A study on the relationship between non-epileptic fast (40 - 200 Hz) oscillations in scalp EEG and development in children.

OBJECTIVE: Physiological gamma and ripple activities may be linked to neurocognitive functions. This study investigated the relationship between development and non-epileptic, probably physiological, fast (40-200 Hz) oscillations (FOs) including gamma (40 - 80 Hz) and ripple (80 - 200 Hz) oscillations in scalp EEG in children with neurodevelopmental disorders. METHODS: Participants were 124 children with autism spectrum disorder (ASD) and/or attention deficit/hyperactivity disorder (ADHD). Gamma and ripple oscillations were explored from 60-second-long sleep EEG data in each subject using a semi-automatic detection tool supplemented with visual confirmation and time-frequency analysis. RESULTS: Gamma and ripple oscillations were detected in 25 (20.2%) and 22 (17.7%) children, respectively. The observation of one or more occurrence(s) of ripple oscillations, but not gamma oscillations, was significantly related to lower age at EEG recording (odds ratio, OR: 0.727 [95% confidence interval, CI: 0.568-0.929]), higher intelligence/developmental quotient (OR: 1.041, 95% CI: 1.002-1.082), and lack of a diagnosis with ADHD (OR: 0.191, 95% CI: 0.039 - 0.937) according to a binominal logistic regression analysis that included diagnosis with ASD, sex, history of perinatal complications, history of febrile seizures, and use of a sedative agent for the EEG recording as the other non-significant parameters. Diagnostic group was not related to frequency or power of spectral peaks of FOs. CONCLUSION: The production of non-epileptic scalp ripples was confirmed to be associated with brain development and function/dysfunction in childhood. Further investigation is necessary to interpret all of the information on higher brain functions that may be embedded in scalp FOs.

Laboratory changes during adrenocorticotropic hormone therapy associated with renal calcified lesions.

BACKGROUND: Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high-risk cases with renal calcified lesions are yet to be clarified. METHODS: In this study, 43 patients with West syndrome aged ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography. RESULTS: After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the seven patients who underwent abdominal CT, ECs or hematuria were found only in those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions. CONCLUSIONS: The risk of renal calcified lesions increased after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy.

Ictal Cardiorespiratory Arrest Associated with Status Epilepticus in Panayiotopoulos Syndrome.

A healthy 10-year-old boy vomited during sleep and later complained of abdominal pain; he became drowsy and uncommunicative. At the nearby hospital E.R., he deteriorated rapidly, and his respiratory movements were absent with cardiac arrest. He was immediately resuscitated. Brain MRI showed no abnormalities. EEG revealed an abnormal pattern with recurrent multifocal epileptiform activity over the bilateral occipital and frontal regions during sleep. Based on the clinical/radiological findings we diagnosed Panayiotopoulos syndrome (PS), a benign form of early-onset pediatric epilepsy characterized by autonomic symptoms. Lifethreating cardiopulmonary arrest is rare in PS, but long seizure duration of PS may associate with apnea and bradycardia.

Intelligence test at preschool-age predicts reading difficulty among school-aged very low birth weight infants in Japan.

OBJECTIVE: To elucidate whether the results of an intelligence test at preschool age are predictive of reading difficulty (RD) at school age among very low birth weight infants (VLBWI). METHODS: Subjects were 48 Japanese children whose birth weight was <1500 g and who regularly visited a follow-up clinic. All subjects completed the Wechsler Intelligence Scale for Children-III (WISC-III) during the last grade of kindergarten, and four reading tasks during the second to fourth grade of elementary school. All participants had a full-scale intelligence quotient score of 85 or higher. Subjects with a standard deviation reading time score greater than 2.0 in two or more tasks were considered to have RD. We evaluated the associations between each WISC-III score and RD using logistic regression analyses. Furthermore, we performed receiver operating characteristic (ROC) analysis to determine a cutoff WISC-III score predictive of RD. RESULTS: In the mutually-adjusted model, the adjusted odds ratio per 1 score increase of freedom from distractibility (FD) was 0.832 (95% confidence interval: 0.720-0.962). In the ROC analysis, an FD score of <95.5 was chosen as the cutoff value for predicting RD (sensitivity, 0.77; specificity, 0.74). CONCLUSION: The present study indicated that a lower FD score at preschool age, which was associated with deficits in verbal working memory and attention, is a risk factor for RD at school age among Japanese VLBWI. Further investigation is desired to clarify the cognitive deficits underlying RD in Japanese-speaking preterm children, and to establish appropriate interventions for these children.

