Sylvain Lanthier

Prevalence of Fabry Disease in Young Patients with Cryptogenic Ischemic Stroke

BACKGROUND A German study diagnosed 4% of young cryptogenic ischemic stroke patients with Fabry disease, an X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A (α-GAL-A) gene resulting in an accumulation of glycosphingolipids. A lower prevalence was found in other geographic regions. AIM To determine the prevalence of Fabry disease in a Canadian population of young cryptogenic ischemic stroke patients. MATERIALS AND METHODS Patients with cryptogenic ischemic stroke at age 16-55 were retrospectively identified in our institutional stroke database and underwent a focused clinical evaluation. We sequenced the α-GAL-A gene and measured the levels of blood globotriaosylsphingosine in subjects with mutations of undetermined pathogenicity. Fabry disease was diagnosed in patients with pathogenic mutations or increased levels of blood globotriaosylsphingosine. RESULTS Ninety-three of 100 study subjects had normal α-GAL-A gene polymorphisms. Seven had mutations of undetermined pathogenicity, including one with increased globotriaosylsphingosine (prevalence, 1%; 95% confidence interval, <.01%-6%). No subjects had angiokeratomas or other clinical manifestations of Fabry disease. Investigation results suggestive of Fabry disease (idiopathic hypertrophic cardiomyopathy, proteinuria, vertebrobasilar dolichoectasia, and the pulvinar sign) were found only in subjects with normal α-GAL-A genes. Apart from the 100 study subjects, our database included another patient with a family history of Fabry disease and a pathogenic mutation identified before her ischemic stroke presentation as the first clinical manifestation of Fabry disease. Both Fabry patients experienced recurrent ischemic stroke. CONCLUSIONS Fabry disease accounts for a small proportion of young Canadians with cryptogenic ischemic stroke. Identification of Fabry biomarkers remains a research priority to delineate stroke patients disserving routine screening.

Silent ischemic lesions in young adults with first stroke are associated with recurrent stroke

Objective: To determine the association between silent ischemic lesions (SILs) on baseline brain MRI and recurrent stroke in young adults with first-ever ischemic stroke. Methods: This was a single-center retrospective study of adult patients aged 18–50 years with first-ever ischemic stroke investigated by brain MRI between 2002 and 2009. Silent brain infarcts (SBIs) were defined as focal T2 hyperintensities ≥3 mm without corresponding focal symptoms, and leukoaraiosis was defined as focal, multifocal, or confluent hyperintensities on T2-weighted sequences. The primary outcome was recurrent stroke. A forward stepwise Cox regression model was used to determine whether SILs were independently associated with recurrent stroke. Results: A total of 271 eligible patients were identified in the database: 89 did not undergo MRI imaging and 12 patients had inadequate follow-up, leaving a study population of 170 patients. MRI demonstrated SILs in 48 of 170 (28.2) patients. No patients had isolated leukoaraiosis. Hypertension (p = 0.049), migraine with aura (p = 0.02), and cardiovascular disease (p = 0.04) were associated with SIL. Mean follow-up duration was 25 ± 7 months. Among patients with SILs, 11 of 48 (23%) had a recurrent stroke vs 8 of 122 (6.5%) patients without SIL (p = 0.003). After multivariate Cox regression, SILs remained independently associated with recurrent stroke (hazard ratio [HR] 3.2, 95% confidence interval [CI] 1.2−8.6, p = 0.02), as did the combination of SBIs and leukoaraiosis (HR 7.3, 95% CI 2.3−22.9, p = 0.003). Conclusions: In adults ≤50 years old with first-ever ischemic stroke, SILs are common and independently predict recurrent stroke.

Good is not Good Enough: The Benchmark Stroke Door-to-Needle Time Should be 30 Minutes.

Noreen Kamal, Oscar Benavente, Karl Boyle, Brian Buck, Ken Butcher, Leanne K. Casaubon,RobertCote,AndrewMDemchuk,YanDeschaintre,DarDowlatshahi,GordonJGubitz,GaryHunter,Tom Jeerakathil, Albert Jin, Eddy Lang, Sylvain Lanthier, Patrice Lindsay, Nancy Newcommon,Jennifer Mandzia, Colleen M. Norris, Wes Oczkowski, Celine Odier, Stephen Phillips,Alexandre Y Poppe, Gustavo Saposnik, Daniel Selchen, Ashfaq Shuaib, Frank Silver, Eric E Smith,Grant Stotts, Michael Suddes, Richard H. Swartz, Philip Teal, Tim Watson, Michael D. Hill

