A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures.

Epilepsy of infancy with migrating focal seizures (EIMFS) is an infantile epileptic encephalopathy characterized by refractory seizures, severe psychomotor delay, and multiple moving epileptic discharges. The genetic etiology of EIMFS is relatively homogeneous with the majority of causative mutations found in KCNT1. Currently, gene panel or whole-exome sequencing is used for testing. To verify the pathogenicity of a variant, co-segregation of the variant and the disorder in a pedigree is important; hence, de novo mutations that are judged to be deleterious may be considered pathogenic because the patients are isolated. In contrast, in cases from non-consanguineous families, genes that cause disorders in a recessive manner should remain as potential candidates. Herein, we performed gene panel sequencing of a patient with EIMFS from a non-consanguineous family, and found a compound heterozygous constellation consisting of a maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5, which encodes the neuronal KCC2 cotransporter. These unique mutations show gene variants that act in a recessive manner may be pathogenic for patients from non-consanguineous families.

Imbalance of interneuron distribution between neocortex and basal ganglia: consideration of epileptogenesis of focal cortical dysplasia.

AIM: The balance of excitation and inhibition of neurons and neuronal network is very important to perform complete neuronal function. Damage or loss of inhibitory γ-aminobutyric acid (GABA)-ergic interneuron is associated with impaired inhibitory control of cortical pyramidal neurons, leading to hyperexcitability and epileptogenesis. Ectopic neurons in the basal ganglia are to be one of the pathological features of epileptogenesis. In the present study, we investigated distribution of interneuron subtypes between neocortex and caudate nucleus. METHODS: We performed immunohistochemistry of GABA, glutamic acid decarboxylase (GAD), calretinin (CR), calbindin (CB), parvalbumin (PV) and neuropeptide. We used surgical materials of four focal cortical dysplasia (FCD) cases, having lesions of neocortex and caudate nucleus, and eight age-matched autopsy controls. RESULTS: The pathology showed three FCD IIa, containing dysmorphic neurons, and one FCD IIb, balloon cells. In the neocortex, the concentrations (each positive cell number/all cell numbers in the evaluated field) of GAD+, CR+ and CB+ cells were significantly lower in FCD than in controls. On the contrary, in the caudate nucleus those of CR+ and CB+ cells were significantly more in FCD than in controls. CONCLUSION: The interneuron imbalance between the neocortex and basal ganglia may affect the epileptogenesis of FCD.

Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.

OBJECTIVE: We conducted a nationwide multicenter study in Japan to elucidate the clinical and laboratory characteristics of acute encephalitis with refractory, repetitive partial seizures (AERRPS). MATERIALS AND METHODS: Clinical and laboratory features, treatment, and outcome were assessed using a structured questionnaire. RESULTS: Twenty-nine children were enrolled in the study. Refractory and repetitive partial seizures accompanied by fever were the cardinal clinical features. Partial seizures consisted principally of eye deviation or facial twitching, being periodically repeated during the acute phase. These seizures were refractory to conventional anticonvulsants and were only suppressed by high-dose intravenous barbiturate administration. Rhythmic activities on electroencephalography and non-specific cerebral atrophy on neuroimaging were common. Serum or cerebrospinal antibodies against GluRepsilon2 were positive in six patients. General prognosis was unfavorable due to intractable epilepsy and cognitive deficits. CONCLUSION: Based on the peculiar and homogenous features, AERRPS can be regarded as a distinct clinical entity.

Asymmetrical interhemispheric fiber tracts in patients with hemimegalencephaly on diffusion tensor magnetic resonance imaging.

