Mutation in the STXBP1 Gene Associated with Early Onset West Syndrome: A Case Report and Literature Review.

Syntaxin-binding protein1 (STXBP1) is a member of the Sec1/Munc18-1 protein family, which comprises important regulators of the secretory and synaptic vesicle fusion machinery underlying hormonal and neuronal transmission, respectively. STXBP1 pathogenic variants are associated with multiple neurological disorders. Herein, we present the case of a Japanese girl with a mutation in the STXBP1 gene, who was born at 40 weeks without neonatal asphyxia. At 15 days old, she developed epilepsy and generalized seizures. Around 88 days old, she presented with a series of nodding spasms, with the seizure frequency gradually increasing. Interictal EEG indicated hypsarrhythmia and she presented with developmental regression. At 1.5 years old, genetic testing was performed and mutational analysis revealed an STXBP1 gene mutation (c.875G > A: p.Arg292His). Accordingly, she was diagnosed with developmental and epileptic encephalopathy, presenting West syndrome's clinical characteristics caused by the STXBP1 gene mutation. Although drug treatment has reduced the frequency of epileptic seizures, her development has remained regressive. The relationship between the location and type of genetic abnormality and the phenotype remains unclear. Future studies should investigate the genotype−phenotype correlation and the underlying pathophysiology to elucidate the causal relationships among the multiple phenotype-determining factors.

Topiramate Blood Levels During Polytherapy for Epilepsy in Children.

BACKGROUND: The therapeutic range of topiramate (TPM) blood level is not set because the efficacy and safety are not considered to be related to the level. However, the therapeutic target without side effects is necessary, so the optimal range of TPM blood level was analyzed in this study. STUDY QUESTION: This study was conducted to evaluate the efficacy of TPM over 2 years and the utility of measuring blood levels of TPM during the follow-up of epileptic patients. STUDY DESIGN: Thirty patients (18 males, 12 females; age range, 6 months-15 years) were treated with TPM for epilepsy. The initial dosage of TPM was 1-3 mg·kg·d. If the effect proved insufficient after 2 weeks, the dosage was increased to 4-9 mg·kg·d. MEASURES AND OUTCOMES: Blood levels of TPM were measured by liquid chromatography-tandem mass spectrometry at 1, 6, 12, and 24 months after levels reached steady state. The efficacy of TPM was evaluated by the reduction in epileptic seizure rate (RR) at the time of blood sampling. Statistical analysis was performed using the Mann-Whitney U test. RESULTS: A positive correlation was seen between blood levels and maintenance dosages, but no correlation was observed between blood levels and RR. Any significant difference was not identified in TPM levels between the effective group (RR ≥50%) and the ineffective group (RR <50%; P = 0.159). In the subgroup of patients who did not use valproic acid, a significant difference in TPM levels was apparent between the effective and ineffective groups (P = 0.029). The optimal range of TPM was advocated 3.5-5.0 µg/mL. The optimal range was set, so that ranges did not overlap between the effective and ineffective groups. No patients experienced any side effects. CONCLUSIONS: Measuring blood levels of TPM based on the classification of concomitant drugs and adjusting the dosage to reach the optimal range were recommended.

Evoked potential studies for predicting functional recovery in a case of acute necrotizing encephalopathy.

Normal-appearing evoked potentials during the acute stage of the disease despite persistent coma may predict subsequent functional recovery of the brain in a pediatric case of acute necrotizing encephalopathy, indicating that evoked potential studies are useful for predicting functional outcome of the brain.

The Effectiveness of Lamotrigine and Its Blood Levels for Pediatric Epilepsy.

