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.

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.

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.

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.

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.

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.

Correction: The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.

The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant.

PURPOSE: CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7-34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7-34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. METHODS: Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1-6 pathogenic variant or an EGFr 7-34 pathogenic variant. The frequencies of NOTCH3 EGFr 1-6 and EGFr 7-34 pathogenic variant were compared between individuals in the genome  Aggregation Database and CADASIL patients. RESULTS: CADASIL patients with an EGFr 1-6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7-34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1-6 pathogenic variant, whereas EGFr 7-34 pathogenic variant strongly predominate in the population. CONCLUSION: NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7-34 pathogenic variant predisposing to a later onset of stroke and longer survival.

Why Are Only Some Subcortical Ischemic Lesions on Diffusion Magnetic Resonance Imaging Associated With Stroke Symptoms in Small Vessel Disease?

Background and Purpose- In cerebral small vessel diseases, small subcortical ischemic lesions (SSIL) on diffusion imaging are responsible for stroke manifestations but can also be occasionally observed in the absence of overt neurological symptoms. We aimed to determine, in a large cohort of young patients with CADASIL (Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic condition leading to SSIL in young patients, the characteristics of SSIL and of surrounding cerebral tissue associated with the presence of stroke symptoms. Methods- Among a cohort of 323 genetically confirmed CADASIL patients who were systematically evaluated every 18 months clinically and with magnetic resonance imaging, we studied all visible SSIL and documented ischemic stroke events with available magnetic resonance imaging data. We used mixed-effect logistic regression models to determine whether the presence of stroke symptoms was associated with age, sex, the volume of SSIL, their location with respect to preexisting white matter hyperintensities and with the load of the different magnetic resonance imaging markers of small vessel disease. Results- We identified 73 SSIL (30 with stroke symptoms and 43 without) in 55 patients. In multivariable models, stroke symptoms were more frequent in male patients (estimate=1.94; SE=0.82; P=0.03) and less frequent when SSIL appeared in contact to preexisting white matter hyperintensities (estimate=-2.12; SE=0.83; P=0.01). Within pyramidal tracts, stroke symptoms were more frequent in patients with extensive white matter hyperintensities (estimate=3.8×10-5; SE=9.3×10-6; P<10-4). Conclusions- Altogether, our results suggest that when SSIL occur, the presence of stroke symptoms may depend on sex and alterations of the surrounding brain tissue rather than on the characteristics of the SSIL itself.

Free water determines diffusion alterations and clinical status in cerebral small vessel disease.

INTRODUCTION: Diffusion tensor imaging detects early tissue alterations in Alzheimer's disease and cerebral small vessel disease (SVD). However, the origin of diffusion alterations in SVD is largely unknown. METHODS: To gain further insight, we applied free water (FW) imaging to patients with genetically defined SVD (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL], n = 57), sporadic SVD (n = 444), and healthy controls (n = 28). We modeled freely diffusing water in the extracellular space (FW) and measures reflecting fiber structure (tissue compartment). We tested associations between these measures and clinical status (processing speed and disability). RESULTS: Diffusion alterations in SVD were mostly driven by increased FW and less by tissue compartment alterations. Among imaging markers, FW showed the strongest association with clinical status (R2 up to 34%, P < .0001). Findings were consistent across patients with CADASIL and sporadic SVD. DISCUSSION: Diffusion alterations and clinical status in SVD are largely determined by extracellular fluid increase rather than alterations of white matter fiber organization.

Focal Macroscopic Cortical Lesions in Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

BACKGROUND AND PURPOSE: Cortical microinfarcts and secondary cortical degeneration have been demonstrated in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a severe monogenic cerebral small vessel disease. The aim of this study was to determine whether focal macroscopic cortical lesions can be detected using a specific in vivo magnetic resonance imaging approach. METHODS: Three-dimensional T1 magnetic resonance imaging scans were obtained in 28 nondemented nondisabled CADASIL patients and 29 age- and sex-matched controls. The cortical mantle of patients and controls were extracted using Brainvisa by an experienced user and then evaluated during a dedicated reading session by a second reader after removing the white matter to stay blind to the clinical status. Thereafter, confirmed focal macroscopic cortical lesions were characterized using all available imaging data, including 7-T magnetic resonance imaging in some patients. RESULTS: Three focal macroscopic cortical lesions were confirmed in 3 of 28 patients (11%) but none in controls. All lesions were observed in the close vicinity of severe signal changes in the underlying white matter. CONCLUSIONS: Focal macroscopic cortical lesions can be detected using specific magnetic resonance imaging approaches in CADASIL patients long before the end stage of the disorder. The underlying mechanisms and precise clinical consequences of these cortical changes still need to be determined.

