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Biomedical subjects

H Oguni

Publications and source records attributed to H Oguni.

At least 19 recordsLinked to original sources

Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity.

BACKGROUND AND METHODS: Many missense mutations in the voltage-gated sodium channel subunit gene SCN1A were identified in patients with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI), although GEFS+ is distinct from SMEI in terms of clinical symptoms, severity, prognosis, and responses to antiepileptic drugs. The authors analyzed the localization of missense mutations in SCN1A identified in patients with GEFS+ and SMEI to clarify the phenotype-genotype relationships. RESULTS: Mutations in SMEI occurred more frequently in the "pore" regions of SCN1A than did those in GEFS+. These SMEI mutations in the "pore" regions were more strongly associated than mutations in other regions with the presence of ataxia and tendency to early onset of disease. The possibility of participation of ion selectivity dysfunction of the channel in the pathogenesis of SMEI was suggested by a mutation in the pore region (R946C) identified in a SMEI patient. CONCLUSIONS: There was a significant phenotype-genotype relationship in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy with SCN1A missense mutations. More severe sodium channel dysfunctions including abnormal ion selectivity that are caused by mutations in the pore regions may be involved in the pathogenesis of SMEI.

Age of Onset↗

Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood.

PURPOSE: We retrospectively studied patients with myoclonic-astatic epilepsy of early childhood (MAE) to investigate the most effective treatment and long-term seizure and intellectual prognosis. SUBJECTS: Eighty-one patients with MAE were recruited from among 3600 patients with childhood epilepsy according to the ILAE criteria of MAE. METHODS: We retrospectively investigated the clinical characteristics and ultimate prognosis of the patients with MAE from the medical records. The effects of various antiepileptic drugs, ketogenic diet and ACTH treatments on myoclonic-astatic seizures (MS/AS), apparently a hallmark of this unique epileptic syndrome, were also studied. RESULTS: MS/AS in 89 % of the patients disappeared within 1 to 3 years despite initial resistance, but generalized tonic-clonic or clonic seizures [G(T)CS] tended to continue. The most effective treatment for the MS/AS was ketogenic diet, followed by ACTH and ESM. At the last follow-up, 55 patients or 68 % of all the patients had remission of epilepsy, 11 patients or 14 % experienced a recurrence of GTCS after a long remission period but easily regained control, and the remaining 15 patients or 18 % continued to have seizures and intellectual outcomes were poor. In one half of these patients with poor outcomes, repeated minor epileptic status and nocturnal generalized tonic seizures persisted. A family history of epilepsy and a combination of minor epileptic status are risk factors for poor outcomes. CONCLUSION: MAE is considered to form a clinical spectrum ranging in its main seizure type from myoclonic to atonic, and in seizure and intellectual outcomes from benign to malignant. The overall prognosis, despite initial resistance to treatment, appears to be much better than originally thought when ILAE definitions excluding SME are followed.

Adolescent↗

Acquired epileptiform opercular syndrome: a case report and results of single photon emission computed tomography and computer-assisted electroencephalographic analysis.

We report here a girl aged 5 years 3 months with cryptogenic localization-related epilepsy who showed a prolonged episode characterized by dysarthria, dysphagia, drooling and paresis of the right arm associated with almost continuous diffuse sharp-slow wave complexes during sleep. These symptoms were not directly related to seizures or to each sharp-slow wave complex revealed by examination during the video electroencephalographic (EEG) recording. The interictal single photon emission compute tomography showed a localized high perfusion area in the left posterior frontal region. The introduction of clonazepam completely controlled the clinical symptoms as well as the EEG abnormality within 2 weeks. After 4 months of remission, a similar episode recurred which was associated with aggravation of EEG. The clinical and EEG characteristics of this patient were identical to those of acquired epileptiform opercular syndrome (AEOS), a newly proposed epileptic syndrome, in which a transient operculum syndrome develops in association with continuous spike-and-wave activity during slow sleep (CSWS). Computer-assisted EEG analysis demonstrated that the epileptic EEG focus was located in the left sylvian fissure, and produced secondary bilateral synchronous sharp-slow complexes. The present study further supports the hypothesis that the electrical interference by CSWS creates bilateral opercular dysfunction through the mechanism of secondary bilateral synchrony, thus producing AEOS.

Child, Preschool↗

Severe myoclonic epilepsy in infants--a review based on the Tokyo Women's Medical University series of 84 cases.