Early CT changes in patients admitted for thrombectomy Intrarater and interrater agreement

Objective: To systematically review the literature and assess agreement on the Alberta Stroke Program Early CT Score (ASPECTS) among clinicians involved in the management of thrombectomy candidates. Methods: Studies assessing agreement using ASPECTS published from 2000 to 2015 were reviewed. Fifteen raters reviewed and scored the anonymized CT scans of 30 patients recruited in a local thrombectomy trial during 2 independent sessions, in order to study intrarater and interrater agreement. Agreement was measured using intraclass correlation coefficients (ICCs) and Fleiss kappa statistics for ASPECTS and dichotomized ASPECTS at various cutoff values. Results: The review yielded 30 articles reporting 40 measures of agreement. Populations, methods, analyses, and results were heterogeneous (slight to excellent agreement), precluding a meta-analysis. When analyzed as a categorical variable, intrarater agreement was slight to moderate (κ = 0.042–0.469); it reached a substantial level (κ > 0.6) in 11/15 raters when the score was dichotomized (0–5 vs 6–10). The interrater ICCs varied between 0.672 and 0.811, but agreement was slight to moderate (κ = 0.129–0.315). Even in the best of cases, when ASPECTS was dichotomized as 0–5 vs 6–10, interrater agreement did not reach a substantial level (κ = 0.561), which translates into at least 5 of 15 raters not giving the same dichotomized verdict in 15% of patients. Conclusions: In patients considered for thrombectomy, there may be insufficient agreement between clinicians for ASPECTS to be reliably used as a criterion for treatment decisions.

Inflammatory Cerebral Amyloid Angiopathy, Amyloid-β–Related Angiitis, and Primary Angiitis of the Central Nervous System Similarities and Differences

Cerebral amyloid angiopathy (CAA) results from deposition of amyloid-β fibrils in the wall of the small and medium-sized blood vessels, mostly arteries of the leptomeninges and cerebral cortex. Architectural disruption of amyloid-β laden vessels, occasionally with fibrinoid necrosis, leads to perivascular leakage. Vascular rupture causes lobar microbleeds or hematomas and high-convexity subarachnoid hemorrhages. The accumulation of amyloid-β causes vessel lumen obliteration, thereby leading to ischemic leukoencephalopathy and cerebral infarction. Varying amounts of perivascular inflammation may be present, involving multinucleated giant cells in the most severe cases.1 However, frank vasculitic destruction of the vessel wall such as is found in amyloid-β–related angiitis (ABRA)2 and primary angiitis of the central nervous system (PACNS)3 is absent in the inflammatory form of CAA (I-CAA). There is substantial clinical overlap in the phenotypes of I-CAA, ABRA, and PACNS. A proper diagnosis of these 3 conditions is necessary because their individual treatment differ. Through 3 cases, we summarize similarities and differences between I-CAA, ABRA, and PACNS. A 52-year-old woman complained about limb paresthesias lasting 3 days. She reported cognitive decline and fatigue lasting 3 months, a relentless headache that had lasted for a year, in addition to episodic migraine and tension-type headaches. Past medical history was unremarkable, except for active cigarette smoking. Physical and neurological examination was normal. Brain magnetic resonance imaging (MRI) showed nonspecific lobar, white matter, nonenhancing hyperintensities on T2-weighted sequences. No treatment was initiated in the absence of a specific diagnosis. Blood tests, including inflammatory and prothrombotic work-up, cardiac ultrasound, Holter monitoring, digital subtraction cerebral angiography, and cerebrospinal fluid (CSF) analysis were normal. She remained stable clinically. Three months later, repeat brain MRI revealed new lobar T2-hyperintensities (Figure 1A) and several lobar microbleeds on gradient-echo sequences. CNS biopsy revealed extensive amyloid-β deposits in the wall of small leptomeningeal and cortical …

Rapid Assessment and Treatment of Transient Ischemic Attacks and Minor Stroke in Canadian Emergency Departments: Time for a Paradigm Shift.

