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Frontiers in Neurology 2022Dravet syndrome (DS) is a severe epileptic encephalopathy mainly caused by haploinsufficiency of the gene , which encodes the voltage-gated sodium channel Na1. 1 in the...
BACKGROUND
Dravet syndrome (DS) is a severe epileptic encephalopathy mainly caused by haploinsufficiency of the gene , which encodes the voltage-gated sodium channel Na1. 1 in the brain. While mutations are known to be the primary cause of DS, other genes that may cause DS are poorly understood. Several genes with pathogenic mutations result in DS or DS-like phenotypes, which may require different drug treatment approaches. Therefore, it is urgent for clinicians, especially epilepsy specialists to fully understand these genes involved in DS in addition to . Particularly for healthcare providers, a deep understanding of these pathogenic genes is useful in properly selecting and adjusting drugs in a more effective and timely manner.
OBJECTIVE
The purpose of this study was to identify genes other than that may also cause DS or DS-like phenotypes.
METHODS
A comprehensive search of relevant Dravet syndrome and severe myoclonic epilepsy in infancy was performed in PubMed, until December 1, 2021. Two independent authors performed the screening for potentially eligible studies. Disagreements were decided by a third, more professional researcher or by all three. The results reported by each study were narratively summarized.
RESULTS
A PubMed search yielded 5,064 items, and other sources search 12 records. A total of 29 studies published between 2009 and 2021 met the inclusion criteria. Regarding the included articles, seven studies on , three on , two on , five on , two on , three on , three on , and three on were included. Only one study was recorded for and , respectively. It is worth noting that a few articles reported on more than one epilepsy gene.
CONCLUSION
DS is not only identified in variants of , but other genes such as can also be involved in DS or DS-like phenotypes. As genetic testing becomes more widely available, more genes associated with DS and DS-like phenotypes may be identified and gene-based diagnosis of subtypes of phenotypes in this spectrum may improve the management of these diseases in the future.
PubMed: 35359639
DOI: 10.3389/fneur.2022.832380 -
The Canadian Journal of Neurological... Sep 2023Long latency reflexes (LLRs) are impaired in a wide array of clinical conditions. We aimed to illustrate the clinical applications and recent advances of LLR in various...
BACKGROUND
Long latency reflexes (LLRs) are impaired in a wide array of clinical conditions. We aimed to illustrate the clinical applications and recent advances of LLR in various neurological disorders from a systematic review of published literature.
METHODS
We reviewed the literature using appropriately chosen MeSH terms on the database platforms of MEDLINE, Web of Sciences, and Google Scholar for all the articles from 1st January 1975 to 2nd February 2021 using the search terms "long loop reflex", "long latency reflex" and "C-reflex". The included articles were analyzed and reported using synthesis without meta-analysis (SWiM) guidelines.
RESULTS
Based on our selection criteria, 40 articles were selected for the systematic review. The various diseases included parkinsonian syndromes (11 studies, 217 patients), Huntington's disease (10 studies, 209 patients), myoclonus of varied etiologies (13 studies, 127 patients) including progressive myoclonic epilepsy (5 studies, 63 patients) and multiple sclerosis (6 studies, 200 patients). Patients with parkinsonian syndromes showed large amplitude LLR II response. Enlarged LLR II was also found in myoclonus of various etiologies. LLR II response was delayed or absent in Huntington's disease. Delayed LLR II response was present in multiple sclerosis. Among the other diseases, LLR response varied according to the location of cerebellar lesions while the results were equivocal in patients with essential tremor.
CONCLUSIONS
Abnormal LLR is observed in many neurological disorders. However, larger systematic studies are required in many neurological disorders in order to establish its role in diagnosis and management.
Topics: Humans; Myoclonus; Huntington Disease; Reflex; Multiple Sclerosis; Neurology; Reaction Time; Electromyography
PubMed: 35801267
DOI: 10.1017/cjn.2022.270 -
CNS Drugs Aug 2021The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary...
BACKGROUND
The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary generalised tonic-clonic seizures (PGTCS) in idiopathic generalised epilepsies (IGEs).
OBJECTIVE
We aimed to identify and review available evidence on outcomes with perampanel in generalised seizures and epilepsies to examine its potential as a broad-spectrum anti-seizure medication.
METHODS
Bibliographic databases of publications, clinical trials, and conference abstracts were searched up to August 2020 to identify studies reporting seizure or safety outcomes in patients of any age, with any type of epilepsy-associated generalised seizures treated with perampanel. Data extracted from selected records were tabulated by seizure type and syndrome, and analysed qualitatively (PROSPERO protocol CRD42020201564).
