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Whole-exome sequencing (WES) is becoming a standard tool for detecting nucleotide changes, and determining whether WES data can be used for the detection of copy-number variations (CNVs) is of interest. To date, several algorithms have been developed for such analyses, although verification is needed to establish if they fit well for the appropriate purpose, depending on the characteristics of each algorithm. Here, we performed WES CNV analysis using the eXome Hidden Markov Model (XHMM). We validated its performance using 27 rare CNVs previously identified by microarray as positive controls, finding that the detection rate was 59%, or higher (89%) with three or more targets. XHMM can be effectively used, especially for the detection of >200 kb CNVs. XHMM may be useful for deletion breakpoint detection. Next, we applied XHMM to genetically unsolved patients, demonstrating successful identification of pathogenic CNVs: 1.5-1.9-Mb deletions involving NSD1 in patients with unknown overgrowth syndrome leading to the diagnosis of Sotos syndrome, and 6.4-Mb duplication involving MECP2 in affected brothers with late-onset spasm and progressive cerebral/cerebellar atrophy confirming the clinical suspect of MECP2 duplication syndrome. The possibility of an 'exome-first' approach for clinical genetic investigation may be considered to save the cost of multiple investigations.

Objective Increasing reports suggest a role for immunological mechanisms in febrile infection‐related epilepsy syndrome (FIRES). The objective of this study was to elucidate the efficacy and safety of intrathecal dexamethasone therapy (IT‐DEX). Methods We assessed six pediatric patients with FIRES who were administered add‐on IT‐DEX in the acute (n = 5) and chronic (n = 1) phases. We evaluated clinical courses and prognosis. We measured cytokines/chemokines in cerebrospinal fluid (CSF) from FIRES patients at several points, including pre‐ and post‐IT‐DEX, and compared them with control patients with chronic epilepsy (n = 12, for cytokines/chemokines) or with noninflammatory neurological disease (NIND, n = 13, for neopterin). Results Anesthesia was weaned after a median of 5.5 days from IT‐DEX initiation (n = 6). There was a positive correlation between the duration from the disease onset to the introduction of IT‐DEX and the length of ICU stay and the duration of mechanical ventilation. No patient experienced severe adverse events. Seizure spreading and background activities on electroencephalography were improved after IT‐DEX in all patients. The levels of CXCL10, CXCL9, IFN‐γ, and neopterin at pre‐IT‐DEX were significantly elevated compared to levels in epilepsy controls, and CXCL10 and neopterin were significantly decreased post‐IT‐DEX, but were still higher compared to patients with chronic epilepsy. IL‐6, IL‐8, and IL‐1β were significantly elevated before IT‐DEX compared to epilepsy controls, though there was no significant decrease post‐treatment. Interpretation IT‐DEX represents a therapeutic option for patients with FIRES that could shorten the duration of the critical stage of the disease. The effect of IT‐DEX on FIRES might include cytokine‐independent mechanisms.

Objective We aimed to analyze the efficiency of corpus callosotomy (CC) and subsequent disconnection surgeries in patients with late‐onset epileptic spasms (LOES) by comparing post‐encephalitis/encephalopathy (PE) and non‐encephalitis/encephalopathy (NE). We hypothesized these surgeries can control potential focal onset epileptic spasms (ES) in the NE group but not in the PE group. Methods We retrospectively included 23 patients (12 with PE and 11 with NE) who initially underwent CC and subsequent disconnection surgeries (five NE). We compared the clinical courses, seizure types, MRI, video‐EEG, epilepsy surgery, and seizure outcomes between the two groups. Results The median age of LOES onset in the PE group was 2.8 (range 1.0–10.1 years) and 2.9 years (range 1.1–12.6) in the NE group. Bilateral MRI abnormalities were observed in both groups (PE, n = 12; NE, n = 3; P < 0.05). The PE group presented ES alone (n = 2), ES + focal seizures (FS) (n = 3), ES + generalized seizures (GS) (n = 3), and ES + FS + GS (n = 4) in addition to stimulus‐induced startle seizures (SS) (n = 8) (mean 3.1 seizure types/patient). The NE group presented ES alone (n = 1), ES + FS (n = 2), and ES + FS + GS (n = 8) (mean 2.7 seizure types/patient). In the PE group, CC stopped ES (n = 1) and SS (n = 1) and achieved <50% SS (n = 3). In the NE group, CC achieved immediate ES‐free status (n = 2) and < 50% ES (n = 1), and additional disconnection surgeries subsided all seizure types (n = 3) based on lateralized interictal/ictal EEG findings. LOES was significantly remitted by surgery in the NE group (6/11 [55%]) compared with the PE group (1/12 [8%]) (P < 0.05). Significance LOES is a drug‐resistant, focal/generalized/unknown onset ES. Lateralization of ES in NE could be achieved after CC and eliminated by further disconnection surgeries because of potential focal onset ES. LOES in PE had little benefit from CC for generalized onset ES. However, CC might reduce SS in patients in the PE group with multiple seizure types.

