Effect of levodopa on pathological gait in Dravet syndrome: A randomized crossover trial using three-dimensional gait analysis.

OBJECTIVE: Individuals with Dravet syndrome (DS) exhibit progressive gait disturbance. No quantitative studies have been conducted to evaluate the effectiveness of medication for gait disturbance. Therefore, the aim of this study was to evaluate the effectiveness of levodopa for pathological gait in people with DS using three-dimensional gait analysis (3DGA). METHODS: Nine individuals with DS, ages 6-20 years, participated in a crossover study of levodopa and were randomly assigned to the levodopa precedence or no levodopa precedence group. Levodopa/carbidopa hydrate was prescribed at a dose of 5 mg/kg/day (body weight <60 kg) or 300 mg/day (body weight ≥60 kg). The medication was taken for 4-6 weeks (4-week washout period). 3DGA was performed three times before the study, with and without levodopa. A mixed-effects model was used to evaluate the effectiveness of levodopa. The primary outcome was the change in the Gait Deviation Index (GDI). In addition, spatiotemporal gait parameters, 6-minute walking distance (6MD), and balance were evaluated. The correlation between the effectiveness of levodopa and age or gait performance before starting levodopa was analyzed. RESULTS: Levodopa improved the GDI by 4.2 points, (p = .029), 6MD by 52 m (p = .002), and balance test result by 4.1 mm (p = .011) in participants with DS. No severe adverse events were observed, with the exception of one participant, who exhibited fever and consequently stopped taking levodopa. Levodopa was more effective in younger participants with a higher baseline gait performance. SIGNIFICANCE: Our randomized crossover trial showed that levodopa has the potential to improve gait disturbance in people with DS.

Repetitive sleep starts: An important differential diagnosis of infantile spasms.

OBJECTIVE: Repetitive sleep starts (RSS) are clusters of nonepileptic, spasm-like movements occurring during sleep onset. However, their characteristics have yet to be defined. We conducted a clinicoelectroencephalographic study of children with RSS to clarify their detailed characteristics. METHODS: To differentiate starts from epileptic spasms, we recruited children with brief "crescendo-decrescendo" muscle contractions that simultaneously involved the limbs and trunk without electroencephalogram changes, and that fulfilled the following criteria: (1) repeated occurrence (five or more) and (2) manifestation during sleep stage N1-N2. A total of nine children met these criteria. Their clinical information and video-electroencephalogram data were analyzed retrospectively. RESULTS: The background conditions observed at onset of RSS were perinatal hypoxic-ischemic encephalopathy (n = 4), West syndrome of unknown etiology (n = 1), and traumatic brain injury (n = 1). The age at onset of RSS, the number of starts in a given RSS cluster, the interval between starts, and the duration of surface electromyogram activity were between 3 and 46 months, 5 and 547, <1 and 60 s, and 0.3 and 5.4 s, respectively. None of the median value of these parameters differed between children with and without corticospinal tract injury. During the median follow-up period of 33 months, RSS disappeared spontaneously in five. CONCLUSION: This is the largest case series of RSS clarifying their clinicoelectroencephalographic characteristics reported to date. To avoid unnecessary antiepileptic therapies, clinicians should be aware of RSS and distinguish it from other disorders involving involuntary movements or seizures, especially epileptic spasms.

Pseudo-sawtooth pattern on amplitude-integrated electroencephalography in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: The objective of this study was to describe a novel amplitude-integrated electroencephalography (aEEG) pattern in infants with hypoxic-ischemic encephalopathy (HIE) and to assess the clinical significance. METHODS: The aEEG traces of infants with HIE who were treated with therapeutic hypothermia (TH) from 2012 to 2017 were analyzed. A pseudo-sawtooth (PST) pattern was defined as a periodic increase of the upper and/or lower margin of the trace on aEEG without showing seizure activities on conventional EEG (CEEG). RESULTS: Of the 46 infants, 6 (13%) had the PST pattern. The PST pattern appeared following a flat trace or a continuous low-voltage pattern and was followed by a burst-suppression pattern. On CEEG, the PST pattern consists of alternating cycles of low-voltage irregular activities and almost flat tracing. The PST pattern was associated with neuroimaging abnormalities and with various degrees of neurodevelopmental outcomes. Positive predictive values of the PST or worse pattern for adverse outcomes were high at 12 h after birth. CONCLUSION: A novel aEEG background pattern in infants with HIE was reported. The PST pattern likely indicates a suppressed background pattern and may be linked to unfavorable outcomes. Further multicenter validation study is needed to clarify its clinical significance.

