High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS.

Importance: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. Objective: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. Design, Setting, and Participants: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. Exposures: Natalizumab, fingolimod, rituximab, and ocrelizumab. Main Outcomes and Measures: Time to first relapse. Results: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. Conclusion and Relevance: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

Functional outcome in low-ASPECTS (0-5) acute ischemic stroke treated with mechanical thrombectomy: impact of laterality explored in a single-center study.

Background: There is no consensus regarding the influence of infarct laterality in patients with acute ischemic stroke due to anterior large vessel occlusion (AIS-LVO) treated with mechanical thrombectomy (MT), particularly in low-ASPECT (0-5) patients who were excluded from the initial MT studies and that participated in dedicated randomized-controlled trials that do not consider the side of the occlusion. We aimed to evaluate the role of infarct laterality on the clinical outcome in low-ASPECT AIS patients treated with MT. Material and methods: We retrospectively analyzed our institutional stroke database in our Thrombectomy-Capable Stroke Center (TCSC), including patient characteristics, procedural variables, and outcomes, between January 2015 and January 2022. Patients with acute intracranial ICA and/or proximal MCA occlusions with ASPECT ≤ 5 either on CT or MRI were included and divided into 2 groups according to the location of ischemia. The primary endpoint was a good clinical outcome at 90 days (modified Rankin Scale (mRS) score of 0-3). Results: Between January 2015 and November 2021, 817 MT were performed, of which 82 were low-ASPECT (10.0%): 41 left-sided and 41 right-sided strokes. The rates of good clinical outcome were 30.8% (12/41) for the left-sided group and 43.6% (17/41) for the right-sided group, with a p-value of 0.349. The morality rate showed no significant difference between the two groups: 39.0% (16/41) in the right stroke group and 36.6% (15/41) in the left stroke group. Conclusion: The clinical outcome was not significantly influenced by stroke laterality. The results of this single-center retrospective study indicate either a lack of strength or equal value in performing mechanical thrombectomy regardless of stroke laterality.

Impact of COVID-19 vaccination or infection on disease activity in a radiologically isolated syndrome cohort: The VaxiRIS study.

BACKGROUND: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised. OBJECTIVES: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS). METHODS: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients' history of COVID-19 infection. RESULTS: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients. CONCLUSION: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.

Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?

PURPOSE: CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease. METHODS: We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47). RESULTS: STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode. CONCLUSION: We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.

Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference.

BACKGROUND AND OBJECTIVES: The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery). METHODS: We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18-45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up). RESULTS: We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [-0.16 to 0.15]) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93-1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate. DISCUSSION: Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.

Recanalization Treatments for Pediatric Acute Ischemic Stroke in France.