Severe myoclonic epilepsy in infants (SME) is one of the most malignant epileptic syndromes recognized in the latest classification of epileptic syndromes. The clinical details and electroencephalographic (EEG) characteristics have been elucidated by Dravet et al. The diagnosis of SME depends largely on the combination of clinical and EEG manifestations at different ages, of which the presence of myoclonic seizures appears to be the most important. However, because of the inclusion of different types of myoclonic attack and the lack of strict criteria for diagnosing SME, there has been some confusion as to whether patients without myoclonic seizures or myoclonus should be classified as SME, despite other identical clinical symptoms (SME borderlands (SMEB) group). Among the various clinical manifestations characterizing SME, special attention has been paid to seizures easily precipitated by fever and hot baths in Japan. We have demonstrated that the onset of myoclonic attack in these patients is very sensitive to the elevation of body temperature itself rather than its etiology. Using simultaneous EEG and rectal temperature monitoring during hot water immersion, we showed that epileptic discharges increased in frequency, and eventually developed into seizures at temperatures over 38 degrees C. We believe that the unique fever sensitivity observed in SME is similar to, but more intense than that of febrile convulsions. We have also identified a group of cases who have had innumerous myoclonic and atypical absence seizures daily which were sensitive to the constant bright light illumination. In these cases, spike discharges increased or decreased depending on the intensity of constant light illumination. Although these cases form the most resistant SME group, they lost the constant light sensitivity with increasing age, leaving only relatively common types of fever-sensitive grand mal seizures (FSGM) at the age of around 5 years. In the long run, only convulsive seizures continue, while myoclonic or absence seizures and photosensitivity disappear with advancing age, thus it is conceivable that SMEB constitutes a basic epileptic condition underlying SME. There is a clinical continuum that extends from the mildest end of SMEB to the severest end of SME with constant light sensitivity, with intermediates of frequent or infrequent myoclonic and absence seizures in-between. This spectrum concept appropriately explains the clinical variabilities between SME and SMEB during early childhood.

Electroencephalography↗

Myoclonic-astatic epilepsy of early childhood--clinical and EEG analysis of myoclonic-astatic seizures, and discussions on the nosology of the syndrome.

PURPOSE: The aim of this study is to elucidate the clinical and neurophysiological characteristics of the myoclonic, myoclonic-astatic, or astatic seizures in patients with myoclonic-astatic epilepsy (MAE) of early childhood, and to discuss on the nosology of this unique epileptic syndrome. SUBJECTS: The subjects included 30 patients, who fulfilled the following modified International League Against Epilepsy (ILAE) criteria for MAE, and whose main seizures were captured by video-electroencephalographs (EEG) or polygraphs. The modified ILAE criteria includes: (1) normal development before onset of epilepsy and absence of organic cerebral abnormalities; (2) onset of myoclonic, myoclonic-astatic or astatic seizures between 7 months and 6 years of age; (3) presence of generalized spike- or polyspike-wave EEG discharges at 2-3 Hz, without focal spike discharges; and (4) exclusion of severe and benign myoclonic epilepsy (SME, BME) in infants and cryptogenic Lennox-Gastaut syndrome based on the ILAE definitions. RESULTS: The seizures were investigated precisely by video-EEG (n=5), polygraph (n=2), and video-polygraph (n=23), which identified myoclonic seizures in 16 cases (myoclonic group), atonic seizures, with or without preceding minor myoclonus, in 11 cases (atonic group), and myoclonic-atonic seizures in three cases. All patients had a history of drop attacks, apart from ten patients with myoclonic seizures. Myoclonic seizures, involving mainly the axial muscles were classified into those with mild intensity not sufficient to cause the patients to fall (n=10) and those that are stronger and sufficient to cause astatic falling due to flexion of the waist or extension of the trunk (n=6). Patients in the atonic group fell straight downward, landed on their buttocks, and recovered immediately. Analysis of the ictal EEGs showed that all attacks corresponded to the generalized spike or polyspikes-and-wave complexes. In the atonic form, the spike-and-wave morphology was characterized by a positive-negative-deep-positive wave followed by a large negative slow wave. In two patients, the intensity of the atonia appeared to correspond to the depth of the positive component of the spike-and-wave complexes. We did not detect any significant differences in the clinical and EEG features and prognosis, between the atonic and myoclonic groups. CONCLUSIONS: Although the determination of exact seizure type is a prerequisite for diagnosing an epileptic syndrome, the strict differentiation of seizure type into either a myoclonic or atonic form, does not appear to have a significant impact on the outcome or in delineating this unique epileptic syndrome. At present, we consider it better to follow the current International Classification of Epileptic Syndromes and Epilepsies until a more appropriate system than the clinico-electrical approach for classifying patients with MAE is available.

Child, Preschool↗

Study on early-onset benign occipital seizure susceptibility syndrome.

