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Attention-deficit/hyperactivity disorder (ADHD) is a common and challenging comorbidity affecting many children with epilepsy. A working group under the International League Against Epilepsy (ILAE) Pediatric Commission identified key questions on the identification and management of ADHD in children with epilepsy. Systematic reviews of the evidence to support approaches to these questions were collated and graded using criteria from the American Academy of Neurology Practice Parameter. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) requirements were followed, with PROSPERO registration (CRD42018094617). No increased risk of ADHD in boys with epilepsy compared to girls with epilepsy was found (Level A). Valproate use in pregnancy is associated with inattentiveness and hyperactivity in offspring (1 class I study), and children with intellectual and developmental disabilities are at increased risk of ADHD (Level A). Impact of early seizure onset on development of ADHD was unclear (Level U), but more evident with poor seizure control (Level B). ADHD screening should be performed from 6 years of age, or at diagnosis, and repeated annually (Level U) and reevaluated after change of antiepileptic drug (AED) (Level U). Diagnosis should involve health practitioners with expert training in ADHD (Level U). Use of the Strength and Difficulties Questionnaire screening tool is supported (Level B). Formal cognitive testing is strongly recommended in children with epilepsy who are struggling at school (Level U). Behavioral problems are more likely with polytherapy than monotherapy (Level C). Valproate can exacerbate attentional issues in children with childhood absence epilepsy (Level A). Methylphenidate is tolerated and effective in children with epilepsy (Level B). Limited evidence supports that atomoxetine is tolerated (Level C). Multidisciplinary involvement in transition and adult ADHD clinics is essential (Level U). In conclusion, although recommendations could be proposed for some of the study questions, this systematic review highlighted the need for more comprehensive and targeted large-population prospective studies., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Purpose: Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders., Methods: A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations., Key Findings: One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features., Significance: We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome., Methods: A questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and their prevalence of early death., Key Findings: Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome died. Data from 59 of these patients were analyzed. The patients' ages at death ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The analysis showed that the risk of mortality remained high up to approximately 12 years of age. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and acute hepatopathy in one patient (1%). The incidence of sudden death reached a first peak at 1-3 years of age and reached a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a sharp peak at 6 years of age. Seven of 10 patients who underwent an SCN1A mutation analysis exhibited positive mutations without a specific mutation site., Significance: In the present study, the prevalence of Dravet syndrome-related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was the highest in infancy (1-3 years) and at early school ages (with a peak at 6 years), respectively. After approximately 12 years of age, the risk of mortality declined sharply. Neither the treatment nor the number of seizures was associated with any cause of mortality. In addition, it is difficult to predict which factors lead to a fatal outcome., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome. The questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and the prevalence of early death due to the disorder. Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome had died. Data from 59 of these patients were analyzed. The age at death for these patients ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and other causes in one patient (1%). The incidence of sudden death reached a first peak at 1-3 years of age and a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a peak at 6 years of age. Seven of the 10 patients who underwent SCN1A mutation analysis exhibited positive mutations but exhibited no consistent phenotype. The prevalence of Dravet syndrome-related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was higher in infancy (1-3 years) and at early school ages (with a peak at 6 years), respectively. Neither the treatment nor the number of seizures was associated with any cause of mortality. Factors leading to a fatal outcome are difficult to predict., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

We performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox-Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct-sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