Importance: There is to date limited evidence that revascularization strategies are associated with improved functional outcome in children with acute ischemic stroke (AIS). Objectives: To report clinical outcomes and provide estimates of revascularization strategy safety and efficacy profiles of intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) in children with AIS. Design, Setting, and Participants: The KidClot multicenter nationwide cohort study retrospectively collected data of children (neonates excluded) with AIS and recanalization treatment between January 1, 2015, and May 31, 2018. Data analysis was performed from January 1, 2015, to May 31, 2019. Exposure: IVT and/or EVT. Main Outcomes and Measures: Primary outcome was day 90 favorable outcome (modified Rankin Scale [mRs] 0-2, with 0 indicating no symptoms and 6 indicating death). Secondary end points included 1-year favorable outcome (mRs, 0-2), mortality, and symptomatic intracerebral hemorrhage. Other measures included the Pediatric National Institutes of Health Stroke Scale (pedNIHSS), with pedNIHSS 0 indicating no symptoms, 1 to 4 corresponding to a minor stroke, 5 to 15 corresponding to a mild stroke, greater than 15 to 20: severe stroke, and the adult Alberta Stroke Program Early CT Score (ASPECTS), which provides segmental assessment of the vascular territory, with 1 point deducted from the initial score of 10 for every region involved (from 10 [no lesion] to 0 [maximum lesions]). Results: Overall, 68 children were included in 30 centers (IVT [n = 44]; EVT [n = 40]; 44 boys [64.7%]; median [IQR] age, 11 [4-16] years; anterior circulation involvement, 57 [83.8%]). Median (IQR) pedNIHSS score at admission was 13 (7-19), higher in the EVT group at 16 (IQR, 10-20) vs 9 (6-17) in the IVT only group (P < .01). Median time from stroke onset to imaging was higher in the EVT group at 3 hours and 7 minutes (IQR, 2 hours and 3 minutes to 6 hours and 24 minutes) vs 2 hours and 39 minutes (IQR, 1 hour and 51 minutes to 4 hours and 13 minutes) (P = .04). Median admission ASPECTS score was 8 (IQR, 6-9). The main stroke etiologies were cardioembolic (21 [30.9%]) and focal cerebral arteriopathy (17 [25.0%]). Median (IQR) time from stroke onset to IVT was 3 hours and 30 minutes (IQR, 2 hours and 33 minutes to 4 hours and 28 minutes). In the EVT group, the rate of postprocedure successful reperfusion (≥modified Treatment in Cerebral Infarction 2b) was 80.0% (32 of 40). Persistent proximal arterial stenosis was more frequent in focal cerebral arteriopathy (P < .01). Death occurred in 3 patients (4.4%). Median pedNIHSS reduction at 24 hours was 4 (IQR, 0-9) points. Intracerebral hemorrhage occurred in 4 patients and symptomatic intracerebral hemorrhage occurred in 1 patient, all in the EVT group. The median mRS was 2 (IQR, 0-3) at day 90 and 1 (IQR, 0-2) at 1 year, which was not significantly different between EVT and IVT only groups, although different in initial severity. Conclusions and Relevance: The findings of this cohort study suggest that use of EVT and/or IVT is safe in children with AIS.

Comparative Effectiveness of Natalizumab Versus Anti-CD20 in Highly Active Relapsing-Remitting Multiple Sclerosis After Fingolimod Withdrawal.

In France, two therapeutic strategies can be offered after fingolimod (FNG) withdrawal to highly active relapsing-remitting multiple sclerosis (RRMS) patients: natalizumab (NTZ) or anti-CD20. We compared the effectiveness of these two strategies as a switch for FNG within the OFSEP database. The primary endpoint was the time to first relapse. Other outcomes were the relapse rates over 3-month periods, time to worsening the EDSS score, proportion of patients with worsened 24-month MRI, time to treatment discontinuation, and incidence rates of serious adverse events. The dynamics of event rates over time were modeled using multidimensional penalized splines, allowing the possibility to model the effects of covariates in a flexible way, considering non-linearity and interactions. A total of 740 patients were included (337 under anti-CD20 and 403 under NTZ). There was no difference between the two treatments regarding the dynamic of the first occurrence of relapse, with a monthly probability of 5.0% at initiation and 1.0% after 6 months. The rate of EDSS worsening increased in both groups until 6 months and then decreased. No difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, a greater risk of NTZ discontinuation was found compared to anti-CD20. This study showed no difference between NTZ and anti-CD20 after the FNG switch regarding the clinical and radiological activity. The effect of these treatments was optimal after 6 months and there was more frequent discontinuation of NTZ after 18 months, probably mainly related to JC virus seroconversions.

Carotid artery direct access for mechanical thrombectomy: the Carotid Artery Puncture Evaluation (CARE) study.

BACKGROUND: In acute ischemic stroke due to anterior large vessel occlusion (AIS-LVO), accessing the target occluded vessel for mechanical thrombectomy (MT) is sometimes impossible through the femoral approach. We aimed to evaluate the safety and efficacy of direct carotid artery puncture (DCP) for MT in patients with failed alternative vascular access. METHODS: We retrospectively analyzed data from 45 stroke centers in France, Switzerland and Germany through two research networks from January 2015 to July 2019. We collected physician-centered data on DCP practices and baseline characteristics, procedural variables and clinical outcome after DCP. Uni- and multivariable models were conducted to assess risk factors for complications. RESULTS: From January 2015 to July 2019, 28 149 MT were performed, of which 108 (0.39%) resulted in DCP due to unsuccessful vascular access. After DCP, 77 patients (71.3%) had successful reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) score ≥2b) and 28 (25.9%) were independent (modified Rankin Scale (mRS) score 0-2) at 3 months. 20 complications (18.5%) attributed to DCP occurred, all of them during or within 1 hour of the procedure. Complications led to extension of the intubation time in the intensive care unit in 7 patients (6.4%) and resulted in death in 3 (2.8%). The absence of use of a hemostatic closure device was associated with a higher complication risk (OR 3.04, 95% CI 1.03 to 8.97; p=0043). CONCLUSION: In this large multicentric study, DCP was scantly performed for vascular access to perform MT (0.39%) in patients with AIS-LVO and had a high rate of complications (18.5%). Our results provide arguments for not closing the cervical access by manual compression after MT.

