Neurostimulation in people with drug-resistant epilepsy: Systematic review and meta-analysis from the ILAE Surgical Therapies Commission.

OBJECTIVE: Summarize the current evidence on efficacy and tolerability of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) through a systematic review and meta-analysis. METHODS: We followed the Preferred Reporting Items of Systematic reviews and Meta-Analyses reporting standards and searched Ovid Medline, Ovid Embase, and the Cochrane Central Register of Controlled Trials. We included published randomized controlled trials (RCTs) and their corresponding open-label extension studies, as well as prospective case series, with ≥20 participants (excluding studies limited to children). Our primary outcome was the mean (or median, when unavailable) percentage decrease in frequency, as compared to baseline, of all epileptic seizures at last follow-up. Secondary outcomes included the proportion of treatment responders and proportion with seizure freedom. RESULTS: We identified 30 eligible studies, six of which were RCTs. At long-term follow-up (mean 1.3 years), five observational studies for VNS reported a pooled mean percentage decrease in seizure frequency of 34.7% (95% confidence interval [CI]: -5.1, 74.5). In the open-label extension studies for RNS, the median seizure reduction was 53%, 66%, and 75% at 2, 5, and 9 years of follow-up, respectively. For DBS, the median reduction was 56%, 65%, and 75% at 2, 5, and 7 years, respectively. The proportion of individuals with seizure freedom at last follow-up increased significantly over time for DBS and RNS, whereas a positive trend was observed for VNS. Quality of life was improved in all modalities. The most common complications included hoarseness, and cough and throat pain for VNS and implant site pain, headache, and dysesthesia for DBS and RNS. SIGNIFICANCE: Neurostimulation modalities are an effective treatment option for drug-resistant epilepsy, with improving outcomes over time and few major complications. Seizure-reduction rates among the three therapies were similar during the initial blinded phase. Recent long-term follow-up studies are encouraging for RNS and DBS but are lacking for VNS.

Non-contrast CT markers of intracerebral hematoma expansion: a reliability study.

OBJECTIVES: We evaluated whether clinicians agree in the detection of non-contrast CT markers of intracerebral hemorrhage (ICH) expansion. METHODS: From our local dataset, we randomly sampled 60 patients diagnosed with spontaneous ICH. Fifteen physicians and trainees (Stroke Neurology, Interventional and Diagnostic Neuroradiology) were trained to identify six density (Barras density, black hole, blend, hypodensity, fluid level, swirl) and three shape (Barras shape, island, satellite) expansion markers, using standardized definitions. Thirteen raters performed a second assessment. Inter- and intra-rater agreement were measured using Gwet's AC1, with a coefficient > 0.60 indicating substantial to almost perfect agreement. RESULTS: Almost perfect inter-rater agreement was observed for the swirl (0.85, 95% CI: 0.78-0.90) and fluid level (0.84, 95% CI: 0.76-0.90) markers, while the hypodensity (0.67, 95% CI: 0.56-0.76) and blend (0.62, 95% CI: 0.51-0.71) markers showed substantial agreement. Inter-rater agreement was otherwise moderate, and comparable between density and shape markers. Inter-rater agreement was lower for the three markers that require the rater to identify one specific axial slice (Barras density, Barras shape, island: 0.46, 95% CI: 0.40-0.52 versus others: 0.60, 95% CI: 0.56-0.63). Inter-observer agreement did not differ when stratified for raters' experience, hematoma location, volume, or anticoagulation status. Intra-rater agreement was substantial to almost perfect for all but the black hole marker. CONCLUSION: In a large sample of raters with different backgrounds and expertise levels, only four of nine non-contrast CT markers of ICH expansion showed substantial to almost perfect inter-rater agreement. KEY POINTS: • In a sample of 15 raters and 60 patients, only four of nine non-contrast CT markers of ICH expansion showed substantial to almost perfect inter-rater agreement (Gwet's AC1> 0.60). • Intra-rater agreement was substantial to almost perfect for eight of nine hematoma expansion markers. • Only the blend, fluid level, and swirl markers achieved substantial to almost perfect agreement across all three measures of reliability (inter-rater agreement, intra-rater agreement, agreement with the results of a reference reading).

Inter-rater reliability of risk of bias tools for non-randomized studies.

