High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics.

OBJECTIVE: To assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments. METHODS: Sixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled 'other') were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection. RESULTS: In 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin. CONCLUSION: This study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.

Incidence of Acute Ischemic Stroke With Visible Arterial Occlusion: A Population-Based Study (Dijon Stroke Registry).

BACKGROUND AND PURPOSE: Because of several methodological limitations, previous studies focusing on the prevalence of large vessel occlusion in ischemic stroke (IS) patients provided conflicting results. We evaluated the incidence of IS with a visible arterial occlusion using a comprehensive population-based registry. METHODS: Patients with acute IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013-2017). All arterial imaging exams were reviewed to assess arterial occlusion. Annual incidence rates of IS (first-ever and recurrent events) and IS with a visible occlusion were calculated. RESULTS: One thousand sixty cases of IS were recorded (mean age: 76.0±15.8 years, 53.9% women). Information about arterial imaging was available in 971 (91.6%) of them, and only preexisting dementia was independently associated with having missing information (odds ratio=0.34 [95% CI, 0.18-0.65], P=0.001). Among these patients, 284 (29.2%) had a visible arterial occlusion. Occlusion site was the anterior circulation in 226 patients (23.3% of overall patients with available data) and the posterior circulation in 58 patients (6.0%). A proximal occlusion of the anterior circulation was observed in 167 patients (17.2%). The crude annual incidence rate of total IS per 100 000 was 138 (95% CI, 129-146). Corresponding standardized rates were 66 (95% CI, 50-82) to the World Health Organization and 141 (95% CI, 118-164) to the 2013 European populations. The crude annual incidence rate of IS with a visible arterial occlusion per 100 000 was 37 (95% CI, 33-41) and that of IS with a proximal occlusion of the anterior circulation was 22 (95% CI, 18-25). Corresponding standardized rates were 18 (95% CI, 10-26) and 10 (95% CI, 8-13) to the World Health Organization population, and 38 (95% CI, 26-50) and 23 (95% CI, 19-26) to the 2013 European population, respectively. CONCLUSIONS: These results will be helpful to plan the need for thrombectomy-capable stroke center resources.

Efficiency of telemedicine for acute stroke: a cost-effectiveness analysis from a French pilot study.

OBJECTIVES: Telestroke is an effective way to improve care and health outcomes for stroke patients. This study evaluates the cost-effectiveness of a French telestroke network. METHODS: A decision analysis model was built using population-based data. We compared short-term clinical outcomes and costs for the management of acute ischemic stroke patients before and after the implementation of a telestroke network from the point of view of the national health insurance system. Three effectiveness endpoints were used: hospital death, death at 3 months, and severe disability 3 months after stroke (assessed with the modified Rankin scale). Most clinical and economic parameters were estimated from the medical files of 742 retrospectively included patients. Sensitivity analyses were performed. RESULTS: The analyses revealed that the telestroke strategy was more effective and slightly more costly than the reference strategy (25 disability cases avoided per 1,000 at 3 months, 6.7 avoided hospital deaths, and 13 avoided deaths at 3 months for an extra cost of EUR 97, EUR 138, and EUR 154, respectively). The results remained robust in the sensitivity analyses. CONCLUSIONS: In France, telestroke is an effective strategy for improving patient outcomes and, despite the extra cost, it has a legitimate place in the national health care system.

Association Between Fatigue and Cognitive Impairment at 6 Months in Patients With Ischemic Stroke Treated With Acute Revascularization Therapy.

Background: Fatigue is a frequent symptom after stroke. We aimed to determine the association between fatigue and cognitive performance in patients with ischemic stroke who received acute revascularization therapy (IV thrombolysis and/or mechanical thrombectomy). Methods: Seventy patients were prospectively included in the stroke unit of the University Hospital of Dijon, France. A follow-up was performed at 6 months with clinical examination, fatigue assessment by the Fatigue Severity Scale (FSS), and a comprehensive neuropsychological evaluation. Patients with fatigue (FSS score >4) were compared with patients without fatigue. Neuropsychological factors associated with fatigue at 6 months were analyzed using multivariable logistic regression models. Results: Fatigue was reported by 34.3% of patients. Patients with fatigue were older, had more frequent residual handicap, depressive symptoms, and impaired quality of life. They had more frequently low score (<26) on the MoCA scale (79.2 vs. 47.8%, OR = 4.15; 95% CI: 1.32-13, p = 0.015), memory impairment (60 vs. 30.6%, OR = 3.41; 95% CI: 1.09-10.7, p = 0.035), and executive dysfunction (65 vs. 30.8%, OR = 4.18; 95% CI: 1.33-13.1, p = 0.014). In multivariable logistic regression analysis, only memory impairment was independently associated with fatigue (OR = 5.70; 95% CI: 1.09-29.6, p = 0.039). Further analyses restricted to non-depressed patients (n = 58, 84.1%) showed in multivariable models that a score < 26 on MoCA scale (OR 5.12; 95% CI: 1.00-26.2, p = 0.05), and a memory impairment (OR = 6.17; 95% CI: 1.06-35.9, p = 0.043) were associated with fatigue. There was also a non-significant trend toward an association between divided attention deficit and fatigue (OR = 6.79; 95% CI: 0.80-57.6, p = 0.079). Conclusion: The association between fatigue and subtle cognitive impairment including memory or attention deficits could be of interest in elaborating future interventional studies to evaluate the impact of therapeutic strategies, including cognitive rehabilitation, on fatigue.

