Saoko Takeshita

Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome

Objective: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). Methods: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. Results: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. Conclusions: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.

Functional recovery in hemiplegic cerebral palsy: ipsilateral electromyographic responses to focal transcranial magnetic stimulation.

The patterns of functional recovery after unilateral cerebral damage occurring in the prenatal to infantile periods were studied in nine patients with hemiplegic cerebral palsy. Motor evoked potentials (MEPs) recorded from the small hand muscles were investigated using focal transcranial magnetic stimulation (TMS). The MEPs findings could be separated into three subtypes based on the features of ipsilateral MEPs elicited by TMS over the unaffected motor cortex. Bilateral MEPs of similar latency were obtained in three patients. These patients each having a congenital lesion invariably exhibited mirror movements and severe hemiparesis. Meanwhile, ipsilateral MEPs with markedly prolonged latency were demonstrated in two other patients, who exhibited synergistic associated movements and severe hemiparesis caused by an acquired lesion. In the remaining four patients, who showed mild hemiparesis without such abnormal interlimb coordinations, there were no ipsilateral MEPs. Thus, we suggest that TMS is useful for confirming the electrophysiological findings relevant to functional recovery in hemiplegic cerebral palsy underlying such abnormal interlimb coordinations. Specifically, bilateral MEPs of similar latency were considered consistent with compensatory mirror movements originating from bilateral motor representation in the unaffected motor cortex.

Clinicopathological features of acute autonomic and sensory neuropathy

Acute autonomic and sensory neuropathy is a rare disorder that has been only anecdotally reported. We characterized the clinical, electrophysiological, pathological and prognostic features of 21 patients with acute autonomic and sensory neuropathy. An antecedent event, mostly an upper respiratory tract or gastrointestinal tract infection, was reported in two-thirds of patients. Profound autonomic failure with various degrees of sensory impairment characterized the neuropathic features in all patients. The initial symptoms were those related to autonomic disturbance or superficial sensory impairment in all patients, while deep sensory impairment accompanied by sensory ataxia subsequently appeared in 12 patients. The severity of sensory ataxia tended to become worse as the duration from the onset to the peak phase of neuropathy became longer (P<0.001). The distribution of sensory manifestations included the proximal regions of the limbs, face, scalp and trunk in most patients. It tended to be asymmetrical and segmental, rather than presenting as a symmetric polyneuropathy. Pain of the involved region was a common and serious symptom. In addition to autonomic and sensory symptoms, coughing episodes, psychiatric symptoms, sleep apnoea and aspiration, pneumonia made it difficult to manage the clinical condition. Nerve conduction studies revealed the reduction of sensory nerve action potentials in patients with sensory ataxia, while it was relatively preserved in patients without sensory ataxia. Magnetic resonance imaging of the spinal cord revealed a high-intensity area in the posterior column on T(2)*-weighted gradient echo image in patients with sensory ataxia but not in those without it. Sural nerve biopsy revealed small-fibre predominant axonal loss without evidence of nerve regeneration. In an autopsy case with impairment of both superficial and deep sensations, we observed severe neuronal cell loss in the thoracic sympathetic and dorsal root ganglia, and Auerbachs plexus with well preserved anterior hone cells. Myelinated fibres in the anterior spinal root were preserved, while those in the posterior spinal root and the posterior column of the spinal cord were depleted. Although recovery of sensory impairment was poor, autonomic dysfunction was ameliorated to some degree within several months in most patients. In conclusion, an immune-mediated mechanism may be associated with acute autonomic and sensory neuropathy. Small neuronal cells in the autonomic and sensory ganglia may be affected in the initial phase, and subsequently, large neuronal cells in the sensory ganglia are damaged.

Clinical and radiological variability of influenza-related encephalopathy or encephalitis

Abstract Background: Influenza‐related encephalopathy or encephalitis is not rare in children. However, it is not well understood why the brain lesion develops from influenza infection. The purpose of this study was to clarify its pathogenesis by analyzing the clinical and neuroradiological findings in patients having influenza‐related brain lesions.

An MRI and MRS study of Pelizaeus-Merzbacher disease

Earlier reports on T2-weighted magnetic resonance imaging (MRI) in the classical form of Pelizaeus-Merzbacher disease seemed to divide the patterns of the high-intensity lesions in the white matter into three subtypes: type I, diffusely hemispheric and corticospinal; type II, diffusely hemispheric without brainstem lesions; and type III, patchy in the hemispheres. The four boys presented in our study, between 10 and 17 years of age, with classical Pelizaeus-Merzbacher disease, who all had a duplicated proteolipid protein gene, invariably manifested type I despite their various clinical severities. Follow-up MRI after an interval of 5 years and proton magnetic resonance spectroscopy was performed in three of the patients. The white matter on the last MRI was unchanged in volume and the distribution of high-intense areas. Proton magnetic resonance spectroscopy revealed no abnormal peaks. These results were consistent with the lack of definite neurologic regression in the last 5 years and with the pathologic characteristics of well-preserved axons and the absence of sclerosis. Further study is required to precisely determine whether the patterns of MRI findings can be divided into subtypes corresponding to those of proteolipid protein gene abnormalities.

