Prevalence, Incidence, and Mortality of Myasthenia Gravis and Myasthenic Syndromes: A Systematic Review.

INTRODUCTION: No systematic reviews were published in the last years investigating epidemiological data, involving myasthenia gravis (MG) and related myasthenic syndromes. This systematic review aimed to estimate the prevalence, incidence, and mortality of all MG types and myasthenic syndromes worldwide. METHODS: All literature published up to February 2024 was retrieved by searching the databases "Medline," "Embase," "ISI Web of Science" and "CINAHL" using the following search terms: (epidemiolog* OR frequency OR prevalence OR incidence OR mortality) AND (myasth* OR "anti-acetylcholine receptor antibody" OR "AChR" OR "MuSK" OR "anti-muscle specific kinase antibody" OR "LRP4" OR "seronegative MG"). RESULTS: A total of 94 studies, performed between 1952 and 2022, were included. Prevalence of MG ranged from 20 to 475 cases per million, with a mean prevalence of 173.3 (95% confidence interval [CI]: 129.7-215.5) cases per million and a median prevalence of 129.6 cases per million. Incidence rates ranged from 2.3 to 61.3 cases per million person-years, with a mean incidence of 15.7 (95% CI: 11.5-19.9) and a median of 13.3 cases. Mortality rates showed a mean of 1.4 (95% CI: 0.8-2.1) cases per million person-years. Acetylcholine receptor (AChR)-MG was the clinical subtype more frequent in terms of prevalence and incidence. DISCUSSION: The prevalence and incidence of MG have significantly increased over the last years worldwide, probably due to the improvement of epidemiological methodologies and current advances in diagnosis. However, we observed a significant variation in frequencies of MG between and within countries because of methodological biases and complex heterogeneity of the disease characterized by several phenotypes and different clinical responses.

Myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications associated with a novel m.5513G>A mutation in the MT-TW gene.

We sequenced the mitochondrial genome from a 40-year-old woman with myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications. Histological and biochemical features of mitochondrial respiratory chain dysfunction were present. Direct sequencing showed a novel heteroplasmic mutation at nucleotide 5513 in the MT-TW gene that encodes tRNATrp. Restriction Fragment Length Polymorphism analysis confirmed that about 80% of muscle mtDNA harboured the mutation while it was present in minor percentages in mtDNA from other tissues. The mutation is predicted to disrupt a highly conserved base pair within the aminoacyl acceptor stem of the tRNA. This is the 17° mutation in MT-TW gene and expands the known causes of late-onset mitochondrial diseases.

Is it worth it, or possible, to measure what matters to patients with epilepsy and their caregivers?

OBJECTIVE: The objective of this study was to collect perspectives, ideas, and values of people affected by epilepsy and their carer to include them in new research in this area. DESIGN: This is a semiquantitative study analyzing needs, emotions, and medical issues emerging from focus groups with patients and carers divided in three severity levels of disease. PARTICIPANTS: The participants were 25 patients and 36 carers attending outpatients' service of tertiary epilepsy center in Umbria, Italy. RESULTS: Assistance was the need expressed by more than 40% of the participants followed by experience-sharing, knowledge, control, clarity, and security. The only significant effect in logistic regression analysis after adjusting for severity was the patients' expressed need for "experience-sharing" more than their carers (OR 7.29, 95%CI: 1.76-30.18). Hope was the emotion expressed by more than 50% of the participants, followed by anger, fear, and resignation. After adjusting for severity, carers were more likely to express anger, in comparison with patients (OR 17.23, 95%CI: 3.55-83.74; P<0.001). The patients were 6.88 times more likely (95%CI 1.84-25.75; P=0.004) to express "resignation" than their carers. The most frequent medical issues were related to: "medications", "frequency of crises", "work impact", "quality of life", "psychomedical integration of care", and "development of new drugs". After adjusting for severity in a logistic regression analysis, patients were more likely to express concerns for the frequency of crises than carers (OR 3.57, 95%CI: 1.16-11.04; P=0.027). CONCLUSIONS: Patients' and carers' priorities, based on intense personal insight, represent a starting point to work for shared outcome measures in clinical trials and shared agenda in research, including research of strong evidence in complex intervention as service models for people with epilepsy.

Piracetam for acute ischaemic stroke.

