ObjectiveThere is a pressing need for reliable automated seizure detection in epilepsy care. Performance evidence on ambulatory non-electroencephalography-based seizure detection devices is low,... Show moreObjectiveThere is a pressing need for reliable automated seizure detection in epilepsy care. Performance evidence on ambulatory non-electroencephalography-based seizure detection devices is low, and evidence on their effect on caregiver's stress, sleep, and quality of life (QoL) is still lacking. We aimed to determine the performance of NightWatch, a wearable nocturnal seizure detection device, in children with epilepsy in the family home setting and to assess its impact on caregiver burden.MethodsWe conducted a phase 4, multicenter, prospective, video-controlled, in-home NightWatch implementation study (NCT03909984). We included children aged 4–16 years, with ≥1 weekly nocturnal major motor seizure, living at home. We compared a 2-month baseline period with a 2-month NightWatch intervention. The primary outcome was the detection performance of NightWatch for major motor seizures (focal to bilateral or generalized tonic–clonic [TC] seizures, focal to bilateral or generalized tonic seizures lasting >30 s, hyperkinetic seizures, and a remainder category of focal to bilateral or generalized clonic seizures and "TC-like" seizures). Secondary outcomes included caregivers' stress (Caregiver Strain Index [CSI]), sleep (Pittsburgh Quality of Sleep Index), and QoL (EuroQol five-dimension five-level scale).ResultsWe included 53 children (55% male, mean age = 9.7 ± 3.6 years, 68% learning disability) and analyzed 2310 nights (28 173 h), including 552 major motor seizures. Nineteen participants did not experience any episode of interest during the trial. The median detection sensitivity per participant was 100% (range = 46%–100%), and the median individual false alarm rate was .04 per hour (range = 0–.53). Caregiver's stress decreased significantly (mean total CSI score = 8.0 vs. 7.1, p = .032), whereas caregiver's sleep and QoL did not change significantly during the trial.SignificanceThe NightWatch system demonstrated high sensitivity for detecting nocturnal major motor seizures in children in a family home setting and reduced caregiver stress. Show less
Depienne, C.; Maagdenberg, A.M.J.M. van den; Kuhnel, T.; Ishiura, H.; Corbett, M.A.; Tsuji, S. 2023
Familial adult myoclonus epilepsy (FAME) results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes encoding proteins with different subcellular... Show moreFamilial adult myoclonus epilepsy (FAME) results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes encoding proteins with different subcellular localizations and very different functions, which poses the issue of what causes the neurobiological disturbances that lead to the clinical phenotype. Postmortem and electrophysiological studies have pointed to cortical hyperexcitability as well as dysfunction and neurodegeneration of both the cortex and cerebellum of FAME subjects. FAME expansions, contrary to the same expansion in DAB1 causing spinocerebellar ataxia type 37, seem to have no or limited impact on their recipient gene expression, which suggests a pathophysiological mechanism independent of the gene and its function. Current hypotheses include toxicity of the RNA molecules carrying UUUCA repeats, or toxicity of polypeptides encoded by the repeats, a mechanism known as repeat-associated non-AUG translation. The analysis of postmortem brains of FAME1 expansion (in SAMD12) carriers has revealed the presence of RNA foci that could be formed by the aggregation of RNA molecules with abnormal UUUCA repeats, but evidence is still lacking for other FAME subtypes. Even when the expansion is located in a gene ubiquitously expressed, expression of repeats remains undetectable in peripheral tissues (blood, skin). Therefore, the development of appropriate cellular models (induced pluripotent stem cell-derived neurons) or the study of affected tissues in patients is required to elucidate how FAME repeat expansions located in unrelated genes lead to disease. Show less
Meer, P.B. van der; Maschio, M.; Dirven, L.; Taphoorn, M.J.B.; Koekkoek, J.A.F.; Italian League Epilepsy Brain Tumo 2022
Objective: This study aimed to directly compare the effectiveness of first-line monotherapy levetiracetam (LEV) versus enzyme-inducing antiseizure medications (EIASMs) in glioma patients. Methods:... Show moreObjective: This study aimed to directly compare the effectiveness of first-line monotherapy levetiracetam (LEV) versus enzyme-inducing antiseizure medications (EIASMs) in glioma patients. Methods: In this nationwide retrospective observational cohort study, Grade 2-4 glioma patients were included, with a maximum duration of follow-up of 36 months. Primary outcome was antiseizure medication (ASM) treatment failure for any reason, and secondary outcomes were treatment failure due to uncontrolled seizures and due to adverse effects. For estimation of the association between ASM treatment and ASM treatment failure, multivariate cause-specific cox proportional hazard models were estimated, adjusting for potential confounders. Results: In the original cohort, a total of 808 brain tumor patients with epilepsy were included, of