Yutaka Awaya

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.

Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the causative gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

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.

Wisconsin card sorting test in children with temporal lobe epilepsy

To search for the origin of frontal lobe dysfunction identified by the Wisconsin card sorting test (WCST) in temporal lobe epilepsy (TLE) patients, we investigated the WCST performance among 19 children with TLE (with hippocampal atrophy (HA group N=12), without structural lesions (NSL group N=7)), 15 patients with frontal lobe epilepsy (FLE group), and age-matched normal controls (N group). The paired verbal association learning test (PVALT) and Benton visual retention test (BVRT) were also performed. HA group and FLE groups achieved significantly fewer categories and demonstrated more perseverative errors on the WCST than NSL and N groups. In addition, category achievement in WCST showed significant inverse correlation to age at the initial status convulsivus in the HA group (P<0.05). The achievement on PVALT and BVRT did not show any significant differences between HA and FLE groups (P>0.05). Thus, the frontal lobe dysfunction in the HA group is found to exist as early as 7 years old, when they seem to have only a short seizure history or to receive a little electrical interference from the temporal lobe focus to the frontal region. These facts would underscore the importance of prefrontal dysfunction persisting from the early insults and only becoming apparent after maturation of the prefrontal region in patients with mesial TLE.

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

UNLABELLEDnThe 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).nnnMETHODSnThe 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.nnnRESULTSnAmong 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%).nnnCONCLUSIONSnDaily 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.

Epileptic seizures precipitated by constant light, movement in daily life, and hot water immersion.

Summary: We describe a patient with epilepsy characterized by eyelid myoclonous, which often evolved into complex partial seizures, hemiconvulsions, or generalized convulsions. The Outstanding feature was that seizures became markedly more frequent on exposure to light, movement in daily life, and hot watr immersion. the patient was highly susceptible to seizures under constant light, but the dopamine level in the cerebrospinal fluid was quite low, and administration of levodopa transiently suppressed the seizures.

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.

Surgical indication for refractory childhood epilepsy.

Summary: 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 deterimental 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 patients age.

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.

A case of a rapidly progressive central nervous system disorder manifesting as a pallidal posture and ocular motor apraxia

We report a case of a rapidly progressive central nervous system disorder, in which the outstanding clinical features were ocular motor apraxia and a pallidal posture. The etiology remains unknown except for the possibility of post-influenza immunization encephalopathy.

Clinical and EEG analysis of initial status epilepticus during infancy in patients with mesial temporal lobe epilepsy

This study investigated the clinical and EEG characteristics of initial status epilepticus (SE) during infancy in patients with mesial temporal lobe epilepsy (MTLE). The subjects were six patients who had been brought to our emergency clinic and treated for their initial SE between 1977 and 1988, and later developed MTLE. We reviewed the medical records and laboratory findings at the time of the initial SE, and the clinical evolution up to the development of MTLE. The six patients included four females and two males. The initial SE developed at ages ranging from 7 months to 2 years and 9 months with a mean of 1 year and 2 months. These episodes were characterized by an elevated temperature of more than 38 degrees C (4/6 cases), clusters of prolonged seizures during one episode of SE (4/6 cases), long-lasting SE (120-380 min, mean 227 min, 6/6 cases), postictal prolonged loss of consciousness (median 5 h, 6/6 cases), and the presence of Todds paralysis (3/6 cases). The lateralization of the ictal or postictal EEGs of the SE in five of the six cases was identical to that of the hippocampal atrophy later confirmed by MRI. Follow-up EEG examinations at a 6 month interval demonstrated temporal spike discharges appearing only after the onset of complex partial seizures. Two patients, who had no fever at the initial SE, were characterized by a very early appearance of epileptic EEG abnormality and a short interval between the initial SE and the development of complex partial seizures, suggesting that the SE was the first epileptic manifestation. The result of this study showed that SE progressing to MTLE tends to have complicated clinical manifestations characterized by clusters of unilateral or generalized SE followed by prolonged postictal unconsciousness, generalized clinical manifestations despite lateralized ictal EEG discharges, and the Todds paresis in addition to the prolonged seizure duration.