Detection of fast (40-150 Hz) oscillations from the ictal scalp EEG data of myoclonic seizures in pediatric patients.

OBJECTIVE: We explored fast (40-150 Hz) oscillations (FOs) from the ictal scalp electroencephalogram (EEG) data of myoclonic seizures in pediatric patients to obtain insight into the pathophysiological mechanisms involved in the generation of myoclonic seizures. SUBJECTS AND METHODS: The participants were 21 children (11 boys, 10 girls; age ranging from 5 months to 17 years 2 months) with myoclonic seizures associated with generalized (poly)spike-wave bursts in the ictal EEG data. The patients had heterogeneous etiologies and epilepsy diagnoses. In the ictal data, we detected FOs that clearly showed oscillatory morphology in filtered EEG traces and an outstanding spectral blob in time-frequency analysis. RESULTS: We identified FOs in 61 (88.4%) of all 69 myoclonic seizures. Every patient had at least one myoclonic seizure-associated FO. The observed FOs were embedded in the spike component of (poly)spike-wave discharges, and they had a focal distribution with frontal predominance. They ranged in frequency from 41.0 to 123.0 Hz and involved both the gamma and ripple bands, and their spectral peak frequencies were higher in the group of patients with a genetic background free of apparent fundamental brain pathology than in the group of other patients (p = 0.019). CONCLUSION: FOs were found to represent at least part of the cortical pathophysiological process in the generation of myoclonic seizures that should involve the thalamocortical network system.

Significance of High-frequency Electrical Brain Activity.

　Electroencephalogram (EEG) data include broadband electrical brain activity ranging from infra-slow bands (< 0.1 Hz) to traditional frequency bands (e.g., the approx. 10 Hz alpha rhythm) to high-frequency bands of up to 500 Hz. High-frequency oscillations (HFOs) including ripple and fast ripple oscillations (80-200 Hz and>200 / 250 Hz, respectively) are particularly of note due to their very close relationship to epileptogenicity, with the possibility that they could function as a surrogate biomarker of epileptogenicity. In contrast, physiological high-frequency activity plays an important role in higher brain functions, and the differentiation between pathological / epileptic and physiological HFOs is a critical issue, especially in epilepsy surgery. HFOs were initially recorded with intracranial electrodes in patients with intractable epilepsy as part of a long-term invasive seizure monitoring study. However, fast oscillations (FOs) in the ripple and gamma bands (40-80 Hz) are now noninvasively detected by scalp EEG and magnetoencephalography, and thus the scope of studies on HFOs /FOs is rapidly expanding.

A case of Dravet syndrome with cortical myoclonus indicated by jerk-locked back-averaging of electroencephalogram data.

We report a female patient with Dravet syndrome (DS) with erratic segmental myoclonus, the origin of which was first identified in the cerebral cortex by the detection of myoclonus-associated cortical discharges. The discharges were disclosed through jerk-locked back-averaging of electroencephalogram (EEG) data using the muscle activity of myoclonus as triggers. The detected spikes on the contralateral parieto-central region preceded myoclonic muscle activity in the forearms by 28-46ms. The patient was six months old at the time of examination, and was developing normally before seizure onset at two months of age. She suffered from recurrent afebrile or febrile generalized tonic-clonic seizures that often developed into status epilepticus. Interictal EEG and brain magnetic resonance imaging (MRI) showed no significant findings. The amplitudes of the somatosensory-evoked potentials were not extremely large. She has a chromosomal microdeletion involving SCN1A and adjacent genes.

A Japanese case of ß-ureidopropionase deficiency with dysmorphic features.

ß-Ureidopropionase deficiency is a rare autosomal recessive disease affecting the last step of pyrimidine degradation, and it is caused by a mutation in the UPB1 gene. Approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. Non-neurological symptoms have been rarely reported. We describe a case of this disease with developmental delay and dysmorphic features. Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant (⩾+4.5 standard deviation after logarithmic transformation) elevations of ß-ureidopropionic acid and ß-ureidoisobutyric acid, strongly suggesting a diagnosis of ß-ureidopropionase deficiency. Subsequent quantitative analysis of pyrimidines by liquid chromatography-tandem mass spectrometry supported this finding. Genetic testing of the UPB1 gene confirmed compound heterozygosity of a novel mutation (c.976C>T) and a previously-reported mutation (c.977G>A) that is common in East Asians. ß-Ureidopropionase deficiency is probably underdiagnosed, considering a wide phenotypical variability, non-specific neurological presentations, and an estimated prevalence of 1/5000-6000. Urine metabolomics should be considered for patients with unexplained neurological symptoms.