PURPOSE: There is limited knowledge on the reliability of risk of bias (ROB) tools for assessing internal validity in systematic reviews of exposure and frequency studies. We aimed to identify and then compare the inter-rater reliability (IRR) of six commonly used tools for frequency (Loney scale, Gyorkos checklist, American Academy of Neurology [AAN] tool) and exposure (Newcastle-Ottawa scale, SIGN50 checklist, AAN tool) studies. METHODS: Six raters independently assessed the ROB of 30 frequency and 30 exposure studies using the three respective ROB tools. Articles were rated as low, intermediate, or high ROB. We calculated an intraclass correlation coefficient (ICC) for each tool and category of ROB tool. We compared the IRR between ROB tools and tool type by inspection of overlapping ICC 95% CIs and by comparing their coefficients after transformation to Fisher's Z values. We assessed the criterion validity of the AAN ROB tools by calculating an ICC for each rater in comparison with the original ratings from the AAN. RESULTS: All individual ROB tools had an IRR in the substantial range or higher (ICC point estimates between 0.61 and 0.80). The IRR was almost perfect (ICC point estimate > 0.80) for the AAN frequency tool and the SIGN50 checklist. All tools were comparable in IRR, except for the AAN frequency tool which had a significantly higher ICC than the Gyorkos checklist (p = 0.021) and trended towards a higher ICC when compared to the Loney scale (p = 0.085). When examined by category of ROB tool, scales, and checklists had a substantial IRR, whereas the AAN tools had an almost perfect IRR. For the criterion validity of the AAN ROB tools, the average agreement between our raters and the original AAN ratings was moderate. CONCLUSION: All tools had substantial IRRs except for the AAN frequency tool and the SIGN50 checklist, which both had an almost perfect IRR. The AAN ROB tools were the only category of ROB tools to demonstrate an almost perfect IRR. This category of ROB tools had fewer and simpler criteria. Overall, parsimonious tools with clear instructions, such as those from the AAN, may provide more reliable ROB assessments.

Screening for cognitive impairment in adults with sickle cell disease: A systematic review and meta-analysis.

Neurovascular disease such as symptomatic stroke, silent brain infarcts and vascular cognitive impairment are common complications of sickle cell disease (SCD) that can have devastating consequences on quality of life, employment, and social functioning.  Early recognition of neurovascular disease is a prerequisite for the timely optimization of medical care and to connect patients to adaptive resources. While cognitive impairment has been well described in children, currently available data are limited in adults. As a result, guidance on the optimal cognitive screening strategies in adults is scarce. We conducted a systematic review to identify the different screening tools that have been evaluated in SCD. A meta-analysis was performed to estimate the prevalence of suspected cognitive impairment in this population. In this qualitative synthesis, we present 8 studies that evaluated 6 different screening tools. Patient characteristics that impacted on cognitive screening performance included age, education level, and a prior history of stroke. We report a pooled prevalence of 38% [14-62%] of suspected cognitive impairment. We discuss the relative benefits and limitations of the different screening tools to help clinicians select an adapted approach tailored to their specific patients' needs. Further studies are needed to establish and validate cognitive screening strategies in patients with diverse cultural and educational backgrounds.

Diagnosis and Management of Central Nervous System Demyelinating Disorders.

The spectrum of demyelinating diseases affecting the central nervous system is broad. Although many have a chronic course, neuroinflammatory conditions often present with acute to subacute onset symptoms requiring hospitalization when severe. This article reviews the acute phase assessment and management of these disorders, with a particular focus on multiple sclerosis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody disorder, and several atypical demyelinating diseases.

Numb Chin Syndrome in Sickle Cell Disease: A Systematic Review and Recommendations for Investigation and Management.

Numb chin syndrome (NCS) is a rare sensory neuropathy resulting from inferior alveolar or mental nerve injury. It manifests as hypoesthesia, paraesthesia, or, rarely, as pain in the chin and lower lip. Several case reports suggest that sickle cell disease (SCD) could be a cause of NCS. However, information about NCS is scarce in this population. Our objectives were to synthesize all the available literature relevant to NCS in SCD and to propose recommendations for diagnosis and management based on the best available evidence. A systematic review was performed on several databases to identify all relevant publications on NCS in adults and children with SCD. We identified 73 publications; fourteen reports met the inclusion/exclusion criteria. These described 33 unique patients. Most episodes of NCS occurred in the context of typical veno-occlusive crises that involved the mandibular area. Radiological signs of bone infarction were found on some imaging, but not all. Neuropathy management was mostly directed toward the underlying cause. Overall, these observations suggest that vaso-occlusion and bone infarction could be important pathophysiological mechanisms of NCS. However, depending on the individual context, we recommend a careful evaluation to rule out differential causes, including infections, local tumors, metastatic disease, and stroke.

Identification and Classification of Rare Variants in NPC1 and NPC2 in Quebec.