This study was conducted to evaluate the effectiveness of lamotrigine (LTG) over 2 years and the usefulness of measuring its blood levels during the follow-up of patients with epilepsy. We measured peak blood LTG levels of 32 patients with epilepsy (9.16 ± 3.34 years old; mean ± SD). The blood levels were measured at 6 months, 1 year, and 2 years after reaching the LTG maintenance dosage. The effectiveness of LTG was evaluated to determine the seizure reduction rate. The patients were classified as effective cases (mean of own seizure reduction rates >50%) and ineffective cases (≤50%). The results were that the dosage and blood level showed positive correlations in the case of combination use with sodium valproate (VPA) (r = 0.690), carbamazepine and/or phenobarbital (r = 0.940), and others (r = 0.548). In several groups, the blood levels and efficacies did not show any positive correlations. In the cases of combination use with VPA, the blood levels of effective cases and ineffective cases were significantly different (P = 0.001). The optimal range was 8-11.5 µg/mL based on the average and SD values in the effective cases. No patients had any side effects. In conclusion, no precise definition of the therapeutic range was possible because of the incomplete correlation between the blood level and seizure frequency. We recommend the optimal range of LTG as a therapeutic target without any side effects, and it was established that the range in the combination with VPA was 8-11.5 µg/mL.

Correlating blood and urinary concentrations of clobazam doses in Japanese children and adolescents with intractable epilepsy.

Clobazam (CLB) is an antiepileptic drug that is metabolized to the major metabolite N-desmethylclobazam (N-CLB). Our aim was to evaluate the utility of corrected urinary concentrations of CLB and N-CLB in Japanese children and adolescents with epilepsy. Blood and urinary concentrations of CLB and N-CLB were evaluated in 42 patients. The urinary and peak blood concentrations were measured 2-3 h after the last dose. The ratio of the blood and urinary creatinine concentrations was used to calculate the corrected urinary concentrations. A moderate correlation was found between the CLB dose and the CLB serum concentration, but this correlation was not found for N-CLB. Patients were dichotomized based on two regression lines, which were detected by statistical analyses with a cumulative distribution function: the lower ratio group (CLB/N-CLB < 0.275) and the higher ratio group (≥0.275). Moderate correlations were observed between the CLB dose and the serum concentration or the corrected value of CLB for the lower ratio group, and moderate to strong correlations were observed for the higher ratio group. The corrected urinary concentration of CLB correlates to the CLB dose when stratified by the CLB/N-CLB ratio and may prove practical for clinical estimation of the CLB serum concentration.

The efficacy of levetiracetam for focal seizures and its blood levels in children.

AIM: To evaluate the efficacy of levetiracetam (LEV) and the usefulness of measurement of its blood levels during the follow-up of patients with focal seizures. METHODS: Twenty-four patients (13 cases without impairment of consciousness or awareness and 11 cases with them or evolving to a bilateral, convulsive seizure) treated with LEV had their peak blood levels measured. The blood concentrations were measured at 2 weeks, 1 year and 2 years after reaching the LEV maintenance dosage. The efficacy of LEV was evaluated with repeated blood sampling to determine the seizure reduction rate. The patients were classified as effective cases (seizure reduction rate>50%) and ineffective cases (⩽50%). RESULTS: In Japanese children treated with LEV, the dosage and blood level showed positive correlations. The blood levels were higher in effective cases than in ineffective cases at all time points (p<0.05). In effective cases, the blood concentration was 23.26±6.88 µg/mL (mean±SD) 2 weeks later, 23.59±8.23 µg/mL 1 year later, and 24.46±7.57 µg/mL 2 years later. However, the blood levels and efficacies showed positive correlations only at 2 weeks and 1 year later. No patients had any side effects. CONCLUSIONS: No precise definition of the therapeutic range was possible because of the incomplete correlation between the blood level and seizure frequency. Instead of a therapeutic range, we recommend an optimal range for LEV of 20-30 µg/mL as a therapeutic target without any side effects.

The efficacy of gabapentin in children of partial seizures and the blood levels.