whom 109 glioma patients were prescribed first-line LEV and 183 glioma patients first-line EIASMs. The EIASM group had a significantly higher risk of treatment failure for any reason compared to LEV (adjusted hazard ratio [aHR] = 1.82, 95% confidence interval [CI] = 1.20-2.75, p = .005). Treatment failure due to uncontrolled seizures did not differ significantly between EIASMs and LEV (aHR = 1.32, 95% CI = .78-2.25, p = .300), but treatment failure due to adverse effects differed significantly (aHR = 4.87, 95% CI = 1.89-12.55, p = .001). Significance: In this study, it was demonstrated that LEV had a significantly better effectiveness (i.e., less ASM treatment failure for any reason or due to adverse effects) compared to EIASMs, supporting the current neuro-oncology guideline recommendations to avoid EIASMs in glioma patients. Show less
Westrhenen, A. van; Wijnen, B.M.; Thijs, R.D. 2022
AbstractObjective: Previous studies identified essential user preferences for seizure detection devices (SDDs), without addressing their relative strength. We performed a discrete choice experiment... Show moreAbstractObjective: Previous studies identified essential user preferences for seizure detection devices (SDDs), without addressing their relative strength. We performed a discrete choice experiment (DCE) to quantify attributes' strength, and to identify the determinants of user SDD preferences. Methods: We designed an online questionnaire targeting parents of children with epilepsy to define the optimal balance between SDD sensitivity and positive predictive value (PPV) while accounting for individual seizure frequency. We selected five DCE attributes from a recent study. Using a Bayesian design, we constructed eleven unique choice tasks and analyzed these using a mixed multinomial logit model. Results: One hundred parents responded to the online questionnaire link; 49 completed all tasks, whereas 28 completed the questions, but not the DCE. Most parents preferred a relatively high sensitivity (80%-90%) over a high PPV (>50%). The preferred sensitivity-to-PPV ratio correlated with seizure frequency (r = −.32), with a preference for relative high sensitivity and low PPV among those with relative low seizure frequency (p = .04). All DCE attributes significantly impacted parental choices. Parents expressed preferences for consulting a neurologist before device use, personally training the device's algorithm, interaction with their child via audio and video, alarms for all seizure types, and an interface detailing measurements during an alarm. Preferences varied between subgroups (learning disability or not, SDD experience, relative low vs. high seizure frequency based on the population median). Significance: Various attributes impact parental SDD preferences and may explain why preferences vary among users. Tailored approaches may help to meet the contrasting needs among SDD users. Show less
Westrhenen, A. van; Wijnen, B.M.; Thijs, R.D. 2022
Objective: Previous studies identified essential user preferences for seizure detection devices (SDDs), without addressing their relative strength. We performed a discrete choice experiment (DCE)... Show moreObjective: Previous studies identified essential user preferences for seizure detection devices (SDDs), without addressing their relative strength. We performed a discrete choice experiment (DCE) to quantify attributes' strength, and to identify the determinants of user SDD preferences. Methods: We designed an online questionnaire targeting parents of children with epilepsy to define the optimal balance between SDD sensitivity and positive predictive value (PPV) while accounting for individual seizure frequency. We selected five DCE attributes from a recent study. Using a Bayesian design, we constructed 11 unique choice tasks and analyzed these using a mixed multinomial logit model. Results: One hundred parents responded to the online questionnaire link; 49 completed all tasks, whereas 28 completed the questions, but not the DCE. Most parents preferred a relatively high sensitivity (80%-90%) over a high PPV (>50%). The preferred sensitivity-to-PPV ratio correlated with seizure frequency (r = -.32), with a preference for relative high sensitivity and low PPV among those with relative low seizure frequency (p = .04). All DCE attributes significantly impacted parental choices. Parents expressed preferences for consulting a neurologist before device use, personally training the device's algorithm, interaction with their child via audio and video, alarms for all seizure types, and an interface detailing measurements during an alarm. Preferences varied between subgroups (learning disability or not, SDD experience, relative low vs. high seizure frequency based on the population median). Significance: Various attributes impact parental SDD preferences and may explain why preferences vary among users. Tailored approaches may help to meet the contrasting needs among SDD users. Show less
CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short... Show moreCSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures. Show less
Meer, P.B. van der; Dirven, L.; Fiocco, M.; Vos, M.J.; Kouwenhoven, M.C.M.; Bent, M.J. van den; ... ; Koekkoek, J.A.F. 2021