Evaluation of interobserver variability in application of the new neonatal seizure classification proposed by the ILAE Task Force.

OBJECTIVE: Clinical identification of neonatal seizures (NS) remains challenging. The International League Against Epilepsy (ILAE) Task Force on Neonatal Seizures has proposed a new classification of NS, based on the 2017 ILAE seizure classification. One of the key points of this proposed NS classification is that seizure types should be determined by the "predominant" clinical feature. However, when the definition of "predominant" is uncertain, interobserver variability may arise. METHODS: We asked 49 health professionals to classify 21 NS video-electroencephalogram (EEG) recordings using the proposed 9 seizure types. RESULTS: The degree of agreement among participants was low, and agreement was weak among experts in neonatal neurology. Among experts, the rate of agreement was <50% for 2 NS. This disagreement was related to differences in the interpretation of "predominant features." Although interobserver variability was present among users of the new NS classification, the reproducibility of the NS classification was satisfactory. CONCLUSION: Education designed to foster consistent application of the standards for NS will be important for reducing interobserver variability and expanding the use of the new NS classification.

Cytotoxic edema at onset in West syndrome of unknown etiology: A longitudinal diffusion tensor imaging study.

OBJECTIVE: To clarify longitudinal changes in white matter microstructures from the onset of disease in patients with West syndrome (WS) of unknown etiology. METHODS: Diffusion tensor imaging (DTI) was prospectively performed at onset and at 12 and 24 months old in 17 children with WS of unknown etiology. DTI was analyzed using tract-based spatial statistics (TBSS) and tract-specific analysis (TSA) of 13 fiber tracts, and fractional anisotropy (FA) and mean diffusivity (MD) were compared with those of 42 age-matched controls. Correlations of FA and MD with developmental quotient (DQ) at age 24 months were analyzed. Multiple comparisons were adjusted for using the false discovery rate (q-value). RESULTS: TBSS analysis at onset showed higher FA and lower MD in the corpus callosum and brainstem in patients. TSA showed lower MD in bilateral uncinate fasciculi (UF) (right: q < 0.001; left: q = 0.03) at onset in patients. TBSS showed a negative correlation between FA at onset and DQ in the right frontal lobe, whereas FA at 24 months old exhibited a positive correlation with DQ in the diffuse white matter. MD for bilateral UF at 24 months old on TSA correlated positively with DQ (q = 0.04, both). SIGNIFICANCE: These findings may indicate the existence of cytotoxic edema in the immature white matter and dorsal brainstem at onset, and subsequent alterations in the diffuse white matter in WS of unknown etiology. Microstructural development in the UF might play important roles in cognitive development in WS.

Apneas observed in trisomy 18 neonates should be differentiated from epileptic apneas.

Many children with trisomy 18 have apneas from the neonatal period. It has been reported that some children with trisomy 18 have epilepsy, including epileptic apneas. However, no previous report has described epileptic apneas in trisomy 18 neonates. We retrospectively reviewed the clinical records of neonates with trisomy 18 who were born at Anjo Kosei Hospital between July 2004 and October 2013 and investigated whether they had epileptic apneas during the neonatal period and whether antiepileptic drugs (AEDs) were effective for treating them. We identified 16 patients with trisomy 18. Nine patients who died within 3 days of birth were excluded. Five of the remaining seven patients had apneas. All five patients underwent electroencephalograms (EEGs) to assess whether they suffered epileptic apneas. Three of the five patients had EEG-confirmed seizures. In two patients, the apneas corresponded to ictal discharges. In one patient, ictal discharges were recorded when she was under mechanical ventilation, but no ictal discharges that corresponded to apneas were recorded after she was extubated. AEDs were effective for treating the apneas and stabilizing the SpO2 in all three patients. Among neonates with trisomy 18 who lived longer than 3 days, three of seven patients had EEG-confirmed seizures. AEDs were useful for treating their epileptic apneas and stabilizing their SpO2. Physicians should keep epileptic apneas in mind when treating apneas in neonates with trisomy 18.