RESULTS
Ninety-one reports met inclusion criteria and were selected: 15 reports of 1 randomised controlled trial (RCT), 8 reports of 4 non-randomised interventional studies, 37 reports of observational studies, 21 case reports and 10 systematic reviews and meta-analyses. Extracted data included 359 patients with PGTCS of any aetiology, 251 with myoclonic seizures, 112 with absence seizures, 50 with tonic seizures and 32 children with epileptic spasms. The most commonly reported epilepsy type was IGE (N = 378) and the most common syndromes were juvenile myoclonic epilepsy (N = 92), progressive myoclonic epilepsies (N = 59) and absence epilepsies (N = 43). The RCT provided Class I evidence of the efficacy and tolerability of adjunctive perampanel for PGTCS in patients aged ≥ 12 years with IGE. Data from other studies provides weaker (observational) evidence of its effectiveness in multiple generalised seizure types, including myoclonic, absence and tonic seizures. There were no patterns suggesting seizure worsening or aggravation in any seizure or epilepsy type.
CONCLUSIONS
The identified studies suggest the potential of perampanel as a broad-spectrum antiseizure medication. Much of the available data, however, come from non-randomised, non-controlled studies and are open to high risk of bias. Further studies are warranted to provide more robust evidence.
Topics: Anticonvulsants; Epilepsy, Generalized; Humans; Myoclonic Epilepsy, Juvenile; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 34232492
DOI: 10.1007/s40263-021-00831-y -
European Journal of Paediatric... Jul 2019Extrapolation of efficacy data from adults to children is accepted for focal epilepsy - the antiepileptic drug, lacosamide, has been approved for the treatment of...
Role of observational studies in supporting extrapolation of efficacy data from adults to children with epilepsy - A systematic review of the literature using lacosamide as an example.
Extrapolation of efficacy data from adults to children is accepted for focal epilepsy - the antiepileptic drug, lacosamide, has been approved for the treatment of children ≥4 years of age on this basis. Since many small-scale, open-label studies are reported in the literature before approval, a systematic review was conducted to ascertain whether results of these could be used to support extrapolation in epilepsy in the future. In the absence of randomised trials, a second analysis was conducted for reports on lacosamide use in adults with generalized epilepsies. Twenty-seven articles were included in the paediatric qualitative synthesis, and 14 in the adult. Paediatric studies were analysed separately based on seizure type: focal, generalised and mixed. In focal epilepsy, safety and seizure-related findings mirrored those observed in the adult Phase II/III trials, supporting the feasibility of data extrapolation. Few studies reported outcomes in children with epilepsies associated with generalised seizures, and those that included children with different seizure types, mostly did not provide results separately. Lacosamide treatment appeared beneficial for children and adults experiencing tonic-clonic and myoclonic seizures. Reports of seizure aggravation were inconsistent and, in many cases, could not be clearly attributed to lacosamide. Given the absence of sufficient data, evidence for the feasibility of extrapolation was not as clear-cut as it was in focal epilepsy. These results highlight the complexities of conducting trials in the generalised epilepsy setting, and the importance of studies in the real-life setting and of analysing efficacy data per generalized seizure type and syndrome.
Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Child; Child, Preschool; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Observational Studies as Topic
PubMed: 31171490
DOI: 10.1016/j.ejpn.2019.05.002 -
Seizure Oct 2021Rufinamide is an antiseizure medication that acts through sodium channels and is found to be efficacious in patients with Lennox Gastaut syndrome (LGS). However, no... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Rufinamide is an antiseizure medication that acts through sodium channels and is found to be efficacious in patients with Lennox Gastaut syndrome (LGS). However, no systematic review has been conducted in LGS patients to provide an estimate of the efficacy and safety of rufinamide.
METHODS
Different electronic databases were searched for articles describing the use of rufinamide in patients with LGS. For determining primary efficacy outcomes as compared to placebo, we included only studies comparing the efficacy of rufinamide with placebo in LGS patients. We performed an additional analysis to include other uncontrolled studies with a minimum sample size of 20 to provide a more comprehensive estimate of efficacy.
RESULTS
A total of ten studies included 557 patients. Out of them, five studies were placebo-controlled, enrolling a total of 265 patients in the rufinamide group and 203 patients in the placebo group. The average percentage reduction in total seizure frequency per 28 days during the double-blind phase was 29.3% in the rufinamide group compared with 8.3% in the placebo group (difference between the two groups was 20.9%, 95%CI-14.4%-27.3%, p <0.00001). Even for individual seizure types like tonic-clonic seizures, atypical absence seizures, atonic seizures, focal seizures, and myoclonic seizures, rufinamide was more efficacious than placebo(p<0.00001). The number of patients with at least one treatment-emergent adverse effects was significantly higher in rufinamide treated patients (60.2%vs50.7%, p=0.02, RR-1.24(1.03,1.51).