Objective This study aimed at estimating the cumulative incidence of antiepileptic drug (AED) treatment failure of first-line monotherapy levetiracetam vs valproic acid in glioma patients with... Show moreObjective This study aimed at estimating the cumulative incidence of antiepileptic drug (AED) treatment failure of first-line monotherapy levetiracetam vs valproic acid in glioma patients with epilepsy.Methods In this retrospective observational study, a competing risks model was used to estimate the cumulative incidence of treatment failure, from AED treatment initiation, for the two AEDs with death as a competing event. Patients were matched on baseline covariates potentially related to treatment assignment and outcomes of interest according to the nearest neighbor propensity score matching technique. Maximum duration of follow-up was 36 months.Results In total, 776 patients using levetiracetam and 659 using valproic acid were identified. Matching resulted in two equal groups of 429 patients, with similar covariate distribution. The cumulative incidence of treatment failure for any reason was significantly lower for levetiracetam compared to valproic acid (12 months: 33% [95% confidence interval (CI) 29%-38%] vs 50% [95% CI 45%-55%]; P < .001). When looking at specific reasons of treatment failure, treatment failure due to uncontrolled seizures was significantly lower for levetiracetam compared to valproic acid (12 months: 16% [95% CI 12%-19%] vs 28% [95% CI 23%-32%]; P < 0.001), but no differences were found for treatment failure due to adverse effects (12 months: 14% [95% CI 11%-18%] vs 15% [95% CI 11%-18%]; P = .636).Significance Our results suggest that levetiracetam may have favorable efficacy compared to valproic acid, whereas level of toxicity seems similar. Therefore, levetiracetam seems to be the preferred choice for first-line AED treatment in patients with glioma. Show less
Seizure detection devices can improve epilepsy care, but wearables are not always tolerated. We previously demonstrated good performance of a real-time video-based algorithm for detection of... Show moreSeizure detection devices can improve epilepsy care, but wearables are not always tolerated. We previously demonstrated good performance of a real-time video-based algorithm for detection of nocturnal convulsive seizures in adults with learning disabilities. The algorithm calculates the relative frequency content based on the group velocity reconstruction from video-sequence optical flow. We aim to validate the video algorithm on nocturnal motor seizures in a pediatric population. We retrospectively analyzed the algorithm performance on a database including 1661 full recorded nights of 22 children (age = 3-17 years) with refractory epilepsy at home or in a residential care setting. The algorithm detected 118 of 125 convulsions (median sensitivity per participant = 100%, overall sensitivity = 94%, 95% confidence interval = 61%-100%) and identified all 135 hyperkinetic seizures. Most children had no false alarms; 81 false alarms occurred in six children (median false alarm rate [FAR] per participant per night = 0 [range = 0-0.47], overall FAR = 0.05 per night). Most false alarms (62%) were behavior-related (eg, awake and playing in bed). Our noncontact detection algorithm reliably detects nocturnal epileptic events with only a limited number of false alarms and is suitable for real-time use. Show less
Jansen, N.A.; Dehghani, A.; Breukel, C.; Tolner, E.A.; Maagdenberg, A.M.J.M. van den 2020
Early onset seizures are a hallmark of Dravet syndrome. Previous studies in rodent models have shown that the epileptic phenotype is caused by loss-of-function of voltage-gated Na(V)1.1 sodium... Show moreEarly onset seizures are a hallmark of Dravet syndrome. Previous studies in rodent models have shown that the epileptic phenotype is caused by loss-of-function of voltage-gated Na(V)1.1 sodium channels, which are chiefly expressed in gamma-aminobutyric acid (GABA)ergic neurons. Recently, a possibly critical role has been attributed to the hippocampus in the seizure phenotype, as local hippocampal ablation of Na(V)1.1 channels decreased the threshold for hyperthermia-induced seizures. However, the effect of ablation of Na(V)1.1 channels restricted to cortical sites has not been tested. Here we studied local field potential (LFP) and behavior in mice following local hippocampal and cortical ablation of Scn1a, a gene encoding the alpha 1 subunit of Na(V)1.1 channels, and we compared seizure characteristics with those of heterozygous global knockout Scn1(-/+) mice. We found a high incidence of spontaneous seizures following either local hippocampal or cortical ablation, notably during a transient time window, similar to Scn1a(-/+) mice. Nonconvulsive seizure activity in the injected area was common and preceded generalized seizures. Moreover, mice were susceptible to hyperthermia-induced seizures. In conclusion, local ablation of Na(V)1.1 channels in the hippocampus and cortex results in focal seizure activity that can generalize. These data indicate that spontaneous epileptic activity may initiate in multiple brain regions in Dravet syndrome. Show less
Lende, M. van der; Arends, J.B.; Lamberts, R.J.; Tan, H.L.; Lange, F.J. de; Sander, J.W.; ... ; Thijs, R.D. 2019