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome.

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown. Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria. Design, Setting, and Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021. Exposure: Diagnosis of RIS. Main Outcomes and Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors. Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%. Conclusions and Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.

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.

Predictors of Early Stroke or Death in Patients Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND/OBJECTIVE: While postoperative stroke is a known complication of Transcatheter Aortic Valve Implantation (TAVI), predictors of early stroke occurrence have not been specifically reviewed. The objective of this study was to estimate the predictors and incidence of stroke during the first 30 days post-TAVI. METHODS: A cohort of 506 consecutive patients having undergone TAVI between January 2017 and June 2019 was extracted from a prospective database. Preoperative, intraoperative and postoperative characteristics were analyzed by univariate analysis followed by logistic regression to find predictors of the occurrence of stroke or death within the first 30 days after the procedure. RESULTS: Incidence of stroke within 30 days post-TAVI was 4.9%, [CI 95% 3.3-7.2], i.e., 25 strokes. Four out of the 25 patients (16%) with a stroke died within 30 days post-TAVI. After logistic regression analysis, the predictors of early stroke related to TAVI were: CHA2Ds2VASc score ≥ 5 (odds ratio [OR] 2.62; 95% CI: 1.06-6.49; p = .037), supra-aortic access vs. femoral access (OR: 9.00, 95%CI: 2.95-27.44; p = .001) and introduction post-TAVI of a single vs. two or three antithrombotic agents (OR: 5.13; CI 95%: 1.99 to 13.19; p = .001). Over the 30-day period, bleeding occurred in 28 patients (5.5%), in 25 of whom, it was associated with femoral or iliac artery access injury. Anti-thrombotic regimen was not associated with bleeding; two patients out of 48 (4.1%) bled with a single anti-thrombotic regimen vs. 26 patients out of 458 (5.6%) with a dual or triple anti-thrombotic regimen (p = 0.94). The overall 30-day mortality rate was 3.9%, [95% CI 2.5-6.0]. Patients with a single post-TAVI antithrombotic agent (OR: 44.07 [CI 95% 13.45-144.39]; p < .0001) and patients with previous coronary artery bypass surgery or coronary artery stenting (OR: 6.16, [CI 95% 1.99-21.29]; p = .002) were at significantly higher risk of death within the 30-day period. CONCLUSION: In this large-scale single-center retrospective study, a single post-TAVI antithrombotic regimen independently predicted occurrence of early stroke or death. Dual or triple antithrombotic regimen was not associated with a higher risk of bleeding and should be considered as an option in patients undergoing TAVI.

Sleep deprivation reduces vagal tone during an inspiratory endurance task in humans.

STUDY OBJECTIVES: Sleep deprivation alters inspiratory endurance by reducing inspiratory motor output. Vagal tone is involved in exercise endurance. This study aimed to investigate the effect of sleep deprivation on vagal tone adaptation in healthy subjects performing an inspiratory effort. METHODS: Vagal tone was assessed using Heart Rate Variability normalized units of frequency domain component HF (high frequency) before, at the start, and the end of an inspiratory loading trial performed until exhaustion by 16 volunteers after one night of sleep deprivation and one night of normal sleep, where sleep deprivation reduced the inspiratory endurance by half compared to the normal sleep condition (30 min vs 60 min). RESULTS: At rest, heart rate was similar in sleep deprivation and normal sleep conditions. In normal sleep condition, heart rate increased during inspiratory loading task; this increase was greater in sleep deprivation condition. In normal sleep condition, vagal tone increased at the beginning of the trial. This vagal tone increase was absent in sleep deprivation condition. CONCLUSIONS: Sleep deprivation abolished vagal tone response to inspiratory load, possibly contributing to a higher heart rate during the trial and to a reduced inspiratory endurance. CLINICAL TRIAL REGISTRATION: NCT02725190.

