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CNS Drugs Jun 2022Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD... (Review)
Review
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD develop refractory epilepsy with multiple seizure types. Management of seizures in CDD remains challenging for clinicians given the highly refractory nature of seizures and the limited number of disease-specific studies that offer a high level of evidence. Epileptic spasms are the most common seizure type in CDD and are more often refractory to standard first-line treatment than are spasms of other etiologies. In other seizure types, the effectiveness of antiseizure medications is limited and wanes over time. Ketogenic diet and palliative surgical treatments have both had mixed results in observational studies. When treating refractory seizures in CDD, we recommend carefully balancing seizure control and treatment-related side effects to optimize each individual's overall quality of life. Clinical trials of medications targeting epilepsy in CDD have been conducted, and additional investigational small molecules, gene therapy, and other disease-modifying therapies are in development for CDD.
Topics: Epilepsy; Epileptic Syndromes; Humans; Protein Serine-Threonine Kinases; Quality of Life; Seizures; Spasm; Spasms, Infantile
PubMed: 35633486
DOI: 10.1007/s40263-022-00921-5 -
Annals of Neurology Feb 2021Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.
METHODS
In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure.
RESULTS
In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223-535) vs 124 days (95% CI = 33-149); OLT: 426 days (95% CI = 258-628) vs 106 days (95% CI = 11-149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted.
INTERPRETATION
Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304-314.
Topics: Anticonvulsants; Drug Resistant Epilepsy; Electroencephalography; Epilepsy; Female; Humans; Infant; Infant, Newborn; Male; Mass Screening; Seizures; Spasms, Infantile; Tuberous Sclerosis; Vigabatrin
PubMed: 33180985
DOI: 10.1002/ana.25956 -
Science Translational Medicine Apr 2022Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models...
Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.
Topics: Animals; Autistic Disorder; Disease Models, Animal; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Infant; Mice; Neurons; Phosphatidylinositol 3-Kinases; Spasms, Infantile; Sudden Unexpected Death in Epilepsy; tau Proteins
PubMed: 35476595
DOI: 10.1126/scitranslmed.abm5527 -
Annals of Neurology Dec 2019Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and...
OBJECTIVE
Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype-phenotype correlations of a large EIMFS cohort.
METHODS
Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study.
RESULTS
We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X-linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months.
INTERPRETATION
We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821-831.
Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Female; Genetic Predisposition to Disease; Humans; Infant; Male; Seizures; Spasms, Infantile
PubMed: 31618474
DOI: 10.1002/ana.25619 -
Epilepsy Research Jul 2021To develop an improved interictal electroencephalogram (EEG) grading scale for children with infantile spasms founded on elements with adequate inter-rater reliability...
OBJECTIVE
To develop an improved interictal electroencephalogram (EEG) grading scale for children with infantile spasms founded on elements with adequate inter-rater reliability (IRR) to justify its further study for clinical and research purposes.
METHODS
Three blinded reviewers assessed five-minute sleep epochs in 93 EEGs from 62 children (31 consecutive controls, 31 consecutive infantile spasms [pretreatment and posttreatment studies]) using a longitudinal bipolar montage. We determined the IRR of background amplitude, epileptiform discharges, >3 spike foci (including <50 % or >50 %), grouped multifocal spikes, paroxysmal voltage attenuations, and symmetry of sleep spindles. Data were used to finalize the 2021 BASED (Burden of AmplitudeS and Epileptiform Discharges) score.
RESULTS
All elements included in the 2021 BASED score had moderate to near perfect IRR. Among controls, >200 μv background waves occurred commonly in the bilateral posterior temporal (T3-T5, T4-T6) and midline (Fz-Cz, Cz-Pz) regions. Excluding midline and occipital channels (which have normal high amplitude background waves), we designated abnormal high amplitude background waves as >200 μv for most channels, but >300 μv for T3-T5 and T4-T6. The IRR was moderate to near perfect for <50 % >3 spike foci, >50 % >3 spike foci, paroxysmal voltage attenuations, grouped multifocal spikes (GMFS), and symmetric sleep spindles. Paroxysmal voltage attenuations, GMFS, and >50 % >3 spike foci all significantly distinguished pretreatment from posttreatment studies whereas symmetric sleep spindles did not (as planned, the latter was not included in the 2021 BASED score). When the 2021 BASED score was applied to the 22 children with infantile spasms achieving clinical remission with treatment, 19 met criteria for electroclinical remission and three did not.