Niemann-Pick disease type C (NPC) is a treatable autosomal recessive neurodegenerative condition which leads to a variety of progressive manifestations. Despite most cases being diagnosed at a young age, disease prevalence may be underestimated, especially in adults, and interpretation of NPC1 and NPC2 variants can be difficult. This study aims to identify potential pathogenic variants in a large cohort of healthy individuals and classify their risk of pathogenicity to assist with future interpretation of variants. The CARTaGENE (CaG) cohort was used to identify possible variants of NPC1 and NPC2. Nine-hundred and eleven RNA samples and 198 exome sequencing were screened for genetic variants through a bio-informatic pipeline performing alignment and variant calling. The identified variants were analyzed using annotations for allelic frequency, pathogenicity and conservation scores. The ACMG guidelines were used to classify the variants. These were then compared to existing databases and previous studies of NPC prevalence, including the Tübingen NPC database. Thirty-two distinct variants were identified after running the samples in the RNA-sequencing pipeline, two of which were classified as pathogenic and 21 of which were not published previously. Furthermore, 46 variants were both identified in our population and with the Tübingen database, the majority of which were of uncertain significance. Ten additional variants were found in our exome-sequencing sample. This study of a sample from a population living in Quebec demonstrates a variety of rare variants, some of which were already described in the literature as well as some novel variants. Classifying these variants is arduous given the scarcity of available literature, even so in a population of healthy individuals. Yet using this data, we were able to identify two pathogenic variants within our population and several new variants not previously identified.

Estimated prevalence of Niemann-Pick type C disease in Quebec.

Niemann-Pick type C (NP-C) disease is an autosomal recessive disease caused by variants in the NPC1 or NPC2 genes. It has a large range of symptoms depending on age of onset, thus making it difficult to diagnose. In adults, symptoms appear mainly in the form of psychiatric problems. The prevalence varies from 0.35 to 2.2 per 100,000 births depending on the country. The aim of this study is to calculate the estimated prevalence of NP-C in Quebec to determine if it is underdiagnosed in this population. The CARTaGENE database is a unique database that regroups individuals between 40 and 69 years old from metropolitan regions of Quebec. RNA-sequencing data was available for 911 individuals and exome sequencing for 198 individuals. We used a bioinformatic pipeline on those individuals to extract the variants in the NPC1/2 genes. The prevalence in Quebec was estimated assuming Hardy-Weinberg Equilibrium. Two pathogenic variants were used. The variant p.Pro543Leu was found in three heterozygous individuals that share a common haplotype, which suggests a founder French-Canadian pathogenic variant. The variant p.Ile1061Thr was found in two heterozygous individuals. Both variants have previously been reported and are usually associated with infantile onset. The estimated prevalence calculated using those two variants is 0.61:100,000 births. This study represents the first estimate of NP-C in Quebec. The estimated prevalence for NP-C is likely underestimated due to misdiagnosis or missed cases. It is therefore important to diagnose all NP-C patients to initiate early treatment.

Frequency and predictors of occult cancer in ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: The optimal approach for cancer screening after an ischemic stroke remains unclear. AIMS: We sought to summarize the existing evidence regarding the frequency and predictors of cancer after an ischemic stroke. SUMMARY OF REVIEW: We searched seven databases from January 1980 to September 2019 for articles reporting malignant tumors and myeloproliferative neoplasms diagnosed after an ischemic stroke (PROSPERO protocol: CRD42019132455). We screened 15,400 records and included 51 articles. The pooled cumulative incidence of cancer within one year after an ischemic stroke was 13.6 per thousand (95% confidence interval [CI], 5.6-24.8), higher in studies focusing on cryptogenic stroke (62.0 per thousand; 95% CI, 13.6-139.3 vs 9.6 per thousand; 95% CI, 4.0-17.3; p = 0.02) and those reporting cancer screening (39.2 per thousand; 95% CI, 16.4-70.6 vs 7.2 per thousand; 95% CI, 2.5-14.1; p = 0.003). Incidence of cancer after stroke was generally higher compared to people without stroke. Most cases were diagnosed within the first few months after stroke. Several predictors of cancer were identified, namely older age, smoking, and involvement of multiple vascular territories as well as elevated C-reactive protein and d-dimers. CONCLUSIONS: The frequency of incident cancer after an ischemic stroke is low, but higher in cryptogenic stroke and after cancer screening. Several predictors may increase the yield of cancer screening after an ischemic stroke. The pooled incidence of post-stroke cancer is likely underestimated, and larger studies with systematic assessment of cancer after stroke are needed to produce more precise and valid estimates.

Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: A critical review.