A majority of acute cerebrovascular syndromes are transient ischemic attacks (TIA) or minor ischemic strokes. They are often thought of and managed as though benign, but are in fact a warning of impending disabling stroke. The risk of stroke progression or recurrence is highest in the first hours to days from initial symptom onset, with a 6.7% risk at 48 hours and a 10% risk by 7 days after a TIA.1,2 The highest risk period is early, with a median time to a recurrence or progression event of 1 day; many events occur overnight after the initial ictus.3 Many strokes are preventable after a TIA. Rapid diagnosis and treatment reduces the risk of stroke by as much as 80%4,5 and significantly reduces mortality, long-term disability, and costs.6,7 The estimated annual cost avoidance in Canada from the rapid assessment and treatment of TIA is

Primary Angiitis of the Central Nervous System: Neurologic Deterioration Despite Treatment

313.8 million (of which

The YOU CALL–WE CALL Randomized Clinical Trial Impact of a Multimodal Support Intervention After a Mild Stroke

269.2 million are indirect costs).8 To be most effective, the diagnosis and treatment of all TIAs and minor strokes must recognize the natural biology of the condition and should ideally occur on the same day as the event. Currently, this is not consistently achieved in Canada. There are several overlapping challenges with TIA/minor stroke management, including (1) establishing an accurate diagnosis of brain ischemia quickly; (2) establishing accurate triage approaches to risk-stratify patients; and (3) establishing systems of care that expedite both the diagnostic evaluation and initiation of treatment. Rapid access to both brain and vascular imaging is a unifying component of the solution to all these challenges. The clinical diagnosis of TIA/minor stroke is not always straightforward because a …

Hydrogel versus Bare Platinum Coils in Patients with Large or Recurrent Aneurysms Prone to Recurrence after Endovascular Treatment: A Randomized Controlled Trial

Primary angiitis of the central nervous system (PACNS) is an idiopathic vasculitis confined to the central nervous system. In children with PACNS, small-vessel (SV) involvement is characterized clinically by progressive neurologic symptoms, multifocal lesions on brain imaging, occasional pseudo-tumor presentation, and normal angiogram results in most patients. Small case series of patients with SV PACNS with short follow-up usually reveal favorable outcomes in children treated with immunosuppressive therapy. We report here the cases of 3 children with biopsy-confirmed SV PACNS and long-term follow-up who developed different patterns of neurologic deterioration despite immunosuppressive therapy. One patient had transient ischemic attacks shortly after initiation of corticosteroid treatment. Early ischemic events probably result from residual thrombogenicity or residual inflammation of recently affected vessels, which supports the use of antiplatelet agents and suggests potential benefits of stronger immunosuppressive therapy. In contrast, the other 2 patients had later neurologic deterioration after corticosteroid withdrawal, which suggests failure of initial immunosuppressant treatment and the need for stronger agents, longer treatment duration, or both. All patients responded to long-term treatment with corticosteroids combined with cytotoxic agents. This particular combination is probably indicated in many cases of SV PACNS, including those with neurologic deterioration that occurs during maintenance corticotherapy or after corticosteroid withdrawal. In 1 case, SV PACNS recurred several years after discontinuation of combination therapy. Long-term relapses may reflect intrinsic predispositions to SV PACNS rather than treatment failure. These cases highlight different chronological patterns of neurologic deterioration despite immunosuppressive therapy, which supports the relevance of monitoring clinical, laboratory, and radiologic responses to treatment and of long-term follow-up of patients with SV PACNS.

Fabry's disease: A prospective multicenter cohort study in young adults with cryptogenic stroke

Background— Comparison of a multimodal intervention WE CALL (study initiated phone support/information provision) versus a passive intervention YOU CALL (participant can contact a resource person) in individuals with first mild stroke. Methods and Results— This study is a single-blinded randomized clinical trial. Primary outcome includes unplanned use of health services (participant diaries) for adverse events and quality of life (Euroquol-5D, Quality of Life Index). Secondary outcomes include planned use of health services (diaries), mood (Beck Depression Inventory II), and participation (Assessment of Life Habits [LIFE-H]). Blind assessments were done at baseline, 6, and 12 months. A mixed model approach for statistical analysis on an intention-to-treat basis was used where the group factor was intervention type and occasion factor time, with a significance level of 0.01. We enrolled 186 patients (WE=92; YOU=94) with a mean age of 62.5±12.5 years, and 42.5% were women. No significant differences were seen between groups at 6 months for any outcomes with both groups improving from baseline on all measures (effect sizes ranged from 0.25 to 0.7). The only significant change for both groups from 6 months to 1 year (n=139) was in the social domains of the LIFE-H (increment in score, 0.4/9±1.3 [95% confidence interval, 0.1–0.7]; effect size, 0.3). Qualitatively, the WE CALL intervention was perceived as reassuring, increased insight, and problem solving while decreasing anxiety. Only 6 of 94 (6.4%) YOU CALL participants availed themselves of the intervention. Conclusions— Although the 2 groups improved equally over time, WE CALL intervention was perceived as helpful, whereas YOU CALL intervention was not used. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN95662526.