Arginase deficiency with parotid gland swelling and hyperamylasemia: A case report.

Arginase deficiency is a progressive neurological disorder characterized by episodic hyperammonemia crises. Our patient had been diagnosed with cerebral palsy (spastic paraplegia) in childhood and received rehabilitation. She had suffered parotid swelling since the age of 5 years, prior to liver dysfunction becoming apparent, and then developed hyperamylasemia at 8 years of age. At age 25 years, she presented with hyperammonemia and elevations of aspartate aminotransferase and alanine aminotransferase. At age 27 years, she was diagnosed with arginase deficiency due to hyperargininemia and absent arginase activity in erythrocytes. Liver cirrhosis was also present. She was hospitalized several times for management of episodic hyperammonemia due to recurrent viral infections, an unbalanced diet, and poor compliance with medications.

CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate.

CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.

A case of Turner's syndrome with Graves' disease and primary hyperparathyroidism.

We report a 21-year-old woman with Turner's syndrome, Graves' disease and primary hyperparathyroidism. At 12 years of age, she was of short stature, and was diagnosed with Turner's syndrome and treated with growth hormone. At the age of 17 years, she was diagnosed with Graves' disease. On treatment with methimazole, her laboratory findings normalized. At the age of 20 years, her serum calcium and intact parathyroid hormone levels were high. The upper left parathyroid gland showed swelling and was resected, and adenoma was diagnosed pathologically. Then, primary hyperparathyroidism induced by the adenoma was diagnosed. After the parathyroidectomy, the patient's serum calcium and intact parathyroid hormone levels normalized. Is likely that Turner's syndrome and Graves' disease were not associated with primary hyperparathyroidism. Multiple endocrine neoplasia type 1 was unlikely considering the clinical, laboratory, ultrasonographic, and scintigraphic findings.

A short form of gross motor function measure for Fukuyama congenital muscular dystrophy.

OBJECTIVES: The objective of this study was to confirm the validity of a short form of gross motor function measure for Fukuyama congenital muscular dystrophy (GMFM for FCMD). METHODS: This study is a case series and was conducted at the Tokyo Women's Medical University. Fifteen patients with FCMD were assessed using both the GMFM for FCMD with 68 items, which was created as a motor function measure for patients with FCMD on the basis of Rasch analysis, and the original GMFM with 88 items. The correlation between the GMFM for FCMD and the Ueda classification was assessed. Time required for each assessment was also evaluated. RESULTS: We found significant correlation between the GMFM for FCMD and the Ueda classification (r = 0.935); furthermore, the mean assessment time tended to decrease when using the GMFM for FCMD. CONCLUSIONS: GMFM for FCMD may be an appropriate motor function scale for patients with FCMD and might help decrease the assessment time.

Microdeletion in Xq28 with a polymorphic inversion in a patient with FLNA-associated progressive lung disease.

Lung phenotype was reported as a novel phenotype in patients with mutations in the filamin A gene (FLNA) in 2011. FLNA mutations can result in pulmonary hyperinflation during the neonatal period or early infancy with progressive respiratory failure, culminating in a diagnosis of FLNA-associated progressive lung disease, particularly if the patient has periventricular nodular heterotopia and cardiac complications, such as patent ductus arteriosus, atrial septal defect, and pulmonary hypertension. We report the first Japanese case of FLNA-associated progressive lung disease caused by a microdeletion in Xq28 encompassing the FLNA gene with a polymorphic inversion.

Efficacy, safety, and pharmacokinetics of intravenous midazolam in Japanese children with status epilepticus.