OBJECTIVE: The internal structures of cerebral white matter in patients with hemimegalencephaly have not yet been investigated except for one, which evaluated aberrant fibers. We examined interhemispheric fiber tracts (FT) passing through the corpus callosum using magnetic resonance (MR) diffusion tensor imaging (DTI). METHODS: MR studies, including DTI, were performed in nine consecutive patients with hemimegalencephaly and in 11 patients with West syndrome as disease controls. The interhemispheric FT passing through the corpus callosum were evaluated in six regional geometric subdivisions in every hemimegalencephaly and West syndrome patient (54 and 66 subregions, respectively), and the distribution and volume differences between affected and unaffected hemispheres were all compared. RESULTS: In patients with hemimegalencephaly, interhemispheric FT were symmetrically distributed in 27 (50%) of the 54 corpus callosum subregions. However, the FT were distributed to different areas in the same lobes in 22 (40%) subregions, and to different lobes in five (9%) subregions. FT volumes were symmetrical in 35 (65%) subregions, while FT volumes on the affected side were greater, but less than those on the unaffected side, in 14 (26%) and five (9%) subregions, respectively. In contrast, in the West syndrome patients, interhemispheric FT showed symmetrical distributions and volumes in all regions. CONCLUSION: Asymmetrical interhemispheric FT are often observed in patients with hemimegalencephaly, and DTI was a useful means of elucidating the internal structures of white matter.

Aberrant midsagittal fiber tracts in patients with hemimegalencephaly.

BACKGROUND AND PURPOSE: In hemimegalencephaly, MR imaging often reveals midsagittal bandlike structures between the 2 lateral ventricles. To determine whether these structures are aberrant midsagittal fibers, we retrospectively reviewed them on conventional MR imaging and prospectively examined them by diffusion tensor MR and fiber tract (FT) reconstruction imaging. MATERIALS AND METHODS: We retrospectively reviewed conventional MR images of 26 consecutive patients with hemimegalencephaly by 2 neuroradiologists, focusing on abnormal midsagittal structures. The distance between the 2 anterior horns and widths of midsagittal bandlike structures were measured. Prospective analysis was performed in 7 consecutive patients with hemimegalencephaly examined for midsagittal aberrant fibers by diffusion tensor imaging, and cortical distribution areas of the fibers were observed. RESULTS: The distance between the 2 anterior horns was wide (>4 mm) due to white matter-intensity structures in 20 of 26 patients (76.9%). Mid-sagittal bandlike structures were observed in 15 patients (57.7%). Asymmetry of the fornices was detected in 7 patients (26.9%), and both fornices were thickened in 7 (26.9%) patients. On FT reconstruction, images showed that 4 of 7 patients with hemimegalencephaly had aberrant midsagittal fibers connecting frontal, occipital, or parietal lobes, bilaterally (n = 3) or ipsilaterally (n = 1). All 4 patients had increased width between the 2 anterior horns, and 3 of them exhibited midsagittal bandlike structures on conventional MR imaging. On the other hand, these MR imaging findings were not noted in 3 patients who did not have aberrant midsagittal fibers on diffusion tensor imaging. CONCLUSIONS: Aberrant midsagittal FTs running intra- or interhemispherically do not infrequently exist in patients with hemimegalencephaly.

Treatment of convulsive status epilepticus in infants and young children in Japan.