AIM: To evaluate the long-term efficacy of gabapentin (GBP) and usefulness of measurement of the blood level for the observation of patients that have partial seizures. METHODS: Thirty patients (20 effective cases and 10 ineffective cases) treated with GBP for the localization related epilepsy had their peak blood levels of GBP. The levels were measured seven time points, one, 6, 12, 18, 24, 30, and 36month after the start of medication. The efficacy of GBP was evaluated at one month after the initiation of medication and every year for 3years, based on the R Ratio and the degree of improvement for the paroxysmal strength and length. RESULTS: GBP levels were higher in the effective cases than the levels in the ineffective cases 6months after and 1year after the initiation of medication (p<0.05). The level 6months after the start in the effective cases was 5.429±2.384µg/ml (mean±SD), and 5.837±3.217µg/ml after 1year. The cases that were effective for 1year maintained approximately the same efficacy for 3years after the initiation of medication, but there was no correlation between the level and the R Ratio, paroxysmal strength and length. CONCLUSIONS: No precise definition of the therapeutic range was recognized because of no correlation between GBP level and the improvement of clinical manifestations. We recommend the GBP optimal range that is established the range within 3-8µg/ml (mean; 5µg/ml) as therapeutic target without the side effect.

Monitoring of body position and motion in children with severe cerebral palsy for 24 hours.

PURPOSE: To investigate differences in position and body movements between children with severe cerebral palsy (CP) and children with typical development (TD) during the daytime and while asleep at night. METHOD: Fifteen children with severe quadriplegic CP living at home (GMFCS level V, 7 males, 8 females; mean age 8 years 3 months; range 3-20 years) and 15 children with TD (6 males, 9 females; mean age 8 years 7 months; range 1-16 years) participated. Body position and movements were recorded for 24 h by a body position monitor and a physical activity monitor, respectively. The amount of time spent in one position and the durations of inactive periods during the daytime and during night-time sleep were computed and analyzed for group differences. RESULTS: In children with CP, the mean longest time spent in one position was longer than that in children with TD during night-time sleep (5.6 ± 3.5 h versus 1.6 ± 1.2 h). In contrast, no significant differences were found between the groups during the daytime (1.9 ± 1.1 h versus 1.6 ± 0.7 h). The mean longest time the body remained inactive was longer in the children with CP during both daytime and nighttime sleep (0.6 ± 0.3 h versus 0.3 ± 0.3 h for daytime, 1.4 ± 0.8 h versus 0.7 ± 0.3 h for nighttime). CONCLUSION: Children with severe CP living at home showed prolonged immobilized posture during night-time sleep when their caregivers would be likely to also be asleep. This may suggest that these children should receive postural care assistance at night.

Progressive diffuse brain atrophy in West syndrome with marked hypomyelination due to SPTAN1 gene mutation.

A 1-year-old male began suffering from West syndrome at 3 months of age, when electroencephalography revealed hypsarrhythmia accompanied by a periodic, brief suppression phase. The administration of adrenocorticotropic hormone was partially effective for stopping the condition, and the seizure type evolved into brief tonic seizures at 6 months. Thereafter, progressive atrophy of the brain became evident by 9 months of age, predominantly at the brainstem and cerebellum. Severe hypomyelination of the cerebral white matter was revealed at the age of 1 year, and a de novo heterozygous mutation in the SPTAN1 gene was confirmed. The patient showed severely impaired psychomotor development, and had gained no visual attention. These findings contribute to the characterization of this recently established entity and facilitate the identification of further patients.

Long-term outcomes of children and adolescents who had cerebral palsy with secondary osteoporosis.