We prospectively studied the early-onset benign occipital seizure susceptibility syndrome to confirm the benign prognosis. The patients were 37 children followed for more than 2 years after meeting the following criteria on the first examination: (1) normal development before the onset of epilepsy, (2) onset between 1 and 8 years of age, (3) normal brain MRI and cranial CT findings, (4) partial seizures manifested both initial ictal vomiting and tonic eye-deviations, and (5) normal background activity with or without epileptic EEG foci regardless of location. The incidence and clinical characteristics of seizures, response to treatment, and EEG findings were analyzed. The total number of seizures ranged from one (n = 6) to 27 times, with a median of five times. Recurrent prolonged attacks resistant to antiepileptic drugs were recognized in 15 children, who had earlier onset of epilepsy and more frequent complications than the remaining 22 children. Interictal EEG revealed occipital foci in 26 children, 17 of whom later revealed a shift in predominant foci. At the final examinations, 28 patients had been seizure-free for at least 2 years. The clinical picture of this syndrome ranges from those with a few seizures to those with recurrent prolonged seizures initially resistant to antiepileptic drugs despite ultimate remission by 12 years of age.

Age Factors↗

Neurophysiological study of secondary synchronous occipito-frontopolar spikes in childhood.

OBJECTIVES: We conducted this latency study to clarify the neurophysiological mechanism underlying the synchronous appearance of independent occipital and frontopolar spike discharges in childhood epilepsies. METHODS: The subjects were 13 children with localization-related epilepsies (LRE) who showed apparently synchronous occipital and frontopolar EEG spike discharges. There was idiopathic LRE in 7 children, symptomatic LRE in 4, and cryptogenic LRE and a history of cryptogenic West syndrome in one patient each. Patient ages at the time of the study ranged from 4 years 3 months to 14 years 0 month with a mean of 9 years 4 months. The EEGs were digitized at 1024 samples/s. The latency was measured between the peak of the occipital and frontopolar spike discharges. The conduction velocity was calculated by dividing the distance between the occipital and frontopolar electrodes by the latencies. RESULTS: We studied 19 EEGs including 6 serial EEGs recorded longitudinally in 5 patients. The number of occipito-frontal spike discharges available for the study ranged from 12 to 70 with an average of 36+/-17 in each EEG record. Occipital spikes always preceded the frontopolar spikes by 11.1-31.6 ms (average 19.3+/-5.4 ms). The estimated conduction velocity ranged from 6.7 to 19.2 m/s with a mean of 12.2+/-3.7 m/s. CONCLUSIONS: The synchronizing spike phenomenon we showed in this study was in the posterior to anterior direction (intrahemispheric synchrony) in contrast to that of secondary bilateral interhemispheric synchrony through the corpus callosum. It is suggested that the long occipito-frontal association fibers play a role in synchronizing both spike discharges. This secondary occipito-frontopolar synchrony should be one of the developmental EEG phenomena related to the maturation of brain, and contribute to the multiplication or diffusion of the pre-existing localized spike discharges often seen in pediatric LRE regardless of etiology.

Action Potentials↗

A study of the effect of color photostimulation from a cathode-ray tube (CRT) display on photosensitive patients: the effect of alternating red-cyan flicker stimulation.

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.

Adolescent↗

Study on photo-pattern sensitivity in patients with electronic screen game-induced seizures (ESGS): effects of spatial resolution, brightness, and pattern movement.

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.

Adolescent↗

Phenytoin-induced choreoathetosis in patients with severe myoclonic epilepsy in infancy.

We describe three patients with severe myoclonic epilepsy in infancy (SME) who suffer from choreoathetosis due to the adverse effect of phenytoin. Choreoathetosis appeared when these patients were 8, 19, and 21 years old, 2 days to 6 months after increasing the phenytoin dosage. Choreoathetosis disappeared when the phenytoin dosage was decreased. The two elder patients experienced episodic and rather paroxysmal onset of long-lasting choreoathetosis, requiring the differential diagnosis from degenerative disease. In one of the patients, an ictal SPECT revealed decreased perfusion in the basal ganglia contralateral to the unilateral choreoathetosis. Polypharmacy, including carbamazepine and zonisamide, may have facilitated the onset of choreoathetosis. Phenytoin-induced choreoathetosis in the patients with SME is an important differential diagnosis among degenerative disorders involving involuntary movements. The episodic and paroxysmal nature of this movement disorder can delay its diagnosis and effective treatment. Patients with SME appear to be particularly vulnerable to this side effect of phenytoin, indicating the possible involvement of basal ganglia in the pathophysiology of this type of epilepsy.

Adolescent↗

[Clinical study on epileptic aura in children with temporal lobe epilepsy].

