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.

Paroxysmal nonepileptic events in children with epilepsy.

OBJECTIVE: The aim of this study was to clarify the characteristics of paroxysmal nonepileptic events (PNEs) suspected as being epileptic seizures by families of children with epilepsy. METHODS: The video-EEG (vEEG) recordings of habitual paroxysmal events in children with epilepsy at Nagoya University Hospital between October 2006 and January 2016 were reviewed. Based on the doctor's suspicion before the vEEG, the PNEs were divided into two groups that included PNEs suspected as epileptic seizures and PNEs suspected as PNEs. PNEs in the former group were classified based on the suspected seizure type. RESULTS: Of 886 habitual paroxysmal events, vEEG confirmed that 83 events (68 children) were PNEs. The median age of the 68 children was 3.2 years. Concurrent epilepsies included focal epilepsies (n=33), infantile spasms (n=16), and other types (n=19). The most common types of PNEs were sleep myoclonus (n=11), followed by stereotypies (n=9), awake myoclonus (n=8), paroxysmal ocular deviations (PODs, n=8), and tonic posturing (n=8). Even after direct observation or video viewing, the doctors suspected epileptic seizures in all three of the PODs and two of the tonic posturing children. Before the vEEG, however, the accurate visual information led to the speculation that the four psychogenic and two sleep myoclonus events were all PNEs. Myoclonus, stereotypies, and head drops were often misdiagnosed as epileptic spasms, while PODs and tonic posturing were often misdiagnosed as focal seizures with motor components. Additionally, staring and motion arrest during a drowsy state were often misdiagnosed as focal dyscognitive seizures. Seven of eight patients with PODs had epileptic spasms that were concurrent with epileptic seizures. A diffuse cerebral lesion or reduced visual acuity was seen in seven patients with PODs. CONCLUSION: We re-emphasize that vEEG is essential for accurate diagnosis and provides evidence for listing POD in the differential diagnosis of oculomotor paroxysmal events.

The effects of co-medications on lamotrigine clearance in Japanese children with epilepsy.

PURPOSE: Although it has been reported that some antiepileptic drugs have inducing or inhibiting effects on lamotrigine (LTG) clearance, whether they have the same effects in Asian epilepsy patients as in those in other countries has not been clarified, especially in children. The aim of this study was to determine the effects of co-medications on LTG clearance in Japanese children with epilepsy. METHODS: A total of 342 routine serum concentration measurements of LTG in 102 Japanese epilepsy patients under 20years of age were reviewed. The dose-corrected concentration (DCC) of LTG was calculated as [concentration]/[dose/(body weight)], and the DCC of LTG was compared by co-medication. The difference in the DCC of LTG was compared between patients with and without valproic acid (VPA) and between those with and without drugs inducing glucuronic acid conjugation (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB)). RESULTS: The DCC of LTG was significantly higher in patients on VPA and significantly lower in patients on drugs inducing glucuronic acid conjugation than in patients on LTG monotherapy. The DCC of LTG was significantly higher in patients on CBZ than in patients on PHT or PB. There was no correlation between the DCC of LTG and the concentration of VPA or metabolic inducers within the therapeutic range. Other antiepileptic drugs including clobazam, clonazepam, zonisamide, and levetiracetam had little effect on LTG concentration. CONCLUSION: LTG concentration changes dramatically with concomitant antiepileptic drugs in Japanese children, as previously reported from other countries, and special attention is required. Although the dose of LTG should be adjusted when starting or discontinuing VPA or metabolic inducers, no adjustment is needed when changing the dose of VPA or metabolic inducers in the therapeutic range.

Seizure characteristics of epilepsy in childhood after acute encephalopathy with biphasic seizures and late reduced diffusion.