OBJECTIVE: To investigate the long-term efficacy and index of treatment with vitamin D alone or with a bisphosphonate in children and adolescents who have cerebral palsy (CP) with secondary osteoporosis. RESEARCH DESIGN AND METHODS: Thirty patients diagnosed with CP and secondary osteoporosis were analyzed for 5 years, and the efficacy of treatment was compared. Treatment was divided into three groups: The monotherapy group, consisting of patients taking only alfacalcidol (0.03 µg/kg/day); the polytherapy group, consisting of those taking alfacalcidol and risedronate (0.05 mg/kg/day); and the control group, consisting of patients who discontinued taking their medications for reasons unrelated to these therapies. Bone mineral density (BMD), bone-specific alkaline phosphate (BAP), and N-telopeptides of type I collagen (NTX/Cr) were measured on each patient just before and at discontinuation of treatment, after 6 months, and again at 1 and 3 years, respectively. The changes in BMD (ΔBMD), BAP (ΔBAP), and NTX/Cr (ΔNTX/Cr) were evaluated at these intervals, because the normal value of each parameter varies over time during childhood. RESULTS: ΔBMD significantly increased in the polytherapy group at ≥1 year (p = 0.006), and the difference in BMD between the polytherapy and the control groups at ≥1 year was also significant (p = 0.005). ΔBAP was increased in the monotherapy and polytherapy groups at ≥1 year (p = 0.021 and p = 0.033). ΔNTX/Cr decreased in the polytherapy group at ≥1 year, which was consistent with the polytherapy group of the period from 1 month to 1 year (p = 0.033). The relation between ΔBMD to ΔBAP was a positive correlation in the second period in the monotherapy group (r = 0.46). And the relations between ΔBMD to ΔNTX/Cr were not recognized negative correlations in the monotherapy and polytherapy groups. Thus, ΔBMD reflected ossification of secondary osteoporosis in patients with CP, and ΔBAP and ΔNTX/Cr was significantly related to the increase and decrease of ΔBMD. There were no effects of other factors except sexual maturity. Limitations of this study include that each index of examination was the evaluation according to rate of change. Therefore, the results of this study were limited to longitudinal evaluations. CONCLUSION: Evaluation according to ΔBMD and both methods of monotherapy and polytherapy were useful for CP patient taking antiepileptic drugs (AEDs) and regardless of sex. Especially, polytherapy for longer than 1 year led to improvement in BMD in children who had CP with secondary osteoporosis. BAP and NTX/Cr were useful for the index of the progression osteoporosis with or without these therapies.

Blood concentrations of midazolam in status epilepticus using an appropriate condition of HPLC.

BACKGROUND: The aim of the present study was to determine an index to evaluate the efficacy and safety of midazolam (MDZ) to treat status epilepticus (SE). An original system was therefore developed to measure blood concentrations of MDZ and 1-hydroxymidazolam (1-OHMDZ) as the main metabolite on high-performance liquid chromatography. METHODS: This system was established through inspection of chromatograms, calibration curves and coefficient of correlations of MDZ. The clinical course of 11 SE patients, ranging from 4 months to 10 years of age, are described. These patients were treated with MDZ and measured at each blood concentration of MDZ. Moreover, patients were evaluated on cranial computed tomography and magnetic resonance imaging and video electroencephalogram (EEG), and it was determined that their seizures disappeared in accordance with the disappearance of convulsions and interictal EEG findings. RESULTS: Reproducibility was good with this system. The standard curves of MDZ and 1-OHMDZ were almost straight, and the correlation coefficients of MDZ and 1-OHMDZ were r = 0.9999 and r = 0.9998, respectively. The convulsions in nine of 11 SE patients disappeared without side-effects and the blood concentrations of MDZ in all the patients were measured. The mean peak blood concentrations of MDZ and 1-OHMDZ were higher than those reported in other studies. CONCLUSIONS: The clinical utility of this system has been demonstrated. An index to evaluate the efficacy and safety of MDZ is necessary, and MDZ blood concentrations measured on the present original precise measuring system could help in establishing a plan to successfully treat SE.

Secondary osteoporosis in long-term bedridden patients with cerebral palsy.