We studied the clinical characteristics of epileptic aura with temporal lobe epilepsy (TLE) in children, by retrospectively reviewing medical records of 33 patients whose first seizures developed under 15 years of age. The diagnosis of TLE was made by interictal EEG and head MRI/SPECT, both of which demonstrated a temporal lesion. The patients were classified into 24 with mesial TLE syndrome, 3 with a temporal lobe tumor, 3 with temporal lobe dysplasia and 3 with other causes. The epileptic aura was not recognized in 5 patients (15%). The age at onset of aura ranged from 4 to 10 years with a median age at 7. In patients older than 10, it was always followed by impairment of consciousness. It was manifested with nausea in 14 patients (42%), vertigo, a sense of fear, palpitation and heating sensation on the back in three patients (9%) each. Thus, clinical manifestations of epileptic aura in children with TLE were largely identical to those of adult patients. Detailed history taking about the aura may provide a clue to the diagnosis of TLE even in children.

Adolescent↗

Successful trial of amantadine hydrochloride for two patients with alternating hemiplegia of childhood.

We report here the efficacy of amantadine hydrochloride for two patients with alternating hemiplegia of childhood (AHC) that did not respond to flunarizine. Amantadine was administered to one patient at age one year and seven months and to the other at age 25 years. The frequencies and duration of the hemiplegic attacks significantly improved in both patients. However, the attacks gradually returned to the previous level after a significant reduction in seizures for three years in the younger patient with ongoing AHC. Our therapeutic results further support the hypothesis that glutamate and NMDA receptors are involved in inducing alternating hemiplegic attacks, because amantadine as well as its derivative, memantine, are clinically available non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, with neuroprotective effects. Amantadine is worth trying when treating patients with AHC as a first trial or a substitute for flunarizine once the latter agent looses effect.

Adult↗

Surgical indication for refractory childhood epilepsy.

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.

Age Factors↗

A comparative study of high-dose and low-dose ACTH therapy for West syndrome.

PURPOSE: A prospective randomized controlled study was conducted for the purpose of identifying the lowest effective ACTH dose, with the fewest adverse effects, for the treatment of West syndrome (WS). SUBJECTS AND METHODS: Twenty-five subjects with cryptogenic (CWS, n = 9) or symptomatic (SWS, n = 16) WS were enrolled in this study. They were randomly assigned to receive either low-dose (0.005 mg/kg per day = 0.2 IU/kg per day) or high-dose (0.025 mg/kg per day = 1 IU/kg per day) synthetic ACTH therapy. ACTH was administered every morning for 2 weeks and tapered to zero over the subsequent 2 weeks. Both effectiveness and adverse effects were compared between the two treatment regimens in each type of WS. RESULT: After completion of the treatment protocol in the CWS group, spasms and hypsarrhythmia were completely suppressed in 3/4 (75%) given the low-dose and 5/5 (100%) given the high-dose treatment. In the SWS group, the spasms and hypsarrhythmia disappeared in 6/8 (75%) in each dose group. There were no significant differences in initial responses between the low-dose and high-dose treatments for either type of WS (P > 0.05). Long-term seizure and developmental outcomes, assessed in the 17 responders who were followed up for longer than 1 year after the completion of ACTH therapy, were also essentially the same. We did not recognize differences in side effect profiles between the two treatment regimens with the exceptions of sleepiness and brain shrinkage estimated by CT scan, both of which were significantly milder in the low-dose than in the high-dose group (P < 0.05). CONCLUSION: Unexpectedly, this prospective randomized controlled study demonstrated the dose of ACTH required for spasm cessation and disappearance of the hypsarrhythmic EEG pattern to be lower than previously believed. A low-dose regimen should thus be considered for CWS, and for SWS associated with significant cerebral atrophy.

Adrenocorticotropic Hormone↗

Study on the early-onset variant of benign childhood epilepsy with occipital paroxysms otherwise described as early-onset benign occipital seizure susceptibility syndrome.

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.

Adolescent↗

Study on surgical treatment of intractable childhood epilepsy.

We studied the clinical details of 14 children with intractable epilepsies, all of whom underwent epilepsy surgery before age 18 years. All 14 suffered catastrophic seizures, which were resistant to the full range of available medical treatments. The ages at operation ranged from 4 years 7 months to 17 years 2 months, with a mean of 9 years 11 months. In nine patients, the age at onset of epilepsy was less than 2 years. The seizure disorders were classified as temporal lobe epilepsy in two patients, extratemporal lobe epilepsy in 10, and symptomatic generalized epilepsy in two. Eight patients had a hemicorporeal deficit (hemiparesis or hemiplegia) preoperatively. All 14 patients showed localized magnetic resonance imaging (MRI), single photon emission computer tomography (SPECT) and/or positron emission tomography (PET) abnormalities, providing crucial information regarding the epileptic focus. As to the surgical outcomes, four patients became seizure-free and the other 10 showed significant improvement during a mean follow-up period of 2 years 5 months. As to etiology, cortical dysplasia was identified in seven patients. Epilepsy surgery should be considered for intractable childhood epilepsy based on individual clinical characteristics, including seizure status, cognitive development, and evidence indicating location of the seizure focus, rather than age.

Adolescent↗