Publications by authors named "Rumiko Takayama"

39 Publications

HPeV3-associated acute encephalitis/encephalopathy among Japanese infants.

Brain Dev 2021 Apr 8;43(4):528-537. Epub 2021 Jan 8.

Department of Pediatrics, Saitama Medical University, Saitama, Japan.

Objective: The current study aimed to identify and compare the clinical characteristics of human parechovirus type 3 (HPeV3)-associated acute encephalitis/encephalopathy (HPeV3E/E) between infants with abnormal brain magnetic resonance imaging (MRI) findings (typical, or MRI-positive HPeV3E/E) and those with MRI-negative findings (MRI-negative HPeV3E/E).

Methods: This is a retrospective study on patients with HPeV3 infection, and a two-step questionnaire survey performed on 837 hospitals in Japan between 2014 and 2016.

Results: We identified 240 infants with HPeV3 infection, of which 34 had been clinically-diagnosed HPeV3E/E (cHPeV3E/E). However, detailed clinical data were provided by 32 of the 34 patients. Among these 32, 23 had undergone MRI and were categorized into two groups, MRI-positive (n = 17) and -negative (n = 6). There were no significant intergroup differences in clinical lab results or symptoms, except for gastrointestinal symptoms that were only present in the MRI-negative patients. The MRI-positive group showed white matter involvement on brain MRI during the acute phase, and 8 patients presented with lesions on follow-up MRI. Furthermore, 4 (50%) of the 8 patients had neurological sequelae.

Conclusion: Clinical characteristics of cHPeV3E/E patients with and without lesions on brain MRI showed no significant differences. Therefore, considering the difficulty in distinguishing febrile infants with cHPeV3E/E from those with a sepsis-like illness, during an HPeV3 infection epidemic, it is imperative to frequently perform brain MRI in febrile infants presenting with severe disease for the early diagnosis of HPeV3E/E presenting with brain lesions.
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http://dx.doi.org/10.1016/j.braindev.2020.12.010DOI Listing
April 2021

Effect of total callosotomy on KCNQ2-related intractable epilepsy.

Brain Dev 2020 Sep 9;42(8):612-616. Epub 2020 Jun 9.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-2606, Japan.

Aim: To describe beneficial effects of callosotomy on KCNQ2-related intractable epilepsy.

Case Report: Our patient was a 10-year-old girl who had developed epilepsy during the neonatal period, accompanied by a suppression-burst pattern on the electroencephalography (EEG). The patient showed profound psychomotor developmental delay since early infancy. Daily seizures of versive posturing and ocular deviation were transiently controlled by carbamazepine and valproate at the age of 1 year; however, the seizures gradually increased to up to 50 times per day. Ictal EEG and positron emission tomography revealed an epileptic focus in the left frontal lobe at age 5 years. Total callosotomy resulted in marked reduction of epileptic seizures thereafter, as well as improved responses to external auditory and visual stimuli. Whole exome sequencing at age 9 identified a de novo missense variant in KCNQ2 (NM_172107.3:c.563A > C:p.(Gln188Pro)).

Conclusion: This case supports that epilepsy surgery could benefit children with epileptic encephalopathy, even with the etiology of channelopathy.
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http://dx.doi.org/10.1016/j.braindev.2020.05.005DOI Listing
September 2020

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Nat Commun 2019 06 7;10(1):2506. Epub 2019 Jun 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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http://dx.doi.org/10.1038/s41467-019-10482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845PMC
June 2019

Risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia.

Brain Dev 2019 Jan 31;41(1):77-84. Epub 2018 Jul 31.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, NHO, Shizuoka, Japan.

Objective: The purpose of this study was to identify the risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia (FCD).

Methods: 77 patients with histopathologically confirmed FCD were studied. The statistical relationship between cognition levels and clinical factors at presurgical evaluation was analyzed. Cognitive function was evaluated by development quotient or intelligence quotient (DQ-IQ).