BACKGROUND: The aim of the present paper was to investigate 20 pediatric patients with cerebral palsy and secondary osteoporosis and consider the efficacy, influence and index of treatment. METHODS: A total of 10 boys and 10 girls, age 1-16 years (mean 7.6 years) with secondary osteoporosis and cerebral palsy treated for 6 months, were studied. Bone mineral density (BMD) was measured. The bone turnover markers were measured just before and 4 months after treatment or at the time of early discontinuation of treatment. The treatment was classified into two groups: vitamin D (alfacarcidol) only; and with bisphosphonate (risedronate). RESULTS: Monotherapy with alfacarcidol was effective for secondary osteoporosis in children, but when used in combination with risedronate it was even more effective in improving BMD. In the two groups, bone-specific alkaline phosphate (BAP) decreased from pretreatment to post-treatment assessment in all but one case, but there was no significant correlation in the difference in DeltaBAP with DeltaBMD. DeltaBAP assumed changes in BAP in treatment either before or after, and DeltaBMD also assumed changes in BMD. N-telopeptides of type I collagen (NTX)/Cr decreased in all cases. The correlation of DeltaNTX/Cr with DeltaBMD was not significant. The therapy and its efficacy did not correlate to the patients' age, sex, medicine regimen or enteral nutrition. CONCLUSIONS: Risedronate therapy is effective for patients presenting with secondary osteoporosis with cerebral palsy. Moreover, it is desirable to treat patients more aggressively from the early stage because risedronate is not affected by the patients' other factors.

Remission associated with human herpesvirus infection in west syndrome.

Generally, West syndrome is an intractable epileptic syndrome in infancy, although spontaneous remission has been reported in some cases. An immunologic response to infection might be one of the factors involved in the remission of West syndrome, but the mechanisms remain unknown. On the other hand, exanthema subitum is a common disease occurring in infancy with the characteristics of fever and rash. Two kinds of human herpesvirus, 6 and 7, have been isolated as causal agents of exanthema subitum. We experienced one symptomatic case and three cryptogenic cases of West syndrome that showed spontaneous remission. In the symptomatic case, the subject showed a temporary remission; however, in the other cases, the remissions were long term. In the present study, we report the patients' improvement and electroencephalographic (EEG) findings. In all of our cases, hypsarrythmia disappeared on the EEG findings, the human herpesvirus 6 IgG antibodies increased in all four cases, and the herpesvirus 7 IgG antibodies increased in two cases. We postulate that the remission of the four cases proceeded from infection by exanthema subitum. The changes in serum antibody values suggest that the spontaneous remission of West syndrome was related to human herpesvirus 6 and 7 infections.

Intractable seizures associated with proximal migration of a ventriculoperitoneal shunt. Case report.

A 6-year-old girl, who had received a ventriculoperitoneal (VP) shunt using the Codman-Hakim programmable valve system at age 3 months, presented with intractable seizures. Neuroimaging studies showed migration of the proximal part of the system, including the prechamber, into the cranium through the right frontal burr hole. Electroencephalography showed spike-and-wave complexes in the right hemisphere including the site of the migration. The ictus was resolved following revision surgery. The clinical findings suggested the seizures were due to irritation of the brain parenchyma by the migrated system. Proximal migration of a VP shunt may cause both shunt failure and additional focal symptoms.

[A case of intractable epilepsy showing frequent gelastic seizures by administration of clobazam].

A 13-year-old boy patient had severe mental retardation and spastic quadriplegia due to fetal distress and hypoxic-ischemic brain damage in the perinatal period. He suffered from West syndrome at the age of 7 months, and subsequently was diagnosed as having symptomatic localization-related epilepsy. His intractable epileptic seizures were not controlled by combination of various antiepileptic drugs. After prescribing nitrazepam and zonisamide for more than 1 year, we added clobazam (CLB), which has been marketed in Japan since 2000, to this combination therapy. After the introduction of CLB, tonic seizures disappeared. However, gelastic seizures laughing with a stiff face and a wry mouth appeared frequently before falling asleep, and sleep disturbance worsened subsequently. It has not been reported previously that gelastic seizures are a side effect of CLB, although irritability and sleep disturbance have been described.