Hideo Shigematsu

Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study

Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme‐replacement and substrate‐reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD.

Long‐term course of Dravet syndrome: A study from an epilepsy center in Japan

This study attempted to clarify the long‐term course of Dravet syndrome (DS).

Etiologic factors and clinical features of symptomatic epilepsy: focus on pediatric cases.

Abstract  We discuss the presumptive etiologic factors of symptomatic epilepsy from the clinical standpoint, based on our experience of 383 inpatients with epilepsy, with a focus on children. The main (top three) presumptive etiologic factors in partial epilepsy are intracranial infection, cerebral malformation and perinatal brain damage. In generalized epilepsy, the main presumptive etiologic factors are perinatal brain damage, intracranial infection, and cerebral malformation. As regards presumptive etiologic factors in partial epilepsy, cerebral malformation was most common in frontal lobe epilepsy, initial convulsive status in temporal lobe epilepsy and perinatal brain damage in occipital lobe epilepsy. Electroclinical characteristics of severe myoclonic epilepsy in infancy, the most intractable epilepsy syndrome in infancy, is the focus and recent advances of genetic research are introduced.

Neuropathological and Golgi study on a case of thanatophotoric dysplasia

Neuropathological examination of a 3-day-old female with thanatophoric dysplasia revealed abnormal sulci with polymicrogyria and neuronal heterotopia in the temporal lobes and cerebellar hypoplasia. Rapid Golgi stainings showed immature or maldeveloped neurons with short dendrites and a reduced number of spines in the cerebral cortex, and abnormal neurons with peculiar dendrites in the subcortical heterotopia. These abnormalities were predominant at the base of the large brain which occupied the hypoplastic middle and posterior cranial fossas.

Nonphotosensitive Video Game-Induced Partial Seizures

Summary: We report a 9‐year‐old boy with a ring 20 chromosome anomaly whose complex partial seizures (CPS), presumably of frontal lobe origin, were often induced by playing video games. Neither photosensitivity nor pattern sensitivity was observed. An intensive video‐EEG investigation showed that video games as well as mental calculation elicited rhythmic runs of bilateral high‐voltage slow waves, which eventually evolved into ictal discharges. This case suggests that higher brain functions can be involved in seizure induction.

Self-induced photogenic seizures in a child with severe myoclonic epilepsy in infancy: optical investigations and treatments.

Summary: In a 2‐year‐old patient with severe myoclonic epilepsy in infancy, we studied self‐induced photogenic seizures using optical filters and blue‐tinted contact lenses. The patient induced absences and/or myoclonic jerks by two kinds of behaviors: flickering hand movement (FHM) and forced eye closure (FEC). The placebo inhibitory effect on FHM by a blank goggle frame indicated that acquisition of learning affected the frequency of FHMs per se. Optical studies suggested that the degree of absorption from ∼600–700 nm might determine the inhibitory effect of filters on FHM. Investigations using contact lenses showed that blue‐tinted lenses gradually reduced photosensitivity and inhibited FHMs.

Developmental outcome after surgery in focal cortical dysplasia patients with early-onset epilepsy

The purpose of this study was to investigate the developmental outcome after surgery for early-onset epilepsy in patients with focal cortical dysplasia (FCD). Among 108 patients with histopathologically confirmed FCD operated between 1985 and 2008, we selected 17 patients with epilepsy onset up to 3 years of age. Development was evaluated by the developmental quotient or intelligence quotient (DQ-IQ) and mental age was measured by the Mother-Child Counseling baby test or the Tanaka-Binet scale of intelligence. Postsurgical development outcome was evaluated by the changes in DQ-IQ and mental age as well as rate of increase in mental age (RIMA) after surgery. RIMA was calculated as the increase in mental age per chronological year (months/year; normal average rate: 12 months/year). Age at epilepsy onset of 17 patients ranged from 15 days to 36 months (mean±SD, 11.0±10.0 months). Age at surgery ranged from 18 to 145 months (75.1±32.4 months). Evaluation just before surgery showed that 13 of 17 (76.4%) patients had DQ-IQ below 70. Ten patients (58.8%) were seizure-free throughout the postsurgical follow-up period. After surgery, DQ-IQ was maintained within 10 points of the presurgical level in 13 patients (76.4%), and increased by more than 10 points in one patient (5.9%). After surgery, RIMA in patients with Engels class I (7.5±3.8) was higher than patients with Engels class II-IV (2.6±3.4) (unpaired t-test with Welchs correction, t=2.99, df=15, p=0.0092). RIMA was particularly low in two patients with spasm. In four patients with presurgical DQ-IQ<70, seizure-free after surgery and without spasm, DQ-IQ did not increase but RIMA improved from 3.6±2.8 before surgery to 6.9±2.5 months/year after surgery. RIMA became better from 2 years after surgery. In four patients with presurgical DQ-IQ≥70 and no spasm, two showed the same or higher RIMA than normal average after surgery. In 58.8% of FCD patients with early onset epilepsy, epilepsy surgery effectively controlled seizures, and in 82.3% of patients, epilepsy surgery preserved or improved development. Residual seizures after surgery and lower DQ-IQ before surgery might be potential risk factors for poor development after surgery. In patients of Engels class I with lower presurgical DQ-IQ, catch-up increase in mental age was observed after two years following surgery.