Results: Ages at seizure onset were younger than 15 years (mean ± SD; 5.0 ± 4.2 years). Mean disease duration was 14.5 ± 8.5 years. Mean age at pre-surgical DQ-IQ evaluation was 34.8 ± 10.7 years. Mean DQ-IQ was 60.5 ± 20.5, and 41 of 77 (53.2%) patients had mental retardation (DQ-IQ < 70). Younger seizure onset and seizure clustering were significantly associated with lower DQ-IQ (p < 0.001). A multiple regression study identified higher seizure frequency pattern, a history of epileptic spasm and status epilepticus as aggravating factors of DQ-IQ decline (R = 0.63, p < 0.001). On the other hand, the risk was decreased in patients with habitual focal aware seizure and transient seizure-free periods up to 6 months in the course of epilepsy. FCD location (FCD site, extent of radiological lesion and laterality) and histopathology of FCD did not affect DQ-IQ.

Conclusions: Our study suggests that seizure characteristics including higher seizure frequency pattern, a history of epileptic spasm, status epilepticus, seizure clustering and early onset of seizure are risk factors of cognitive impairment in FCD patients.
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http://dx.doi.org/10.1016/j.braindev.2018.07.014DOI Listing
January 2019

Successful hemispherotomy in two refractory epilepsy patients with cerebral hemiatrophy and contralateral EEG abnormalities.

Brain Dev 2018 Aug 15;40(7):601-606. Epub 2018 Mar 15.

Department of Psychiatry, National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Japan.

We describe two cases of refractory epilepsy with cerebral hemiatrophy and contralateral electroencephalographic (EEG) abnormalities, in which hemispherotomy of the atrophic hemisphere effectively controlled seizures. Case 1 was a 5-year-1-month-old girl with refractory bilateral asymmetrical tonic posturing seizures predominantly in the right arm. Magnetic resonance imaging showed left porencephaly corresponding to a left middle cerebral artery infarction. Case 2 was a 3-year-8-month-old boy with refractory bilateral asymmetrical tonic posturing seizures predominantly in the right arm due to atrophy of the left cerebral hemisphere after septic meningitis. Both patients had right hemiparesis and was incapable of pinching by the right hand. Contralateral interictal and ictal EEG abnormalities were observed. Interictal Tc-ethyl cysteinate dimer (Tc-ECD) single photon emission computed tomography (SPECT) showed hypoperfusion and ictal Tc-ECD-SPECT showed hyperperfusion within the left cerebral hemisphere. Left hemispherotomy was performed. Cases 1 and 2 remained seizure-free at the last follow-up 18 months and 15 months, respectively, after surgery, and contralateral interictal EEG abnormalities disappeared. In patients with cerebral hemiatrophy and contralateral EEG abnormalities, epilepsy surgery may be considered when the laterality of seizure semiology, functional imaging findings and motor deficits were concordant with the atrophic side. Ictal SPECT is effective to confirm the epileptogenic hemisphere.
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http://dx.doi.org/10.1016/j.braindev.2018.02.014DOI Listing
August 2018

Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination.

J Neuroimmunol 2016 09 7;298:71-8. Epub 2016 Jul 7.

Department of Pediatrics, JA Toride Medical Center, 2-1-1, Hongo, Toride, Japan. Electronic address:

In 32 patients with prolonged central nervous system symptoms after human papillomavirus (HPV) vaccination, we measured conventional and immunological markers in cerebrospinal fluid (CSF) and compared with the levels in disease controls. Our studies revealed significantly decreased chloride and neuron-specific enolase (NSE) levels in CSF of patients with CNS symptoms after HPV vaccination compared to disease controls. IL-4, IL-13, and CD4(+) T cells increased significantly in patients, and IL-17 increased significantly from 12 to 24months after symptom onset. Chemokines (IL-8 and MCP-1) were also elevated, but CD8(+) T cells, PDGF-bb and IL-12 were reduced. Antibodies to GluN2B-NT2, GluN2B-CT and GluN1-NT increased significantly. These results suggest biological, mainly immunological, changes in the CSF of patients after HPV vaccination.
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http://dx.doi.org/10.1016/j.jneuroim.2016.07.003DOI Listing
September 2016

Short-term efficacy and safety of rufinamide for Lennox-Gastaut syndrome.