Two siblings with cortical dysplasia: Clinico-electroencephalographic features.

The older of two siblings began to have spasms and partial seizures at 1 month of age. Head magnetic resonance imaging showed an abnormal area in the left temporo-parieto-occipital region. Interictal electroencephalogram (EEG) showed a suppression-burst pattern. Adrenocorticotropic hormone stopped the spasms, but the seizures continued. Clonazepam, carbamazepine, zonisamide, and clobazam were ineffective. She underwent focal resection at age 8 months. Postoperatively, the seizures disappeared. Histopathologically, the lesion appeared to be focal cortical dysplasia type IIa. The younger sibling had spasms from birth. Head magnetic resonance imaging showed left hemi-megalencephaly. Interictal EEG showed a suppression-burst pattern. Phenobarbital, valproic acid, and zonisamide were ineffective. He underwent hemispherotomy at age 2 months and became seizure free. The histopathological features were consistent with those of hemi-megalencephaly. The siblings' EEG and clinical courses had some similarities. These siblings' conditions may have the same genetic background.

Is focal cortical dysplasia sporadic? Family evidence for genetic susceptibility.

Focal cortical dysplasia is a common cortical malformation and an important cause of epilepsy. There is evidence for shared molecular mechanisms underlying cortical dysplasia, ganglioglioma, hemimegalencephaly, and dysembryoplastic neuroepithelial tumor. However, there are no familial reports of typical cortical dysplasia or co-occurrence of cortical dysplasia and related lesions within the same pedigree. We report the clinical, imaging, and histologic features of six pedigrees with familial cortical dysplasia and related lesions. Twelve patients from six pedigrees were ascertained from pediatric and adult epilepsy centers, eleven of whom underwent epilepsy surgery. Pedigree data, clinical information, neuroimaging findings, and histopathologic features are presented. The families comprise brothers with focal cortical dysplasia, a male and his sister with focal cortical dysplasia, a female with focal cortical dysplasia and her brother with hemimegalencephaly, a female with focal cortical dysplasia and her female first cousin with ganglioglioma, a female with focal cortical dysplasia and her male cousin with dysembryoplastic neuroepithelial tumor, and a female and her nephew with focal cortical dysplasia. This series shows that focal cortical dysplasia can be familial and provides clinical evidence suggesting that cortical dysplasia, hemimegalencephaly, ganglioglioma, and dysembryoplastic neuroepithelial tumors may share common genetic determinants.

Acute Bacterial Prostatitis in a 12-Year-Old Boy Without Any Underlying Disease.

Acute bacterial prostatitis (ABP) is a common disease in adults but uncommon in children. Here, we report the case of a pediatric patient without any underlying disease who was diagnosed with ABP while trying to determine the cause of fever refractory to antimicrobial therapy. A previously healthy 12-year-old boy presented with a 13-day history of fever and malaise despite initial antimicrobial treatment. Further tests revealed pyuria and enlarged prostate with possible abscesses, which led to the diagnosis of ABP based on a contrast-enhanced computed tomography (CT) scan. Although initial urine cultures were negative, Corynebacterium pyruviciproducens was detected in subsequent cultures. Antimicrobial therapy for 10 weeks led to improvement without relapse. This case demonstrates that ABP can cause fever in children. Moreover, it shows that contrast-enhanced CT imaging can help identify the cause of fever and that administration of antimicrobials before adequate investigations can confound the diagnosis and complicate the treatment.