Predicting the reading skill of Japanese children.

OBJECTIVE: To clarify cognitive processes underlining the development of reading in children speaking Japanese as their first language, we examined relationships between performances of cognitive tasks in the preschool period and later reading abilities. METHODS: Ninety-one normally developing preschoolers (41 girls and 50 boys; 5years 4months to 6years 4months, mean 5years 10months) participated as subjects. We conducted seven cognitive tasks including phonological awareness tasks, naming tasks, and working memory tasks in the preschool period. In terms of reading tasks, the hiragana naming task was administered in the preschool period; the reading times, which is a composite score of the monomoraic syllable reading task, the word and the non-word reading tasks, and the single sentence reading task, was evaluated in first and second grade; and the kanji reading task (naming task) was tested in second grade. Raven's colored progressive matrices and picture vocabulary test revised were also conducted in first grade. Correlation analyses between task scores and stepwise multiple regression analyses were implemented. RESULTS: Tasks tapping phonological awareness, lexical access, and verbal working memory showed significant correlations with reading tasks. In the multiple regression analyses the performances in the verbal working memory task played a key role in predicting character naming task scores (the hiragana naming task and the kanji reading task) while the digit naming task was an important predictor of reading times. Unexpectedly, the role of phonological (mora) awareness was modest among children speaking Japanese. CONCLUSION: Cognitive functions including phonological awareness, digit naming, and verbal working memory (especially the latter two) were involved in the development of reading skills of children speaking Japanese.

Complex observation of scalp fast (40-150 Hz) oscillations in West syndrome and related disorders with structural brain pathology.

We investigated the relationship between the scalp distribution of fast (40-150 Hz) oscillations (FOs) and epileptogenic lesions in West syndrome (WS) and related disorders. Subjects were 9 pediatric patients with surgically confirmed structural epileptogenic pathology (age at initial electroencephalogram [EEG] recording: mean 7.1 months, range 1-22 months). The diagnosis was WS in 7 patients, Ohtahara syndrome in 1, and a transitional state from Ohtahara syndrome to WS in the other. In the scalp EEG data of these patients, we conservatively detected FOs, and then examined the distribution of FOs. In five patients, the scalp distribution of FOs was consistent and concordant with the lateralization of cerebral pathology. In another patient, FOs were consistently dominant over the healthy cerebral hemisphere, and the EEG was relatively low in amplitude over the pathological atrophic hemisphere. In the remaining 3 patients, the dominance of FOs was inconsistent and, in 2 of these patients, the epileptogenic hemisphere was reduced in volume, which may result from atrophy or hypoplasia. The correspondence between the scalp distribution of FOs and the epileptogenic lesion should be studied, taking the type of lesion into account. The factors affecting scalp FOs remain to be elucidated.

Importance of the multisystem follow-up in patients with tuberous sclerosis complex.

Objective: Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by the formation of hamartoma in multiple organ systems of the body. However, without a well-established cooperative system involving related departments, some organ lesions might be overlooked until symptoms appear or even until the disorder progresses. Therefore, the purpose of this study is to investigate the current status of follow-ups in the TSC patients in the Department of Child Neurology at Okayama University Medical Hospital. Methods: We performed a retrospective chart review of 38 patients with TSC who visited our hospital at least twice between January 2005 and December 2014. Patients were between 3 years and 48 years of age at their latest visit. We divided the patients into a child group and an adult group, and investigated the patients' follow-up data while focusing on the various multiorgan systems. Results: The follow-ups were well conducted in the child group in terms of every organ. In the adult group, neuroimaging tests were unsatisfactorily performed. The kidney has not been examined in seven patients more than five years even though these patients all had kidney lesions. The lung was not been examined in 7 out of 14 female patients over 18 years of age who are most at risk for lymphangioleiomyomatosis (LAM). In 12 out of 18 child patients, echocardiograms were performed every few years, while electrocardiograms to assess underlying conduction defects were rarely performed in either age group. Conclusions: In Europe, guidelines for the management of TSC have been well established. However, in our hospital, the multiorgan system follow-up is not satisfactorily performed especially in adult patients. We decided the establishment of a TSC board in our hospital for the management of this multiorgan disorder.

Fast (40-150Hz) oscillations are associated with positive slow waves in the ictal EEGs of epileptic spasms in West syndrome.