OBJECTIVE: The aim of this study was to clarify characteristics of post-encephalopathic epilepsy (PEE) in children after acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), paying particular attention to precise diagnosis of seizure types. METHODS: Among 262 children with acute encephalopathy/encephalitis registered in a database of the Tokai Pediatric Neurology Society between 2005 and 2012, 44 were diagnosed with AESD according to the clinical course and magnetic resonance imaging (MRI) findings and were included in this study. Medical records were reviewed to investigate clinical data, MRI findings, neurologic outcomes, and presence or absence of PEE. Seizure types of PEE were determined by both clinical observation by pediatric neurologists and ictal video-electroencephalography (EEG) recordings. RESULTS: Of the 44 patients after AESD, 10 (23%) had PEE. The period between the onset of encephalopathy and PEE ranged from 2 to 39 months (median 8.5 months). Cognitive impairment was more severe in patients with PEE than in those without. Biphasic seizures and status epilepticus during the acute phase of encephalopathy did not influence the risk of PEE. The most common seizure type of PEE on clinical observation was focal seizures (n = 5), followed by epileptic spasms (n = 4), myoclonic seizures (n = 3), and tonic seizures (n = 2). In six patients with PEE, seizures were induced by sudden unexpected sounds. Seizure types confirmed by ictal video-EEG recordings were epileptic spasms and focal seizures with frontal onset, and all focal seizures were startle seizures induced by sudden acoustic stimulation. Intractable daily seizures remain in six patients with PEE. SIGNIFICANCE: We demonstrate seizure characteristics of PEE in children after AESD. Epileptic spasms and startle focal seizures are common seizure types. The specific seizure types may be determined by the pattern of diffuse subcortical white matter injury in AESD and age-dependent reorganization of the brain network.

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.

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.

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.

Characteristics of epilepsy occurring in the first four months.

INTRODUCTION: Epilepsies with an onset during the early infantile period are relatively rare and their characteristics are not well recognized. The aim of this study was to determine the clinical characteristics of epilepsies with an onset during the early infantile period. METHODS: Clinical information on 73 patients with the onset of epilepsy within the first four months was collected from hospitals affiliated with Nagoya University. Patients were categorized into three groups: the idiopathic (20 patients), cryptogenic (19 patients), and symptomatic groups (34 patients). RESULTS: Fourteen (70%) of the 20 patients in the idiopathic group, nine (47%) of the 19 patients in the cryptogenic group, and 10 (29%) of the 34 patients in the symptomatic group had their first seizure within the first month of life. All patients in the idiopathic group, 12 patients (63%) in the cryptogenic group, and 18 patients (53%) in the symptomatic group had partial seizures (PS) alone throughout their clinical course. Four patients in the cryptogenic group and nine in the symptomatic group had PS at the onset, but evolved into spasms later. All patients in the idiopathic group, 13 patients (68%) in the cryptogenic group, and 13 patients (38%) in symptomatic group had experienced no seizures for at least one year at the time of the last follow-up. CONCLUSIONS: In patients with non-idiopathic epilepsy, an age-dependent evolution of seizure types was often observed. Recognition of this subgroup of patients could be important for the identification of appropriate candidates for early epilepsy surgery.

[The relationship between the severity of periventricular leukomalacia and the fractional anisotropy values of diffusion tensor imaging].

OBJECTIVE: We performed diffusion tensor imaging (DTI) in children with periventricular leukomalacia (PVL) to quantify the relationship between the fractional anisotropy (FA) values of DTI and the severity of PVL. METHODS: In this study, we performed DTI in 16 children (seven males, nine females) with PVL. To evaluate the FA values, we used region-of-interest (ROI) measurements and tractography-based measurements. We classified the patients into two groups based on the severity of the magnetic resonance imaging (MRI) findings: the mild group had white matter injury limited to a triangular zone around the lateral ventricle (n = 9) and the severe group had it extended forward (n = 7). Then, we performed ROI measurements for these two groups to evaluate the FA values. We also divided the patients into two groups based on their motor ability :those that could (n = 10) and could not (n = 6) stand. We used tractography-based measurements to evaluate the FA values. To reduce the bias caused by age, we divided the patients into two groups: those younger than 3 years and those 3 years of age and older. All data were analyzed using the Mann-Whitney U-test, and p < 0.05 was considered statistically significant. RESULTS: In the ROI measurements, regardless of age, the severe group showed a more significant FA reduction in the white matter of the parietal and occipital lobes, including the middle/posterior part of the centrum ovale, superior longitudinal fasciculus, arcuate fascicullus, and thalamic radiation. In the tractography-based measurements, regardless of age, the measured FA values were significantly lower in the group that could not stand. CONCLUSIONS: This study suggested that the measured FA values could be used to evaluate the severity of PVL quantitatively, and that DTI provides much more information for understanding the pathophysiology of PVL, as compared with conventional MRI.

