Kuniaki Iyoda

Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome) – A nationwide questionnaire survey in Japan

UNLABELLED The aim of this study was to establish strategies for prophylaxis against status epilepticus (SE) associated with high fever and for management of ongoing SE in children with severe myoclonic epilepsy in infancy (SMEI). METHODS The investigation was performed retrospectively using a questionnaire, asking about medications, which was distributed to epilepsy specialists throughout Japan. All respondents were members of the Japan Epilepsy Society (JES) and/or the Japanese Society of Child Neurology (JSCN). Data from 109 SMEI patients (51 males and 58 females), 1-37 (M+/-SD, 10.7+/-6.53) years old, were used for this study. Of these 109 patients, 10 were excluded because they had not experienced SE, such that data from 99 patients were analyzed. RESULTS Among the anti-epileptic drugs (AEDs) used daily, excellent efficacy against SE evolution was obtained with the following: potassium bromide (KBr) (41.7%), zonisamide (ZNS) (13.5%), clobazam (CLB) (10.0%), valproate (VPA) (8.0%), phenobarbital (PB) (6.7%), and phenytoin (PHT) (2.6%). Excellent efficacy was not obtained with either clonazepam (CZP) or carbamazepine (CBZ). The diazepam (DZP) suppository was the most frequently given drug for prophylaxis against SE triggered by fever, but only 2 (2.4%) cases showed excellent results. Excellent efficacy in terminating ongoing SE was obtained with the following medications; intravenous barbiturates (75-100%), intravenous midazolam (MDZ) (68.8%), intravenous DZP (54.3%), intravenous lidocaine (Lid) (21.4%), and intravenous PHT (15.4%). CONCLUSIONS Daily KBr was most efficacious for controlling seizures in SMEI patients. Early use of intravenous barbiturates is the most effective strategy in stopping SE in a subset of patients. Reliable efficacy in SE was not obtained with prophylactic DZP, intravenous benzodiazepines (BZPs), PHT and Lid.

Longitudinal clinicoelectrophysiologic study of a case of Lafora disease proven by skin biopsy

Summary A longitudinal clinicoelectrophysiologic study was undertaken of a 15‐year 2‐month‐old girl with Lafora disease who was diagnosed by skin biopsy and an immunohistochemical method with antisera against Lafora bodies. From age 10 years 5 months, 4 months after onset, EEG disclosed progressive deterioration of background activity and incremental increase in epileptic discharges. Photosensitivity was unique: Occipital spikes and diffuse spike‐wave discharges were provoked by low‐frequency repetitive photic stimuli but without elicitation of myoclonic seizures. Photosensitivity completely disappeared after age 13 years 10 months. High‐voltage somatosensory evoked potentials (SEPs) and high‐voltage flash visual evoked potentials (F‐VEPs) were seen before age 13. After age 13, progressive prolongation of I‐III and I‐V interpeak latencies of auditory brainstem responses (ABRs), progressive prolongation of latencies of photoevoked eyelid microvibrations, delayed latencies of pattern‐reversal visual evoked potentials, and a decrease in the V/I amplitude ratio of ABRs and the previously high F‐VEP amplitudes were observed.

Rufinamide as an adjunctive therapy for Lennox—Gastaut syndrome: A randomized double-blind placebo-controlled trial in Japan

PURPOSE To evaluate the efficacy, safety, and pharmacokinetics of rufinamide as an adjunctive therapy for patients with Lennox-Gastaut syndrome (LGS) in a randomized, double-blind, placebo-controlled trial. METHODS We conducted a multicenter clinical trial with a 4-week baseline, a 2-week titration, a 10-week maintenance, and either a follow-up visit or entry into an open-label extension. Patients with LGS (4 to 30 years old) taking between one and three antiepileptic drugs were recruited. After the baseline period, patients were randomly assigned to rufinamide or placebo. The primary efficacy variable was the percent change in the tonic-atonic seizure frequency per 28 days. KEY FINDINGS Of the 59 patients, 29 were randomized to the rufinamide group and 30 to the placebo group. The frequency of epileptic seizures was significantly decreased in the rufinamide group than in the placebo group; the median percent change in frequency of tonic-atonic seizures was -24.2% and -3.3%, respectively, (p=0.003) and that of total seizures was -32.9% and -3.1%, respectively (p<0.001). Subgroup analyses indicated that the efficacy of rufinamide was consistent independent of clinical background characteristics. The common treatment-related adverse events in the rufinamide group were decreased appetite (17.2%), somnolence (17.2%), and vomiting (13.8%). Transient seizure aggravations were observed in 13 (22.0%) of the 59 patients, though a causal relationship with rufinamide was suspected in only one patient. All adverse events were mild to moderate in severity. The mean plasma concentration of rufinamide between 1 and 9 within 12h after administration was 17.2 μg/mL. SIGNIFICANCE The present results showed a favorable risk-benefit profile for rufinamide as an adjunctive therapy for patients with LGS.