Self-induced seizures presumably by peri-orbital somatosensory self-stimulation: A report of two cases

Self-induced seizures by somatosensory stimulation are rare. We describe two epileptic patients with self-induced seizures presumably by peri-orbital somatosensory stimulation. Two infants with severely delayed psychomotor development and poor visual acuity after acute subdural hemorrhage in early infancy had been diagnosed as having West syndrome. They evolutionally became to show serial self-induced seizures preceded by rubbing eye with finger in one case and touching right eyebrow with the back of left hand in the other case. Video-electroencephalography (EEG) monitoring was useful to confirm self-induced seizure by peri-orbital self-stimulation. In patients with serial seizures preceded by peculiar behaviors, we need to consider the possibility of self-induced seizures, even if they have a history of West syndrome and severe psychomotor retardation.

Lamotrigine is favourable for startle-induced seizures

Falling due to startle-induced seizures (SISs) often leads to injury. The triggers of SIS are mostly unexpected auditory stimuli, which are too common to avoid in daily life. As SISs are often refractory to conventional medications, effective therapeutic options have to be established. We report a small series of six patients treated with lamotrigine (LTG) as add-on therapy. Seizure control was improved greatly in three of the six patients, resulting in less restricted daily life, but no effect was observed in two and a skin rash developed in one. Patient 1 was a 19-year-old man. His seizure comprised of a sudden tonic extension of the extremities induced by auditory or visual stimulus. He fell down due to SISs, five to ten times a day, with frequent injuries. After adding LTG to treatment with valproate (VPA) and clobazam (CLB), SISs were reduced to once a month. Patient 2 was a 51-year-old woman. Sudden tonic extension of all limbs induced by unexpected sounds frequently threw her down onto the floor. Addition of LTG to treatment with CLB, zonisamide and phenytoin reduced her SISs from several to less than once a day. Patient 3 was a seven-year-old girl with postencephalitic epilepsy. After adjunctive treatment of LTG to VPA, the severity of SISs became milder thus avoiding injury, although seizure frequency did not decrease. LTG is potentially effective for the treatment of SISs and may prevent falling. The addition of LTG treatment dramatically improved the lives of the patients presented here and should be considered as an option for startle-induced seizures.

Individualized phenytoin therapy for Japanese pediatric patients with epilepsy based on CYP2C9 and CYP2C19 genotypes.

Background: The aims of this study were to identify the target dose of phenytoin (PHT) and to compare the treatment continuation rate between patients receiving conventional therapy and patients receiving individualized therapy based on genotyping of the CYP2C9*3, CYP2C19*2, and CYP2C19*3 alleles. The operational definition for the target dose of PHT used in this study was the dose that yielded a steady-state PHT concentration within the range of 15–20 mcg/mL without dose-related adverse effects. Methods: We investigated 394 samples from 170 Japanese pediatric patients aged 9 months to 15 years to identify factors that influenced the target dose of PHT. We also analyzed the clinical records of 156 patients who commenced PHT therapy at our hospital and retrospectively assessed the time to treatment failure within 1 year after starting PHT therapy. During the study period, 17 patients underwent genotyping at the start of PHT therapy. If the patients had the CYP2C9*3, CYP2C19*2, or CYP2C19*3 alleles, the initial dose of PHT was reduced by 10%–50% according to previous reports. The other 139 patients received conventional PHT therapy. Results: According to multiple regression analysis, the body weight, concomitant use of sulthiame, and the CYP2C9*3, CYP2C19*2, and CYP2C19*3 alleles influenced the target dose of PHT. Our model explained 74% of the interindividual variability of the target dose of PHT. The total withdrawal rate in the individualized therapy group and the conventional therapy group was 23.5% and 33.1%, respectively. The adjusted hazard ratio for withdrawal of PHT therapy in the individualized therapy group was 0.37 (95% confidence interval; 0.12–1.10, P = 0.074). Conclusions: These findings suggest that genotyping can help to estimate the optimum target dose of PHT and may contribute to avoid intoxication and concentration-dependent adverse effects.