Objective: We conducted a video-polygraphic study of myoclonic seizures (MS) in different epileptic syndromes to clarify semiologic and electroencephalography (EEG) differences among them., Subjects and Methods: The subjects were 26 children with MS, including benign myoclonic epilepsy in infants (BME) in 10, severe myoclonic epilepsy in infants (SME) in 6, idiopathic epilepsy with myoclonic-astatic seizures (IEMAS) in 4, and juvenile myoclonic epilepsy (JME) in 6. We reviewed the video-polygraphs of MS, including the predominant area of muscle involvement (neck, trunk, and proximal or distal upper extremities), postural changes including astatic falling, and mode of appearance. We also analyzed the frequency of a corresponding generalized spike-and-wave complex (GSW) and the duration of myoclonic electromyography (EMG) activity., Results: A total of 550 MS were documented in the 26 cases. MS manifested with proximal predominance/forward flexion/single occurrence in BME, proximal predominance/forward astatic flexion/single occurrence in IEMAS, proximal predominance/extension/succession in SME, and distal predominance/extension/succession in JME. The median frequency of GSW was 1.5, 1.3, 3.2, and 3.1 Hz, respectively, and the median duration of the myoclonic EMG activity was 387, 587, 81, and 65 ms, respectively., Conclusion: MS in the four different epileptic syndromes show significant semiologic and EEG differences, as well as similarities. Although our study has the limitations of the small number of patients and retrospective methodology, these results should be considered in the classification and differential diagnosis of myoclonic epileptic syndromes.

Purpose: We analyzed the short- and long-term effects of adrenocorticotropic hormone (ACTH) therapy for patients with epileptic spasms (ESs) who did not meet the criteria of West syndrome (WS)., Methods: The subjects were 30 patients, including 13 boys and 17 girls, who had received ACTH therapy between 1970 and 2003. We excluded patients with WS, but included those with a history of WS who no longer showed hypsarrhythmia at the period of ACTH therapy. The age at onset of ESs and at ACTH therapy ranged from 2 to 82 months with a median of 18 months, and from 11 to 86 months with a median of 29 months, respectively., Results: Excellent and poor responses were obtained in 19 (63%) and 11 (37%) patients, respectively, as a short-term effect. Although the patients could be subclassified into five subgroups according to the previous reports, no difference was seen in short- term response to ACTH. Among 17 of the 19 patients with excellent short-term outcomes and a follow-up of >1 year after the ACTH therapy, eight patients have continued to be seizure free (29%; excellent long-term effect), whereas the remaining nine patients had a recurrence of seizures (complex partial seizures, four; generalized tonic seizures, three; ESs, two) at 9 months to 198 months (median, 49 months) after ACTH therapy. In addition, nine of the 17 patients demonstrated a localized frontal EEG focus after the ACTH therapy, although most of these had previously shown diffuse epileptic EEG abnormality., Conclusions: ACTH therapy is worth trying for patients with resistant ESs, even without features of WS. However, the long-term effect is uncertain because recurrences of various types of seizures, including focal, were frequently observed.

Purpose: Benign familial infantile convulsions (BFIC) is a form of idiopathic epilepsy. It is characterized by clusters of afebrile seizures occurring around the sixth month of life. The disease has a benign course with a normal development and rare seizures in adulthood. Previous linkage analyses defined three susceptibility loci on chromosomes 19q12-q13.11, 16p12-q12, and 2q23-31. However, a responsible gene has not been identified. We studied linkage in 16 further BFIC families., Methods: We collected 16 BFIC families, without an additional paroxysmal movement disorder, of German, Turkish, or Japanese origin with two to eight affected individuals. Standard two-point linkage analysis was performed., Results: The clinical picture included a large variety of seizure semiologies ranging from paleness and cyanosis with altered consciousness to generalized tonic-clonic seizures. Interictal EEGs showed focal epileptiform discharges in six patients, and three ictal EEGs in three distinct patients revealed a focal seizure onset in different brain regions. In all analyzed families, we found no evidence for linkage to the BFIC loci on chromosomes 19q and 2q, as well as to the known loci for benign familial neonatal convulsions on chromosomes 8q and 20q. In 14 of the families, the chromosome 16 locus could be confirmed with a cumulative maximum two-point lod score of 6.1 at marker D16S411, and the known region for BFIC could be narrowed to 22.5 Mbp between markers D16S690 and D16S3136., Conclusions: Our data confirm the importance of the chromosome 16 locus for BFIC and may narrow the relevant interval.