Procedural Learning Improves Cognition in Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is considered a neurodegenerative disease and an inflammatory demyelinating neuropathology in young population. Procedural memory has been poorly investigated in MS. OBJECTIVE: We assessed whether the MS group was able to develop a motor-cognitive skill, using a procedural task (PLSC) developed in our laboratory, applying a manual and serial reaction time (RT) paradigm to semantic categorization. METHODS: We evaluated 26 MS patients and 26 socio-demographic matched control participants using the PLSC task. RESULTS: Using non-parametric statistical analyses, we observed a significant improvement of semantic categorization RTs with practice (p = 0.002), even with new verbal material to categorize in MS patients (p = 0.006), despite their motor and executive moderate deficits. This same profile of semantic procedural learning in MS was observed in previous studies carried out with Alzheimer's and Parkinson's diseases. Moreover, the visual-motor RTs remained stable or slightly improved over the five blocks in both groups, as well as in the AD groups of previous studies. The MS group showed longer visual-motor reaction times than those of the control group (p < 0.042), except in motor initiation aspect (p = 0.064). Both groups showed no significant differences for any type of error. Additionally, disability level and cognitive performances were not associated with the ratio of semantic procedural learning. CONCLUSION: The present results support the notion that MS patients may be capable of acquiring semantic skill, despite their motor disabilities and executive troubles. This work also addresses the possibilities to improve motor-cognitive skill RTs in neurodegenerative diseases.

Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.

The coexistence of recurrent cerebral tumefactive demyelinating lesions with longitudinally extensive transverse myelitis and demyelinating neuropathy.

Combined central and peripheral demyelination (CCPD) is a rare chronic inflammatory disorder of the nervous system. In this article, we report on a CCPD patient with a very unusual pattern of central demyelination, comprising recurrent cerebral tumefactive demyelinating lesions (three times, each one in a new area of the brain) and one episode of longitudinally extensive transverse myelitis. This patient could not be classified as having multiple sclerosis, or neuromyelitis optica spectrum disorder, or any other well-known inflammatory disorder of the central nervous system, associated with demyelinating neuropathy. A diagnosis of idiopathic inflammatory demyelinating disorder (IIDD) was made while waiting for more knowledge concerning the diseases currently characterized as IIDD.

Transcranial Doppler to detect right-to-left shunt in cryptogenic acute ischemic stroke.

OBJECTIVES: We aimed to confirm the sensitivity and specificity of contrast transcranial Doppler (cTCD) in the detection of right-to-left shunt (RLS) compared to the current reference standard (i.e., transesophageal echocardiography-TEE) in patients aged <55 years with a cryptogenic acute ischemic stroke (AIS) or high-risk (ABCD2 score ≥4) transient ischemic attack (TIA), and to calculate the real life delay in detecting RLS by cTCD versus TEE in a tertiary care academic stroke center. METHODS: Consecutive 16- to 54-year-old patients with AIS or high-risk TIA underwent complete diagnostic workup which included, in case of undetermined etiology, cTCD and TEE. Sensitivity and specificity of cTCD, RLS characteristics, and median delay between the two tests were calculated. RESULTS: Of the 98 included patients, 52 (53%) had a cryptogenic cerebrovascular ischemic event, which displayed a 56% prevalence of RLS related to a patent foramen ovale (PFO) mainly with a high-grade shunt. When comparing TCD with "bubble test" to TEE, sensitivity and specificity were both 100%. Median delays from symptom onset to examination were 2 (min-max 1-10) and 21 (min-max 1-60) days, respectively, for cTCD and TEE. No adverse event occurred during or after cTDC examination. CONCLUSIONS: Transcranial Doppler with "bubble test" appears as the best screening test for the detection of RLS in young and middle-aged adults with cryptogenic acute cerebral ischemic events to select patients potentially suitable for closure procedure after TEE confirmation.

Neuromyelitis optica spectrum disorder mimicking extensive leukodystrophy.