BACKGROUND: No dosing regimen has been established for the initial treatment of pediatric status epilepticus with intravenous midazolam. We therefore evaluated the efficacy, safety, and pharmacokinetics of bolus and continuous midazolam infusion. METHODS: This open-label, prospective, multicenter study involved 34 Japanese children with status epilepticus unresponsive to diazepam. An initial bolus of 0.15 mg/kg midazolam was given, with additional doses of 0.1-0.3 mg/kg up to a cumulative dose of 0.6 mg/kg. A continuous infusion was initiated at 0.1 mg/kg/h (maximum 0.4 mg/kg/h) for patients at high risk of recurrence or in whom seizure reduction was achieved, and continued for 24 h after seizure cessation. Seizure cessation was assessed based on clinical observation (disappearance of motor symptoms regardless of recovery of consciousness), rather than the disappearance of electroencephalography abnormalities. RESULTS: The seizure cessation rate with bolus midazolam was 88%. The cumulative dose was ≤0.3 mg/kg in 90% of patients who responded to bolus administration. Adverse events were observed in three patients; one had mild respiratory depression that required supplemental oxygen and bag-valve-mask ventilation. Elimination half-life was 0.999 ±â€¯0.241 h in seven patients. Total body clearance ranged from 423 to 1220 mL/h/kg in older children but was notably higher in a 10-month-old infant (2010 mL/h/kg). CONCLUSIONS: The efficacy and safety of midazolam were demonstrated in children with status epilepticus, suggesting that intravenous midazolam is suitable as first-line treatment.

Renal dysfunction is rare in Fukuyama congenital muscular dystrophy.

BACKGROUND: The leading cause of death in patients with Fukuyama congenital muscular dystrophy (FCMD) is congestive heart failure or respiratory dysfunction, which is same as that in Duchenne muscular dystrophy (DMD). Recent studies reported that renal dysfunction is a common complication and an increasing cause of death in advanced DMD. It can be attributable to circulatory instability or inappropriate use of drugs for treating cardiac dysfunction. METHODS: We retrospectively evaluated renal function in 38 genetically diagnosed patients with FCMD (range, 1.3-32.9 years; mean age, 13.7 ±â€¯6.9 years) using cystatin C. We examined possible relationships of cystatin C with blood natriuretic peptide and creatinine levels along with cardiac echocardiography findings. RESULTS: Twenty-five patients were treated for cardiac dysfunction. Elevated cystatin C level was detected only in two, who also showed proteinuria, glycosuria, hematuria, and extremely high ß2-microglobulin levels on urine tests, and were thus diagnosed with renal tubular cell damage. Because both patients were treated for intractable epilepsy with various antiepileptic drugs, including valproic acid (VPA), and had low serum carnitine levels, renal tubular cell damage was considered as an adverse effect of VPA. Unlike patients with DMD, no patient with FCMD had renal dysfunction. Such a rare occurrence of renal dysfunction can be attributable to mild cardiac dysfunction, short disease duration, and careful and early fluid management. CONCLUSION: Renal dysfunction is rare in patients with FCMD; however, renal tubular cell damage should be ascertained, particularly in those undergoing VPA treatment for epilepsy.

Systematic review of the screening, diagnosis, and management of ADHD in children with epilepsy. Consensus paper of the Task Force on Comorbidities of the ILAE Pediatric Commission.

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.

Characteristic findings of skeletal muscle MRI in caveolinopathies.

Caveolinopathies, caused by CAV3 mutations, can include several phenotypes such as rippling muscle disease, limb-girdle muscular dystrophy type 1C, distal myopathy, familial hypertrophic cardiomyopathy, and idiopathic hyperCKemia. Here we present characteristic skeletal muscle imaging findings in four patients with genetically defined childhood-onset RMD caused by CAV3 mutations and in one patient with congenital generalized lipodystrophy type 4 with muscular dystrophy due to polymerase I and transcript release factor (PTRF) mutations, which may have caused secondary deficiency of caveolin-3. Muscle MRI revealed that the rectus femoris and semitendinosus muscles were most commonly affected in the rippling muscle disease patients. Peripheral changes in the rectus femoris were specific and observed even in one of the younger patients in this study. Furthermore, muscle involvement extended to the semitendinosus muscles, biceps femoris, and gracilis with disease progression or increase in its severity. Similar patterns of involvement were observed on reviewing skeletal muscle images of various previously reported phenotypes of caveolinopathy; interestingly, patients with secondary deficiency of caveolin due to PTRF mutations revealed the same pattern. Thus, primary caveolinopathies and secondary deficiency of caveolin demonstrated specific findings on skeletal muscle imaging, regardless of the broad phenotypic spectrum of these two conditions.