We review the types and causes of convulsive status epilepticus (CSE) in infants and young children in Japan, and discuss the current recommendations for the use of intravenous (IV) drugs in managing this condition, and report on our clinical experiences. There are prolonged or continuous CSE and clustered or intermittent CSE, and treatments are different between them. In Japan, fosphenytoin and IV preparation of lorazepam and phenobarbital are not available. Recently, midazolam and lidocaine (LDC) have been widely used, although neither of these drugs have official approval for the management of CSE. Febrile seizures and epilepsies are common causes of CSE in infants and young children in Japan, followed by benign infantile convulsions (BIC), convulsions with gastroenteritis (CwG), and acute encephalitis with refractory CSE and intractable epilepsy (AECSEE), which are familiar disorders in Japan. BIC and CwG frequently present with clustered CSE and do not respond to IV diazepam, but have an excellent response with oral carbamazepine or IV LDC. CSE in AECSEE requires control with barbiturate coma. The Research Committee on Clinical Evidence of Medical Treatment for Status Epilepticus in Childhood has developed a proposed guideline for the treatment of CSE in childhood in Japan by an evidence-based approach and consensus conference. Initial management of seizures should be attempted mainly with IV diazepam, the second-line treatment involves IV midazolam followed by IV phenytoin if seizures persist, and the third-line treatment requires barbiturate coma. However, our experience of 247 episodes of CSE in 77 patients, predominantly with chronic epilepsy, required different second-line treatments for prolonged CSE compared with clustered CSE: the former were treated with IV midazolam or pentobarbital, and the latter were given IV phenytoin or LDC. We propose modifications to the guideline for CSE that the second-line treatment is divided by prolonged CSE and clustered CSE, and that the procedures for brain protection and systemic management are added.

Hemimegalencephaly: a study of abnormalities occurring outside the involved hemisphere.

BACKGROUND AND PURPOSE: Hemimegalencephaly is a rare but well-known congenital malformation with ipsilateral enlargement of the hemicerebrum. However, very little is known about changes in structures outside the involved hemisphere in patients with this condition. We investigated morphologic abnormalities occurring outside the affected hemisphere by MR imaging in a large series of patients with hemimegalencephaly. MATERIALS AND METHODS: MR imaging findings for 30 patients with hemimegalencephaly were retrospectively reviewed and evaluated for structures outside the involved hemisphere on routine MR images, such as cranial nerves (I, II, V), brain vessels, subdural and subarachnoid spaces, brain stem, and cerebellum, on both the ipsilateral and contralateral sides. RESULTS: The ipsilateral olfactory and optic nerves were enlarged in 8 (26.7%) and 1 (3.3%) of the 30 patients, respectively, without enlargement on the contralateral side. No asymmetry was noted in the trigeminal nerves. Asymmetric vascular dilations in the ipsilateral cerebral hemisphere were observed in 12 of the 30 patients (40%), in deep cerebral vessels in 11 patients (36.7%), and in superficial cerebral vessels in 8 patients (26.7%). Ipsilateral brain stem and hemicerebellar asymmetric enlargement was detected in 2 patients (6.7%) and 14 patients (46.7%), respectively. Abnormal cerebellar folia were observed on the ipsilateral side in 6 patients (20%) and on the contralateral side in 3 patients (10%). CONCLUSION: Ipsilateral olfactory nerve enlargement, cerebral vascular dilations, cerebellar enlargement, and bilateral or ipsilateral abnormal architecture of the cerebellar folia are often associated with hemimegalencephaly.

Treatment of convulsive status epilepticus in infants and young children in Japan.

We review the types and causes of convulsive status epilepticus (CSE) in infants and young children in Japan, and discuss the current recommendations for the use of intravenous (IV) drugs in managing this condition, and report on our clinical experiences. There are prolonged or continuous CSE and clustered or intermittent CSE, and treatments are different between them. In Japan, fosphenytoin and IV preparation of lorazepam and phenobarbital are not available. Recently, midazolam and lidocaine (LDC) have been widely used, although neither of these drugs have official approval for the management of CSE. Febrile seizures and epilepsies are common causes of CSE in infants and young children in Japan, followed by benign infantile convulsions (BIC), convulsions with gastroenteritis (CwG), and acute encephalitis with refractory CSE and intractable epilepsy (AECSEE), which are familiar disorders in Japan. BIC and CwG frequently present with clustered CSE and do not respond to IV diazepam, but have an excellent response with oral carbamazepine or IV LDC. CSE in AECSEE requires control with barbiturate coma. The Research Committee on Clinical Evidence of Medical Treatment for Status Epilepticus in Childhood has developed a proposed guideline for the treatment of CSE in childhood in Japan by an evidence-based approach and consensus conference. Initial management of seizures should be attempted mainly with IV diazepam, the second-line treatment involves IV midazolam followed by IV phenytoin if seizures persist, and the third-line treatment requires barbiturate coma. However, our experience of 247 episodes of CSE in 77 patients, predominantly with chronic epilepsy, required different second-line treatments for prolonged CSE compared with clustered CSE: the former were treated with IV midazolam or pentobarbital, and the latter were given IV phenytoin or LDC. We propose modifications to the guideline for CSE that the second-line treatment is divided by prolonged CSE and clustered CSE, and that the procedures for brain protection and systemic management are added.