BACKGROUND: Piracetam has neuroprotective and antithrombotic effects that may help to reduce death and disability in people with acute stroke. This is an update of a Cochrane Review first published in 1999, and previously updated in 2006 and 2009. OBJECTIVES: To assess the effects of piracetam in acute, presumed ischaemic stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 15 May 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), MEDLINE (1966 to May 2011), EMBASE (1980 to May 2011), and ISI Science Citation Index (1981 to May 2011). We also contacted the manufacturer of piracetam to identify further published and unpublished studies. SELECTION CRITERIA: Randomised trials comparing piracetam with control, with at least mortality reported and entry to the trial within three days of stroke onset. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed trial quality and this was checked by the other two review authors. We contacted study authors for missing information. MAIN RESULTS: We included three trials involving 1002 patients, with one trial contributing 93% of the data. Participants' ages ranged from 40 to 85 years, and both sexes were equally represented. Piracetam was associated with a statistically non-significant increase in death at one month (approximately 31% increase, 95% confidence interval 81% increase to 5% reduction). This trend was no longer apparent in the large trial after correction for imbalance in stroke severity. Limited data showed no difference between the treatment and control groups for functional outcome, dependence or proportion of patients dead or dependent. Adverse effects were not reported. AUTHORS' CONCLUSIONS: There is some suggestion (but no statistically significant result) of an unfavourable effect of piracetam on early death, but this may have been caused by baseline differences in stroke severity in the trials. There is not enough evidence to assess the effect of piracetam on dependence.

Identifying unanswered questions and setting the agenda for future systematic research in Multiple Sclerosis. A worldwide, multi-stakeholder Priority Setting project.

BACKGROUND: Eliciting the research priorities of people affected by a condition, carers and health care professionals can increase research value and reduce research waste. The Cochrane Multiple Sclerosis and Rare Disease of CNS Group, in collaboration with the Cochrane Neurological Sciences Field, launched a priority setting exercise with the aim of prioritizing pressing questions to ensure that future systematic reviews are as useful as possible to the people who need them, in all countries, regardless of their economic status. METHOD: Sixteen high priority questions on different aspects of MS were developed by members of a multi-stakeholder priority setting Steering Group (SG). In an anonymous online survey translated into 12 languages researchers, clinicians, people with MS (PwMS) and carers were asked to identify and rank, 5 out of 16 questions as high priority and to provide an explanation for their choice. An additional free-text priority research topic suggestion was allowed. RESULTS: The survey was accessible through MS advocacy associations' social media and Cochrane web pages from October 20, 2020 to February 6, 2021. 1.190 responses (86.73% of all web contacts) were evaluable and included in the analysis. Responses came from 55 countries worldwide, 7 of which provided >75% of respondents and 95% of which were high and upper-middle income countries. 58.8% of respondents live in the EU, 23% in the Americas, 8.9% in the Western Pacific, 2.8% in the Eastern Mediterranean and 0.3% in South Eastern Asia. About 75% of the respondents were PwMS. The five research questions to be answered with the highest priority were: Question (Q)1 "Does MRI help predict disability worsening of PwMS?" (19.9%), Q5 "What are the benefits and harms of treating PwMS with one disease-modifying drug compared to another?" (19.3%), Q3 "Does multidisciplinary care by teams of different social and health professionals improve health outcomes and experiences for PwMS?" (11.9%), Q16 "Does psychological health affect disease progression in PwMS?" (9.2%) and Q10 "What are the benefits and harms of exercise for PwMS?" (7.2%). The multivariable logistic regression analysis indicated a significant influence of geographic area and income level on the ranking of Q1 and a marginal for Q16 as top a priority after accounting for the effect of all other predictors. Approximately 50% of the respondents indicated that they had an important additional suggestion to be considered. CONCLUSION: This international collaborative initiative in the field of MS offers a worldwide perspective on the research questions perceived as pivotal by a geographically representative sample of multiple stakeholders in the field of MS. The results of the survey could guide the prioritization of research on pharmacological and non-pharmacological interventions which could be meaningful and useful for PwMS and carers, avoiding the duplication of efforts and research waste. High quality systematic reviews elicited by priority setting exercises may offer the best available evidence and inform decisions by healthcare providers and policy-makers which can be adapted to the different realities around the world.