Brain MRI was originally considered to appear normal in neuromyelitis optica spectrum disorders (NMO-SD). Typical brain lesions are now well described and have been integrated in the latest revision of NMO-SD criteria, but the NMO-SD MRI pattern remains not yet comprehensive. We report here extensive white matter lesions (EWML) mimicking leukodystrophy in a 50-year-old woman with long-lasting anti-AQP4+ NMO-SD. We suggest that EWML could be a possible brain MRI presentation of NMO-SD patients.

Controlled Education of patients after Stroke (CEOPS)- nurse-led multimodal and long-term interventional program involving a patient's caregiver to optimize secondary prevention of stroke: study protocol for a randomized controlled trial.

BACKGROUND: Setting up a follow-up secondary prevention program after stroke is difficult due to motor and cognitive impairment, but necessary to prevent recurrence and improve patients' quality of life. To involve a referent nurse and a caregiver from the patient's social circle in nurse-led multimodal and long-term management of risk factors after stroke could be an advantage due to their easier access to the patient and family. The aim of this study is to compare the benefit of optimized follow up by nursing personnel from the vascular neurology department including therapeutic follow up, and an interventional program directed to the patient and a caregiving member of their social circle, as compared with typical follow up in order to develop a specific follow-up program of secondary prevention of stroke. METHODS/DESIGN: The design is a randomized, controlled, clinical trial conducted in the French Stroke Unit of the Strokavenir network. In total, 410 patients will be recruited and randomized in optimized follow up or usual follow up for 2 years. In both group, patients will be seen by a neurologist at 6, 12 and 24 months. The optimized follow up will include follow up by a nurse from the vascular neurology department, including therapeutic follow up, and a training program on secondary prevention directed to the patient and a caregiving member of their social circle. After discharge, a monthly telephone interview, in the first year and every 3 months in the second year, will be performed by the nurse. At 6, 12 and 24 month, the nurse will give the patient and caregiver another training session. Usual follow up is only done by the patient's general practitioner, after classical information on secondary prevention of risk factors during hospitalization. The primary outcome measure is blood pressure measured after the first year of follow up. Blood pressure will be measured by nursing personnel who do not know the group into which the patient has been randomized. Secondary endpoints are associated mortality, morbidity, recurrence, drug side-effects and medico-economic analysis. DISCUSSION: The result of this trial is expected to provide the benefit of a nurse-led optimized multimodal and long-term interventional program for management of risk factors after stroke, personalizing the role of the nurse and including the patient's caregiver. TRIAL REGISTRATION: ClinicalTrials.gov, NCT 02132364. Registered on 7 May 2014. EUDRACT, A 00473-40.

Should We Screen for Janus Kinase 2 V617F Mutation in Cerebral Venous Thrombosis?

BACKGROUND: The presence of Janus Kinase 2 (JAK2) V617F mutation represents a major diagnostic criterion for detecting myeloproliferative neoplasms (MPN) and even in the absence of overt MPN, JAK2 V617F mutation is associated with splanchnic vein thrombosis. However, the actual prevalence and diagnostic value of the JAK2 V617F mutation in patients with cerebral venous thrombosis (CVT) are not known. The aims of this study were to assess the prevalence of JAK2 V617F mutation in a large group of consecutive CVT patients, to detect clinical, biological, and radiological features associated with the mutation, and to determine the long-term venous thrombosis recurrence rate in CVT patients with JAK2 mutation but without overt MPN in order to recommend the best preventive treatment. METHODS: This was a prospective study conducted on consecutive patients with a first-ever radiologically confirmed CVT. JAK2 V617F mutation analysis was assessed in all the study subjects. JAK2 V617F-positive patients were followed up to detect new venous thrombotic events. RESULTS: Of the 125 included subjects, 7 were found to have JAK2 V617F mutation (5.6%; 95% CI 2.3-11.2). Older age (p = 0.039) and higher platelet count (p = 0.004) were independently associated with JAK2 V617F positivity in patients without overt MPN. During a mean follow-up period of 59 (SD 46) months, 2 JAK2 V617F-positive patients presented with 4 new venous thromboembolic events. CONCLUSIONS: Screening for the JAK2 V617F mutation in CVT patients seems to be useful even in the absence of overt MPN and/or in the presence of other risk factors for CVT because of its relatively high prevalence and the risk of thrombosis recurrence.