Abnormal cortical activation during an auditory word comprehension task in benign childhood epilepsy with centrotemporal spikes: A magnetoencephalographic study.

OBJECTIVE: Benign childhood epilepsy with centrotemporal spikes (BECTS), also known as rolandic epilepsy, has recently been reported to be associated with variable degrees of cognitive dysfunction. Many studies reported poor language ability in children with BECTS compared with healthy control children. To elucidate the harmful effects of BECTS on language cognition, we studied the magnetoencephalographic activity elicited by an auditory language comprehension task. METHODS: The participants (N = 20) included 10 children diagnosed with BECTS (aged 10.8 ±â€¯2.8 years) and 10 age-matched healthy children (control) (aged 10.6 ±â€¯1.6 years). Cognitive function was assessed using general intellectual function and language ability. In patients with BECTS, we reviewed the clinical course and electroencephalogram (EEG) findings. We recorded the cortical responses elicited by an auditory language comprehension task using magnetoencephalography (MEG). We compared those results between groups and analyzed the correlation with cognitive scores and frequency of spikes. RESULTS: The full-scale intelligence quotient (FSIQ) by the Wechsler Intelligence Scale for Children-4th edition was significantly reduced in the group with BECTS (96.4 ±â€¯12.3) compared with the control group (110.0 ±â€¯7.4). In half of the group with BECTS, the auditory comprehension score fell below the age-standard level. In the group with BECTS, the cortical activation during the task showed reduced intensity in language-associated areas such as the bilateral primary auditory cortex, left superior and mid-temporal areas, and inferior frontal area compared with those in the control group. In addition, the cortical activation in the left superior temporal area was negatively correlated with spike frequency and positively correlated with FSIQ in the group with BECTS. Conversely, the right inferior frontal and mid-temporal areas had increased the activations in the group with BECTS. From the time frequency analysis, low gamma band event-related desynchronization was reduced in the group with BECTS. CONCLUSION: Epileptic spikes negatively influenced responsiveness to the auditory language comprehension task in the language-associated cortices. These findings suggest that epileptic spikes could have a negative impact on the functional activity in rolandic areas and become a reason to change the functional development of the language network.

Inter-hemispheric somatosensory coherence and parental stress in hypersensitivity at 8 months old: An electroencephalography study.

OBJECTIVE: Infant hypersensitivity affects daily challenges and parental stress. Although the crucial role of tactile sensation in infants' brain function has been highlighted, hypersensitive infants and their families lack support. Electroencephalography may be useful for understanding hypersensitivity traits. We investigated the relationship between infant perceptual hypersensitivity and parental stress, somatosensory-evoked potential (SEP), and magnitude-squared coherence (MSC) in the general population. METHODS: Infants aged 8 months (n = 63) were evaluated for hypersensitivity and parental stress using a questionnaire and for cortical activity using electroencephalography. Vibration stimuli were applied to the infant's left foot. SEP components that peaked around 150 ms (N2) and at 200 ms (P2) after stimulus onset were evaluated by amplitude and latency at the midline electrode (Cz) and MSC between the midline electrodes (C3-C4). RESULTS: Parental stress was associated with infant hypersensitivity. The latency of Cz was delayed, and C3-C4 delta MSC was high in infants with hypersensitivity. CONCLUSIONS: Increasing inter-hemispheric MSC synchrony in the stimulated condition in infants with hypersensitivity suggested atypical somatosensory cortical function. SIGNIFICANCE: These findings contribute to identifying, understanding the mechanisms of, and developing effective coping strategies for early-stage hypersensitivity.

[Cyclophosphamide pulse therapy effective for childhood-onset refractory multiple sclerosis: a case report].