Cerebral Microbleeds and the Risk of Incident Ischemic Stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy).

BACKGROUND AND PURPOSE: Cerebral microbleeds are associated with an increased risk of intracerebral hemorrhage. Recent data suggest that microbleeds may also predict the risk of incident ischemic stroke. However, these results were observed in elderly individuals undertaking various medications and for whom causes of microbleeds and ischemic stroke may differ. We aimed to test the relationship between the presence of microbleeds and incident stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)-a severe monogenic small vessel disease known to be responsible for both highly prevalent microbleeds and a high incidence of ischemic stroke in young patients. METHODS: We assessed microbleeds on baseline MRI in all 378 patients from the Paris-Munich cohort study. Incident ischemic strokes were recorded during 54 months. Survival analyses were used to test the relationship between microbleeds and incident ischemic stroke. RESULTS: Three hundred sixty-nine patients (mean age, 51.4±11.4 years) were followed-up during a median time of 39 months (interquartile range, 19 months). The risk of incident ischemic stroke was higher in patients with microbleeds than in patients without (35.8% versus 19.6%, hazard ratio, 1.87; 95% confidence interval, 1.16-3.01; P=0.009). These results persisted after adjustment for history of ischemic stroke, age, sex, vascular risk factors, and antiplatelet agents use (hazard ratio, 1.89; 95% confidence interval, 1.10-3.26; P=0.02). CONCLUSIONS: The presence of microbleeds is an independent risk marker of incident ischemic stroke in CADASIL, emphasizing the need to carefully interpret MRI data.

Predictors and Clinical Impact of Incident Lacunes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

BACKGROUND AND PURPOSE: Previous studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy showed that accumulation of lacunes strongly relate to clinical severity. However, the potential predictors of incident lacunes and their clinical consequences over a short time frame have not been investigated. This study aimed to determine the predictors and clinical impact of such lesions in a large cohort of patients. METHODS: Two hundred and six NOTCH3 mutation carriers (mean age, 49.5±10.6 years) were followed up over 3 years. Incident lacunes were identified using difference imaging from 3-dimensional T1 images. Clinical events and change in different clinical scores such as the Mattis Dementia Rating Scale, Modified Rankin Scale, Barthel index, and time to complete part A and part B of Trail Making Test were recorded. Associations were analyzed with multivariable logistic regression analysis and ANCOVA. RESULTS: Over a mean period of 3.4±0.7 years, incident lacunes occurred in 51 of 206 patients. Both the number of lacunes (P<0.0001) and systolic blood pressure at baseline (P<0.01) were independent predictors of incident lacunes during follow-up. The results were still significant after excluding patients with systolic blood pressure >140 mm Hg. Incident lacunes were also associated with incident stroke and with change in time to complete Trail Making Test part B, initiation/perseveration subscale of the Mattis Dementia Rating Scale and Barthel Index over the study period. CONCLUSIONS: Systolic blood pressure and the number of prevalent lacunes are independent predictors of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These lesions mainly impact executive performances and functional independence over 3 years.