[Diffusion tensor imaging at term-equivalent age in extremely-low-birth-weight infants with periventricular leukomalacia].

It is important to predict the neurological prognoses of preterm infants as part of their normal follow-up. Previous reports have shown that conventional magnetic resonance imaging (MRI) and electroencephalography are useful in predicting neurological prognoses. Diffusion tensor imaging (DTI) is a relatively new method of evaluating the central nervous system (CNS) that can detect abnormalities quantitatively. We compared DTI at term-equivalent age in two extremely-low-birth-weight infants diagnosed with periventricular leukomalacia (PVL) with conventional MRI and DTI in three control extremely-low-birth-weight infants. DTI was analyzed using the free software, "Volume-one" and "dTVII SR." We compared the fractional anisotropy (FA) values at the corpus callosum, posterior limbs of the internal capsule, cerebral peduncle, and corticospinal tract using manual region of interest (ROI) analysis, and at the commissural fibers and corticospinal tract using tract-specific analysis. The FA values were lower in patients with PVL than in control infants at all measurement points, except the commissural fibers on tract-specific analysis. These measurement points showed no abnormality using conventional MRI. This suggests that DTI can detect CNS abnormalities that cannot be detected with conventional MRI. However, our sample size was very small and we examined only cases in which PVL was detected with conventional MRI. Further study is necessary to examine the correlation of DTI findings and neurological prognoses in infants who have no abnormality on conventional MRI.

Acute encephalopathy with biphasic seizures and late reduced diffusion: Predictive EEG findings.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a common type of acute encephalopathy in Japan; the condition is clinically characterized by prolonged seizures as the initial neurological symptom, followed by late seizures 4-6 days later. It is difficult to differentiate AESD from prolonged febrile seizures (PFSs). Here, we explored the use of electroencephalography to differentiate AESD from PFSs. METHODS: We studied the electroencephalograms (EEGs) of children <6 years of age diagnosed with AESD or PFSs; all EEGs were recorded within 48 h of seizure onset (i.e., before the late seizures of AESD). Two pediatric neurologists evaluated all EEGs, focusing on the basic rhythm, slowing during wakefulness/arousal by stimuli, spindles, fast waves, and slowing during sleep. RESULTS: The EEGs of 14 children with AESD and 31 children with PFSs were evaluated. Spindles were more commonly reduced or absent in children with AESD than in those with PFSs (71% vs. 31%, p = 0.021). Fast waves were also more commonly reduced or absent in children with AESD (21% vs. 0%, p = 0.030). The rates of all types of slowing did not differ between children with AESD and those with PFSs, but continuous or frequent slowing during sleep was more common in the former (50% vs. 17%, p = 0.035). CONCLUSIONS: EEG findings may usefully differentiate AESD from PFSs. Reduced or absent spindles/fast waves and continuous or frequent slowing during sleep are suggestive of AESD in children with prolonged seizures associated with fever.

Trajectory of the incidence of brushes on preterm electroencephalogram and its association with neurodevelopment in extremely low birth weight infants.

BACKGROUND: Brush or delta brush is a well-known characteristic waveform in preterm electroencephalograms. However, the longitudinal trajectory of brushes and its association with neurodevelopment remain uncertain. METHODS: We analyzed the longitudinal incidence of brushes in 36 extremely low birth weight infants without severe brain lesions and its association with neurodevelopment and white matter abnormality. Conventional eight-channel electroencephalograms were recorded at 30, 32, 36, and 40 postmenstrual weeks (PMW). Incidence of brushes was calculated as the sum of brushes from each channel separated by active sleep and quiet sleep. A developmental delay was defined as a developmental quotient of <85 assessed at corrected age of 18 months. White matter abnormalities were evaluated with term-equivalent magnetic resonance imaging. RESULTS: The median incidence of brushes (per minute) in 36 infants at PMW 30, 32, 36, and 40 was 16.4, 20.4, 22.5, and 1.8 during active sleep and 7.5, 10.3, 11.5, and 1.7 during quiet sleep, respectively. Among the 36 infants, 14 infants were diagnosed with developmental delay. Longitudinal trajectories of the incidence of brushes were different between the normal and the delayed development groups. Brushes were observed most frequently at 36 PMW in the delayed development group. The incidence of brushes at 36 PMW was significantly correlated with the severity of white matter abnormalities and negatively correlated with the developmental quotient. CONCLUSION: The incidence of brushes at 36 PMW can be a unique predictor of early neurodevelopment in extremely low birth weight infants without severe brain lesions.