Objective Kinesin family member 5A (KIF5A) is a molecular motor protein responsible for intracellular transport, specifically in neurons. While abnormalities in the KIF5A gene have been reported in the onset of various neurological diseases, there are no studies demonstrating an association between this gene and West syndrome. Methods In the case presented here, epileptic spasms appeared at 7 months; electroencephalogram (EEG) investigation confirmed hypsarrhythmia, resulting in a diagnosis of West syndrome. The patient exhibited peculiar facies, hypotonia, failure to thrive, and severe global developmental delay. Results Cranial magnetic resonance imaging (MRI) revealed severe delayed myelination. 123I‐iomazenil SPECT image at 7 months demonstrated decreased accumulation in bilateral areas, including the primary somatosensory and motor cortices, and the primary and association visual areas compared to an age‐matched control. Whole exome sequencing analysis demonstrated a novel de novo heterozygous missense variant in KIF5A, (NM_004984.4:c.710A>T: p. Glu237Val). Significance It was concluded that the KIF5A variant impaired the transport of GABAA receptors to the cell membrane surface, thus leading to an imbalance of these receptors between regions of the cerebrum and resulting in the onset of epilepsy.

Purpose Coherence analysis in electroencephalography (EEG) allows measurement of the degree of consistency of amplitude between pairs of electrodes. Theoretically, disconnective epilepsy surgery should decrease coherence between corresponding areas. The study aimed to evaluate postoperative changes in interhemispheric coherence values after corpus callosotomy (CC). Methods Non-lesional, drug-resistant, generalized epilepsy patients who underwent total CC were retrospectively collected. To evaluate coherence, we divided the scalp interictal EEG into “baseline” and “discharge” states after excluding periods with artifacts. Interhemispheric coherence values were obtained between eight pairs of symmetrically opposite scalp electrodes in six different frequency bands. We analyzed both pre- and postoperative EEG sessions and calculated the percentage of difference (POD) in coherence values. Results We collected 13 patients and analyzed 2496 interhemispheric coherence values. Preoperative coherence values differed significantly between baseline and discharge states ( p  = 0.0003), but postoperative values did not ( p  = 0.11). For baseline state, coherence values were decreased after CC and median POD was − 22.3% ( p  < 0.0001). Delta frequency showed the most decreased POD (-44.3%, p  = 0.0009). Median POD was lowest in the Fp1-Fp2 pair of electrodes. For discharge state, coherence values were decreased after CC and median POD was − 24.7% ( p  < 0.0001). Delta frequency again showed the most decreased POD (-55.9%, p  = 0.0016). Median POD was lowest in the F7-F8 pair. Conclusion After total CC, interhemispheric coherence decreased significantly in both baseline and discharge states. The most decreased frequency band was the delta band, which may be used as a representative frequency band in future studies.

Surgical resections for lesions associated with intractable temporal lobe epilepsy (TLE) offers good seizure outcomes.However, the necessity of hippocampectomy in addition to lesionectomy is controversial, especially when the hippocampus is not involved by the lesion. Lesionectomy alone, preserving the hippocampus by an appropriate surgical approach, might offer good seizure outcomes while maintaining neurocognitive function. In the present study, the aims were to examine the surgical strategy for lesions associated with TLE and to present how to select surgical approaches to preserve the hippocampus. A total of 22 consecutive lesion-associated TLE patients who underwent lesionectomy alone were retrospectively reviewed. The surgical approach, transsylvian, transorbital, subtemporal, supracerebellar transtentorial, or transcortical approach, was selected based on the location of the lesion. Postoperative seizure outcomes were classified by the Engel classification. Neurocognitive outcomes were assessed before and after surgery if possible. The pathology, the extent of resection, and lesion recurrence were reviewed. The transsylvian approach was selected in six patients, the transorbital approach in one patient, the subtemporal approach in three patients, the supracerebellar transtentorial approach in five patients, and the transcortical approach in seven patients. Eighteen of 22 (81.8 %) patients achieved Engel’s class I or II good seizure outcomes. No patients had neurocognitive deterioration after surgery. Twelve patients had various types of brain tumors, and ten patients had non-tumorous lesions. Gross total resection was achieved in 21 patients. All patients had no recurrence. For patients with lesion-associated TLE, lesionectomy alone by the appropriate surgical approach offers satisfactory seizure outcomes while preserving hippocampus. •The surgical strategy for lesion-associated TLE remains unestablished.•We adopted a strategy with lesionectomy alone while preserving the hippocampus.•The choice of surgical approach depended on the lesion's location.•Our strategy resulted in satisfactory seizure outcomes.