CONCLUSION
Rufinamide is efficacious as adjunctive therapy in patients with LGS in terms of reduction in total seizure frequency and has mild adverse reaction.
Topics: Anticonvulsants; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures; Triazoles
PubMed: 34273668
DOI: 10.1016/j.seizure.2021.07.004 -
The Cochrane Database of Systematic... Jul 2020This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic-clonic seizures are a type of generalised... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic-clonic seizures are a type of generalised seizure. Other types of seizures include: absence, myoclonic, and atonic seizures. Effective control of tonic-clonic seizures reduces the risk of injury and death, and improves quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not, and require a combination of antiepileptic drugs.
OBJECTIVES
To assess the effectiveness and tolerability of add-on lamotrigine for drug-resistant primary generalised tonic-clonic seizures.
SEARCH METHODS
For the latest update, we searched these databases on 19 March 2019: Cochrane Register of Studies (CRS) Web, MEDLINE Ovid, and the WHO International Clinical Trials Registry Platform (ICTRP). The CRS includes records from the Cochrane Epilepsy Group Specialized Register, CENTRAL, Embase, and ClinicalTrials.gov. We imposed no language restrictions. We also contacted GlaxoSmithKline, manufacturers of lamotrigine.
SELECTION CRITERIA
Randomised controlled parallel or cross-over trials of add-on lamotrigine for people of any age with drug-resistant primary generalised tonic-clonic seizures.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methodology; two review authors independently assessed trials for inclusion, evaluated risk of bias, extracted relevant data, and GRADE-assessed evidence. We investigated these outcomes: (1) 50% or greater reduction in primary generalised tonic-clonic seizure frequency; (2) seizure freedom; (3) treatment withdrawal; (4) adverse effects; (5) cognitive effects; and (6) quality of life. We used an intention-to-treat (ITT) population for all analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs); for adverse effects, we used 99% CIs to compensate for multiple hypothesis testing.
MAIN RESULTS
We included three studies (total 300 participants): two parallel-group studies and one cross-over study. We assessed varied risks of bias across studies; most limitations arose from the poor reporting of methodological details. We meta-analysed data extracted from the two parallel-group studies, and conducted a narrative synthesis for data from the cross-over study. Both parallel-group studies (270 participants) reported all dichotomous outcomes. Participants taking lamotrigine were almost twice as likely to attain a 50% or greater reduction in primary generalised tonic-clonic seizure frequency than those taking a placebo (RR 1.88, 95% CI 1.43 to 2.45; low-certainty evidence). The results between groups were inconclusive for the likelihood of seizure freedom (RR 1.55, 95% CI 0.89 to 2.72; very low-certainty evidence); treatment withdrawal (RR 1.20, 95% CI 0.72 to 1.99; very low-certainty evidence); and individual adverse effects: ataxia (RR 3.05, 99% CI 0.05 to 199.36); dizziness (RR 0.91, 99% CI 0.29 to 2.86; very low-certainty evidence); fatigue (RR 1.02, 99% CI 0.13 to 8.14; very low-certainty evidence); nausea (RR 1.60, 99% CI 0.48 to 5.32; very low-certainty evidence); and somnolence (RR 3.73, 99% CI 0.36 to 38.90; low-certainty evidence). The cross-over trial (26 participants) reported that 7/14 participants with generalised tonic-clonic seizures experienced a 50% or greater reduction in seizure frequency with add-on lamotrigine compared to placebo. The authors reported four treatment withdrawals, but did not specify during which treatment allocation they occurred. Rash (seven lamotrigine participants; zero placebo participants) and fatigue (five lamotrigine participants; zero placebo participants) were the most frequently reported adverse effects. None of the included studies measured cognition. One parallel-group study (N = 153) evaluated quality of life. They reported inconclusive results for the overall quality of life score between groups (P = 0.74).
AUTHORS' CONCLUSIONS
This review provides insufficient information to inform clinical practice. Low-certainty evidence suggests that lamotrigine reduces the rate of generalised tonic-clonic seizures by 50% or more. Very low-certainty evidence found inconclusive results between groups for all other outcomes. Therefore, we are uncertain to very uncertain that the results reported are accurate, and suggest that the true effect could be grossly different. More trials, recruiting larger populations, over longer periods, are necessary to determine lamotrigine's clinical use.