National registry of patients with Fukuyama congenital muscular dystrophy in Japan.

Fukuyama congenital muscular dystrophy (FCMD) is the second most common form of muscular dystrophy in the Japanese population and is caused by mutations in the fukutin (FKTN) gene. In 2011, the Japan Muscular Dystrophy Association (JMDA) developed a nationwide registry of genetically confirmed patients with FCMD. We retrospectively reviewed the registry dataset of patients with FCMD to obtain data, including age, sex, developmental milestones, intellectual level, complications, and primary treatments. In total, 207 patients with FCMD (104 boys and 103 girls) were registered by the end of September 2013. Mean patient age at first registration was 8.1 ±â€¯7.8 years (median, 6 years; range, 0-42 years). A homozygous 3-kb founder insertion mutation in the FKTN gene was present in 80% of registrants, whereas 20% had a compound heterozygous mutation. Sixty-nine patients (33%) had febrile seizures and/or epilepsy. Myopia was the most frequently detected abnormality (8.7%), followed by strabismus (5.9%). Overall, 16% of patients required respiratory support and this percentage increased with age. Cardiac dysfunction was detected in 16%, and dysphagia was observed in 22% of patients with FCMD. The FCMD patient registry is useful for clarifying the natural history of FCMD and recruiting patients for clinical trials.

Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy.

BACKGROUND: In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. METHODS: Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. RESULTS: A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia. CONCLUSIONS: Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).

Outcome of vagus nerve stimulation for drug-resistant epilepsy: the first three years of a prospective Japanese registry.

Vagus nerve stimulation (VNS) is an established option of adjunctive treatment for patients with drug-resistant epilepsy, however, evidence for long-term efficacy is still limited. Studies on clinical outcomes of VNS in Asia are also limited. We report the overall outcome of a national, prospective registry that included all patients implanted in Japan. The registry included patients of all ages with all seizure types who underwent VNS implantation for drug-resistant epilepsy in the first three years after approval of VNS in 2010. The registry excluded patients who were expected to benefit from resective surgery. Efficacy analysis was assessed based on the change in frequency of all seizure types and the rate of responders. Changes in cognitive, behavioural and social status, quality of life (QOL), antiepileptic drug (AED) use, and overall AED burden were analysed as other efficacy indices. A total of 385 patients were initially registered. Efficacy analyses included data from 362 patients. Age range at the time of VNS implantation was 12 months to 72 years; 21.5% of patients were under 12 years of age and 49.7% had prior epilepsy surgery. Follow-up rate was >90%, even at 36 months. Seizure control improved over time with median seizure reduction of 25.0%, 40.9%, 53.3%, 60.0%, and 66.2%, and responder rates of 38.9%, 46.8%, 55.8%, 57.7%, and 58.8% at three, six, 12, 24, and 36 months of VNS therapy, respectively. There were no substantial changes in other indices throughout the three years of the study, except for self/family-accessed QOL which improved over time. No new safety issues were identified. Although this was not a controlled comparative study, this prospective national registry of Japanese patients with drug-resistant epilepsy, with >90% follow-up rate, indicates long-term efficacy of VNS therapy which increased over time, over a period of up to three years. The limits of such trials, in terms of AED modifications and during follow-up and difficulties in seizure counting are also discussed.

Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan.

Fukuyama congenital muscular dystrophy (FCMD), which is caused by mutations in the fukutin gene, is the second most common form of childhood muscular dystrophy in Japan. The founder haplotype is the most prevalent in the chromosomes of Japanese FCMD patients, and corresponds to an SVA retrotransposal insertion in the 3'-untranslated region of fukutin. Although other mutations have been reported, the mutation corresponding to the second most prevalent haplotype in Japanese FCMD patients remained unknown. Recently a deep-intronic point mutation c.647+2084G>T was identified in Korean patients with congenital muscular dystrophy. Here, we performed mutational analysis of 10 patients with the second most prevalent haplotype and found that all of them were compound-heterozygous for the SVA insertion and this c.647+2084G>T mutation. The fukutin mRNA of these patients contained a pseudoexon between exon 5 and exon 6, which was consistent with the previous Korean study. As expected, the mutated fukutin protein was smaller than the normal protein, reflecting the truncation of fukutin due to a premature stop codon. Immunostaining analysis showed a decrease in the signal for the glycosylated form of α-dystroglycan. These findings indicated that this mutation is the second most prevalent loss-of-function mutation in Japanese FCMD patients.