Efficacy of long-term adrenocorticotropic hormone therapy for West syndrome: A retrospective multicenter case series.

OBJECTIVES: Long-term adrenocorticotropic therapy (LT-ACTH), which consisted of 2-4 weeks of daily injections of adrenocorticotropic hormone (ACTH) and subsequent months of weekly injections, was tried for relapsed West syndrome (WS) or other intractable epilepsies in small case reports. Our aim was to explore the efficacy of LT-ACTH for preventing WS relapse, as well as the prevalence of its adverse events. METHODS: This is a retrospective, nationwide, multicenter case series of patients with WS who underwent LT-ACTH. Clinical information of the patients and protocol of LT-ACTH were collected from participating institutes in this study. We defined clinical response to ACTH as achievement of hypsarrhythmia and epileptic spasms resolution. Patients who responded to daily ACTH injections were identified and assessed whether they experienced WS relapse during/after the weekly ACTH injection period. The outcome was measured by the nonrelapse rate at 24 months after daily ACTH injections using the Kaplan-Meier method. RESULTS: Clinical information of 16 children with WS was analyzed. The median age at LT-ACTH initiation was 14.5 months (range: 7-68 months). Thirteen (81%) patients had previously undergone conventional ACTH treatment. The LT-ACTH regimens comprised a median of 16 days of daily injections (range: 11-28 days) and 10 months of weekly injections (range: 3-22 months). Seven patients experienced WS relapse during/after subsequent weekly ACTH period, and the nonrelapse rate at 24 months after daily injections was estimated at 60.6% (95% confidence interval: 32.3%-80.0%). Height stagnation, hypertension, and irritability were observed; lethal adverse events were not reported. SIGNIFICANCE: Our study firstly explored the efficacy of LT-ACTH for preventing WS relapse. LT-ACTH might be a treatment option for patients with relapsed or intractable WS; however, we note that our study is limited by its small sample size and the lack of an appropriate control group.

Prolonged EEG depression in term and near-term infants with hypoxic ischemic encephalopathy and later development of West syndrome.

PURPOSE: This study was performed to clarify the relationship between prolonged depression of electroencephalography (EEG) in term and near-term infants with hypoxic ischemic encephalopathy (HIE) and the later development of West syndrome (WS). METHODS: We investigated 17 term and near-term infants with HIE. Inclusion criteria were as follows: ≥35 weeks of gestation, clinical signs of HIE, magnetic resonance imaging (MRI) lesions corresponding to HIE, assessment of outcome at >18 months of age, depression of EEG, and serial EEG examinations. The 17 infants were divided into the following two groups: Group A (n = 4) with prolonged EEG depression over 21 days of age, and group B (n = 13) with disappearance of EEG depression by 21 days of age. RESULTS: WS developed in all four infants in group A, but in only one of 13 infants in group B. WS occurred significantly more frequently in group A than in group B. For the prediction of subsequent development of WS, prolonged EEG depression over 21 days of age showed sensitivity of 0.80 and specificity of 1.0. In both groups, abnormal irregular faster waves with or without EEG depression were seen in 11 infants between 2 and 28 days of age. They had no significant relationship with WS, but were significantly related to an adverse developmental outcome. CONCLUSIONS: Prolonged depression of EEG over 21 days of age in term or near-term infants with HIE is a valuable predictor of the later development of WS.