No To Hattatsu 2016 09;48(5):322-6

Objective: We examined the short-term efficacy and safety of rufinamide (RFN) in patients with Lennox-Gastaut syndrome (LGS). Methods: We performed a retrospective review of clinical records of patients with LGS who started RFN treatment between July 2013 and June 2014 at the Hokkaido Medical Center for Child Health and Rehabilitation and Midorigaoka Ryo-iku-en. Efficacy and safety were evaluated when the patients had completed three months of treatment. Patients were classified into four categories according to percent seizure reduction : remission (seizure-free), response (seizure reduction≥50%), no change (seizure reduction<50% or increase) and aggravation (seizure increase≥50%). Responder rate (RR) was the percentage of patients with≥50% decrease in seizure frequency. Results: Thirteen LGS patients (8 males, 5 females) were studied. The efficacy for tonic seizures (13 patients) was remission 1 patient, response 3 patients, no change 8 patients and aggravation 1 patient, with RR of 30.8%. Two patients discontinued LGS due to seizure aggravation. Four patients experienced transient remission. For generalized tonic clonic seizures (2 patients), 1 patient achieved remission and 1 patient showed no change. Two patients of atonic seizures showed no change. Of 2 patients of atypical absence, 1 patient showed response and 1 patient no change. Eight patients had adverse effects such as somnolence (6 patients), sleep disturbance (1 patient), and appetite loss (4 patients) including weight loss in 2 patients. There were no severe adverse effects and no discontinuation due to adverse effects. Conclusions: Short-term effectiveness for tonic seizures was observed when patients with LGS were treated with RFN, with transient remission in some patients. We consider that RFN is worth trying in patients with LGS due to its efficacy for tonic seizures and absence of severe adverse effects.
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September 2016

Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.

Ann Clin Transl Neurol 2016 Mar 2;3(3):200-15. Epub 2016 Feb 2.

Tokyo Metropolitan Institute of Medical Science Tokyo Japan.

Objective: Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme-replacement and substrate-reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD.

Methods: This open-label pilot study included five patients who received high-dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies.

Results: High-dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood-brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again.

Interpretation: Pharmacological chaperone therapy with high-dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.
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http://dx.doi.org/10.1002/acn3.292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774255PMC
March 2016

Long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome receiving adjunctive rufinamide therapy: An open-label study following a randomized clinical trial.

Epilepsy Res 2016 Mar 12;121:1-7. Epub 2016 Jan 12.

Department of Pediatrics, Hiroshima City Hospital, 7-33 Motomachi, Naka-ku, Hiroshima 730-8518, Japan.

Purpose: To evaluate the long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive rufinamide therapy.

Subjects And Methods: We conducted an open-label extension study following a 12-week multicenter, randomized, double-blind, placebo-controlled study of adjunctive rufinamide therapy in Japanese patients with LGS. Fifty-four patients participated in the extension study. Seizure frequency was evaluated until 52 weeks after the start of the extension study. Adverse events (AEs) were evaluated throughout both studies.

Key Findings: Of the 54 patients, 41 (75.9%) completed the extension study. The median duration of exposure to rufinamide was 818.0 days in all 54 patients, and 38 patients (70.4%) received rufinamide for 2 years or more. The median percent change in the frequency of tonic-atonic seizures relative to the frequency at the start of the double-blind study was -39.3% (12 weeks), -40.6% (24 weeks), -46.8% (32 weeks), -47.6% (40 weeks), and -36.1% (52 weeks). Reduction of total seizure frequency was also maintained until 52 weeks. Frequent treatment-related AEs were somnolence (20.4%), decreased appetite (16.7%), transient seizure aggravation including status epilepticus (13.0%), vomiting (11.1%), and constipation (11.1%). Adverse events were mild or moderate, except for transient seizure aggravation in three patients. Adverse events resulting in discontinuation of rufinamide were decreased appetite, drug eruption, and worsening of underlying autism. When clinically notable weight loss was defined as a decrease ≥ 7% relative to baseline, 22 patients (40.7%) experienced weight loss at least once during long-term observation, although weight loss was reported as an AE in only three patients.