Increasing early ambulation disability in spontaneous intracerebral hemorrhage survivors.

OBJECTIVE: To evaluate temporal trends in early ambulatory status in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: All patients with ICH between 1985 and 2011 were prospectively registered in a population-based registry in Dijon, France, and included in the study. Outcomes of ICH survivors were assessed at discharge from their stay in an acute care ward with the use of a 4-grade ambulation scale. Time trends in ambulation disability and place of discharge were analyzed in 3 periods (1985-1993, 1994-2002, and 2003-2011). Multivariable ordinal and logistic regression models were applied. RESULTS: Five hundred thirty-one patients with ICH were registered, of whom 200 (37.7%) died in the acute care ward. While the proportion of deaths decreased over time, that of patients with ambulation disability increased (odds ratio [OR] 1.67, 95% confidence interval [CI] 0.87-3.23, p = 0.124 for 1994-2002; and OR 1.97, 95% CI, 1.08-3.60, p = 0.027 for 2003-2011 vs 1985-1993 in ordinal logistic regression). The proportion of patients dependent in walking rose (OR 2.11, 95% CI 1.16-3.82, p = 0.014 for 1994-2002; and OR 2.73; 95% CI 1.54-4.84, p = 0.001 for 2003-2011), and the proportion of patients discharged to home decreased (OR 0.49, 95% CI 0.24-0.99, p = 0.048 for 1994-2002; and OR 0.32, 95% CI 0.16-0.64, p = 0.001 for 2003-2011). CONCLUSION: The decrease in in-hospital mortality of patients with ICH translated into a rising proportion of patients with ambulation disability at discharge. A lower proportion of patients returned home. These results have major implications for the organization of postacute ICH care.

Temporal trends in the premorbid use of preventive treatments in patients with acute ischemic cerebrovascular events and a history of vascular disease: The Dijon Stroke Registry (1985-2010).

INTRODUCTION: Although secondary prevention in patients with arterial vascular diseases has improved, a gap between recommendations and clinical practice may exist. OBJECTIVES: We aimed to evaluate temporal trends in the premorbid use of preventive treatments in patients with ischemic cerebrovascular events (ICVE) and prior vascular disease. METHODS: Patients with acute ICVE (ischemic stroke/TIA) were identified through the population-based stroke registry of Dijon, France (1985-2010). Only those with history of arterial vascular disease were included and were classified into four groups: patients with previous coronary artery disease only (CAD), previous peripheral artery disease only (PAD), previous ICVE only, and patients with at least two different past vascular diseases (polyvascular group). We assessed trends in the proportion of patients who were treated with antihypertensive treatments and antithrombotics at the time of their ICVE using multivariable logistic regression models. RESULTS: Among the 5309 patients with acute ICVE, 2128 had a history of vascular disease (mean age 77.3±11.9, 51% men; 25.1% CAD 7.5% PAD, 39.8% ICVE, and 27.5% poylvascular). A total of 45.8% of them were on antithrombotics, 64.1% on antihypertensive treatment, and 34.4% on both. Compared with period 1985-1993, periods 1994-2002 and 2003-2010 were associated with a greater frequency of prior-to-ICVE use of antithrombotics (adjusted OR=5.94; 95% CI: 4.61-7.65, P<0.01, and adjusted OR=6.92; 95% CI: 5.33-8.98, P<0.01, respectively) but not of antihypertensive drugs. Consistent results were found when analyses were stratified according to the type of history of arterial vascular disease. CONCLUSION: Patients with ICVE and previous vascular disease were still undertreated with recommended preventive therapies.

Temporal trends in early case-fatality rates in patients with intracerebral hemorrhage.