The gross motor function measure is valid for Fukuyama congenital muscular dystrophy.

Fukuyama congenital muscular dystrophy (FCMD) is the second most common muscular dystrophy in Japan. FCMD is an autosomal recessive disorder caused by mutations in the fukutin gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities, and mental retardation associated with cortical migration defects, and most patients are never able to walk. To date, the development of a quantitative motor scale for FMCD has been difficult due to the moderate-to-severe intellectual impairment that accompanies FCMD. Gross motor function measure (GMFM), originally developed as a quantitative motor scale for cerebral palsy, can precisely and quantitatively assess motor function without complicated instructions, and was recently reported to be useful in the assessment of Down syndrome and spinal muscular atrophy. To confirm the validity of GMFM for the assessment of FCMD, 41 FCMD patients (age range: 0.6-24.4 years) were recruited for this study. The GMFM scores correlated significantly with those of two previously used motor scales, and the time-dependent change in GMFM scores was consistent with the natural course of FCMD. The inter-rater reliability, based on determinations made by four physiotherapists blinded to each other's assessment results, was excellent. We concluded GMFM to be a useful and valid measure of motor function in FCMD patients.

Respiratory management of patients with Fukuyama congenital muscular dystrophy.

BACKGROUND: Fukuyama congenital muscular dystrophy (FCMD), characterized by intellectual impairment associated with cortical migration defects, is an autosomal recessive disorder caused by mutation in the fukutin gene. It is the second most common type of muscular dystrophy in Japan. Respiratory dysfunction, along with cardiomyopathy, can be life-threatening in patients with advanced-stage FCMD. However, few reports have focused on this issue. METHODS: We retrospectively studied respiratory dysfunction and therapeutic management in 48 genetically diagnosed FCMD patients (mean age 11.0 years; range 3.6-31.9 years). RESULTS: Mechanical ventilation was initiated at a median age of 12.1 years in 16 patients, 14 of whom received non-invasive positive pressure ventilation (NPPV) while the other 2 underwent tracheostomy with invasive ventilation (TIV). The two TIV cases had unexpectedly required the initiation of ventilatory support at the ages of 15.7 and 18.0 years, respectively, because of unsuccessful extubation followed by serious respiratory infections, despite rather good respiratory function before these episodes. Patients carrying a compound heterozygous founder mutation or with a severe phenotype tended to need ventilatory support 2-3 years earlier than homozygous patients and those with the typical or mild phenotype. Mechanical insufflation-exsufflation (MI-E) interventions were also employed in six patients with serious dysphagia and were well-tolerated in all cases. CONCLUSION: For respiratory management, it is important to regularly evaluate respiratory function in FCMD patients over 10 years of age, since intellectual impairment and insomnia often mask the signs of respiratory dysfunction. Most patients, despite poor cooperation due to intellectual impairment, can tolerate NPPV and MI-E provided that a carefully worked-out plan is adopted.

[Effects of Long-Term Treatment with Levetiracetam as an Adjunctive Therapy in Japanese Children with Uncontrolled Partial-Onset Seizures: A Multicenter, Open-Label Study].