SIGNIFICANCE
The 2021 BASED score includes elements with high levels of IRR and correlates well with the presence or absence of infantile spasms.
Topics: Child; Electroencephalography; Humans; Infant; Reproducibility of Results; Sleep; Spasm; Spasms, Infantile
PubMed: 33839516
DOI: 10.1016/j.eplepsyres.2021.106631 -
Ugeskrift For Laeger Apr 2020Infantile spasms (IS) is a severe developmental and epileptic encephalopathy, occurring mainly in children aged 3-18 months. IS have multiple aetiologies, and the... (Review)
Review
Infantile spasms (IS) is a severe developmental and epileptic encephalopathy, occurring mainly in children aged 3-18 months. IS have multiple aetiologies, and the treatment differs accordingly. Early diagnosis and treatment may improve the outcome, but many patients are initially misdiagnosed. Evaluation includes seizure semiology, electroencephalography, cerebral magnetic resonance imaging and genetic and metabolic testing. Treatment varies among centres, and initial treatment may include vigabatrin and/or corticosteroids. In recent years, as summarised in this review, knowledge has substantially increased regarding genetic aetiologies and treatment regimens.
Topics: Anticonvulsants; Child; Electroencephalography; Humans; Infant; Magnetic Resonance Imaging; Spasms, Infantile; Vigabatrin
PubMed: 32286217
DOI: No ID Found -
Developmental Medicine and Child... Apr 2023To explore the phenotypic spectrum and refine the genotype-phenotype correlation of DYNC1H1-related epilepsy.
AIM
To explore the phenotypic spectrum and refine the genotype-phenotype correlation of DYNC1H1-related epilepsy.
METHOD
The clinical data of 15 patients with epilepsy in our cohort and 50 patients with epilepsy from 24 published studies with the DYNC1H1 variants were evaluated.
RESULTS
In our cohort, 13 variants were identified from 15 patients (seven males, eight females). Twelve variants were de novo and seven were new. Age at seizure onset ranged from 3 months to 4 years 5 months (median age 1 year). Common seizure types were epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. Mild-to-severe developmental delay was present in all patients. Six patients were diagnosed with West syndrome and one was diagnosed with epileptic encephalopathy with continuous spikes and waves during slow sleep (CSWS). Collectively, in our cohort and published studies, 17% had ophthalmic diseases, 31% of variants were located in the stalk domain, and 92% patients with epilepsy had a malformation of cortical development (MCD).
INTERPRETATION
The phenotypes of DYNC1H1-related epilepsy included multiple seizure types; the most common epileptic syndrome was West syndrome. CSWS is a new phenotype of DYNC1H1-related epilepsy. One-third of the variants in patients with epilepsy were located in the stalk domain. Most patients had a MCD and developmental delay.
WHAT THIS PAPER ADDS
Nearly 40% of patients with DYNC1H1 variants had epilepsy. Ninety-two percent of patients with DYNC1H1-related epilepsy had malformation of cortical development. More than 10% of patients with DYNC1H1-related epilepsy were diagnosed with West syndrome. Continuous spikes and waves during slow sleep could be a new phenotype of DYNC1H1 variants. One-third of the variants in patients with epilepsy were located in the stalk domain.
Topics: Male; Female; Humans; Spasms, Infantile; Mutation; Epilepsy; Seizures; Genetic Association Studies; Electroencephalography; Cytoplasmic Dyneins
PubMed: 36175372
DOI: 10.1111/dmcn.15414