Cortical Superficial Siderosis in Different Types of Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Cortical superficial siderosis (cSS) has emerged as a clinically relevant imaging feature of cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is also present in nonamyloid-associated small vessel disease and whether patients with cSS differ in terms of other small vessel disease imaging features. METHODS: Three hundred sixty-four CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, 372 population-based controls, and 100 CAA patients with cSS (fulfilling the modified Boston criteria for possible/probable CAA) were included. cSS and cerebral microbleeds were visually rated on T2*-weighted magnetic resonance imaging. White matter hyperintensities were segmented on fluid-attenauted inversion recovery images, and their spatial distribution was compared between groups using colocalization analysis. Cerebral microbleeds location was determined in an observer-independent way using an atlas in standard space. RESULTS: cSS was absent in CADASIL and present in only 2 population-based controls (0.5%). Cerebral microbleeds were present in 64% of CAA patients with cSS, 34% of patients with CADASIL, and 12% of population-based controls. Among patients with cerebral microbleeds, lobar location was found in 95% of CAA patients with cSS, 48% of CADASIL patients, and 69% of population-based controls. The spatial distribution of white matter hyperintensities was comparable between CAA with cSS and CADASIL as indicated by high colocalization coefficients. CONCLUSIONS: cSS was absent in CADASIL, whereas other small vessel disease imaging features were similar to CAA patients with cSS. Our findings suggest that cSS in combination with other small vessel disease imaging markers is highly indicative of CAA.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients.

A Novel Imaging Marker for Small Vessel Disease Based on Skeletonization of White Matter Tracts and Diffusion Histograms.

OBJECTIVE: To establish a fully automated, robust imaging marker for cerebral small vessel disease (SVD) and related cognitive impairment that is easy to implement, reflects disease burden, and is strongly associated with processing speed, the predominantly affected cognitive domain in SVD. METHODS: We developed a novel magnetic resonance imaging marker based on diffusion tensor imaging, skeletonization of white matter tracts, and histogram analysis. The marker (peak width of skeletonized mean diffusivity [PSMD]) was assessed along with conventional SVD imaging markers. We first evaluated associations with processing speed in patients with genetically defined SVD (n = 113). Next, we validated our findings in independent samples of inherited SVD (n = 57), sporadic SVD (n = 444), and memory clinic patients with SVD (n = 105). The new marker was further applied to healthy controls (n = 241) and to patients with Alzheimer's disease (n = 153). We further conducted a longitudinal analysis and interscanner reproducibility study. RESULTS: PSMD was associated with processing speed in all study samples with SVD (p-values between 2.8 × 10(-3) and 1.8 × 10(-10) ). PSMD explained most of the variance in processing speed (R(2) ranging from 8.8% to 46%) and consistently outperformed conventional imaging markers (white matter hyperintensity volume, lacune volume, and brain volume) in multiple regression analyses. Increases in PSMD were linked to vascular but not to neurodegenerative disease. In longitudinal analysis, PSMD captured SVD progression better than other imaging markers. INTERPRETATION: PSMD is a new, fully automated, and robust imaging marker for SVD. PSMD can easily be applied to large samples and may be of great utility for both research studies and clinical use. Ann Neurol 2016;80:581-592.

Features and Determinants of Lacune Shape: Relationship With Fiber Tracts and Perforating Arteries.

BACKGROUND AND PURPOSE: Lacunes are a major manifestation of cerebral small vessel disease. Although still debated, the morphological features of lacunes may offer mechanistic insights. We systematically analyzed the shape of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a genetically defined small vessel disease. METHODS: A total of 88 incident lacunes from 57 patients were segmented from 3-dimensional T1 magnetic resonance images and 3 dimensionally reconstructed. Anatomic location, diameter, volume, surface area, and compactness of lacunes were assessed. The shape was analyzed using a size, orientation, and position invariant spectral shape descriptor. We further investigated the relationship with perforating arteries and fiber tracts. RESULTS: Lacunes were most abundant in the centrum semiovale and the basal ganglia. Diameter, volume, and surface area of lacunes in the basal ganglia and centrum semiovale were larger than in other brain regions. The spectral shape descriptor revealed a continuum of shapes with no evidence for distinct classes of lacunes. Shapes varied mostly in elongation and planarity. The main axis and plane of lacunes were found to align with the orientation of perforating arteries but not with fiber tracts. CONCLUSIONS: Elongation and planarity are the primary shape principles of lacunes. Their main axis and plane align with perforating arteries. Our findings add to current concepts on the mechanisms of lacunes.

Shape of the Central Sulcus and Disability After Subcortical Stroke: A Motor Reserve Hypothesis.