Significance: This study demonstrated a long-term benefit of rufinamide as adjunctive therapy for Japanese patients with LGS. Exacerbation of seizures and decreased appetite/weight loss should be monitored carefully.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.01.002DOI Listing
March 2016

Loss-of-function mutations of STXBP1 in patients with epileptic encephalopathy.

Brain Dev 2016 Mar 16;38(3):280-4. Epub 2015 Sep 16.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.

Epileptic encephalopathy, which commences during early infancy, is a severe epileptic syndrome that manifests as age-dependent seizures and severe developmental delay. The syntaxin-binding protein 1 gene (STXBP1) is one of the genes responsible for epileptic encephalopathy. We conducted a cohort study to analyze STXBP1 in 42 patients with epileptic encephalopathy. We identified four novel mutations: two splicing mutations, a frameshift mutation, and a nonsense mutation. All of these mutations were predicted to cause loss-of-function. This result suggests loss-of-function is a common mechanism underlying STXBP1-related epileptic encephalopathy. The four patients showed epileptic features consistent with STXBP1-related epileptic encephalopathy, but showed variable radiological findings, including brain volume loss and myelination delay.
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http://dx.doi.org/10.1016/j.braindev.2015.09.004DOI Listing
March 2016

Recurrent occurrences of CDKL5 mutations in patients with epileptic encephalopathy.

Hum Genome Var 2015 5;2:15042. Epub 2015 Nov 5.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders , Shizuoka, Japan.

The cyclin-dependent kinase-like 5 gene (CDKL5) is recognized as one of the genes responsible for epileptic encephalopathy. We identified CDKL5 mutations in five Japanese patients (one male and four female) with epileptic encephalopathy. Although all mutations were of de novo origin, they were located in the same positions as previously reported pathogenic mutations. These recurrent occurrences of de novo mutations in the same loci may indicate hot spots of nucleotide alteration.
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http://dx.doi.org/10.1038/hgv.2015.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785533PMC
April 2016

Paroxysmal tonic upward gaze complicating Angelman syndrome.

Pediatr Neurol 2015 Jan 4;52(1):125-7. Epub 2014 Sep 4.

Department of Pediatrics, School of Medicine, Sapporo Medical University, Sapporo, Japan.

Background: Paroxysmal tonic upward gaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis is unknown, and the etiology is heterogeneous.

Patient Description: We describe a 2-year-old girl with Angelman syndrome who developed paroxysmal tonic upward gaze at 9 months of age. She presented with developmental delay, blond hair, jerky movements, ataxia, and epilepsy. Genetic testing revealed a maternal deletion of 15q11-13, confirming Angelman syndrome.

Conclusions: This is the first report of Angelman syndrome complicated by paroxysmal tonic upward gaze. Both transient paroxysmal tonic upward gaze and Angelman syndrome have been associated with dopaminergic neurons. We speculate that the dopaminergic abnormalities present in Angelman syndrome may cause paroxysmal tonic upward gaze.
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http://dx.doi.org/10.1016/j.pediatrneurol.2014.08.022DOI Listing
January 2015

Abnormal pupillary light reflex with chromatic pupillometry in Gaucher disease.

Ann Clin Transl Neurol 2014 Feb 4;1(2):135-40. Epub 2014 Feb 4.

Division of Child Neurology, Institute of Neurological Science, Tottori University Faculty of Medicine Yonago, Japan.