Low-dose prednisolone ameliorates acute renal failure caused by cholesterol crystal embolism.

AIMS: The prognosis of renal cholesterol crystal embolism (CCE) is poor. Although various treatments for CCE have been attempted, there is no optimal therapy. We tested the effect of low-dose prednisolone (PS) on CCE-related acute renal failure (ARF). PATIENTS AND METHODS: 7 patients (mean age 69 years) diagnosed with CCE-related ARF were treated with oral PS at 15-20 mg/day for 2-4 weeks, which was then tapered at 5 mg/day over 2-4 weeks, followed by 5 mg/day maintenance dose. Recurrent ARF during PS tapering was treated with a larger dose of PS. RESULTS: Inciting factors were identified in four patients: coronary angiography (n=3) and cerebral angiography (n=1). On admission, serum creatinine (SCr) was 2.1 +/- 0.3 mg/dl (mean +/- SEM). SCr and eosinophil count before treatment were 4.2 +/- 0.4 mg/dl and 682 +/- 73/microl, respectively. PS therapy improved ARF in all cases at week 2 (SCr 3.8 +/- 0.5 mg/dl) parallel to a decrease in eosinophilia (116 +/- 30/microl), and at week 4 (3.1 +/- 0.4 mg/dl and 134 +/- 20/microl, respectively). At last follow-up, renal function was improved or maintained in 5 patients compared with that at week 4 post-treatment. One patient died of lung cancer. Another required LDL apheresis and hemodialysis but died due to CCE-related multi-organ failure. A third patient had recurrent ARF and was re-treated with a larger dose of PS, which resulted in an immediate decrease in SCr. However, the patient developed acute renal dysfunction due to congestive heart failure, and required hemodialysis. CONCLUSIONS: Low-dose PS improved CCE-related ARF, probably through amelioration of inflammatory reaction surrounding affected renal vessels.

Undetectable levels of CSF hypocretin-1 (orexin-A) in two prepubertal boys with narcolepsy.

We report on two prepubertal narcoleptic boys with undetectable levels of hypocretin-1 (orexin-A) in their cerebrospinal fluid (CSF). The disease onset times were 6 and 8 years, and CSF was collected 8 and 20 months after the onset, respectively. The initial symptoms were excessive daytime sleepiness, cataplexy and disrupted nocturnal sleep. Both subjects are DRB1*1501 and DQB1*0602 positive. The measurement of CSF hypocretin-1 is valuable for the decisive diagnosis of narcolepsy and for selecting the type of treatment in prepubertal children. Our results suggest that a significant degree of hypocretin deficiency is already present at the disease onset.

Clinical and pedigree study on familial cases of West syndrome in Japan.