Neurophysiologic dysfunction in hypomelanosis of Ito: EEG and evoked potential studies

To evaluate neurological involvements in hypomelanosis of Ito (HI), we conducted electroencephalographic and evoked potential studies in 3 children with HI. Patient 1 presented with the West syndrome, and was severely handicapped. Patient 2 had mild mental retardation. Patient 3 appeared neurologically normal, but chromosome analysis showed a 46,XX/46,XX,12p + mosaic karyotype. EEGs of Patient 1 initially showed asymmetric hypsarrhythmia, and later diffusely increased fast waves, occipital dominant alpha rhythm plus multifocal spikes. Patients 2 and 3 had minimal and no EEG abnormalities, respectively. Brainstem auditory evoked potentials showed prolongation of wave I latency as well as I-III and I-V interpeak latencies in Patient 1, and prolonged wave I latency in Patient 3. Flash visual evoked potential studies disclosed a significant difference between the right and left latencies of wave IV in Patient 2. The fact that there were no specific EEG or evoked potential findings for HI seems to be consistent with the pathogenetically heterogeneous nature of this disorders. We emphasize the usefulness of neurophysiologic examinations in evaluating diverse CNS dysfunctions in HI patients.

A pilot study on the changes in immunity after ACTH therapy in patients with West syndrome

Adrenocorticotropic hormone (ACTH) has been the first-line drug for the treatment of West syndrome, although the therapy has various adverse effects. ACTH depresses resistance to a variety of bacterial, viral, protozoal, and fungal agents. The timing of the various vaccinations is delayed after ACTH therapy in Japan, because the immune system is believed to be affected for approximately 6 months. However, the duration of the effect of ACTH on the immune system is not known. Therefore, we examined changes in the immunity levels before and after ACTH therapy. We measured white blood cell counts, lymphocyte counts, T/B cell counts, CD4(+) and CD8(+) T cell counts, CD 4/8 ratio, lymphocyte blastoid transformation by PHA or Con-A, and the levels of IgA, IgM, and IgG before, immediately after, and 1, 3, 6, and 12 months after ACTH therapy. The lymphocyte counts and CD4(+) T cell counts were significantly decreased immediately after and at 1 and 3 months after the therapy, and did not return to the previous levels even at 6 months and 12 months after ACTH treatment; however, these levels returned to within normal limits (within the 95% confidence interval). Immunoglobulin levels did not change after the ACTH therapy. Helper T cells were more depressed than cytotoxic T cells after ACTH therapy.

The Clinical Usefulness of Liquid Human Growth Hormone (hGH) (Norditropin® SimpleXxTM) in the Treatment of GH Deficiency

Human growth hormone (hGH) is an essential therapeutic drug for the treatment of GH deficiency. The development of recombinant GH using a pen injection system has enabled easy and safe treatment of GH-deficient patients; however, the process of dissolving hGH in the powder form is complicated and dangerous. In this study, we investigated the usefulness of a newly developed liquid form of hGH (Norditropin® SimpleXxTM) in the treatment of 51 patients with GH deficiency. Fifteen previously untreated patients with GH deficiency were treated with liquid hGH (group A), and 36 patients who had previously used hGH in the powder form were changed to the liquid form (group B). Both groups were treated with liquid hGH 0.5 IU/kg per week for 6 months. The growth rate of patients in group A increased from 4.0 ± 2.4 cm/year to 9.2 ± 2.9 cm/year. The patients in group B continued to grow at the same rate as before using the liquid hGH therapy. Questionnaires to the patients in group B demonstrated that 85% preferred the convenience of using the new liquid form of hGH. Our results indicate that liquid hGH has similar efficacy to that of powder hGH, but its improved convenience may have a beneficial effect on patient compliance.