Topics: Anticonvulsants; Chemotherapy, Adjuvant; Dizziness; Drug Eruptions; Drug Resistant Epilepsy; Epilepsy, Tonic-Clonic; Exanthema; Fatigue; Humans; Lamotrigine; Nausea; Patient Dropouts; Randomized Controlled Trials as Topic; Sleepiness
PubMed: 32609387
DOI: 10.1002/14651858.CD007783.pub3 -
European Journal of Nuclear Medicine... Jun 2020To describe cerebral glucose metabolism pattern as assessed by F-fluorodeoxyglucose positron emission tomography (FDG-PET) in Lafora disease (LD), a rare, lethal form of...
PURPOSE
To describe cerebral glucose metabolism pattern as assessed by F-fluorodeoxyglucose positron emission tomography (FDG-PET) in Lafora disease (LD), a rare, lethal form of progressive myoclonus epilepsy caused by biallelic mutations in EPM2A or NHLRC1.
METHODS
We retrospectively included patients with genetically confirmed LD who underwent FDG-PET scan referred to three Italian epilepsy centers. FDG-PET images were evaluated both visually and using SPM12 software. Subgroup analysis was performed on the basis of genetic and clinical features employing SPM. Moreover, we performed a systematic literature review of LD cases that underwent FDG-PET assessment.
RESULTS
Eight Italian patients (3M/5F, 3 EPM2A/5 NHLRC1) underwent FDG-PET examination after a mean of 6 years from disease onset (range 1-12 years). All patients showed bilateral hypometabolic areas, more diffuse and pronounced in advanced disease stages. Most frequently, the hypometabolic regions were the temporal (8/8), parietal (7/8), and frontal lobes (7/8), as well as the thalamus (6/8). In three cases, the FDG-PET repeated after a mean of 17 months (range 7-36 months) showed a metabolic worsening compared with the baseline examination. The SPM subgroup analysis found no significant differences based on genetics, whereas it showed a more significant temporoparietal hypometabolism in patients with visual symptoms compared with those without. In nine additional cases identified from eight publications, FDG-PET showed heterogeneous findings, ranging from diffusely decreased cerebral glucose metabolism to unremarkable examinations in two cases.
CONCLUSIONS
FDG-PET seems highly sensitive to evaluate LD at any stage and may correlate with disease progression. Areas of decreased glucose metabolism in LD are extensive, often involving multiple cortical and subcortical regions, with thalamus, temporal, frontal, and parietal lobes being the most severely affected. Prospective longitudinal collaborative studies are needed to validate our findings.
Topics: Brain; Fluorodeoxyglucose F18; Humans; Lafora Disease; Positron-Emission Tomography; Prospective Studies; Retrospective Studies; Ubiquitin-Protein Ligases
PubMed: 31858178
DOI: 10.1007/s00259-019-04647-3 -
Acta Neurologica Scandinavica Apr 2021Dravet syndrome (DS) is a severe, drug-resistant, developmental epileptic encephalopathy. Despite multiple anti-epileptic drug regimens, the syndrome remains poorly... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dravet syndrome (DS) is a severe, drug-resistant, developmental epileptic encephalopathy. Despite multiple anti-epileptic drug regimens, the syndrome remains poorly controlled and nearly half of patients still experience at least four tonic-clonic seizure per month. Recently, several clinical trials demonstrated that fenfluramine may provide a significant reduction in convulsive seizure frequency in the treatment of Dravet syndrome.
METHODS
A computerized literature search of Web of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE, and Google Scholar was performed from inception until December 31, 2019. We included randomized placebo-controlled trials for the treatment of Dravet syndrome. We calculated the risk ratio (RR) of ≥50% and 100% reduction seizure frequency from baseline, along with the treatment-related withdrawals and serious adverse events, using the fixed-effect model. Quality assessment of included studies was performed with the Cochrane Collaboration's tool.
KEY RESULTS
Two trials with a total of 206 patients were included. The pooled RR of 5.49 (95% CI 3.13-9.65) showed that a significantly greater proportion in the fenfluramine group achieved ≥50% reduction in monthly convulsive seizure frequency (MCSF). As for the complete seizure free rate, the pooled RR of 5.75 (95% CI 1.03-32.07) also demonstrated the favorable efficacy of fenfluramine, even though the difference was not statistically significant (p = 0.046). However, a significantly greater proportion of patients in the fenfluramine group experienced no more than one seizure during the treatment period (RR 13.82, 95% CI 2.68-71.27, p = 0.002). There were no significant differences in withdrawals and serious adverse events between the two treatment groups. No valvular heart disease or pulmonary arterial hypertension was observed in participants. The most common adverse events reported by included trials were diarrhea, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, decreased appetite, and weight loss.
