Parent-completed scales for measuring seizure severity and severity of side-effects of antiepileptic drugs in childhood epilepsy: development and psychometric analysis.

We have developed two outcome measures for childhood epilepsy: a seizure severity (SS) scale and a side-effects (SE) scale. Both scales have been designed for completion by parents. The scales were tested in two pilot phases and the results of this stepwise analysis are described here. The final scales' psychometric properties were assessed in a group of 80 children with active epilepsy, representative of the population at whom the scales were aimed: children with chronic epilepsy, aged 4-16 years, including all seizure types and epilepsies, as well as children with neurological comorbidity. The SS scale and SE scale showed good internal consistency and test-retest stability. Although there was a significant positive correlation between the SS scale and the SE scale, this was low, indicating that the scales measure a different clinical trait. The SE scale consisted of two subscales: a Toxic subscale, measuring the severity of dose-related side-effects, and a Chronic subscale, measuring the severity of long-term behavioural and cognitive side-effects. These subscales for side-effects showed a high correlation and can be used as a joint scale. These scales have the potential to improve outcome assessment in childhood epilepsy and they can be used to assess important aspects of quality of life in this population

Should every child with epilepsy undergo screening for psychiatric comorbidities?

Purpose: We aimed to build a classification system that uses resting-state (no visible scalp epileptic activity) EEG-based directed functional connectivity values to assign a patient to one of three classes: left TLE (LTLE), right TLE (RTLE) or healthy control. Methods: Twenty LTLE, 20 RTLE and 35 healthy controls underwent resting-state high-density EEG. For each subject, sixty 1-sec epochs free of artifacts or interictal spikes were selected. The source activity was obtained for 82 regions of interest using an individual head model and distributed linear inverse solution. The summed outflow and whole-brain directed functional connectivity were estimated in the theta, alpha and beta frequency bands using Granger-causal modeling. A Random Forest classifier (an ensemble of decision tree classifiers) was then used to assign the subject to one of three classes. The mean classification accuracy was computed with a leave-one-out procedure. We selected a maximum of six connectivity values for classification, using a greedy forward selection algorithm. Finally, three classifiers were built: ‘Control vs. LTLE’, ‘Control vs. RTLE’ and ‘LTLE vs. RTLE’. In the final classification system, a new subject is assigned to the class that was most voted by these three classifiers. Results: The ‘Control vs. RTLE’ classifier achieved an accuracy of 78.2% (sensitivity: 80.0%, specificity 77.2%), ‘Control vs. LTLE’ an accuracy of 83.6% (sensitivity 85.0%, specificity 82.9%) and ‘LTLE vs. RTLE’ an accuracy of 85.0% (sensitivity 85.0%, specificity 85.0%). Combining these classifiers into one system yielded that 16, 15 and 27 subjects were correctly classified as being, respectively, RTLE, LTLE and control. Conclusion: The high accuracy achieved demonstrates the potential of resting-state EEG-based directed functional connectivity for the diagnosis and lateralization of TLE. This could constitute a new clinical biomarker for surgical candidates and earlier in the course of the disease

Benign familial infantile convulsions: A clinical study of seven Dutch families

Benign familial infantile convulsions (BFIC) is a recently identified partial epilepsy syndrome with onset between 3 and 12 months of age. We describe the clinical characteristics and outcome of 43 patients with BFIC from six Dutch families and one Dutch-Canadian family and the encountered difficulties in classifying the syndrome. Four families had a pure BFIC phenotype; in two families BFIC was accompanied by paroxysmal kinesigenic dyskinesias; in one family BFIC was associated with later onset focal epilepsy in older generations. Onset of seizures was between 6 weeks and 10 months, and seizures remitted before the age of 3 years in all patients with BFIC. In all, 29 (67%) of the 43 patients had been treated with anti-epileptic drugs for a certain period of time. BFIC is often not recognized as (hereditary) epilepsy by the treating physician. Seizures often remit shortly after the start of anti-epileptic drugs but, because of the benign course of the syndrome and the spontaneous remission of seizures, patients with low seizure fr

A detailed description of the phenotypic spectrum of North Sea Progressive Myoclonus Epilepsy in a large cohort of seventeen patients

Introduction: In 2011, a homozygous mutation in GOSR2 (c.430G > T; p. Gly144Trp) was reported as a novel cause of Progressive Myoclonus Epilepsy (PME) with early-onset ataxia. Interestingly, the ancestors of patients originate from countries bound to the North Sea, hence the condition was termed North Sea PME (NSPME). Until now, only 20 patients have been reported in literature. Here, we provide a detailed description of clinical and neurophysiological data of seventeen patients. Methods: We collected clinical and neurophysiological data from the medical records of seventeen NSPME patients (5–46 years). In addition, we conducted an interview focused on factors influencing myoclonus severity. Results: The core clinical features of NSPME are early-onset ataxia, myoclonus and seizures, with additionally areflexia and scoliosis. Factors such as fever, illness, heat, emotions, stress, noise and light (flashes) all exacerbated myoclonic jerks. Epilepsy severity ranged from the absence of or incidental clinical seizures to frequent daily seizures and status epilepticus. Some patients made use of a wheelchair during their first decade, whereas others still walked independently during their third decade. Neurophysiological features suggesting neuromuscular involvement in NSPME were variable, with findings ranging from indicative of sensory neuronopathy and anterior horn cell involvement to an isolated absent H-reflex. Conclusion: Although the sequence of symptoms is rather homogeneous, the severity of symptoms and rate of progression varied considerably among individual patients. Common triggers for myoclonus can be identified and myoclonus is difficult to treat; to what extent neuromuscular involvement contributes to the phenotype remains

Denitrificatie in de zone tussen bouwvoor en het bovenste grondwater in zandgronden

Er zijn grote variaties in de nitraatconcentratie in het bovenste grondwater van uitspoelings-gevoelige zandgronden geconstateerd. Deze variaties worden waarschijnlijk veroorzaakt door denitrificatie. In het kader van de evaluatie van de Meststoffenwet 2004 zijn studies uitgevoerd om kwantitatief inzicht te krijgen in de denitrificatie in de bodemlaag tussen de onderkant van de bouwvoor en het bovenste grondwater. De resultaten geven aan dat veenlagen en/of moerige lagen leiden tot lagere nitraatconcentraties in het bovenste grondwater. Andere bodem-eigenschappen zoals het voorkomen van klei- en leemlagen en de uitspoeling van organische stof uit de bouwvoor hebben geen duidelijk effect op denitrificatie. Geconcludeerd wordt dat de aanwezigheid van veenlagen of moerige lagen in zandgronden een extra criterium zou kunnen zijn om uitspoelingsgevoelige gronden te differentiëren. Dit geldt met name voor grondwatertrap VI. In veel zandgronden heeft afbraak van veen plaatsgevonden, zodat een bodemkartering nodig is om het areaal uitspoelingsgevoelige zandgronden met veenlagen te bepalen

PRRT2-related phenotypes in patients with a 16p11.2 deletion

We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p = 0.069), PKD in six (p < 0.001) and PKD/IC in two (p = 0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2-related phenotypes

Cohesin complex-associated holoprosencephaly

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly