Masanori Takeoka

Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders

Background: Segmental duplications at breakpoints (BP4–BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities. Patients: DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children’s Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository. Results: We report the clinical features of five patients with a BP4–BP5 deletion, three with a BP4–BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4–BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4–BP5 covers ∼1.5 Mb (chr15:28.719–30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover ∼500 kb (chr15:28.902–29.404 Mb) and contain three reference genes and one miRNA gene. The BP4–BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG. Conclusions: The phenotype of chromosome 15q13.2q13.3 BP4–BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.

Abnormal asymmetry in language association cortex in autism

Autism is a neurodevelopmental disorder affecting cognitive, language, and social functioning. Although language and social communication abnormalities are characteristic, prior structural imaging studies have not examined language‐related cortex in autistic and control subjects. Subjects included 16 boys with autism (aged 7–11 years), with nonverbal IQ greater than 80, and 15 age‐ and handedness‐matched controls. Magnetic resonance brain images were segmented into gray and white matter; cerebral cortex was parcellated into 48 gyral‐based divisions per hemisphere. Asymmetry was assessed a priori in language‐related inferior lateral frontal and posterior superior temporal regions and assessed post hoc in all regions to determine specificity of asymmetry abnormalities. Boys with autism had significant asymmetry reversal in frontal language‐related cortex: 27% larger on the right in autism and 17% larger on the left in controls. Only one additional region had significant asymmetry differences on post hoc analysis: posterior temporal fusiform gyrus (more left‐sided in autism), whereas adjacent fusiform gyrus and temporooccipital inferior temporal gyrus both approached significance (more right‐sided in autism). These inferior temporal regions are involved in visual face processing. In boys with autism, language and social/face processing–related regions displayed abnormal asymmetry. These structural abnormalities may relate to language and social disturbances observed in autism.

Exercise Effects on Methylation of ASC Gene

Chronic moderate exercise has been reported to reduce pro-inflammatory cytokines. To analyze the molecular mechanisms by which training exerts these effects, the epigenetic influences of age and exercise on the ASC gene, which is responsible for IL-1beta and IL-18 secretion, were investigated by ASC gene methylation. Further, the relationship between carcinogenesis and exercise, and methylation of the P15 tumor suppressive gene was also analyzed. High-intensity interval walking exercise, consisting of 3 min low-intensity walking at 40% of peak aerobic capacity followed by a 3 min high-intensity walking period above 70% of peak aerobic capacity, was continued for 6 months. Peripheral blood DNA extracts from young control (n=34), older control (n=153), and older exercise (n=230) groups were then analyzed by pyrosequencing for DNA methylation. Methylation of ASC decreased significantly with age (young control vs. older control, p<0.01), which is indicative of an age-dependent increase in ASC expression. Compared to the older control group, the degree of ASC methylation was higher in the older exercise group (older control vs. older exercise: p<0.01), and presumably lower ASC expression. Neither exercise nor age affected the methylation of the P15. In summary, chronic moderate exercise appears to attenuate the age-dependent decrease in ASC methylation, implying suppression of excess pro-inflammatory cytokines through reduction of ASC expression.

Copy number variation plays an important role in clinical epilepsy

To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center.

Repetitive transcranial magnetic stimulation in the treatment of epilepsia partialis continua

OBJECTIVE Repetitive transcranial magnetic stimulation (rTMS) is a technique for noninvasive focal brain stimulation by which small intracranial electrical currents are generated by a fluctuating extracranial magnetic field. In clinical epilepsy, rTMS has been applied most often interictally to reduce seizure frequency. Less often, rTMS has been used to terminate ongoing seizures, as in instances of epilepsia partialis continua (EPC). Whether ictal rTMS is effective and safe in the treatment of EPC has not been extensively studied. Here, we describe our recent experience with rTMS in the treatment of EPC, as an early step toward evaluating the safety and efficacy of rTMS in the treatment of intractable ongoing focal seizures. METHODS Seven patients with EPC of mixed etiologies were treated with rTMS applied over the seizure. rTMS was delivered in high-frequency (20-100 Hz) bursts or as prolonged low-frequency (1 Hz) trains. The EEG was recorded for three of the seven patients. RESULTS rTMS resulted in a brief (20-30 min) pause in seizures in three of seven patients and a lasting (>or=1 day) pause in two of seven. A literature search identified six additional reports of EPC treated with rTMS where seizures were suppressed in three of six. Seizures were not exacerbated by rTMS in any patient. Generally mild side effects included transient head and limb pain, and limb stiffening during high-frequency rTMS trains. CONCLUSIONS Our clinical observations in a small number of patients suggest that rTMS may be safe and effective in suppressing ongoing seizures associated with EPC. However, a controlled trial is needed to assess the safety and anticonvulsive efficacy of rTMS in the treatment of EPC.

Topiramate and Metabolic Acidosis in Pediatric Epilepsy

Summary:  Purpose: Topiramate (TPM) has been widely used as an adjunctive therapy for treating epilepsy. TPM is reported to have multiple mechanisms of action, including inhibition of carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate (HCO3‐).

Infectious and inflammatory disorders of the circulatory system and stroke in childhood

The role of infectious and inflammatory causes of stroke is much more significant in children than in adults. Conversely, that of atherosclerotic disease, ischaemic heart disease and hypertensive haemorrhages has a lesser prominence in children. Bacterial meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae, or Neiserria meningitidis has been known to cause stroke in children. The mechanism appears to be the spread of meningeal inflammation to involve the walls of intracranial vessels, resulting in arterial thrombosis with ischaemia or rupture with haemorrhage. Other infections caused by atypical bacterial agents such as Mycoplasma tuberculosis and viral agents such as varicella-zoster virus have also been well documented as causes of stroke. Non-infectious, inflammatory causes of stroke, such as collagen vascular disease and primary angiitis of the central nervous system, have been reported in children as well as adults. In this review, we will focus on recent advances in the field of childhood stroke caused by infectious and inflammatory disorders.

Experience with lacosamide in a series of children with drug-resistant focal epilepsy

We report our pediatric experience with lacosamide, a new antiepileptic drug, approved by the US Food and Drug Administration as adjunctive therapy in focal epilepsy in patients more than 17 years old. We retrospectively reviewed charts for lacosamide use and seizure frequency outcome in patients with focal epilepsy (Wilcoxon signed rank test). Sixteen patients (7 boys) were identified (median dose 275 mg daily, 4.7 mg/kg daily; mean age 14.9 years, range 8-21 years). Patients were receiving a median of 2 antiepileptic drugs (interquartile range [IQR] 1.7-3) in addition to having undergone previous epilepsy surgery (n=3), vagus nerve stimulation (n=9), and ketogenic diet (n=3). Causes included structural (encephalomalacia and diffuse encephalitis, 1 each; stroke in 2) and genetic abnormalities (Aarskog and Rett syndromes, 1 each) or cause not known (n=10). Median seizure frequency at baseline was 57 per month (IQR 7-75), and after a median follow-up of 4 months (range 1-13 months) of receiving lacosamide, it was 12.5 per month (IQR 3-75), (P<0.01). Six patients (37.5%; 3 seizure free) were classified as having disease that responded to therapy (≥50% reduction seizure frequency) and 10 as having disease that did not respond to therapy (<50% in 3; increase in 1; unchanged in 6). Adverse events (tics, behavioral disturbance, seizure worsening, and depression with suicidal ideation in 1 patient each) prompted lacosamide discontinuation in 4/16 (25%). This retrospective study of 16 children with drug-resistant focal epilepsy demonstrated good response to adjunctive lacosamide therapy (median seizure reduction of 39.6%; 37.5% with ≥50% seizure reduction) without severe adverse events.

Concomitant Treatment with Topiramate and Ketogenic Diet in Pediatric Epilepsy

Summary:  Purpose: Topiramate (TPM) is widely used as add‐on therapy for epilepsy. TPM inhibits carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate. The ketogenic diet (KGD) predisposes patients to metabolic acidosis, especially during induction. In children with refractory epilepsy, cotreatment with TPM and KGD may be considered, but special attention should be paid to the combined risks for metabolic acidosis and nephrolithiasis. We report our experience in 14 children cotreated with TPM and the KGD.

Diffusion-Weighted Imaging in Neonatal Cerebral Infarction: Clinical Utility and Follow-Up

We describe the clinical utility of echo-planar diffusion-weighted imaging in neonatal cerebral infarction. Eight full-term neonates aged 1 to 8 days referred for neonatal seizures were studied. Patients were followed for a mean of 17 months with detailed neurologic examinations at regular intervals. Head computed tomography (CT) and conventional magnetic resonance (MRI) and diffusion-weighted images were obtained. Percent lesion contrast was evaluated for 19 lesions on T 2-weighted and diffusion-weighted images. Follow-up conventional MRIs were obtained in seven patients. The findings on diffusion-weighted imaging were correlated with CT and conventional MRI findings as well as with short-term neuro-developmental outcome. Four patients had focal cerebral infarctions. Four patients had diffuse injury consistent with hypoxic-ischemic encephalopathy. Percent lesion contrast of all 19 lesions was significantly higher on diffusion-weighted images when compared with T2-weighted images. In five patients, there were lesions visualized only with diffusion-weighted imaging. In all patients, there was increased lesion conspicuity and better definition of lesion extent on the diffusion-weighted images compared with the CT and T 2-weighted MR images. In seven of eight patients follow-up imaging confirmed prior infarctions. Short-term neurologic outcome correlated with the extent of injury seen on the initial diffusion-weighted imaging scans for all patients. Diffusion-weighted imaging is useful in the evaluation of acute ischemic brain injury and seizure etiology in neonates. In the acute setting, diffusion-weighted imaging provides information not available on CT and conventional MRI. This information correlates with short-term clinical outcome. (J Child Neurol 2000;15:592-602).