Treatment of electrical status epilepticus in sleep: A pooled analysis of 575 cases.

OBJECTIVE: Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is a pediatric epilepsy syndrome with sleep-induced epileptic discharges and acquired impairment of cognition or behavior. Treatment of ESES is assumed to improve cognitive outcome. The aim of this study is to create an overview of the current evidence for different treatment regimens in children with ESES syndrome. METHODS: A literature search using PubMed and Embase was performed. Articles were selected that contain original treatment data of patients with ESES syndrome. Authors were contacted for additional information. Individual patient data were collected, coded, and analyzed using logistic regression analysis. The three predefined main outcome measures were improvement in cognitive function, electroencephalography (EEG) pattern, and any improvement (cognition or EEG). RESULTS: The literature search yielded 1,766 articles. After applying inclusion and exclusion criteria, 112 articles and 950 treatments in 575 patients could be analyzed. Antiepileptic drugs (AEDs, n = 495) were associated with improvement (i.e., cognition or EEG) in 49% of patients, benzodiazepines (n = 171) in 68%, and steroids (n = 166) in 81%. Surgery (n = 62) resulted in improvement in 90% of patients. In a subgroup analysis of patients who were consecutively reported (585 treatments in 282 patients), we found improvement in a smaller proportion treated with AEDs (34%), benzodiazepines (59%), and steroids (75%), whereas the improvement percentage after surgery was preserved (93%). Possible predictors of improved outcome were treatment category, normal development before ESES onset, and the absence of structural abnormalities. SIGNIFICANCE: Although most included studies were small and retrospective and their heterogeneity allowed analysis of only qualitative outcome data, this pooled analysis suggests superior efficacy of steroids and surgery in encephalopathy with ESES.

Dravet syndrome: new potential genetic modifiers, imaging abnormalities, and ictal findings.

PURPOSE: Dravet syndrome is an autosomal dominant epileptic encephalopathy of childhood, which is caused mainly by SCN1A and PCHD19 mutations. Although Dravet syndrome is well recognized, the causes of acute encephalopathy are still elusive, and reported data on ictal electroencephalography (EEG) and structural brain abnormalities are scarce. METHODS: We studied 30 children who fulfilled the clinical criteria for Dravet syndrome. All patients were screened for SCN1A mutations and 25 for POLG mutations with bidirectional sequencing. Clinical data, including etiologic studies done as part of the clinical workup, were collected from hospital charts. Ictal video-EEG recordings and magnetic resonance (MR) images were reanalyzed by the authors. KEY FINDINGS: SCN1A mutations were found in 25 patients (83%). Two SCN1A mutation-negative patients had chromosomal translocations involving chromosomes 9 and X, and one had a mutation in PCDH19. Prolonged seizures were associated with acute encephalopathy in three SCN1A mutation-positive patients. One showed evidence of a significant hypoxic-ischemic event during status epilepticus. The other two demonstrated new persistent neurologic deficits postictally; they both carried heterozygous POLG variants (p.Trp748Ser or p.Gly517Val). Hippocampal sclerosis or loss of gray-white matter definition in the temporal lobe was observed in 7 of 18 patients who had MRI after age 3 years (39%). Motor seizures were recorded on video-EEG for 15 patients, of whom 12 were younger than 6 years at recording; 11 patients (73%) showed posterior onsets. SIGNIFICANCE: Our data imply that a heterozygous X;9 translocation and rare POLG variants may modify the clinical features of Dravet syndrome. The latter may increase susceptibility for acute encephalopathy. Temporal lobe abnormalities are common in patients imaged after 3 years of age. Focal seizures seem to localize predominantly in the posterior regions in young children with Dravet syndrome.

The effect of surgery in encephalopathy with electrical status epilepticus during sleep.