The hallmark of neuronopathic Gaucher disease (GD) is oculomotor abnormalities, but ophthalmological assessment is difficult in uncooperative patients. Chromatic pupillometry is a quantitative method to assess the pupillary light reflex (PLR) with minimal patient cooperation. Thus, we investigated whether chromatic pupillometry could be useful for neurological evaluations in GD. In our neuronopathic GD patients, red light-induced PLR was markedly impaired, whereas blue light-induced PLR was relatively spared. In addition, patients with non-neuronopathic GD showed no abnormalities. These novel findings show that chromatic pupillometry is a convenient method to detect neurological signs and monitor the course of disease in neuronopathic GD.
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http://dx.doi.org/10.1002/acn3.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212477PMC
February 2014

Developmental outcome after surgery in focal cortical dysplasia patients with early-onset epilepsy.

Epilepsy Res 2014 Dec 22;108(10):1845-52. Epub 2014 Sep 22.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, NHO, 886 Urushiyama, Aoi-Ku, Shizuoka, Shizuoka, Japan.

The purpose of this study was to investigate the developmental outcome after surgery for early-onset epilepsy in patients with focal cortical dysplasia (FCD). Among 108 patients with histopathologically confirmed FCD operated between 1985 and 2008, we selected 17 patients with epilepsy onset up to 3 years of age. Development was evaluated by the developmental quotient or intelligence quotient (DQ-IQ) and mental age was measured by the Mother-Child Counseling baby test or the Tanaka-Binet scale of intelligence. Postsurgical development outcome was evaluated by the changes in DQ-IQ and mental age as well as rate of increase in mental age (RIMA) after surgery. RIMA was calculated as the increase in mental age per chronological year (months/year; normal average rate: 12 months/year). Age at epilepsy onset of 17 patients ranged from 15 days to 36 months (mean±SD, 11.0±10.0 months). Age at surgery ranged from 18 to 145 months (75.1±32.4 months). Evaluation just before surgery showed that 13 of 17 (76.4%) patients had DQ-IQ below 70. Ten patients (58.8%) were seizure-free throughout the postsurgical follow-up period. After surgery, DQ-IQ was maintained within 10 points of the presurgical level in 13 patients (76.4%), and increased by more than 10 points in one patient (5.9%). After surgery, RIMA in patients with Engel's class I (7.5±3.8) was higher than patients with Engel's class II-IV (2.6±3.4) (unpaired t-test with Welch's correction, t=2.99, df=15, p=0.0092). RIMA was particularly low in two patients with spasm. In four patients with presurgical DQ-IQ<70, seizure-free after surgery and without spasm, DQ-IQ did not increase but RIMA improved from 3.6±2.8 before surgery to 6.9±2.5 months/year after surgery. RIMA became better from 2 years after surgery. In four patients with presurgical DQ-IQ≥70 and no spasm, two showed the same or higher RIMA than normal average after surgery. In 58.8% of FCD patients with early onset epilepsy, epilepsy surgery effectively controlled seizures, and in 82.3% of patients, epilepsy surgery preserved or improved development. Residual seizures after surgery and lower DQ-IQ before surgery might be potential risk factors for poor development after surgery. In patients of Engel's class I with lower presurgical DQ-IQ, catch-up increase in mental age was observed after two years following surgery.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.09.010DOI Listing
December 2014

Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan.

Epilepsy Res 2014 Nov 2;108(9):1627-36. Epub 2014 Sep 2.

Department of Pediatrics, Hiroshima City Hospital, 7-33 Motomachi, Naka-ku, Hiroshima 730-8518, Japan.

Purpose: To evaluate the efficacy, safety, and pharmacokinetics of rufinamide as an adjunctive therapy for patients with Lennox-Gastaut syndrome (LGS) in a randomized, double-blind, placebo-controlled trial.

Methods: We conducted a multicenter clinical trial with a 4-week baseline, a 2-week titration, a 10-week maintenance, and either a follow-up visit or entry into an open-label extension. Patients with LGS (4 to 30 years old) taking between one and three antiepileptic drugs were recruited. After the baseline period, patients were randomly assigned to rufinamide or placebo. The primary efficacy variable was the percent change in the tonic-atonic seizure frequency per 28 days.