People with amyotrophic lateral sclerosis and their caregivers: what matters most?

OBJECTIVES: The aim of this study is to collect the perspectives and values of people affected by amyotrophic lateral sclerosis (ALS) and their carers to offer clinicians, researchers and policymakers aspects which are precious in prioritising future research questions and reshaping care service organisations in a participatory approach. DESIGN AND SETTING: Cohort study using ALS Umbria, the electronic database in Italy. PARTICIPANTS: Eleven patients and 33 carers who agreed to participate in the study were divided into six focus groups by 'status' (patient or carer) and by four severity levels of 'burden of disease'. METHODS: A semiquantitative analysis was undertaken. Each recorded group discussion was transcribed into text file and independently read by two psychologists and two ALS specialists to blindly identify needs, emotions and medical issues, which are the key semantic meanings expressed. Any disagreement in interpretation was resolved through consultation among authors. RESULTS: Carers pronounced significantly more words related to patient's disease burden they cared. 40% of subjects expressed the need for 'assistance', regardless of the disease burden. 'Anger' alone represented more than 1/4 of all expressed emotions and was more common in patients than in carers (73% vs 36%, p=0.077). The most frequent medical issue expressed by 1/3 of participants was 'difficulty in communication'. CONCLUSION: This study has given voice to the expectations of those affected by the burden of ALS. 'Welfare assistance', 'anger management' and resolution of 'difficulties in communication' represent issues that need to be analysed in a common prioritised research agenda with sensible and shared outcome measures to implement patient-centred medicine.

Progressive Myoclonus Epilepsies: Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases.

BACKGROUND AND OBJECTIVES: To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort. METHODS: Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: "Unverricht-Lundborg disease-like PME," "late-onset PME," "PME plus developmental delay," and "PME plus dementia." RESULTS: Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories. DISCUSSION: The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

Is there inter-observer variation in the interpretation of SSEPs in comatose cardiac arrest survivors? Further considerations following the Italian multicenter ProNeCa study.

BACKGROUND: Bilateral absence of N20 peak in median nerve Somatosensory Evoked Potentials (SSEPs) is considered the most valid predictor of poor outcome in comatose survivors after cardiopulmonary resuscitation. We investigated the consistency in interpreting SSEP recordings in a multicentre study. METHODS: 44 SSEP recordings randomly extracted from 600 recordings of 392 patients included in the "Prognostication of Neurological outcome after Cardiac Arrest (ProNeCa) study" were blindly read by three expert neurophysiologists. Agreement between raters, and individual agreement of each rater vs. reference standard (RS), were calculated using Kappa Coefficients. Inter-rater reliability was calculated with Intra-class Correlation Coefficient (ICC). RESULTS: When raters had to evaluate the presence of N20 with normal amplitude, the inter-rater agreement was very high (Kappa = 0.84). In the case of N20 absence the agreement was good (Kappa = 0.66), but when N20 amplitude was low, the agreement decreased to moderate (Kappa = 0.579) becoming even weaker when it was "Non Assessable" (Kappa = 0.107). The agreement of each rater with the RS had a range from moderate to very good; rater1 Kappa = 0.589 (95%CI 0.397-0.781; p < 0.001), rater2 Kappa = 0.644 (95%CI 0.460-0.828; p < 0.001), rater3 Kappa = 0.859 (95%CI 0.698-1.000; p < 0.001). The ICC was barely good, 0.682 (95%CI 0.539-0.798; p = 0.0075). CONCLUSION: Different health professionals, using different equipment in a multicentre study, had very good inter-rater agreement in interpreting SSEP records. The interpretation of "Non Assessable" SEPPs, mainly in relation to noise level, is still a crucial issue because it increases rater uncertainty. For this reason, it is important to focus on improving recording quality and interpretation of records.

Chemotherapy-Related Encephalopathy With Super-Refractory Status Epilepticus in a Child With Osteosarcoma: A Case Report With a Review of Literature.