PURPOSE: We analyzed clinical and electroencephalography (EEG) outcomes of 13 patients with pharmacoresistant encephalopathy with electrical status epilepticus during sleep (ESES) following epilepsy surgery. METHODS: All patients had symptomatic etiology of ESES and preoperative neuropsychological deterioration. Ten patients had daily atypical absences. Clinical outcome was assessed at 6 months and at 2 years after surgery. Clinical and EEG data were reviewed retrospectively. The spike propagation pattern and area and source strength in source montage were analyzed from preoperative and postoperative EEG studies. KEY FINDINGS: Preoperative sleep EEG showed electrical status epilepticus during sleep (SES) with one-way interhemispheric propagation in nine patients and with two-way interhemispheric propagation in four. The age of the patients at the time of surgery ranged from 3.6-9.9 years. Focal resection (two patients) or hemispherotomy (one patient with postoperative EEG) either terminated SES or restricted the discharge to one region. Either reduced SES propagation area or source strength was found in four of eight callosotomy patients with postoperative EEG. Of patients who had seizures preoperatively, Engel class I-II seizure outcome was observed in two of three children after focal resection or hemispherotomy and in two of eight children after callosotomy. None of these patients with Engel class I-II outcome had SES with two-way interhemispheric propagation on preoperative EEG. Cognitive deterioration was halted postoperatively in all except one patient. Cognitive catch-up of more than 10 IQ points was seen in three patients, all of whom had shown a first measured IQ of >75. SIGNIFICANCE: Patients with pharmacoresistant ESES based on symptomatic etiology may benefit from resective surgery or corpus callosotomy regarding both seizure outcome and cognitive prognosis.

Long-term outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome.

PURPOSE: To prospectively evaluate the efficacy of drug treatment and long-term cognitive outcome in children with encephalopathy with status epilepticus during sleep (ESESS). METHODS: Thirty-two children were diagnosed and prospectively followed up for at least 3 years at our unit between 1991 and 2007. Twenty-seven children were included in the prospective treatment study with valproate (VPA) and 17 with VPA combined with ethosuximide (ESM). Treatment response of disappearance of electrical status epilepticus during sleep (SES) was documented with overnight EEG recordings. Neuropsychological follow up for at least 5 years was available in 18 patients. RESULTS: Six children had atypical rolandic (AR) epilepsy, nine Landau-Kleffner syndrome (LKS), and 17 symptomatic epilepsy. Before ESESS, 20 children were cognitively normal. Prospective treatment with VPA and ESM was effective in 3 of the 17 children (18%) treated. Abolition of SES with drug treatment was observed in 16 patients. In all, 10 children (31%), 4 with AR (67%), 3 with LKS (33%), and 3 with symptomatic etiology (19%), including 9 with treatment response regained the pre-ESESS cognitive level. Unfavorable cognitive outcome was predicted by younger age at ESESS diagnosis, lower IQ at the time of the diagnosis, and no response to drug treatment when compared with those with favorable cognitive outcome. Eight of the 16 nonresponders underwent epilepsy surgery. DISCUSSION: Treatment response with VPA combined with ESM was observed more often than with other drug combinations. Most children with ESESS experienced permanent cognitive impairment. Cognitive outcome depends on treatment response on electroencephalography (EEG) and seizures, and on underlying etiology.

Two-year follow-up of intelligence after pediatric epilepsy surgery.

Research findings concerning cognitive effects of pediatric epilepsy surgery form an important basis for decisions about surgery. However, most follow-up studies have been of limited duration. In this study, a 2-year follow-up of intelligence was undertaken. Risk factors were analyzed. Included were 38 patients aged 3 to 17 years. Surgery was left in 19 patients and right in 19 patients. Types of surgery included temporal lobe resection (n = 23), extratemporal or multilobar resection (n = 8), and hemispherectomy (n = 7). The Wechsler Scales of Intelligence were administered presurgically, 6 months postsurgically, and 2 years postsurgically. No significant change in verbal or performance intelligence quotient (IQ) was demonstrated on a group level. Lateralization, type of surgery, age at surgery, sex, and presurgical IQ did not affect outcome. Across assessments, IQ scores of left-hemisphere patients were lower than those of right-hemisphere patients. Scores of patients in the hemispherectomy group were lower than those of the extratemporal or multilobar resection group, which were lower than the temporal lobe resection group. Scores improved significantly in six patients and deteriorated in seven. In conclusion, epilepsy surgery in children and adolescents does not, in general, have a significant impact on cognitive development in a 2-year perspective. In individual patients, poor seizure control and extensive surgery for Rasmussen's encephalitis were related to a deterioration of IQ.

PRRT2-related disorders: further PKD and ICCA cases and review of the literature.

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307, c.388delG/p.Ala130Profs 46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80-100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.