Key Findings: Of the 59 patients, 29 were randomized to the rufinamide group and 30 to the placebo group. The frequency of epileptic seizures was significantly decreased in the rufinamide group than in the placebo group; the median percent change in frequency of tonic-atonic seizures was -24.2% and -3.3%, respectively, (p=0.003) and that of total seizures was -32.9% and -3.1%, respectively (p<0.001). Subgroup analyses indicated that the efficacy of rufinamide was consistent independent of clinical background characteristics. The common treatment-related adverse events in the rufinamide group were decreased appetite (17.2%), somnolence (17.2%), and vomiting (13.8%). Transient seizure aggravations were observed in 13 (22.0%) of the 59 patients, though a causal relationship with rufinamide was suspected in only one patient. All adverse events were mild to moderate in severity. The mean plasma concentration of rufinamide between 1 and 9 within 12h after administration was 17.2 μg/mL.

Significance: The present results showed a favorable risk-benefit profile for rufinamide as an adjunctive therapy for patients with LGS.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.08.019DOI Listing
November 2014

Everolimus Treatment for an Early Infantile Subependymal Giant Cell Astrocytoma With Tuberous Sclerosis Complex.

J Child Neurol 2015 Aug 19;30(9):1192-5. Epub 2014 Aug 19.

Department of Pediatrics, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Japan.

Subependymal giant cell astrocytomas are benign tumors often observed with tuberous sclerosis complex. These tumors are rarely diagnosed during fetal life or early infancy. Until recently, the only available treatment has been surgical resection. Current clinical research has demonstrated that everolimus can induce these tumors' regression. We report a 19-month-old boy with tuberous sclerosis complex. At 2 months of age, he presented with congenital subependymal giant cell astrocytoma that was complicated by refractory epilepsy and severe mental retardation. Treatment with everolimus was started when he was 10 months old. Three months after initiating everolimus, the tumor was significantly reduced in size, and the reduction was subsequently maintained. His seizures decreased and he showed cognitive and developmental improvement. No severe adverse events have been observed to date. Everolimus has promise as an effective alternative to surgery for subependymal giant cell astrocytomas during early infancy.
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http://dx.doi.org/10.1177/0883073814544703DOI Listing
August 2015

In response to terminology and prognosis of Dravet syndrome.

Epilepsia 2014 Jun;55(6):943

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.

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http://dx.doi.org/10.1111/epi.12640DOI Listing
June 2014

PIGA mutations cause early-onset epileptic encephalopathies and distinctive features.

Neurology 2014 May 4;82(18):1587-96. Epub 2014 Apr 4.

From the Department of Pediatrics (M.K., K.H.), Yamagata University Faculty of Medicine, Yamagata; Department of Human Genetics (H.S., C.O., M.N., Y.T., N. Miyake, N. Matsumoto), Yokohama City University Graduate School of Medicine, Yokohama; Department of Immunoregulation (Y.M., T.K.), Research Institute for Microbial Diseases, and WPI Immunology Frontier Research Center, Osaka University, Suita; Division of Neurology (K.K., R.M., S.-i.H.), Saitama Children's Medical Center, Saitama; Division of Neurology (S.W.), Miyagi Children's Hospital, Sendai; Division of Neurology (M.I., H.O.), Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama; Department of Pediatrics (K.M.), Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama; Department of Pediatrics (R.T.), Aomori Prefectural Central Hospital, Aomori; and Department of Pediatrics (H.O.), Jichi Medical School, Tochigi, Japan.

Objective: To investigate the clinical spectrum caused by mutations in PIGA at Xp22.2, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, among patients with early-onset epileptic encephalopathies (EOEEs).

Methods: Whole-exome sequencing was performed as a comprehensive genetic analysis for a cohort of 172 patients with EOEEs including early myoclonic encephalopathy, Ohtahara syndrome, and West syndrome, and PIGA mutations were carefully investigated.