Osteosarcoma is the most frequent primary cancer of the bones, and a combination of primary chemotherapy, surgery, and adjuvant chemotherapy is its current treatment. In adults, some authors have reported problems with memory and concentration following chemotherapy, but in children, severe neurologic dysfunction has been rarely reported. This report describes a 13-year-old patient with primary high-grade nonmetastatic osteosarcoma of the tibia who developed encephalopathy with super-refractory status epilepticus related to chemotherapy. He received methotrexate (MTX) and cisplatin (CDDP)-containing polychemotherapy, and after the first course of drug administration, he developed fever, confusion, a state of psychomotor agitation, and super-refractory status epilepticus with normal laboratory and imaging findings. The causal relationship between the administration of the first polychemotherapy course and his neurological manifestations may be supported by the evaluation and exclusion of other causes. The administration of antiepileptic drugs and off-label atypical antipsychotics was necessary to treat his neurological complications and behavioral changes. This patient represents the first known example of super-refractory status epilepticus in a child treated with MTX and CDDP-containing chemotherapy. Physicians should be aware that encephalopathy and seizures are possible consequences of CDDP therapy when administered alone or in combination with other chemotherapeutic agents. Further studies are needed to better define this relationship in children.

Different measures for assessing stroke outcome: an analysis from the International Stroke Trial in Italy.

BACKGROUND AND PURPOSE: We sought to assess the relationship between 2 simple questions on recovery (question 1: do you feel that you have made a complete recovery from your stroke?) and dependency (question 2: do you require help from another person for everyday activities?) and the Barthel Index (BI) and Oxford Handicap Scale (OHS), as well as the relationship between BI and OHS, in a large number of Italian stroke survivors who participated in the International Stroke Trial (IST). METHODS: We used data from 2423 patients interviewed by telephone at 6 months after the event. The kappa statistic, sensitivity, and specificity were calculated for several comparisons. Internal consistency for BI was calculated. RESULTS: The reliability of the dependency question compared with BI=20 (kappa=0.93) and the reliability of the recovery question compared with OHS=0 (kappa=0.89) were good. Sensitivity of the dependency question in predicting whether patients scored BI >18 was 0.98; sensitivity of the recovery question in predicting whether patients scored OHS=0 was 0.99. The reliability of BI=20 compared with OHS <3 was good (kappa=0.87). Internal consistency of BI was very high (Cronbach's alpha=0.96). CONCLUSIONS: The 2 simple questions are a good means of evaluating outcome from a patient's view and of dichotomizing the stroke survivor in a time-effective and reliable way.

Glycerol for acute stroke: a Cochrane systematic review.

Brain oedema is a major cause of early death after stroke. Glycerol is a hyperosmolar agent that is claimed to reduce brain oedema. We sought to determine whether I. V. glycerol treatment in acute stroke, either ischaemic or haemorrhagic, influences death rates and functional outcome in the short or long term and whether the treatment is safe. The Cochrane Stroke Group Trials Register was searched, conference proceedings were screened and some trialists were personally contacted. We considered all completed, controlled, published and unpublished comparisons, evaluating clinical outcome, in which intravenous glycerol treatment was initiated within the first days after stroke onset. Death from all causes, functional outcome and adverse effects were analysed. Analysis of short term death for acute ischaemic and/or haemorrhagic stroke was possible in ten trials where 482 glycerol treated patients were compared with 463 control patients. Glycerol was associated with a non-significant reduction in the odds of death within the scheduled treatment period (OR 0.78, 95 % Confidence Intervals 0.58-1.06). Among patients with definite or probable ischaemic stroke, glycerol was associated with a significant reduction in the odds of death during the scheduled treatment period (odds ratio 0.65, 95 % CI 0.44-0.97). However, at the end of the scheduled follow up period there was no significant difference in the odds of death (odds ratio 0.98, 95 % CI 0.73-1.31). Functional outcome was reported in only two studies and there was a non-significant positive effect on outcome at the end of scheduled follow up (odds ratio 0.73, 95 % CI 0.37-1.42). Haemolysis seems to be the only relevant adverse effect of glycerol treatment. This systematic review suggests a favourable effect of glycerol treatment on short term survival in probable or definite ischaemic stroke, but the magnitude of the treatment effect may be minimal (as low as a 3 % reduction in odds). Because of the relatively small number of patients and because the trials have been performed in the pre-CT era, the results must be interpreted cautiously. The lack of evidence of benefit in long term survival does not support the routine or selective use of glycerol treatment in patients with acute stroke.