Since 1963, the association between antiepileptic drugs (AEDs) and congenital malformations in the offspring of women with epilepsy has received attention. A number of articles reported affirmative as well as some negative findings regarding an increased risk of congenital malformations. Although a consensus has not been regarding the presence of the specific malformation syndromes in relation to individual AEDs, such as fetal hydantoin syndrome, it is evident that women taking AEDs carry a two- to sevenfold higher risk of congenital malformations than do the general population. In most recent studies, special attention has been placed on polytherapy, including the specific AED, or AED combinations, and high AED serum concentrations, responsible for the higher risk of congenital malformations. Based on these cumulative results, therapy guidelines for women of childbearing age with epilepsy have been established.

Background: A 6-year-old girl with Rasmussen syndrome (RS) showed multiple small high-signal-intensity areas independently in the right hemisphere by fluid-attenuated inversion recovery (FLAIR) imaging on magnetic resonance imaging (MRI) 1 year after the onset of epilepsy., Methods: MRI performed 4 months later demonstrated a further increase in the number of these foci and enlargement in the size of the previous FLAIR lesions., Results: An [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) study showed a strong, spotty uptake in the right temporooccipital regions, corresponding to the sites of continuous EEG seizure discharges. In contrast, [11C]methionine PET demonstrated multifocal uptake regions, which corresponded anatomically to the FLAIR lesions, suggesting sites of underlying chronic inflammation., Conclusions: These neuroimaging findings suggested that the inflammatory process in RS spreads either multifocally at the same time, as seen in this case, or from one discrete area to the adjacent region, as reported previously.

Purpose: We analyzed sequential changes in the localization of EEG foci along with age to identify a specific EEG pattern, and the relation between the clinical manifestations and the EEG pattern in patients with Panayiotopoulos syndrome (PS)., Methods: The subjects were 76 children, who had been followed up >2 years with repeated EEG examinations at 6-month intervals. Analysis of EEG findings included the determination of localization of spike foci, as a function of age, by using cross-sectional data, and the identification of subgroups with homogeneous EEG patterns. Then we compared certain clinical features among these subgroups., Results: In the cross-sectional EEG study, the occipital EEG spike focus was most frequently seen between ages 2 and 5 years. Independent and synchronous frontopolar and occipital spikes (Fp-O spikes) and centroparietotemporal (CPT) EEG spike foci had increased incidences between ages 4 and 7 years, and between ages 6 and 10 years, respectively. We subclassified the 76 patients into the following five subgroups based on the evolutional changes in epileptic EEG foci, which frequently showed shifting, multiplications, and generalization: (a) persistent occipital focus group (O group), (b) Fp-O spikes group (Fp-O pattern group), (c) generalized EEG pattern group, (d) CPT foci group (CPT group), and (e) no epileptic EEG focus group. The Fp-O group showed the latest age at onset of epilepsy. The generalized EEG pattern group had the highest frequency of seizures as well as recurrences of status epilepticus (SE), as well as the longest active seizure period among the five groups., Conclusions: These results indicated that the EEG foci in most of patients with PS are frequently shifting location, multiplying, and propagating diffusely with age, rather than persistently localizing in the occipital region. In addition, the EEG patterns showed a certain trend and roughly corresponded to certain clinical characteristics. However, the prognosis of the seizures appeared to be favorable regardless of the EEG pattern.

Purpose: With the ever-increasing popularity of computers, electronic screen game-induced seizure (ESGS) is beginning to pose a serious social problem. To elucidate the pathophysiology of ESGS, with the ultimate goal of prevention, we have been studying photo-pattern sensitivity in detail with a pattern-stimulation test using a CRT (cathode ray tube) display. This method is referred to as the "CRT-pattern test.", Methods: We studied 17 patients brought to our department for evaluation of ESGS. EEG responses were recorded during exposure to various patterns consisting of three elements: spatial resolution, brightness perception, and pattern-movement recognition displayed on a CRT monitor. Photo-paroxysmal response (PPR) frequencies were compiled for each stimulation., Results: PPR was induced by the CRT-pattern test in nine of the 17 cases. In four cases, PPR induction was obtained only after introducing CRT-pattern tests in addition to standard intermittent photic stimulation (IPS). The rate of PPR induction differed according to the type of pattern, spatial frequency, and pattern-reversal frequency. However, neither the clarity of the edges of a pattern nor changes in the brightness of a pattern element had any effect on the rate of PPR induction. With the exception of a few subjects, the stimulation caused by pattern movement was not effective in eliciting PPR. Six cases in whom spatial resolution was involved showed occipital dominance in PPR provocation, and three in whom brightness perception and pattern movement recognition was involved showed frontal dominance., Conclusions: The CRT-pattern test is useful for identifying patients with photosensitivity among patients considered to have incidental or nonphotosensitive seizures unresponsive to standard IPS. Patients with ESGS caused by photosensitivity can be divided into two groups: those with occipital dominance for PPR provocation, in whom spatial resolution is involved; and another group with frontal dominance, in whom brightness perception and pattern-movement recognition (or possibly perception of colors) are involved.