Results: We identified 4 PIGA mutations in probands showing early myoclonic encephalopathy, West syndrome, or unclassified EOEE. Flow cytometry of blood granulocytes from patients demonstrated reduced expression of GPI-anchored proteins. Expression of GPI-anchored proteins in PIGA-deficient JY5 cells was only partially or hardly restored by transient expression of PIGA mutants with a weak TATA box promoter, indicating a variable loss of PIGA activity. The phenotypic consequences of PIGA mutations can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations. Severe forms involved myoclonus and asymmetrical suppression bursts on EEG, multiple anomalies with a dysmorphic face, and delayed myelination with restricted diffusion patterns in specific areas. The less severe form presented with intellectual disability and treatable seizures without facial dysmorphism.

Conclusions: Our study confirmed that PIGA mutations are one genetic cause of EOEE, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE.
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http://dx.doi.org/10.1212/WNL.0000000000000389DOI Listing
May 2014

Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.

Epilepsia 2014 Apr 6;55(4):528-38. Epub 2014 Feb 6.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.

Objective: This study attempted to clarify the long-term course of Dravet syndrome (DS).

Methods: Sixty-four patients diagnosed with DS (44 with typical DS, and 20 with atypical DS) were studied. The long-term outcomes of clinical seizures, electroencephalographic findings, neuropsychological findings, and social situation were analyzed. The follow-up period ranged from 11 to 34 years 5 months (median 24 years).

Results: At the last visit, the ages ranged from 19 years to 45 years (median 30 years). Fifty-nine patients continued to have generalized tonic-clonic seizures (GTCS). Status epilepticus and unilateral seizures were not observed and myoclonic seizures, atypical absence seizures, and photosensitive seizures were resolved in most patients. The frequency of complex partial seizures was equally low, with five patients at presentation and six patients at the last visit, respectively. Five patients achieved seizure remission (seizure-free for 1 year or longer). Only 1 of 44 patients with typical DS had seizure remission, whereas 4 of 20 patients with atypical DS remitted, with a statistically significant difference between the two phenotypes (p = 0.03). Intellectual disability was found in all patients; especially, severe intellectual disability was prevalent. Patients with atypical DS tended to have milder intellectual disability compared to those with typical DS (p = 0.0283). Occipital alpha rhythm in the basic activity was associated with milder intellectual disability (p = 0.0085). The freedom from seizures correlated with appearance of occipital alpha rhythms (p = 0.0008) and disappearance of epileptic discharges (p = 0.0004). Two patients with GTCS died. Mutations of the neuronal voltage-gated sodium channel alpha subunit type 1 gene were detected at a high frequency (33 of 36 patients examined). Seizure remission was found only in the missense mutation group.

Significance: The long-term seizure and intellectual outcomes are extremely poor in patients with typical DS compared to those with atypical DS. Epilepsy phenotype may influence long-term course of DS.
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http://dx.doi.org/10.1111/epi.12532DOI Listing
April 2014

[Efficacy of repeated adrenocorticotropic hormone therapy in patients with intractable epileptic spasms].

No To Hattatsu 2013 Jul;45(4):281-7

Department of Pediatrics, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, Shizuoka.

Objective: We examined the effectiveness of repeated adrenocorticotropic hormone (ACTH) therapy in short-term and long-term seizure control in patients with intractable epileptic spasms.

Methods: Twenty-five patients with intractable spasms, in whom epileptic seizures were not controlled or relapsed after the first ACTH therapy, were given repeated ACTH therapy. The short-term effect (seizure control longer than two months) of repeated ACTH therapy was analyzed, and the long-term effect was estimated by Kaplan-Meier method.