Transient cortical diffusion restriction in children immediately after prolonged febrile seizures.

AIM: Little is known about acute febrile status epilepticus-induced injury of extrahippocampal structures. To clarify the presence and clinical significance of acute extrahippocampal injuries, we performed diffusion-weighted imaging (DWI) in children immediately after prolonged febrile seizure (PFS). METHOD: We performed a retrospective cohort study in children younger than 6 years old who visited one of two hospitals due to PFSs between January 2013 and October 2018. PFS was defined as a febrile seizure that persisted for 15 min or longer. We collected brain DWI data within 6 h of the end of PFS. When the initial DWI detected an abnormality, a follow-up DWI was performed a few days later. RESULTS: The study population consisted of 101 patients with PFSs. DWI was performed within 6 h in 51 patients, while the remaining 50 patients did not undergo imaging because of good recovery of consciousness. Restricted cortical diffusion was evident in 9 (18%) patients on initial DWI. All of them underwent DWI within 100 min after PFS. Restricted cortical diffusion was associated with male sex, asymmetrical PFS symptoms, and a shorter duration between the end of the seizure and DWI, but was not associated with seizure duration. All cortical abnormalities had resolved on follow-up DWI of these patients within 72 h after the initial imaging, but ipsilateral hippocampal hyperintensity appeared in one patient. All 9 patients with restricted cortical diffusion were finally diagnosed with PFS and discharged without sequelae. CONCLUSIONS: Some children with PFSs exhibit transient restricted diffusion in the regional cortex on DWI performed immediately after the end of PFS. These transient diffusion changes were not associated with unfavorable epileptic sequelae or neuroimaging in the short-term.

Splenial Lesions in Benign Convulsions With Gastroenteritis Associated With Rotavirus Infection.

OBJECTIVE: To investigate clinical risk factors for acute magnetic resonance imaging (MRI) abnormalities in patients with benign convulsions with mild gastroenteritis or benign infantile epilepsy. STUDY DESIGN: We investigated clinical and diffusion-weighted imaging findings in 32 patients with benign convulsions with mild gastroenteritis and 22 patients with benign infantile epilepsy who underwent MRI within seven days of seizure onset between 2010 and 2015. RESULTS: Diffusion-weighted imaging showed signal hyperintensity in the splenium of the corpus callosum in seven patients with benign convulsions with mild gastroenteritis, but no abnormalities in patients with benign infantile epilepsy. Patients with benign convulsions with mild gastroenteritis with splenial lesions showed a higher rate of rotavirus detection from feces (P = 0.006), higher serum level of C-reactive protein (P = 0.04), and shorter interval between seizure onset and MRI (P = 0.002) than patients with benign convulsions with mild gastroenteritis without splenial lesions. Multivariate analysis revealed rotavirus infection as a significant risk factor for splenial lesions on diffusion-weighted imaging in patients with benign convulsions with mild gastroenteritis (P = 0.02). CONCLUSIONS: Splenial lesions are often seen during acute period in patients with benign convulsions with mild gastroenteritis. Rotavirus infection is a risk factor for splenial lesions in patients with benign convulsions with mild gastroenteritis, suggesting the role of rotavirus to cause edema in the corpus callosum. From our observations, benign convulsions with mild gastroenteritis with a splenial lesion on diffusion-weighted imaging suggests good outcomes, and extensive evaluation of these patients may be unnecessary.

Effect of corticosteroids in a twin child with idiopathic localization-related epilepsy.

Corticosteroids have been used only in the treatment of special epileptic syndromes or epileptic encephalopathies, such as infantile spasms. We report an antiepileptic effect of corticosteroids that were used for treatment of nephropathy in a monozygotic twin child with idiopathic localization-related epilepsy (I-LRE). The patient and her monozygotic twin sister exhibited repeated partial seizures at two years of age and electroencephalogram (EEG) showed focal spikes in the occipital area and, on other occasions, the centro-parietal areas. After oral antiepileptic drugs were started, the twins still exhibited occasional seizures. The patient had IgA nephropathy at four years of age and intravenous methylprednisolone and oral prednisolone were administered. Her seizures and epileptiform discharges on EEG disappeared, while her sister continued to have seizures and EEG abnormalities. When the dose of oral predonisone was reduced, the seizures relapsed and EEG again revealed focal spikes. We conclude that corticosteroids exhibit efficacy towards seizures and epileptiform discharges on EEG in patients with I-LRE without epileptic encephalopathies.