Purpose: In an attempt to establish evidence for developing better guidelines for the production of animation programs that would not induce photosensitive seizures in Japan, we evaluated the effects of red flicker, alternating red/cyan (complementary color to red) flicker stimuli, and of contrast between the red and cyan frames from a cathode-ray tube (CRT) display in photosensitive patients., Methods: We studied 35 photosensitive patients. They were exposed to seven types of flicker. The first three types were alternating red/cyan flicker (R/C) with the luminance of cyan set at three different levels, high, equal, and low luminance (65, 20, and 16 cd/m2, respectively) relative to the red (20 cd/m2). The following four types were red, cyan, yellow, and magenta flicker stimuli. EEGs were recorded while the patients watched these stimuli on a CRT display., Results: Rates of photoparoxysmal response (PPR) provocation were 11.4, 13.7, and 14.0% with high-, no- and low-contrast R/C flicker, respectively, and 3.7% with red flicker. The differences between red and each of the other R/C flicker stimuli were all statistically significant (p<0.05, 0.01, 0.01). No significant differences were found between the effects by each of the three levels of contrast in alternating R/C flicker (p > 0.05)., Conclusions: These findings suggest that alternating R/C flicker is more provocative than simple red flicker, and that contrast between frames of different colors may play some role in the effects of alternating flicker stimuli from a CRT display in photosensitive patients. Therefore, caution against the use of the combination of red and cyan, in addition to the red flicker stimulus, should be included in any guidelines drawn up to prevent photosensitive seizures.

Recent progress in surgical intervention for medically refractory epilepsy has helped to shed light on more complex epileptogenic problems in children and infants. Surgical treatment increasingly is being used in pediatric patients, but the indications for surgery in this age group have not been well defined. The developing child with a seizure disorder has several problems that are different from adults, such as neural plasticity, deleterious effects of seizures on developmental status, and spontaneous resolution of epilepsy. The critical age for irreversible brain dysfunction and the timing of surgery are the main issues for the treatment of children. Thus, earlier surgical intervention is generally recommended to prevent further detrimental seizure effects, but we still do not know the optimal age. Until the establishment of guidelines for pediatric epilepsy surgery, surgical indications should be determined by the prognosis and the presence of a resectable epileptogenic focus, which in turn are based on the localization of the epileptic focus, seizure frequency, severity, and cognitive function of each case, rather than just the patient's age.

Purpose: We studied the early-onset variant of benign childhood epilepsy with occipital paroxysms (EVBCEOP) proposed by Panayiotopoulos, to confirm whether his five criteria are sufficient to delineate EVBCEOP as a new epileptic syndrome, as well as to predict a good outcome prospectively at the time of the first examination., Subjects: The subjects were 649 children with localization-related epilepsies (LREs) observed in our hospital for >4 years., Methods: We applied the International Classification of Epilepsies and Epileptic Syndromes to the 649 patients and identified patients who had EVBCEOP from among those with nonspecific idiopathic LRE. The inclusion criteria were to satisfy all five criteria and all but one criterion (i.e., either ictal vomiting or occipital EEG paroxysms). We were blind as to the outcomes and selected patients who satisfied the following three of the five criteria at the time of the first examination, (a) normal development before the onset, (b) epilepsy onset age between 2 and 8 years, and (c) occipital EEG foci. We attempted to determine whether the outcome can be predicted prospectively, and whether the presence or absence of ictal vomiting affects the prognosis., Results: We identified 19 patients who satisfied all five criteria, 22 who exhibited all but occipital EEG foci, and 21 who exhibited all but ictal vomiting. The incidence of status convulsivus was higher in those with ictal vomiting than in those without ictal vomiting (p < 0.05). Interictal EEG performed every 6 months showed shifting and multiplication of EEG foci in 42 and 52% of all subjects, respectively. We identified 57 patients, 42 (74%) of whom were in remission by age 12 years. The number of patients who experienced remission did not differ significantly between those with (76%, n = 25) and without (72%, n = 32) ictal vomiting (p > 0.05)., Conclusions: Nosologically, EVBCEOP appears to constitute the earliest form of idiopathic epileptic syndrome different from classic BCEOP. However, its clinical spectrum, ranging from the absence of ictal vomiting to a combination of extraoccipital and multifocal EEG foci, is broad, such that further prospective study is expected to reveal the exact prerequisite criteria for determining the border of this epileptic syndrome and for clarifying the clinical spectrum within this syndrome.