Long-term safety and seizure outcome in Japanese patients with Lennox–Gastaut syndrome receiving adjunctive rufinamide therapy: An open-label study following a randomized clinical trial

PURPOSE To evaluate the long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive rufinamide therapy. SUBJECTS AND METHODS We conducted an open-label extension study following a 12-week multicenter, randomized, double-blind, placebo-controlled study of adjunctive rufinamide therapy in Japanese patients with LGS. Fifty-four patients participated in the extension study. Seizure frequency was evaluated until 52 weeks after the start of the extension study. Adverse events (AEs) were evaluated throughout both studies. KEY FINDINGS Of the 54 patients, 41 (75.9%) completed the extension study. The median duration of exposure to rufinamide was 818.0 days in all 54 patients, and 38 patients (70.4%) received rufinamide for 2 years or more. The median percent change in the frequency of tonic-atonic seizures relative to the frequency at the start of the double-blind study was -39.3% (12 weeks), -40.6% (24 weeks), -46.8% (32 weeks), -47.6% (40 weeks), and -36.1% (52 weeks). Reduction of total seizure frequency was also maintained until 52 weeks. Frequent treatment-related AEs were somnolence (20.4%), decreased appetite (16.7%), transient seizure aggravation including status epilepticus (13.0%), vomiting (11.1%), and constipation (11.1%). Adverse events were mild or moderate, except for transient seizure aggravation in three patients. Adverse events resulting in discontinuation of rufinamide were decreased appetite, drug eruption, and worsening of underlying autism. When clinically notable weight loss was defined as a decrease ≥ 7% relative to baseline, 22 patients (40.7%) experienced weight loss at least once during long-term observation, although weight loss was reported as an AE in only three patients. SIGNIFICANCE This study demonstrated a long-term benefit of rufinamide as adjunctive therapy for Japanese patients with LGS. Exacerbation of seizures and decreased appetite/weight loss should be monitored carefully.

Histopathologic and biochemical analysis of classic Pelizaeus-Merzbacher disease

An autopsy study of an 11-year-old boy with the classic type of Pelizaeus-Merzbacher disease is presented. He developed normally until 5 years of age when he began to deteriorate with scanning speech and gait abnormality. Auditory brainstem responses were normally preserved. At the age of 11 years, 8 months, he died of pneumonia while in a vegetative state. The neuropathologic findings suggested a typical classic type of Pelizaeus-Merzbacher disease and biochemical analysis of cerebral white matter demonstrated a decreased ratio of long-chain fatty acids (greater than or equal to C19) to short- and medium-chain fatty acids (less than C19). These findings suggested defective myelin synthesis as the etiology of Pelizaeus-Merzbacher disease; comprehensive classifications of the disease are expected to include both pathologic and biochemical parameters.

Suppression of nocturnal growth hormone secretion in epilepsy with continuous spike‐waves during slow‐wave sleep

modify hormone secretion from the anterior pituitary gland.1–3 That is, transient postictal rises of serum prolactin (PRL) have been recorded following generalized tonic–clonic and some partial seizures.1,2 However, it remains unsettled what effect epileptiform discharges have on growth hormone (GH) secretion. Matthew and Woods4 and Valdizan et al.5 reported that there were no significant changes in nocturnal GH secretion observed in patients with various types of seizures. Takeshita et al., however, reported that serum GH levels were elevated after generalized tonic–clonic seizures.3 Epilepsy with continuous spike-waves during slow-wave sleep (CSWS)6 is characterized by electrical status epilepticus during slow-wave sleep.7 As nocturnal GH secretion usually shows its highest level during the first slow-wave sleep phase (stages III and IV),8 massive spike-wave discharges during slow-wave sleep in patients with CSWS may affect nocturnal GH secretion. We, therefore, studied the effects of diffuse spike and wave discharges on nocturnal GH secretion in epileptic patients with CSWS.

Clinical and EEG studies on fragile-X syndrome

Clinical and EEG studies on fragile-X syndrome Kuniaki Iyoda “s”, Masae Murakami 4 Terumi Horiuchi “, Masato Kimura ‘, Isaku Horiuchi b, Harumi Yoshinaga ’ and Shunsuke Ohtahara ’ e Department of Pediatrics, NKK Fukuyama Hospital, Fukuyama, Hiroshima, Japan; b Department of Child Neurology, Asahikawa Jidoin Children’s Hospital, Asahikawa, Hokkaido, Japan; ’ Department of Child Neurology, Okayama University Medical School, Okayama, Japan) Case 4: A 19-year-old woman had typical absence seizures from age 10 years. The seizures were controlled with ESM. At age 19 years, she had generalized clonic convulsions and PB was added. Conclusion: Some epileptic children who seem to have a good clinical course have relapses beyond adolescence. We must be more cautious about a too optimistic view of prognosis in childhood epilepsy, and how and when the medication should be stopped is a difficult problem to answer.