Clinical and radiologic improvements in mitochondrial encephalomyelopathy following sodium dichloroacetate therapy

We administered sodium dichloroacetate (DCA), which reduces the circulating lactate and pyruvate concentrations by stimulating the activity of the pyruvate dehydrogenase complex (PDHC), to three children with mitochondrial encephalomyelopathy. Significant clinical, biochemical and radiologic improvements were obtained following DCA therapy (approximately 30 mg/kg per day, divided into three doses). All three patients had non-pyruvate dehydrogenase complex (PDHC) deficiencies: two exhibited Leigh syndrome (complex I deficiency and unknown etiology), and one abnormal myelination (multienzyme deficiency), demonstrated on magnetic resonance imaging (MRI). The lactic and pyruvic acid concentrations in serum and cerebrospinal fluid (CSF) were decreased significantly by the oral DCA treatment. The lactic acid peak on MR spectroscopy also markedly decreased in parallel with the CSF level. In addition, the brain lesions observed on MRI were improved in all patients. No exacerbation was observed in any of the patients, who have been followed-up more than 21 months following the DCA therapy. These results suggest that DCA therapy should be considered in all patients with a mitochondria-related enzyme deficiency.

De novo GABRA1 mutations in Ohtahara and West syndromes

GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations.

Characteristic response to transcranial magnetic stimulation in Rett syndrome

To pathophysiologically evaluate the corticospinal tracts (CSTs) in Rett syndrome (RS), transcranial magnetic stimulation (TMS) was performed in 3 patients aged 4, 6 and 13 years. The two younger cases exhibited the clinical characteristics of the pseudostationary stage (stage III), while ambulation was lost in the oldest case at the age of 11 years (stage IV). The motor cortex and cervical spinal roots were magnetically stimulated to obtain motor evoked potentials (MEPs) from the relaxed first dorsal interosseous muscle. Compared with the central motor conduction time (CMCT) in age-matched normal children, CMCT in the stage III cases was significantly short (6.9-7.1 ms, P < 0.05). In the stage IV case, CMCT was markedly short but not significantly so (6.6 ms, P = 0.06), which was partly due to a significant increase in the threshold intensity of TMS (100%, P < 0.05). Thus, the CMCT shortening, which implied unique cortical hyperexcitability, was considered consistent and characteristic of RS. The CSTs in the stage IV case were certainly impaired, corresponding well to the progressive spastic paresis.

Acute encephalopathy of Bacillus cereus mimicking Reye syndrome

We present an 11-year-old boy diagnosed as having acute encephalopathy and liver failure with the underlying condition of a metabolic dysfunction. He developed convulsions and severe consciousness disturbance following gastroenteritis after the ingestion of some fried rice. He showed excessive elevation of transaminases, non-ketotic hypoglycemia and hyperammonemia, which were presumed to reflect a metabolic dysfunction of the mitochondrial beta-oxidation, and he exhibited severe brain edema throughout the 5th hospital day. He was subjected to mild hypothermia therapy for encephalopathy, and treated with high-dose methylprednisolone, cyclosporine and continuous hemodiafiltration for liver failure, systemic organ damage and hyperammonemia. The patient recovered with the sequela of just mild intelligence impairment. In this case, Bacillus cereus, producing emetic toxin cereulide, was detected in a gastric fluid specimen, a stool specimen and the fried rice. It was suggested that the cereulide had toxicity to mitochondria and induced a dysfunction of the beta-oxidation process. The patient was considered as having an acute encephalopathy mimicking Reye syndrome due to food poisoning caused by cereulide produced by B. cereus.

Topographical differences in the developmental profile of central motor conduction time

OBJECTIVES To study the topographical difference in the developmental profile of the central motor conduction time (CMCT) in upper extremity muscles, electromyographic (EMG) responses to transcranical magnetic stimulation (TMS) were examined in the first dorsal interosseous, extensor carpi radialis (ECR), biceps (BCP), and deltoid (DT) muscles of 25 neurologically normal subjects aged from 2 to 26 years. METHODS The motor cortex and cervical spinal roots were magnetically stimulated, and CMCT was measured as the onset latency difference between these EMG responses. RESULTS CMCT in children was shorter in the more proximal muscle of each adjacent muscle pair, despite the tendency of a higher threshold intensity for TMS of the more proximal muscle. This topographical difference tended to be more distinct in younger children, whereas CMCT in adults did not show such a topographical difference. Consequently, the linear decrease in CMCT during maturation was less pronounced in the proximal muscles. CONCLUSIONS We speculate that direct activation of corticospinal neurons to the more proximal muscles was preferentially produced by TMS in younger children, depending on the relationship between the spatial direction of axons, head circumference, and stimulating coil diameter.