Susac syndrome: A prospective cohort study.

BACKGROUND: Susac syndrome (SuS) is a rare occlusive microvessel disease of the brain, retina and inner ear. We aimed to determine whether brain lesion load at the acute phase predicts poor outcomes in SuS. METHODS: A prospective national cohort study was conducted from December 2012 to December 2019 in 20 centres in France. Patients included at the principal investigator's center with available brain magnetic resonance imaging (MRI) at diagnosis were analyzed. MRI was reviewed by an experienced neuroradiologist blinded to clinical status. The size, topography and number of hyperintense lesions on diffusion-weighted imaging (DWI-HL) were analyzed at diagnosis and during follow-up. Outcomes involved descriptive characteristics of patients at onset and last follow-up. RESULTS: Twenty-three patients (38.1 [18.8-56.5] years, 16 females) were prospectively studied. The triad (i.e., brain, eye and ear involvement) was complete at onset in 17 patients. Brain MRI was performed 1.1 (0.1-3.4) months after the first symptom. All patients had DWI-HL at the acute phase. Patients were separated into two groups according to the number of DWI-HL on first MRI: a first group of patients (n=15) displaying low brain lesion load (<50 DWI-HL per patient) and a second group of patients (n=8) displaying high brain lesion load (≥100 DWI-HL). The median follow-up was 57.9 (9.7-98) months. Clinical features, treatment, relapse rate, time to disappearance of DWI-HL, disabilities and professional outcome did not differ according to brain lesion load. CONCLUSION: Brain lesion load assessed by DWI at the acute phase is not associated with risks of disability in SuS.

Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, including HTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P = 3.12 × 10-17, odds ratio (OR) = 21.9], TOPMed freeze 5 (P = 7.6 × 10-18, OR = 27.1) and 1000 Genomes (P = 1.5 × 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counselling.

Vanishing White Matter Hyperintensities in CADASIL: A Case Report with Insight into Disease Mechanisms.

In a woman with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) followed for 15 years, we observed magnetic resonance imaging white matter hyperintensities that vanished in the anterior temporal poles while the brain volume decreased unexpectedly. These imaging changes were transient and detected when the patient was being treated by valproic acid for stabilizing mood disturbances. This intriguing case supports that mechanisms underlying white matter hyperintensities can vary from one brain area to another and that important modifications of water influx into the brain tissue might be involved in some imaging features of CADASIL.

Cognitive dysfunction and brain atrophy in Susac syndrome.

BACKGROUND: Susac syndrome is a very rare cerebral small vessel disease, which can leave patients with cognitive impairment. We aimed at evaluating processing speed slowing, executive dysfunction and apathy and their relationships with whole brain and callosal atrophy. METHODS: Patients with Susac syndrome included in a prospective observational cohort study were evaluated, while clinically steady-state, with standardized brain MRI and a neuropsychological battery specifically designed to capture minimal cognitive alterations in non-disabled young patients. Brain volume and corpus callosum area were measured using 3D-T1 sequences, repeatedly overtime. Relationships between neuropsychological data and brain volumetric measures obtained the same day were tested with linear regression while controlling for sex, age, level of education, scores of depression and of apathy. RESULTS: Nineteen patients aged 37.5 ± 10.5 years were included. Mean follow-up time was 2.6 ± 1.3 years (5.8 ± 2.2 evaluations). While Montreal Cognitive Assessment scores were 25.1 ± 3.6, processing speed slowing was obvious (Trail Making Test version A: 43.1 ± 16.2 s; version B: 95.5 ± 67.9 s; reaction time: 314.6 ± 79.6 ms). Brain and corpus callosum atrophy was striking. No relationship was found between cognitive performances and brain volume or corpus callosum area. CONCLUSION: Patients with Susac syndrome show largely preserved global cognitive functions but important processing speed alterations. Although brain and corpus callosum area atrophy is prominent and evolving, we did not find any relationship with cognitive alterations, questioning the mechanisms underlying cognitive alterations in these patients. TRIAL REGISTRATION: Clinical Trial Registration-URL: https://www.clinicaltrials.gov Unique Identifier: NCT01481662.

Acute ischemic stroke in adolescents.

OBJECTIVE: Adolescence represents a transition period between childhood and adulthood, and only limited information exists about stroke characteristics in this population. Our aim was to describe the clinical and neuroradiologic features, etiologies, initial management, and outcome of ischemic stroke in adolescents. METHODS: This retrospective cohort study evaluated all consecutive patients 10 to 18 years with a first-ever ischemic stroke hospitalized between 2007 and 2017 in 10 French academic centers representing a population of ≈10 million. Extracted data from the national database served as validation. RESULTS: A total of 60 patients were included (53% male, median age 15.2 years). Diagnosis at first medical contact was misevaluated in 36%, more frequently in posterior than anterior circulation strokes (55% vs 20% respectively, odds ratio 4.8, 95% confidence interval 1.41-16.40, p = 0.01). Recanalization treatment rate was high (n = 19, 32%): IV thrombolysis (17%), endovascular therapy (11.7%), or both IV and intra-arterial thrombolysis (3.3%); safety was good (only 1 asymptomatic hemorrhagic transformation). Despite thorough etiologic workup, 50% of strokes remained cryptogenic. The most common determined etiologies were cardioembolism (15%), vasculitis and autoimmune disorders (12%, occurring exclusively in female patients), and arterial dissections (10%, exclusively in male patients). Recurrent ischemic cerebrovascular events occurred in 12% (median follow-up 19 months). Recurrence rate was 50% in patients with identified vasculopathy but 0% after cryptogenic stroke. Functional outcome was favorable (Rankin Scale score 0-2 at day 90) in 80% of cases. CONCLUSIONS: Ischemic strokes in adolescents harbor both pediatric and adult features, emphasizing the need for multidisciplinary collaboration in their management. Recanalization treatments appear feasible and safe.