We report a case of a 15-year-old girl with relapsing-remitting multiple sclerosis (MS) who received cyclophosphamide pulse therapy. At the age of 5 years, she displayed symptoms such as headache and unconsciousness after varicella infection as the first episode of MS. She had been treated with methylprednisolone pulse therapy, intravenous immunoglobulin, interferon-beta1b, and azathioprine. However, she had relapsed 12 times by the age of 15 years. At this time, she showed weakness and severe paralysis of her left leg, and even 1 month after methylprednisolone pulse therapy, she still had gait impairment and showed gadolinium-enhanced lesion on brain magnetic resonance imaging. We then started cyclophosphamide pulse therapy (600 mg/m2) once a month for 12 months combined with interferon-beta1a. She had no serious side effects and she could walk again after 4 months on cyclophosphamide treatment. She has been free from relapse for 2 years and 8 months until the present time. Although only a few studies have indicated the efficacy of cyclophosphamide pulse therapy for childhood MS, we consider careful use of cyclophosphamide could be one of the options for refractory childhood MS.

Extension of microglial activation is associated with epilepsy and cognitive dysfunction in Tuberous sclerosis complex: A TSPO-PET study.

BACKGROUND AND OBJECTIVES: Neuroinflammation contributes to the severity of various neurological disorders, including epilepsy. Tuberous sclerosis complex (TSC) is a condition that results in the overactivation of the mammalian target of rapamycin (mTOR) pathway, which has been linked to the activation of microglia responsible for neuroinflammation. To clarify the involvement of neuroinflammation in the neuropathophysiology of TSC, we performed a positron emission tomography (PET) study using the translocator protein (TSPO) radioligand, [11C] DPA713, and investigated microglial activation in relation to neurological manifestations, especially epilepsy and cognitive function. METHODS: This cross-sectional study included 18 patients with TSC (6 in the no-seizure group, 6 in the refractory seizure group, and 6 in the mTOR-inhibitor [mTOR-i] group). All participants underwent [11C] DPA713-PET. PET results were superimposed with a 3D T2-weighted fluid-attenuated inversion-recovery (FLAIR) and T1-weighted image (T1WI) to evaluate the location of cortical tubers. Microglial activation was assessed using the standardized uptake value ratio (SUVr) of DPA713 binding. The volume ratio of the DPA713-positive area to the intracranial volume (volume ratio of DPA713/ICV) was calculated to evaluate the extent of microglial activation. A correlation analysis was performed to examine the relationship between volume ratio of DPA713/ICV and severity of epilepsy and cognitive function. RESULTS: Most cortical tubers with hyperintensity on FLAIR and hypo- or isointensity on T1WI showed microglial activation. The extent of microglial activation was significantly greater in the refractory seizure group than in the no-seizure or mTOR-i groups (p < 0.001). The extent of microglial activation in subjects without mTOR-i treatment correlated positively with epilepsy severity (r = 0.822, P = 0.001) and negatively with cognitive function (r = -0.846, p = 0.001), but these correlations were not present in the mTOR-i group (r = 0.232, P = 0.658, r = 0.371, P = 0.469, respectively). CONCLUSION: Neuroinflammation is associated with the severity of epilepsy and cognitive dysfunction in brains with TSC. mTOR-i may suppress the extent of neuroinflammation in TSC. Investigating the spread of microglial activation using TSPO-PET in these patients may help to predict the progression of neuropathy by assessing the degree of neuroinflammation and therefore be useful for determining how aggressive the treatment should be and in assessing the effectiveness of such treatment in patients with TSC.

Abnormal White Matter Microstructure in the Limbic System Is Associated With Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders.

Objective: Tuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI). Methods: A total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers. Results: The TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC. Conclusion: The disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.

Prognostic factors for acute encephalopathy with bright tree appearance.