Following the first period of the multicenter, open-label, single-armed N01223 trial, the second period of the N01223 trial was conducted to evaluate long-term safety, along with the efficacy of adjunctive levetiracetam treatment (individualized dose range, 20-60 mg/kg/day or 1,000-3,000 mg/day) in Japanese pediatric patients with uncontrolled partial-onset seizures (POS). Of the 62 children who completed the first period, 55 children [age: 10.4 ± 3.4 years (mean ± standard deviation)] were elected to enter the second period for a maximum of 39 months. Twenty children were withdrawn during this second period. Frequencies of treatment-emergent adverse events (TEAEs) and adverse drug reactions (ADRs) were 98.2% (54/55 cases) and 27.3% (15/55 cases), respectively. The most common TEAEs were nasopharyngitis (76.4%), influenza (36.4%) and pyrexia (25.5%). The only frequent ADR (>2%) was somnolence (3.6%). Although serious TEAEs and death were reported in 8 cases and 1 case (drowning), respectively, a serious ADR was only reported in 1 case (vomiting). The median percentage reduction and 50% response rate for POS were 43.32% and 41.8%, respectively. One child showed a maximum seizure-free period of 163 days. In conclusion, levetiracetam demonstrated long-term safety and good tolerance with beneficial efficacy as an adjunctive therapy in Japanese children with uncontrolled POS. (Received June 30, 2015; Accepted July 14, 2015: Published November 1, 2015).

Ketogenic diet therapy can improve ACTH-resistant West syndrome in Japan.

PURPOSE: Ketogenic diet therapy (KD) has been used to treat children with refractory generalized epilepsy. We herein reported the efficacy of KD for West syndrome (WS) resistant to ACTH therapy. SUBJECTS: SUBJECTS, consisting of 6 patients (3 boys, 3 girls) with WS who continued to have epileptic spasms (ES) and hypsarrhythmia, received KD because other treatments including ACTH therapy failed to control WS. METHODS: We retrospectively studied the clinical details of these patients and the efficacy of KD. RESULTS: The mean age at the onset of epilepsy was 4 months (0-15 months). The underlying etiology consisted of lissencephaly, Down's syndrome, and focal cortical dysplasia. Hypsarrhythmia disappeared 1 month after the introduction of KD in 5 patients. The disappearance of ES was achieved in 2 patients, the frequency of ES episodes was 80% less in 3, and no change was observed in 1. Psychomotor development was promoted in 5 patients, along with improvements in ES and EEG. Gastrointestinal complications and lethargy, presumably caused by rapid ketosis, were reported as side effects in 3 patients during the first week of KD. Side effects including lethargy, anorexia, and unfavorable weight gain continued thereafter in these patients in spite of tolerance to KD. CONCLUSION: KD was effective for WS resistant to ACTH therapy, although gastrointestinal side effects should be considered when introducing KD to milk-fed infants.

Study of epileptic drop attacks in symptomatic epilepsy of early childhood - differences from those in myoclonic-astatic epilepsy.

OBJECTIVES: We studied epileptic drop attacks (EDA) in symptomatic epilepsy of early childhood by means of video-polygraphic recordings and compared clinico-electrical differences in EDA among patients with idiopathic myoclonic-astatic epilepsy (MAE). SUBJECTS AND METHODS: Subjects consisted of 21 children with symptomatic epilepsy and 20 with idiopathic MAE whose EDA were documented at an age between 7 months and 6 years. The seizure types causing EDA as well as other demographic data were compared between the two epilepsy types. RESULTS: A video-polygraphic study captured a total of 188 EDA (median: 8) in patients with symptomatic epilepsy and 182 EDA (median: 7) in those with idiopathic MAE. In the former, EDA were caused by epileptic spasms (ES) corresponding to generalized biphasic slow discharges, sharp-and-slow wave complexes, or the flattening of ongoing background activity in 15 patients, atonic seizures associated with runs of generalized spike-and-wave complexes in four patients, and myoclonic-atonic seizures in the remaining two patients. The mode of occurrence of EDA in ES was periodic clustering in eight of 15 patients. Interictal EEG revealed generalized irregular multiple spikes-and-waves with focal or multifocal accentuations. Sixteen idiopathic MAE patients had myoclonic-atonic seizures while the remaining four had myoclonic-flexor seizures, all corresponding to generalized high amplitude spikes or polyspike-and-wave complexes and occurring singly. CONCLUSION: EDA often seen in young children with symptomatic epilepsy were most frequently caused by flexor type ES and rarely by myoclonic-atonic seizures, a hallmark seizure type of MAE. In a clinical setting, the occurrence of periodic clusters and independent focal or multifocal accentuations of generalized spike-and-wave complexes in interictal EEG may indicate EDA caused by ES.