Efficacy of a diazepam suppository at preventing febrile seizure recurrence during a single febrile illness.

PURPOSE: To assess the efficacy of diazepam suppositories at preventing febrile seizure recurrence during a single febrile illness to determine how to treat children with a febrile seizure on presentation at the hospital. METHODS: We studied 203 children with febrile seizures from December 2004 through March 2006. On admission between December 2004 and May 2005, a diazepam suppository was administered to the patients. Patients seen between June 2005 and March 2006 were not treated with antiepileptic drugs on admission. RESULTS: We saw a significant difference in the rate of recurrence of febrile seizures between children treated with diazepam and those who were not. Recurrences were observed in 2 (2.1%) of 95 children treated with diazepam and in 16 (14.8%) of 108 untreated children. For the 108 untreated patients, the median age was 22.8 months in those with recurrences and 30.6 months in those without, confirming that a younger age was related to a recurrence. CONCLUSIONS: A diazepam suppository after a febrile seizure will reduce the incidence of recurrent febrile seizures during the same febrile illness. However, a diazepam suppository after a febrile seizure should be used after carefully considering the benefits and potential adverse effects.

Dyschromatosis symmetrica hereditaria associated with neurological disorders.

Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis of autosomal dominant inheritance caused by a mutation of adenosine deaminase acting on the RNA 1 gene (ADAR1). It is characterized by a mixture of hyper- and hypopigmented macules on the back of the hands and feet. The pathomechanism by which the ADAR1 gene mutation induces DSH has not been clarified yet. We experienced an 11-year-old male DSH patient associated with dystonia, mental deterioration and brain calcification, who had a mutation of p.G1007R in the ADAR1 gene. This mutation had already been reported in a patient with similar neurological symptoms by Tojo et al. Additionally, a patient with DSH associated with torsion dystonia was reported by Patrizi et al., but gene analysis was not carried out. Only three cases with neurological disorders have been reported, although more than 50 mutations of the ADAR1 gene causing DSH have been reported and none of them had any neurological symptoms. Therefore, we suggest that neurological disorders rarely develop in DSH.

[Drug-induced hypersensitivity due to phenytoin].

This study aimed to clarify factors associated with intravenous administered phenytoin-induced hypersensitivity reaction. The incidence of hypersensitivity was significantly more frequent in boys than in girls (P < 0.05). Patients with hypersensitivity were relatively younger than those without hypersensitivity, although the difference was not statistically significant. There was no relation between the initial dose or maximum blood level of phenytoin and the occurrence of hypersensitivity. The initial serum level of phenytoin was significantly lower in patients with hypersensitivity than in those without hypersensitivity (P < 0.05), whereas the total dose of phenytoin was relatively larger in patients with hypersensitivity than those without. Reactivation of human herpes virus-6 was not recognized in all 3 patients in whom virological examination was performed using real-time polymerase chain reaction.

Brain malformation of the surviving twin of intrauterine co-twin demise.

The authors report the case of a surviving twin patient with severe brain malformation due to intrauterine fetal demise of the other twin. The patient was a boy with 37 weeks of gestational age. Intrauterine death of the co-twin was discovered at 18 weeks of gestation. No major anomalies were recognized at birth except for microcephalus. Magnetic resonance imaging demonstrated wide sylvian fissures, bilateral ventriculomegaly, and smooth brain surface of the temporoparieto-occipital lobes. He had spastic quadriplegia and severe mental retardation. Brief tonic seizures appeared at 7 months of age. Clonazepam was administered, and seizures disappeared at 24 months of age. Complex partial seizures began at 8 years of age. Seizures were observed weekly despite treatment with carbamazepine. The malformation of our patient was considered to be a result of a mixture of destructive process and disorders of neuronal proliferation and migration.

Transient hypogammaglobulinemia after antiepileptic drug hypersensitivity.