A new method of blood sampling reduces pain for newborn infants: a prospective, randomized controlled clinical trial.

BACKGROUND: Using a new simple blood glucose measurement device (Free Style), blood can thus be sampled from the forearm, which is less sensitive to pain than from the heel. Measuring the blood glucose levels in newborn infants using Free Style is therefore a potentially less painful testing modality than traditional blood sampling methods. OBJECTIVE: To compare the pain intensity at the time of blood sampling from the forearm using the Free Style with the conventional method from the heel. DESIGN: A prospective, randomized controlled clinical trial. PATIENTS AND METHODS: Sixty healthy neonates were randomized by the sealed envelope method into two groups-Group F, in which blood was sampled from the forearm using the Free Style, and Group H, in which blood was conventionally sampled from the heel using a lancet. The pain intensity was assessed based on their crying, the Neonatal Facial Coding System (NFCS) and the Neonatal Infant Pain Scale (NIPS). RESULTS: After skin puncture, 12 (40%) of the infants cried in Group F and 27 (90%) in Group H. The duration of crying was also significantly shorter in Group F than in Group H. Both of pain scores between the two groups differed significantly, these findings indicated less pain for Group F. CONCLUSION: The new blood sampling method from the forearm was found to be less painful than the conventional method, thus making it possible to clinically use this product as an innovative method for blood sampling in neonatal medicine.

A case of recurrent encephalopathy with SCN2A missense mutation.

Voltage-gated sodium channels regulate neuronal excitability, as well as survival and the patterning of neuronal connectivity during development. Mutations in SCN2A, which encodes the Na(+) channel Nav1.2, cause epilepsy syndromes and predispose children to acute encephalopathy. Here, we report the case of a young male with recurrent acute encephalopathy who carried a novel missense mutation in the SCN2A gene. He was born by normal delivery and developed repetitive apneic episodes at 2days of age. Diffusion-weighted imaging revealed high-intensity areas in diffuse subcortical white matter, bilateral thalami, and basal nuclei. His symptoms improved gradually without any specific treatment, but he exhibited a motor milestone delay after the episode. At the age of 10months, he developed acute cerebellopathy associated with a respiratory syncytial viral infection. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy and seemed to have no obvious sequelae after the episode. He then developed severe diffuse encephalopathy associated with gastroenteritis at the age of 14months. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy but was left with severe neurological sequelae. PCR-based analysis revealed a novel de novo missense mutation, c.4979T>G (p.Leu1660Trp), in the SCN2A gene. This case suggests that SCN2A mutations might predispose children to repetitive encephalopathy with variable clinical and imaging findings.

Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures.

Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been identified in most patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2. In this study, we performed whole exome sequencing analysis for a large family affected with PRRT2-unrelated BPEI. We identified a non-synonymous single nucleotide variation (SNV) in the voltage-sensitive chloride channel 6 gene (CLCN6). A cohort study of 48 BPEI patients without PRRT2 mutations revealed a different CLCN6 SNV in a patient, his sibling and his father who had a history of febrile seizures (FS) but not BPEI. Another study of 48 patients with FS identified an additional SNV in CLCN6. Chloride channels (CLCs) are involved in a multitude of physiologic processes and some members of the CLC family have been linked to inherited diseases. However, a phenotypic correlation has not been confirmed for CLCN6. Although we could not detect significant biological effects linked to the identified CLCN6 SNVs, further studies should investigate potential CLCN6 variants that may underlie the genetic susceptibility to convulsive disorders.