Three decades after its introduction as an adjuvant therapeutic option in the management of selective drug-resistant epilepsy cases (DRE), vagus nerve stimulation (VNS) retains growing interest. An implantable device was first approved for epilepsy in Europe in 1994 and in the United States (US) in 1997. Subsequent modifications improved the safety and the efficacy of the system. The most recent application of vagal neurostimulation is represented by transcutaneous devices that are claimed to have strong therapeutic potential. In this review, we sought to analyze the most meaningful available data describing the indications, safety and efficacy of the different approaches of VNS in clinical practice. Therefore, we identified studies reporting VNS efficacy and/or safety in epilepsy and its comorbidities from January 1990 to February 2020 from various databases including PubMed, Scopus, Cochrane, US government databases and VNS manufacturer published resources. In general, VNS efficacy becomes optimal around the sixth month of treatment and a 50-100 % seizure frequency reduction is achieved in approximately 45-65 % of the patients. However, some clinically relevant differences have been reported with specific factors such as epilepsy etiology or type, patient age as well as the delay of VNS therapy onset. VNS efficacy on seizure frequency has been demonstrated in both children and adults, in lesional and non-lesional cases, in focal and generalized epilepsies, on both seizures and epilepsy comorbidities. Regarding the latter, VNS can lead to an improvement of about 25-35 % in depression scores, 35 % in anxiety scores and 25 % in mood assessment scores. If non-invasive devices are undeniably safer, their efficacy is limited due to the scarcity of large cohort studies and the disparity of methodological approaches (study design and stimulation parameters). Overall, we believe that there is a progress margin for improving the safety of implantable devices and, above all, the effectiveness of the various VNS approaches.

Transcatheter Arterial Embolization of Spontaneous Soft Tissue Hematomas: A Systematic Review.

BACKGROUND: Severe spontaneous soft tissue hematomas (SSTH) are usually treated with transcatheter arterial embolization (TAE) although only limited retrospective studies exist evaluating this treatment option. The aim of this study was to systematically assess the efficacy and safety of TAE for the management of SSTH. METHODS: Medline, EMBASE, PubMed and Cochrane Library were searched from inception to July 2017 using MeSH headings and a combination of keywords. Eligibility was restricted to original studies with patients suffering from SSTH treated with TAE. Patients with traumatic hematomas or who were treated with solely conservative or surgical management were excluded. For each publication, clinical success based on the control of the bleed, rebleeding rates and complications (including mortality) was collected, as well as technical details. RESULTS: Sixty-three studies met the inclusion criteria, with an aggregate total of 267 patients. Follow-up extended from 1 day to 10 years. Bleeding was mainly localized to the iliopsoas (n = 113/267, 42.3%) and anterior abdominal wall (n = 145/266, 54.7%). When information was available, 81.0% (n = 158/195) of patients were on anticoagulant therapy prior to the bleeding episode. Initial stabilization with control of the bleed was obtained in 93.1% (n = 242 patients, n = 60 studies). The most common embolic materials were coils (n = 129, 54.4%). Rebleeding was reported in 25 patients (9.4%). Only two embolization complications were reported (0.7%). The 30-day mortality was 22.7% (n = 42/1857). CONCLUSION: TAE represents a safe and effective procedure in the management of SSTH. We present a management algorithm based on these data, but further studies are needed to address the knowledge gap.

Stent Retrievers for the Treatment of Acute Ischemic Stroke: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

IMPORTANCE: Stent retrievers are a promising alternative for the treatment of acute ischemic stroke (AIS). Several recently completed clinical trials have examined the use of stent retrievers with intravenous recombinant tissue plasminogen activator (rtPA) compared with rtPA alone. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized clinical trials to quantify the benefits and risks of using stent retrievers in addition to rtPA for the treatment of AIS. DATA SOURCES: The MEDLINE, EMBASE, and Cochrane Library of Clinical Trials databases were searched from inception to July 2015 for the keywords stent*, retriev*, Solitaire, Trevo, Revive, and stroke. Trial registries were also searched. A total of 326 publications were identified and 213 potentially relevant records were screened. STUDY SELECTION: Randomized clinical trials that examined stent retrievers with rtPA vs rtPA alone were included in the meta-analysis. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted study data and performed quality assessment using the Cochrane Risk of Bias Tool. DerSimonian and Laird random-effects models were used to estimate relative risks (RRs), risk differences (RDs), and numbers needed to treat. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients achieving functional independence (defined as a score of 0-2 on the modified Rankin Scale, with 0 indicating no disability and 6 indicating death) at 90 days. Risks of all-cause mortality, intracranial hemorrhage, and parenchymal hematoma at 90 days were also assessed. RESULTS: Five randomized clinical trials met our inclusion criteria (n = 1287 patients). Patients randomized to stent-retriever therapy with rtPA had significantly improved rates of functional independence at 90 days compared with those randomized to rtPA alone (RR, 1.72; 95% CI, 1.48-1.99; RD, 0.19; 95% CI, 0.13-0.25). When data were pooled across trials, the effect of stent-retriever therapy on all-cause mortality at 90 days was inconclusive (RR, 0.82; 95% CI, 0.60-1.11; RD, -0.04; 95% CI, -0.08 to 0.1). There were similarly no detectable differences in the risks of intracranial hemorrhage (RR, 1.15; 95% CI, 0.67-1.97; RD, 0.00; 95% CI, -0.02 to 0.03) or parenchymal hematoma (RR, 1.18; 95% CI, 0.71-1.94; RD, 0.01; 95% CI, -0.01 to 0.04), although the 95% CIs were wide. Fixed-effects sensitivity analyses produced similar results for all outcomes. CONCLUSIONS AND RELEVANCE: The use of stent retrievers in conjunction with rtPA vs rtPA alone is associated with significant improvement of functional independence 90 days after AIS.