BACKGROUND AND PURPOSE: Both brain and cognitive reserves modulate the clinical impact of chronic brain diseases. Whether a motor reserve also modulates the relationships between stroke and disability is unknown. We aimed to determine whether the shape of the central sulcus, a marker of the development of underlying motor connections, is independently associated with disability in patients with a positive history of small subcortical ischemic stroke. METHODS: Shapes of central sulci were reconstructed from high-resolution magnetic resonance imaging and ordered without supervision according to a validated algorithm in 166 patients with a positive history of small subcortical ischemic stroke caused by CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic cerebral small vessel disease affecting young patients. Ordinal logistic regression modeling was used to test the relationships between modified Rankin scale, a disability scale strongly weighted toward motor disability, and sulcal shape. RESULTS: Modified Rankin scale was strongly associated with sulcal shape, independent of age, sex, and level of education (proportional odds ratio =1.19, 95% confidence interval =1.06-1.35; P=0.002). Results remained significant after further adjustment for brain atrophy, volume of lacunes, and volume of white matter hyperintensities of presumed vascular origin. CONCLUSIONS: The severity of disability in patients with a positive history of small subcortical ischemic stroke caused by a severe cerebral small vessel disease is related to the shape of the central sulcus, independently of the main determinants of disability. These results support the concept of a motor reserve that could modulate the clinical severity in patients with a positive history of small subcortical ischemic stroke.

Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prospective Cohort Study.

BACKGROUND AND PURPOSE: Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy remain unknown. This study aims to identify demographic, clinical, and magnetic resonance imaging predictors of incident strokes, incident dementia, clinical deterioration, and death in patients with this genetically proven disease. METHODS: Two hundred ninety subjects (mean age, 50.6±11.4 years) were assessed at baseline and followed up for 36 months. Incident clinical events were recorded, and clinical scores included the Mini Mental State Examination, Mattis Dementia Rating Scale, modified Rankin Scale, and Barthel index. The number of lacunes and microbleeds, the volume of white-matter hyperintensities, and brain parenchymal fraction were assessed on baseline magnetic resonance imaging. Data were analyzed by ANCOVA, multivariable logistic regression, and Cox proportional hazard models. RESULTS: Incident stroke occurred in 55 of 278 patients (19.8%). Moderate or severe disability developed in 19 of 210 (9%) nondisabled individuals, incident dementia in 49 of 231 (20%) nondemented subjects, and 4.8% of patients died. Active smoking, the number of lacunes, and brain parenchymal fraction independently predicted incident stroke during follow-up. Gait disturbance, dementia, and brain parenchymal fraction predicted progression toward moderate or severe disability. Active smoking, disability, and brain parenchymal fraction predicted incident dementia. Age was the only significant predictor of death. CONCLUSIONS: Clinical assessment and brain magnetic resonance imaging aid in predicting incident clinical events and clinical deterioration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There is a bidirectional relationship between dementia and moderate or severe disability in predicting each other's onset. Active smoking is a modifiable risk factor associated with clinical progression in Notch3 mutation carriers.

Prevalence and characteristics of migraine in CADASIL.

Background and objective Migraine with aura (MA) is a major symptom of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We assessed the spectrum of migraine symptoms and their potential correlates in a large prospective cohort of CADASIL individuals. Methods A standardized questionnaire was used in 378 CADASIL patients for assessing headache symptoms, trigger factors, age at first attack, frequency of attacks and associated symptoms. MRI lesions and brain atrophy were quantified. Results A total of 54.5% of individuals had a history of migraine, mostly MA in 84% of them; 62.4% of individuals with MA were women and age at onset of MA was lower in women than in men. Atypical aura symptoms were experienced by 59.3% of individuals with MA, and for 19.7% of patients with MA the aura was never accompanied by headache. MA was the inaugural manifestation in 41% of symptomatic patients and an isolated symptom in 12.1% of individuals. Slightly higher MMSE and MDRS scores and lower Rankin score were detected in the MA group. Conclusion MA is observed in almost half of all CADASIL patients. Atypical aura symptoms are reported by more than one in two of them. MA is often inaugural, can remain isolated and is not associated with the severity of the disorder.