OBJECTIVE: To determine the prognostic factors for encephalopathy with bright tree appearance (BTA) in the acute phase through retrospective case evaluation. METHODS: We recruited 10 children with encephalopathy who presented with BTA and classified them into 2 groups. Six patients with evident regression and severe psychomotor developmental delay after encephalopathy were included in the severe group, while the remaining 4 patients with mild mental retardation were included in the mild group. We retrospectively analyzed their clinical symptoms, laboratory data, and magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings. RESULTS: Patients in the severe group developed subsequent complications such as epilepsy and severe motor impairment. Univariate analysis revealed that higher maximum lactate dehydrogenase (LDH) levels (p=0.055) were a weak predictor of poor outcome. Maximum creatinine levels were significantly higher (p<0.05) and minimal platelet counts were significantly lower (p<0.05) in the severe group than in the mild group. Acute renal failure was not observed in any patient throughout the study. MRS of the BTA lesion during the BTA period showed elevated lactate levels in 5 children in the severe group and 1 child in the mild group. MRI performed during the chronic phase revealed severe brain atrophy in all patients in the severe group. CONCLUSIONS: Higher creatinine and LDH levels and lower platelet counts in the acute phase correlated with poor prognosis. Increased lactate levels in the BTA lesion during the BTA period on MRS may predict severe physical and mental disability.

Clinicogenetical features of a Japanese patient with giant axonal neuropathy.

Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder that affects both the peripheral nerves and central nervous system. Since the discovery in 2000 of the gigaxonin gene on chromosome 16q24.1 to be causative, more than 40 GAN mutations have been reported from different racial backgrounds. We report the clinicogenetic findings of a 24-year-old Japanese man with GAN. He had consanguineous parents and showed the phenotype of classical severe GAN. We found a novel homozygous nonsense mutation (p.R162X) in the GAN gene. This is the first genetically-determined Japanese case of GAN, with a follow-up period of more than 15 years. In addition, this mutation is novel. We also reviewed previous reports of GAN to see whether there is any genotype-phenotype correlation.

Ictal high-frequency oscillations on scalp EEG recordings in symptomatic West syndrome.

OBJECTIVES: High-frequency oscillations (HFOs) on intracranial electroencephalography (EEG) recordings have been reported to be useful to identify the epileptogenic zone in intractable epilepsy. We investigated whether the ictal HFOs on scalp EEG seen during spasms contributed to identification of the epileptogenic zone in symptomatic West syndrome (S-WS). METHODS: In S-WS, ictal scalp EEGs were recorded during a series of spasms. The HFOs associated with spasms were visualized in the temporally expanded EEG traces and subjected to time-frequency analysis. The results on the distribution of HFOs were compared with that of cortical lesions indicated by neuroimaging. RESULTS: In the 4 children examined, HFOs at 80-150 Hz preceded the clinical onsets of spasms. The maximum augmentation of these HFOs was larger than that of HFOs at 20-70 Hz. The regions of the maximum augmentation of HFOs at 80-150 Hz were identical to the lesions detected by neuroimaging. Two patients who underwent dissection of the area including the area with HFOs resulted in Engel class I. CONCLUSION: Ictal HFOs of spasms on scalp EEG showed a strong association with neuroimaging abnormalities presumed to be the epileptogenic zone in S-WS. Ictal HFOs can thus be a useful marker for exploring lesions for epilepsy surgery.

Long-term developmental outcome in patients with West syndrome after epilepsy surgery.

It has been hypothesized that early seizure control may prevent children with intractable epileptic spasms (ES) from developmental regression and may contribute to better developmental outcome. The effectiveness of surgery for ES has been reported. We investigated long-term post-operative outcomes of seizure control and development in patients with symptomatic West syndrome (S-WS) who underwent epilepsy surgery. Six children who underwent surgical intervention for intractable ES were retrospectively investigated. Cortical malformations were observed on pre-operative MRI in all patients, with hemispheric or multilobar involvement in four children and focal lesions in two. Following surgery, we measured motor function, developmental age (DA), language skills, and sociopsychological function for up to 7years (mean, 4.9years). Post-operative seizure outcome was Engel Class I (n=4) or III (n=2). Motor function and DA was increased following surgery in six and five patients, respectively. Two patients started to speak in sentences following focal resection. Autistic features were noted in four of the five examined patients post-operatively. None of the patients showed developmental regression following surgery. Epilepsy surgery for S-WS with ES may result in good seizure control and improvement in motor development. Improvement in cognitive function was modest in this small cohort of children and autistic features were noted post-operatively in a substantial proportion of the children. While seizure control can be obtained by epilepsy surgery, early intervention for sociopsychological comorbidities may be warranted in children with S-WS.