Varenicline and Adverse Cardiovascular Events: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Varenicline is an efficacious smoking-cessation drug. However, previous meta-analyses provide conflicting results regarding its cardiovascular safety. The publication of several new randomized controlled trials (RCTs) provides an opportunity to reassess this potential adverse drug reaction. METHODS AND RESULTS: We searched MEDLINE, EMBASE, and the Cochrane Library for RCTs that compare varenicline with placebo for smoking cessation. RCTs reporting cardiovascular serious adverse events and/or all-cause mortality during the treatment period or within 30 days of treatment discontinuation were eligible for inclusion. Relative risks (RRs) with 95% CIs were generated by using DerSimonian-Laird random-effects models. Thirty-eight RCTs met our inclusion criteria (N=12 706). Events were rare in both varenicline (57/7213) and placebo (43/5493) arms. No difference was observed for cardiovascular serious adverse events when comparing varenicline with placebo (RR 1.03, 95% CI 0.72-1.49). Similar findings were obtained when examining cardiovascular (RR 1.04, 95% CI 0.57-1.89) and noncardiovascular patients (RR 1.03, 95% CI 0.64-1.64). Deaths were rare in both varenicline (11/7213) and placebo (9/5493) arms. Although 95% CIs were wide, pooling of all-cause mortality found no difference between groups (RR 0.88, 95% CI 0.50-1.52), including when stratified by participants with (RR 1.24, 95% CI 0.40-3.83) and without (RR 0.77, 95% CI 0.40-1.48) cardiovascular disease. CONCLUSIONS: We found no evidence that varenicline increases the rate of cardiovascular serious adverse events. Results were similar among those with and without cardiovascular disease. Given varenicline's efficacy as a smoking cessation drug and the long-term cardiovascular benefits of cessation, it should continue to be prescribed for smoking cessation.

A meta-analysis of randomized controlled trials of the risk of bleeding with apixaban versus vitamin K antagonists.

Apixaban is one of the new oral anticoagulants, which is prescribed as an alternative to vitamin K antagonists (VKAs). Concerns regarding its bleeding profile persist and require further evaluation. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) to compare the risks of bleeding and all-cause mortality between apixaban and VKAs. The MEDLINE, EMBASE, and Cochrane Library of Clinical Trials databases were systematically searched for RCTs comparing the risks of bleeding and all-cause mortality of apixaban (2.5 or 5 mg twice daily) with those of VKAs. We included RCTs conducted in adults and published in English or French. Data were pooled across RCTs using random-effects meta-analytical models. Our systematic search identified 5 RCTs meeting our inclusion criteria (n = 24,435). They included patients with atrial fibrillation (n = 18,358), total knee replacement surgery (n = 458), and venous thromboembolism (n = 5,619). Data pooled across RCTs revealed that apixaban was associated with reduced risks of any bleeding (relative risk [RR] 0.73, 95% confidence interval [CI] 0.59 to 0.90) and a composite of major or clinically relevant nonmajor bleeding (RR 0.60, 95% CI 0.40 to 0.88). Apixaban was also associated with a lower risk of intracranial bleeding (RR 0.42, 95% CI 0.31 to 0.58) whereas analyses of major and minor bleeding were inconclusive. Moreover, apixaban was associated with decreased all-cause mortality (RR 0.89, 95% CI 0.81 to 0.99) although this finding was driven by the results of the ARISTOTLE trial. In conclusion, our meta-analysis found that apixaban is associated with a lower risk of bleeding than VKAs, providing some reassurance regarding its safety.