OBJECTIVE: To elucidate the generative mechanisms of epileptic spasms (ESs) in West syndrome, we investigated the temporal relationship between scalp fast (40-150Hz) oscillations (FOs) and slow waves in the ictal electroencephalograms (EEGs) of ESs. METHODS: In 11 infants with WS, ictal FOs were detected in a bipolar montage based on spectral and waveform criteria. Their temporal distribution was analyzed in terms of the positive peaks (trough point, TT) of identical EEG data in a referential montage. Among six EEG data sections defined according to TT, the number of FOs, peak power values, and peak frequencies were compared. RESULTS: We identified a total of 1014 FOs (946 gamma and 68 ripple oscillations), which clustered closely at TT. The number of gamma oscillations in the 1s epoch including TT was significantly higher than those in the prior and subsequent phases. Peak power values and frequencies tended to be higher in these positive phase sections. CONCLUSIONS: The temporal association of FO clustering and positive slow waves in the ictal EEGs of ES indicated that active neuronal firing related to FOs underlies the generation of ESs and their ictal slow waves.

Occurrence of bilaterally independent epileptic spasms after a corpus callosotomy in West syndrome.

We report a patient with intractable West syndrome whose epileptic spasms (ESs) were initially bilaterally synchronous, as is typical; after a complete corpus callosotomy, however, bilaterally independent ESs originated in either hemisphere. Activity of probable cortical origin associated with ESs was detected by observing ictal gamma oscillations. Brain MRI revealed no structural abnormality before surgery. This case suggests that ESs with a hemispheric origin may appear generalized because of synchronizing effects in the corpus callosum in some patients.

Acute respiratory distress syndrome in a child with severe epileptic disorder treated successfully by extracorporeal membrane oxygenation: a case report.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is now a candidate therapy for children with acute respiratory failure. CASE PRESENTATION: We report our experience of using central ECMO therapy for acute respiratory distress syndrome followed by seizure in a 15-month-old girl with a severe epileptic disorder. Her respiratory distress was refractory to standard medical treatment and mechanical ventilatory support. Her condition was complicated by development of a pneumothorax. The patient was successfully weaned off ECMO and discharged without deterioration of her neurological status. CONCLUSION: The successful outcome in this case resulted from the central ECMO, which enabled "lung rest" and adequate cerebral blood flow. In skilled ECMO facilities, early implementation of ECMO would give some advantages to patients such as the one presented here. Given the invasiveness and the ease of the procedure, introduction of dual-lumen catheters adequately sized for pediatric patients in Japan is required.

Phenotypic variability in childhood of skeletal muscle sodium channelopathies.

BACKGROUND: Mutations of the SCN4A gene cause several skeletal muscle channelopathies and overlapping forms of these disorders. However, the variability of the clinical presentation in childhood is confusing and not fully understood among pediatric neurologists. PATIENTS: We found three different mutations (p.V445M, p.I693L, and a novel mutation, p.V1149L) in SCN4A but not in the CLCN1 gene. The patient with p.V445M showed the clinical phenotype of sodium channel myotonia, but her clear symptoms did not appear until 11 years of age. Her younger sister and mother, who have the same mutation, displayed marked intrafamilial phenotypic heterogeneity from mild to severe painful myotonia with persistent weakness. The patient with p.I693L exhibited various symptoms that evolved with age, including apneic episodes, tonic muscular contractions during sleep, fluctuating severe episodic myotonia, and finally episodic paralyses. The patient with the novel p.V1149L mutation exhibited episodic paralyses starting at 3 years of age, and myotonic discharges were detected at 11 years of age for the first time. CONCLUSION: The present cohort reveals the complexity, variability, and overlapping nature of the clinical features of skeletal muscle sodium channelopathies. These are basically treatable disorders, so it is essential to consider genetic testing before the full development of a patient's condition.

Late-onset epileptic spasms in a female patient with a CASK mutation.

We report a female patient with late-onset epileptic spasms (ESs) of a rare form, distinct from those seen in typical West syndrome, in association with a heterozygous frameshift CASK mutation (c.1896dupC (p.C633fs(∗)2)). She has a phenotype of microcephaly with pontine and cerebellar hypoplasia (MICPCH), and has had intractable ESs in clusters since 3 years 8 months of age with multifocal, particularly bifrontal, epileptic discharges in electroencephalogram. The available literature on patients with both ESs and CASK mutations has been reviewed, revealing that four of the five female children, including the present girl, had late-onset ESs, in contrast to the four males, who tended toward early-onset ESs.

Manifestation of both emetic seizures and sylvian seizures in the same patients with benign partial epilepsy.