CONCLUSIONS
Fenfluramine is an effective antiepileptic drug for pediatric patients with Dravet syndrome, demonstrating clinically meaningful reduction in convulsive frequency, and generally could be well tolerated.
Topics: Anticonvulsants; Child; Child, Preschool; Epilepsies, Myoclonic; Fatigue; Fenfluramine; Fever; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Seizures
PubMed: 33336426
DOI: 10.1111/ane.13387 -
European Journal of Paediatric... May 2019Dravet Syndrome is a rare developmental and epileptic encephalopathy characterised by epileptic seizures, cognitive impairment and motor disorders. Gait is markedly...
BACKGROUND
Dravet Syndrome is a rare developmental and epileptic encephalopathy characterised by epileptic seizures, cognitive impairment and motor disorders. Gait is markedly impaired and could benefit from targeted intervention to improve quality of life for patient and caregivers.
OBJECTIVE
To establish the state of the art regarding gait deviations in patients with Dravet Syndrome.
METHODS
A systematic search was performed in Pubmed, Web of Science, Science Direct and Embase. Studies that assessed gait deviations in patients diagnosed with Dravet Syndrome using clinical observation, video gait analysis or three dimensional (3D) gait analysis and reported gait characteristics, spatiotemporal or kinematic outcomes were included. Screening, quality assessment and data extraction were performed by independent reviewers.
RESULTS
Out of a total of 478 citations, nine articles were included. The total study population had an age range from 2.5 to 47 years. Three studies used clinical observation, three studies video analysis and three studies 3D gait analysis. Crouch gait was observed in about half of the population next to a variety of other gait deviations such as parkinsonian and cerebellar gait. Other findings included abnormalities in spatiotemporal parameters and kinematics, passive knee extension deficits, skeletal malalignment and neurological signs.
CONCLUSIONS
A variety of gait characteristics was observed with crouch gait being the most reported gait pattern. Inconsistency in methods and findings from clinical and instrumented evaluation impede thorough understanding of the causal mechanism and evolution behind these deviations.
PROSPERO REGISTRATION NUMBER
CRD42017070370.
Topics: Adolescent; Adult; Child; Child, Preschool; Epilepsies, Myoclonic; Female; Gait Disorders, Neurologic; Humans; Male; Middle Aged; Young Adult
PubMed: 30940509
DOI: 10.1016/j.ejpn.2019.03.003 -
PloS One 2017We aimed to identify the consistent regions of gray matter volume (GMV) abnormalities in idiopathic generalized epilepsy (IGE), and to study the difference of GMV... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We aimed to identify the consistent regions of gray matter volume (GMV) abnormalities in idiopathic generalized epilepsy (IGE), and to study the difference of GMV abnormalities among IGE subsyndromes by applying activation likelihood estimation (ALE) meta-analysis.
METHODS
A systematic review of VBM studies on GMV of patients with absence epilepsy (AE), juvenile myoclonic epilepsy (JME), IGE and controls indexed in PubMed and ScienceDirect from January 1999 to June 2016 was conducted. A total of 12 IGE studies, including 7 JME and 3 AE studies, were selected. Meta-analysis was performed on these studies by using the pooled and within-subtypes analysis (www.brainmap.org). Based on the above results, between-subtypes contrast analysis was carried out to detect the abnormal GMV regions common in and unique to each subtype as well.
RESULTS
IGE demonstrated significant GMV increase in right ventral lateral nucleus (VL) and right medial frontal gyrus, and significant GMV decrease in bilateral pulvinar. For JME, significant GMV increase was seen in right medial frontal gyrus, right anterior cingulate cortex (ACC), while significant GMV decrease was found in right pulvinar. In AE, the most significant GMV increase was found in right VL, and slight GMV reduction was seen in right medial dorsal nucleus, right subcallosal gyrus, left caudate and left precuneus. No overlapped and unique regions with significant GMV abnormalities were found between JME and AE.
SIGNIFICANCE
This meta-analysis demonstrated that thalamo-frontal network was a structure with significant GMV abnormality in IGE, and the IGE subsyndromes showed different GMV abnormal regions. These observations may provide instructions on the clinical diagnosis of IGE.
Topics: Epilepsy, Generalized; Female; Gray Matter; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Organ Size
PubMed: 28060866
DOI: 10.1371/journal.pone.0169076