OBJECTIVE: To assess whether temporal trends in very early (within 48 hours) case-fatality rates may differ from those occurring between 48 hours and 30 days in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: All cases of ICH that occurred in Dijon, France (151,000 inhabitants), were prospectively collected between 1985 and 2011, using a population-based registry. Time trends in 30-day case fatality were analyzed in 3 periods: 1985-1993, 1994-2002, and 2003-2011. Cox regression models were used to evaluate associations between time periods and case fatality within 48 hours and between 48 hours and 30 days, after adjustments for demographics, risk factors, severity, and ICH location. RESULTS: A total of 531 ICH cases were recorded (mean age 72.9 ± 15.8, 52.7% women). Thirty-day case fatality gradually decreased with time from 40.9% in 1985-1993 to 33.5% 1994-2002 and to 29.6% in 2003-2011 (adjusted hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.47-1.07, p = 0.106, for 1994-2002, and adjusted HR 0.49, 95% CI 0.32-0.73, p < 0.001, for 2003-2011). Over the whole study period, 43.6% of 1-month deaths occurred within the first 48 hours following ICH onset. There was no temporal change in case fatality occurring within the first 48 hours but a decrease in deaths occurring between 48 hours and 30 days was observed with time (HR 0.53, 95% CI 0.31-0.90, p = 0.02, for 1994-2002, and HR 0.32, 95% CI 0.32-0.55, p < 0.01, for 2003-2011, compared with 1985-1993). CONCLUSION: Although 30-day case fatality significantly decreased over the last 27 years, additional improvements in acute management of ICH are needed since very early case-fatality rates (within 48 hours) did not improve.

Impact of Mechanical Thrombectomy on the Organization of the Management of Acute Ischemic Stroke.

BACKGROUND: Several trials and meta-analyses have recently demonstrated the superiority of endovascular therapy over standard medical treatment in patients presenting with acute ischemic stroke. In order to offer the best possible treatment to a maximum number of patients, many stroke care networks probably have to be reorganized. After analyzing the reliability of data in the literature, an algorithm is suggested for a pre-hospital and in-hospital alert system to improve the timeliness of subsequent treatment: a drip-and-ship approach. SUMMARY: Five recent well-designed randomized studies have demonstrated the benefit of endovascular therapy associated with intravenous fibrinolysis by recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke with confirmation by recent meta-analyses. The keys for success are a very short time to reperfusion, within 6 h, a moderate to severe pre-treatment deficit (National Institute of Health around 17), cerebral imaging able to identify proximal large vessel occlusion in the anterior circulation, a limited infarct core and a reversible penumbra, the use of the most recent devices (stent retriever) and a procedure that avoids general anesthesia, which reduces blood pressure. To meet these goals, every country must build a national stroke infrastructure plan to offer the best possible treatment to all patients eligible for intravenous fibrinolysis and endovascular therapy. The plan may include the following actions: inform the population about the first symptoms of stroke, provide the call number to improve the timeliness of treatment, increase the number of comprehensive stroke centers, link these to secondary and primary stroke centers by telemedicine, teach and train paramedics, emergency doctors and radiologists to identify the stroke infarct, proximal large vessel occlusion and the infarct core quickly, train a new generation of endovascular radiologists to improve access to this therapy. KEY MESSAGE: After 20 years of rt-PA, this new evidence-based therapy is a revolution in stroke medicine that will benefit patients. However, a new robust and multi-disciplinary care strategy is necessary to transfer the scientific data into clinical practice. It will require reorganization of the stroke infrastructure, which will include comprehensive stroke centers and secondary and primary stroke centers. The winners will be patients with severe stroke.

[If I had a stroke in 2015]. / Si j'avais un accident vasculaire cérébral aigu en 2015.

The management of stroke is now recognized as a real medical emergency as well as myocardial infarct, because we have now an efficacious treatment in cerebral infarct, intravenous fibrinolysis that decreases the risk of death and motor and cognitive handicap. The second characteristic is its very important frequency, and its risk that increases in young people. This medical emergency enforces the care systems because it needs a speedy network for the patient, his family and the care professionals, useful for intravenous fibrinolysis before 3 hours after 80 years and before 4 hours and a half before 80 years. It is necessary to start treatment as soon as possible because it is most effective when given early. The consequences to avoid the lost of chance, need several actions: inform the public about the interest of FAST score to identify the first signs (facial palsy, palsy of arm, aphasia and time of stroke onset); call 15; translate the patient towards an appropriate medical center; use tele-stroke when the hospital has no neurologist; and manage the patient in a stroke unit, to introduce in a second time secondary prevention thanks to therapeutical education. Therefore, stroke care is a real multiprofessional emergency around the neurologist.

Factors associated with early recurrence at the first evaluation of patients with transient ischemic attack.