PURPOSE: Benign childhood epilepsy with centro-temporal spikes (BECTS) and Panayiotopoulos syndrome (PS) have different pathophysiologies and show different types of seizures, yet they overlap in some important respects. In an attempt to understand the ways in which they differ from each other and overlap each other, we performed a detailed investigation on patients who had both characteristic types of seizure manifestations, namely, sylvian seizures and emetic seizures. SUBJECTS AND METHODS: We recruited consecutive subjects from the EEG database of outpatients who had visited our hospital between 2008 and 2010 and who had been diagnosed with BECTS or PS. As a result, 45 patients with BECTS and 50 patients with PS were selected from the database. Viewing the clinical records of these 95 patients, five patients were selected who had experienced both sylvian seizures and emetic seizures. Next, the clinical features and EEG findings of these five patients were retrospectively observed at the date of investigation: October 1, 2011. RESULTS: We found that all the patients showed rolandic spikes when they had sylvian seizures, and occipital spikes or multifocal spikes when they had emetic seizures. We also report in detail on one patient who showed two different types of ictal EEG patterns: one of which started in the occipital area and the other of which was located in the rolandic area. CONCLUSION: Based on these findings, we conclude that widespread cortical hyperexcitability that includes the occipital area is necessary to produce the autonomic seizure manifestations seen in PS.

Novel PLA2G6 mutations associated with an exonic deletion due to non-allelic homologous recombination in a patient with infantile neuroaxonal dystrophy.

Novel PLA2G6 mutations associated with p.Asp283Asn and a unique intragenic deletion of exons 4 and 5 due to non-allelic homologous recombination were identified in a Japanese female patient with typical infantile neuroaxonal dystrophy. The patient showed progressive tetraplegia beginning at 9 months. An electroencephalogram showed a diffuse increase in fast waves, and brain magnetic resonance imaging showed progressive brain atrophy and T2 hypointensity in the globus pallidus.

Trend figures assist with untrained emergency electroencephalogram interpretation.

OBJECTIVE: Acute electroencephalogram (EEG) findings are important for diagnosing emergency patients with suspected neurological disorders, but they can be difficult for untrained medical staff to interpret. In this research, we will develop an emergency EEG trend figure that we hypothesize will be more easily understood by untrained staff compared with the raw original traces. METHODS: For each of several EEG patterns (wakefulness, sleep, seizure activity, and encephalopathy), trend figures incorporating information on both amplitude and frequency were built. The accuracy of untrained reviewers' interpretation was compared with that of the raw EEG trace interpretation. RESULTS: The rate of correct answers was significantly higher in response to the EEG trend figures than to the raw traces showing wakefulness, sleep, and encephalopathy, but there was no difference when seizure activity patterns were viewed. The rates of misjudging normal or abnormal findings were significantly lower with the trend figures in the wakefulness pattern; in the other patterns, misjudgments were equally low for the trend figures and the raw traces. CONCLUSION: EEG trend figures improved the accuracy with which untrained medical staff interpreted emergency EEGs. Emergency EEG figures that can be understood intuitively with minimal training might improve the accuracy of emergency EEG interpretation. However, additional studies are required to confirm these results because there may be many types of clinical EEGs that are difficult to interpret.

A storm of fast (40-150Hz) oscillations during hypsarrhythmia in West syndrome.

OBJECTIVE: Fast oscillations (FOs) were first explored from scalp electroencephalographic (EEG) data from hypsarrhythmia in West syndrome (infantile spasms) to investigate the meaning of FOs in this epileptic encephalopathy. METHODS: In 17 infants with West syndrome, we conservatively detected fast frequency peaks that stood out from the time-frequency spectral background with square root power > 1µV (spectral criterion) and corresponded to clear FOs with at least 4 oscillations in the filtered EEG traces (waveform criterion) in sleep EEGs. RESULTS: We found a total of 1,519 interictal FOs that fulfilled both the spectral and waveform criteria. The FOs with a median frequency of 56.6Hz (range = 41.0-140.6Hz) were dense, with a median rate of 66 (range = 24-171) per minute before adrenocorticotropic hormone (ACTH) treatment, which was significantly higher than that in control infants without seizures (median = 1, p < 0.001). The FOs were reduced by treatment. The mean gamma and ripple oscillation rates that were detected using the waveform criterion alone were 40.62/min and 15.75/min, respectively, per channel; these results were 112.8 and 98.4 times higher, respectively, than the previously reported corresponding rates in adult epilepsy patients. INTERPRETATION: The observed FOs corresponded to epileptogenicity because of their close relation to the severity of hypsarrhythmia during the course of ACTH treatment. The very high epileptic FO rates in hypsarrhythmia are thought to affect the process of neurodevelopment by interfering with physiological functions in West syndrome, taking into account that high frequencies are also important in physiological higher brain functions.