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Background Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is an epilepsy syndrome occurring almost exclusively in children, usually at an age between 4 and 12 years. It is characterised by abundant sleep-induced epileptic activity in the electroencephalogram (EEG) and by acquired cognitive and behavioural deficits. The goal of treatment is to prevent further decline or even improve cognitive functioning. Based on mostly small and retrospective studies, corticosteroids and clobazam are regarded by many clinicians as the most effective pharmacological treatments. This European multicentre randomised controlled trial is designed to compare the effects of corticosteroids and clobazam on cognitive functioning after 6 months. Secondary outcomes include cognitive functioning after 18 months, EEG abnormalities in sleep, safety and tolerability, and seizure frequency. We also aimed at investigating whether treatment response in epileptic encephalopathy with ESES can be predicted by measurement of inflammatory mediators and autoantibodies in serum. Methods The pragmatic study will be performed in centres with expertise in the treatment of rare paediatric epilepsy syndromes across Europe. A total of 130 patients, 2 to 12 years of age, with epileptic encephalopathy with ESES will be enrolled and randomised in a 1:1 ratio to receive either corticosteroids (monthly intravenous methylprednisolone pulses or daily oral prednisolone) or oral clobazam for 6 months according to an open-label parallel-group design. Follow-up visits with clinical assessment, EEGs, and neuropsychological testing are scheduled for up to 18 months. Blood samples for cytokine and autoantibody testing are obtained before treatment and 8 months after treatment initiation. Discussion The treatment of epileptic encephalopathy with ESES aims at improving cognitive outcome. This randomised controlled study will compare the most frequently used treatments, i.e. corticosteroids and clobazam. If the study proves superiority of one treatment over the other or identifies biomarkers of treatment response, results will guide clinicians in the early treatment of this severe epilepsy syndrome. Trial registration ISRCTN, ISRCTN42686094. Registered on 24 May 2013.

LIISA METSÄHONKALA (puheenjohtaja), EIJA GAILY, OLGA GILBERT, JARKKO KIRJAVAINEN, JORMA KOMULAINEN, TUIRE LÄHDESMÄKI, PÄIVI VIEIRA, Suomalaisen Lääkäriseuran Duodecimin ja Suomen Lastenneurologinen Yhdistys ry:n asettama työryhmä

Vertaisarvioitu Dravet’n oireyhtymä on harvinainen, mutta todennäköisesti alidiagnosoitu sairaus. Sen tavallisin syy on hermosolujen natriumkanavien toimintaa säätelevän SCN1A-geenin virhe. Sairaus alkaa infektioon, rokotukseen tai muuhun lämmönnousuun liittyvillä pitkittyneillä kuumekouristuksilla ensimmäisen ikävuoden aikana. Vaikea epilepsia on tunnetuin oire, mutta useimmilla on myös vaikeita kognitiivisia ja motorisia häiriöitä. Diagnoosilla on merkitystä, koska epilepsialääkkeiden oikealla valinnalla voidaan estää sarjakohtaukset ja lievittää oireita. Lapset tulee rokottaa normaalisti diagnoosista huolimatta.

English summary

BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. METHODS: We sent out a survey to 16 genetic centers performing SCN1A testing. RESULTS: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. CONCLUSION: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.

Infan­tii­lis­pas­mioi­reyh­tymä on etio­lo­gialtaan hete­ro­gee­ninen, ime­väi­siässä al­kava epi­lepsia. Tyypil­linen koh­taus on infan­tii­lis­pas­mi­sarja, mut­ta myös yksit­täisiä spas­meja tai muun­laisia koh­tauksia voi esiintyä. Oireyh­tymään liit­tyy kehi­tyksen pysäh­ty­minen tai taantu­minen, jo­ka voi al­kaa jo en­nen klii­nisten spasmien havait­se­mista. Infan­tii­lis­pas­meja tai kehi­tyksen hidas­tu­mista epäil­täessä lap­si tu­lee lä­hettää kiireel­li­sesti jatko­tut­ki­muksiin lasten­neu­ro­lo­giseen yk­sikköön. Yli puo­lella poti­laista spasmien etio­logia sel­viää esi­tie­tojen, sta­tuksen ja ai­vojen magneet­ti­ku­vauksen avulla. Etio­lo­gialla ja no­pealla asian­mu­kaisen hoi­don aloi­tuk­sella on merki­tystä en­nusteen kan­nalta.

Raskau­de­nai­kainen valproaat­ti­hoito li­sää si­kiön kehi­tys­häi­riöiden ris­kiä. Valproaat­ti­hoidon aloit­ta­minen nuo­relle ty­tölle edel­lyttää tark­kaa epi­lep­siaoi­reyh­ty­mä­diag­noosia ja ­pe­rus­teel­lista har­kintaa. Valp­roaatti on ensi­si­jais­lääke useissa lap­suusiän epi­lep­siaoi­reyh­ty­missä suku­puo­lesta riippu­matta. Valp­roaatin meta­boliaan vaikut­tavat se­kä geneet­tiset et­tä ul­koiset te­kijät. Va­kavat haitta­vai­ku­tukset ovat harvi­naisia, mut­ta POLG- ja Twink­le-gee­ni­mu­taatiot li­säävät nii­den ris­kiä.

CO₂ has been long recognized for its anticonvulsant properties. We aimed to determine whether inhaling 5% CO₂ can be used to suppress seizures in epilepsy patients. The effect of CO₂ on cortical epileptic activity accompanying behavioral seizures was studied in rats and nonhuman primates, and based on these data, preliminary tests were carried out in humans. In freely moving rats, cortical afterdischarges paralleled by myoclonic convulsions were evoked by sensorimotor cortex stimulation. Five percent CO₂ was applied for 5 min, 3 min before stimulation. In macaque monkeys, hypercarbia was induced by hypoventilation while seizure activity was electrically or chemically evoked in the sensorimotor cortex. Seven patients with drug-resistant partial epilepsy were examined with video-EEG (electroencephalography) and received 5% CO₂ in medical carbogen shortly after electrographic seizure onset.In rats, 5% CO₂ strongly suppressed cortical afterdischarges, by approximately 75%, whereas responses to single-pulse stimulation were reduced by about 15% only. In macaques, increasing pCO₂) from 37 to 44-45 mm Hg (corresponding to inhalation of 5% CO₂ or less) suppressed stimulation-induced cortical afterdischarges by about 70% and single, bicuculline-induced epileptiform spikes by approximately 25%. In a pilot trial carried out in seven patients, a rapid termination of electrographic seizures was seen despite the fact that the application of 5% CO₂ was started after seizure generalization.Five percent CO₂ has a fast and potent anticonvulsant action. The present data suggest that medical carbogen with 5% CO₂ can be used for acute treatment to suppress seizures in epilepsy patients.