We aimed to identify factors easily collected at admission in patients with transient ischemic attack (TIA) that were associated with early recurrence, so as to guide clinicians' decision-making about hospitalization in routine practice. From September 2011 to January 2013, all TIA patients who were referred to the University Hospital of Dijon, France, were identified. Vascular risk factors and clinical information were collected. The etiology of the TIA was defined according to the results of complementary examinations performed at admission as follows: large artery atherosclerosis (LAA-TIA) TIA, TIA due to atrial fibrillation (AF-TIA), other causes, and undetermined TIA. Logistic regression analyses were performed to identify factors associated with any recurrence at 48 hours (stroke or TIA). Among the 312 TIA patients, the etiology was LAA-TIA in 33 patients (10.6%), AF-TIA in 57 (18.3%), other causes in 23 (7.3%), and undetermined in 199 (63.8%). Early recurrence rates were 12.1% in patients with LAA-TIA, 5.3% in patients with AF-TIA, 4.3% in patients with another cause of TIA, and 1.0% in patients with undetermined TIA. In multivariable analysis, the LAA etiology was independently associated with early recurrence (odds ratio [OR]: 12.03; 95% confidence interval [CI]: 1.84-78.48, p=0.009). A non-significant trend was also observed for AF-TIA (OR: 3.82; 95% CI: 0.40-36.62, p=0.25) and other causes (OR: 3.73; 95% CI: 0.30-46.26, p=0.31). A simple initial assessment of TIA patients in the emergency room would be helpful in targeting those with a high risk of early recurrence and who therefore need to be hospitalized.

The impact of World and European Football Cups on stroke in the population of Dijon, France: a longitudinal study from 1986 to 2006.

BACKGROUND: Acute stress may trigger vascular events. We aimed to investigate whether important football competitions involving the French football team increased the occurrence of stroke. METHODS: We retrospectively retrieved data of fatal and nonfatal stroke during 4 World Football Cups (1986, 1998, 2002, and 2006) and 4 European Championships (1992, 1996, 2000, and 2004), based on data from the population-based Stroke Registry of Dijon, France. One period of exposure was analyzed: the period of competition extended to 15 days before and after the competitions. The number of strokes was compared between exposed and unexposed corresponding periods of preceding and following years using Poisson regression. RESULTS: A total of 175 strokes were observed during the exposed periods compared with 192 and 217 strokes in the unexposed preceding and following periods. Multivariate regression analyses showed an overall 30% significant decrease in stroke numbers between periods of competition and unexposed periods of following year (risk ratio (RR) = 1.3; 95% confidence interval [CI] = 1.0-1.6; P = .029) but not with that of preceding year (RR = 1.1; 95% CI = .9-1.3; P = .367). This was mostly explained by a 40% decrease in stroke numbers during European Championships, compared with the unexposed following periods (RR = 1.4; 95% CI = 1.0-1.9; P = .044) in stratified analyses by football competitions. CONCLUSIONS: Watching European football competitions had a positive impact in the city of Dijon with a decrease of stroke numbers. European championship is possibly associated with higher television audience and long-lasting euphoria although other factors may be involved. Further studies using nationwide data are recommended to validate these findings.

[Stroke in children: a medical emergency]. / Accidents vasculaires cérébraux de l'enfant : une urgence médicale qui doit bénéficier des filières neurovasculaires régionales mises en place par le Plan National AVC.

Stroke in children is an important public health problem because, even if it is 10 folds less frequent than in adults, it may have severe consequences, related to the lack of dedicated stroke network in childhood. Therefore, it is important to know the initial clinical symptoms of stroke in children as well as the lack of aphasia opposed to the great frequency of epilepsy, and dystonia. The causes are different compared to the great frequency of cerebral hemorrhage from vascular malformations, cerebral infarct from genetic, cardiac or thrombophilic origin. Prognosis is more favourable compared to that of adults. The management of stroke in childhood must be included in the stroke network of adults, associating the paediatricians. Fibrinolysis is possible in children with a similar efficacy compared to that of adults.

[Epidemiology of stroke in the elderly : "the silver tsunami"]. / Epidémiologie des accidents vasculaires cérébraux du sujet âgé : "The silver tsunami".

Stroke in the elderly has more major differences compared to young people. The first cause remains the atherothrombosis disease associated to the following risk factors: hypertension, diabetes, hypercholesterolemia, tobacco consumption. Lipohyalinosis of perforating arteries linked to blood hypertension inducing lacunar infarcts and atrial fibrillation are the 2nd and 3rd causes linked to age. The increase of the ageing population explains the rise of the number of stroke over 80 years. On a clinical point of view, the pseudo-bulbar syndrome is very frequent and explains the swallowing troubles and incontinence. Prognosis is characterized by a high risk of dementia (20 %). Primary and secondary prevention is very effective even in very old patients, on the risk of stroke. Fibrinolysis and stroke units have demonstrated their efficacy in stroke treatments over 80 years. We observed a decrease of case-fatality rates at any day with a delay in age of onset of stroke of 5 years in men and 8 years in women, suggesting an increase of life expectancy without stroke, reflecting a certain efficacy of prevention. The elderly may be more often included in therapeutic trials.