The case is described of a 32-month-old male with transient but long-lasting severe hypogammaglobulinemia subsequent to multiple drug hypersensitivity. The patient had remarkably decreased immunoglobulin levels (IgG 136 mg/dL, IgA 11 mg/dL, and IgM 10 mg/dL) 3 months after hypersensitivity to phenobarbital and phenytoin. Immunological study revealed reduction of B-cell count and decreased lymphocyte proliferation response to Staphylococcus aureus Cowan. IgM secretory response to pokeweed mitogen and S. aureus Cowan was almost preserved, whereas IgG secretory response was markedly decreased. The patient was treated with intravenous immunoglobulin, although recurrent infection was not observed before treatment. His immunoglobulin levels became normal more than 5 years after the onset of hypogammaglobulinemia.

Phenytoin desensitization monitored by antigen specific T cell response using carboxyfluorescein succinimidyl ester dilution assay.

We evaluated drug-specific T cell responses in a patient with refractory partial seizures and paroxysmal kinesigenic choreoathetosis successfully treated with clinical desensitization to phenytoin. Drug-induced lymphocyte transformation test before desensitization was negative with a stimulation index of 130%. The frequencies and cytokine-producing phenotypes of phenytoin-specific T cells were examined simultaneously by using a carboxyfluorescein succinimidyl ester (CFSE) dilution assay. Before desensitization, the proportion of CFSElow CD4+ cells in whole CD4+ was 3.09%; 13.6% of CFSElow CD4+ cells were stained with anti-interferon gamma antibody. After desensitization, phenytoin-specific CFSElow CD4+ cells decreased to background level. These results indicate that CFSE dilution assay will be useful for the diagnosis and monitoring of drug hypersensitivity.

Transient splenial lesions in children with "benign convulsions with gastroenteritis".

"Benign convulsions with mild gastroenteritis (CwG)" is recognized as a benign situation-related seizure. Neuroimaging studies usually do not reveal any abnormalities. We report MRI diffusion-weighted image (DWI) findings of two patients who were clinically diagnosed with CwG. DWI demonstrated a transient abnormality in the splenium of the corpus callosum. Although viral encephalitis or encephalopathy should be carefully differentiated in patients clinically diagnosed with CwG, frequent seizures might cause transient splenial abnormality in patients with CwG.

Phenytoin desensitization in a child with symptomatic localization-related epilepsy.

We reported a child with refractory partial seizures successfully managed by clinical desensitization to phenytoin. The patient had ischemic brain lesions due to cardiopulmonary arrest at 39 weeks of corrected age. He had complex partial seizures refractory to several antiepileptic drugs since 4 years of age. At 8 years 1 month of age, phenytoin was first administered. Fever and maculopapular rashes appeared at 10 days after phenytoin initiation, and then the drug was discontinued. At 8 years 8 months of age, desensitization was attempted because of refractoriness of seizures to drugs other than phenytoin. Desensitization was started at 1mg daily, and then the dose was doubled every week. His seizures were controlled by 150mg/day of phenytoin in combination with primidone. No problems have been observed during desensitization.

Ictal EEG in benign partial epilepsy in infancy.

The aim of this study is to further clarify ictal electroencephalographic findings of patients with benign partial epilepsy in infancy in order to better understand its neurophysiologic features. The study group consisted of 13 infants with definite benign partial epilepsy in infancy, in whom ictal electroencephalograms were recorded and its benignity was confirmed at 8 years or more. The seizure manifestation was reviewed on the basis of video findings in eight patients in whom simultaneous video-electroencephalography recording was available. In the other five patients, the seizure manifestations were determined according to the observations of physicians, nurses, or technicians. Thirteen seizures from eight patients were complex partial, and six seizures from six patients were secondarily generalized ones. Ictal discharges at the onset of a seizure were focal in all seizures. The site of the origin of seizures was in the temporal area in 10 of 13 complex partial seizures, whereas it was in the parietal or occipital area in all 6 secondarily generalized seizures. Among 13 complex partial seizures, paroxysmal discharges remained focal throughout the seizures in 6 seizures, whereas they spread to one hemisphere in the other 7 seizures. Motion arrest or decreased responsiveness was uniformly observed. Lateral eye deviation was commonly recognized in complex partial seizures, whereas head rotation was observed only in seizures in which hemispheric propagation of ictal discharges was observed. Ictal electroencephalographic findings of patients with benign partial epilepsy in infancy were relatively uniform, suggesting the homogeneity of patients with benign partial epilepsy in infancy.