Nationwide survey on familial cases of West syndrome (WS) in first- and second-degree relatives was conducted by mailing a questionnaire to 64 major university hospitals, children's hospitals, and epilepsy centers in Japan, and by review of the Japanese cases in the literatures. Thirty-four familial cases, 20 males and 14 females, were obtained in 15 families including one with five affected members in two generations and another with three affected male siblings including a half brother by a different father (X-linked WS). A mother and the child or children were involved in three families. Nine families had 21 cryptogenic cases and six families had 13 symptomatic cases, and the etiologies were same among the affected members in each family. Familial cases of WS have characteristic clinical features and genetic mechanisms. Age of onset, seizure types, electroencephalographic abnormalities, early seizure outcome, effective treatment, long-term seizure prognosis, and long-term developmental prognosis were concordant among the affected members in each family. Long-term seizure and developmental prognoses were far better than those in WS in general, with seizure-free rate of 82% and normal mental development rate of 44%. Poor prognosis was limited to specific symptomatic cases. Adrenocorticotropic hormone (ACTH) was a treatment of choice, and even in relapse of WS after ACTH therapy, the patients well responded to antiepileptic drugs. Specific inheritance pattern was difficult to imagine in the majority of the present cases, except for one family with X-linked WS and another family with five patients of maternal inheritance. These results are helpful for the treatment choice and prognostication of clinical course for familial cases of WS.

Surgical treatment of early-infantile epileptic encephalopathy with suppression-bursts associated with focal cortical dysplasia.

A surgically treated case of early-infantile epileptic encephalopathy (EIEE) with suppression-bursts associated with focal cortical dysplasia is reported. Tonic-clonic seizures followed by a series of spasms occurred at age of a few days. Interictal electroencephalogram (EEG) revealed a suppression-burst pattern and magnetic resonance imaging suggested focal cortical dysplasia in the left prefrontal area. Combination therapies of antiepileptic treatments showed only partial efficacy. The patient underwent lesionectomy at 4 months of age and the spasms decreased to zero to two series daily. At age 2 years, his seizures increased in number and EEG showed that residual left hemisphere was the main epileptogenic focus. Modified functional hemispherectomy of the left hemisphere was applied at age 3 years. The patient, now 5 years old, is free from seizure and gaining psychomotor development gradually. In cases of EIEE with focal cortical dysplasia, surgical treatment may have beneficial effects on both psychomotor development and seizure control.

Paroxysmal discharges on EEG in young autistic patients are frequent in frontal regions.

EEGs were recorded in 86 autistic patients during sleep. Epileptic discharges were observed in 37 cases (43%). Twenty-seven (73%) of these 37 cases had localized spikes, 8 had multiple spike foci, one had generalized spikes, and one had both multiple spike foci and generalized spikes. Forty-seven epileptic discharge foci were registered in 36 cases, the exception being one with generalized spikes. Thirty-six (76.6%) of the registered 47 epileptic discharge foci were in the frontal region, one (2.1%) in the temporal region, 7 (14.1%) in the centro-parietal region, and 3 (6.4%) in the occipital region. Twenty (55.6%) of the 36 frontal spikes were at midline (11 at Fz and 9 at Cz), 8 on the left side, and 8 on the right side. The dipole of midline spikes was in the deep midline frontal region. These results suggest that frontal dysfunctions are important in the mechanism of symptoms in autism.

Mechanical ventilation care in severe childhood neurological disorders.

Forty-five patients underwent long-term life-sustaining mechanical ventilation care in the Child Neurology Ward, National Center Hospital for Mental, Nervous and Muscular Disorders from 1990 to 2000. Twenty patients had chronic respiratory insufficiency due to neuromuscular disorders, nine of whom underwent home mechanical ventilation care. Nineteen of the 45 patients had chronic respiratory insufficiency due to progressive central nervous system disorders, three of whom underwent home mechanical ventilation care. Six patients with chronic respiratory insufficiency due to the sequelae of transient events were on ventilation, two of whom underwent home mechanical ventilation care. In some patients, especially ones with neuromuscular disorders, mechanical ventilation care is very useful for improving their daily activity and quality of life. In other patients, however, mechanical ventilation care is merely a means of prolonging life without visible improvement of their quality of life. As medical resources are limited, home mechanical ventilation care is a recommended method for patients who need life-sustaining mechanical ventilation care. Considering an individual or social consensus, the indication of long-term life-sustaining mechanical ventilation care for chronic respiratory insufficiency due to severe childhood neurological disorders should be further discussed.