Purpose: To study the effectiveness of surgical therapy on 2 patients with startle epilepsy with infantile brain damage (SEIBD), a rare but distinctive epileptic syndrome characterized by motor seizures resistant to antiepileptic drugs (AEDs)., Methods: The patients with SEIBD both had hemiplegia, due to gross contralateral hemispheric lesions, and suffered from tonic postural seizures, frequently provoked by sudden unexpected somatosensory stimuli on the paretic side of the body. These attacks occasionally caused the patients to drop to the floor, and mild-to-moderate injuries had been sustained; they were resistant to all currently available AEDs. Consequently, these daily drop attacks severely restricted the patients' social lives and school participation. Both patients underwent corpus callosotomy and resection of epileptogenic premotor and supplementary motor lesions. One patient also underwent additional multiple subpial transections of the primary sensorimotor area., Results: Seizures, as well as quality of life, improved dramatically in both patients after surgery., Conclusions: Startle epilepsy with infantile hemiplegia is a distinct epileptic syndrome characterized by structural brain damage restricted primarily to one hemisphere, large ipsilateral epileptogenic lesions involving the perisensorimotor area, refractory startle-provoked drop attacks, and a good response to epilepsy surgery.

Purpose: We studied falling manifestations of atonic epileptic drop attacks (AEDA) in 2 patients with cryptogenic epilepsy with myoclonic-astatic seizures., Methods: Using video-polygraphic examinations. For analysis, we recorded 51 seizures in 1 patient and 18 seizures in the other. The extent of AEDA ranged from collapsing and landing on the buttocks to head nodding only without falling., Results: Detailed video analysis of the drop attacks, with the patient in standing position, demonstrated the first manifestations to be flexion at the waist and knees, followed by further knee flexion, leading to falling straight down and landing on the buttocks. Ictal polygraphs demonstrated diffuse interruptions of ongoing EMG discharges corresponding to the falls, indicating that these attacks are true atonic seizures., Conclusions: The falling manifestations of AEDA appeared to be characteristic and different from those of tonic drop seizures, which have been described as falling forward with tonic flexion of the hips, upper trunk, and head, as well as abduction or elevation of the arms.

We investigated the long-term prognosis of Lennox-Gastaut syndrome (LGS) in 72 patients followed up for > 10 years. Long-term seizure and intellectual outcomes were poor, as previously reported. The diagnosis of LGS was first made in the age range from 2 to 15 years with peak occurrence at 5 years. Progressive IQ score deterioration with age was apparent. At the last examination, 33% of patients with cryptogenic and 55% with symptomatic LGS had lost the characteristics of LGS, and their seizure disorders were classifiable as symptomatic generalized epilepsies, severe epilepsy with multiple independent spike foci, or localization-related epilepsies. Disabling drop attacks appeared in 46% of patients and tended to occur at older than 10 years. Gait deterioration was recognized in 12 patients and seemed to be due largely to progression of the epileptic encephalopathy. The gait disturbances, as well as increased frequency of violent drop attacks, were disabling in daily life and resulted in some patients being wheelchair bound.