Results: Short-term seizure control by repeated ACTH therapy was achieved in 13 of 25 patients (52.0%), and in 5 of 13 patients, seizures were controlled by ACTH therapy at higher doses compared with the first ACTH therapy. Short-term effectiveness was obtained in 76.5% of patients who had epileptic spasms alone at the time of the second ACTH therapy, but was ineffective in all 8 patients who had multiple types of seizures, with relapses within 2 months. Short-term effectiveness was not associated with clinical factors such as onset age, age of repeated ACTH treatment, and EEG findings. Regarding the long-term effect of repeated ACTH therapy, the period until seizure relapse was significantly longer in patients with epileptic spasms alone compared to patients with multiple seizure types. Spasms were controlled in 5 of 25 cases (20.0%) at the final observation. In patients with multiple seizure types and patients with onset age older than eight months, seizure control was not obtained. Long-term outcome was good in patients with treatment lag within 2 months.

Conclusion: In repeated ACTH therapy, seizure type seems to be one of the major determinants for short- and long-term seizure outcome.
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July 2013

Influence of CYP2C19 polymorphism and concomitant antiepileptic drugs on serum clobazam and N-desmethyl clobazam concentrations in patients with epilepsy.

Ther Drug Monit 2013 Jun;35(3):305-12

Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Ulushiyama, Aoi-ku, Japan.

Objective: The aims of this study were to identify the factors influencing the metabolism of clobazam (CLB) and its active metabolite [N-desmethyl clobazam (NCLB)] and to evaluate the NCLB concentration as an indicator for CYP2C19 polymorphism in epileptic patients.

Methods: A total of 302 serum samples from 238 Japanese patients were evaluated. The ratios of the serum CLB and NCLB concentrations to the CLB dose (CD ratios) were calculated and compared with CYP2C19 phenotypes.

Results: The mean CD ratio of NCLB in extensive metabolizers (EM: *1/*1), intermediate metabolizers (IM: *1/*2 or *1/*3), and poor metabolizers (PM: *2/*2, *3/*3, or *2/*3) was 3.1, 4.9, and 21.6 (μg/mL)/(mg/kg), respectively. In the EM and IM groups, the concomitant use of hepatic enzyme inducers (phenytoin and carbamazepine) reduced the CD ratio of CLB and increased that of NCLB. In the PM group, these inducers also decreased the CD ratio for CLB but did not elevate the CD ratio for NCLB. Using multiple regression analysis, body weight showed a positive correlation with an increased CD ratio for NCLB. The concomitant use of zonisamide and stiripentol also elevated the CD ratio for NCLB in the EM and IM groups, but that of the PM group was almost unchanged. When the cut-off value of the CD ratio for NCLB was set as 10.0 (μg/mL)/(mg/kg) for predicting the CYP2C19 PM status, the sensitivity and specificity were 94.4% and 95.7%, respectively.

Conclusions: The interaction between NCLB and other antiepileptic drugs showed marked differences among CYP2C19 phenotypes. Measurement of the serum NCLB concentration is clinically useful for identifying the PM phenotype.
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http://dx.doi.org/10.1097/FTD.0b013e318283b49aDOI Listing
June 2013

[Sleepiness:a frequent adverse reaction of antiepileptic drugs in patients with epilepsy after encephalitis/encephalopathy].

No To Hattatsu 2012 Nov;44(6):472-6

Department of Pediatrics and Psychiatry, National Epilepsy Center Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka.

Objective: Patients with epilepsy after encephalitis/encephalopathy (EAE) are often on polytherapy with anti-epileptic drugs (AEDs), and are at risk of adverse reactions. We examined the adverse effects of AEDs, especially sleepiness, in these patients.

Methods: In this retrospective study, the medical records of 66 patients who were diagnosed with EAE in our hospital were reviewed and the clinical characteristics were analyzed. Immunological biomarkers including cytokines, chemokines, granzyme B, soluble tumor necrosis factor receptor 1, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 were also investigated.

Result: The mean onset age of acute encephalitis was 9 years and 1 month and the mean interval from onset of acute encephalitis to onset of epilepsy was 6.4 months. Sleepiness induced by AEDs was observed in 26 of 66 patients (39.3%). The incidence of sleepiness was high in patients treated with clorazepate (75%), lamotrigine (66.7%), and ethosuximide (40%). Comparing the AEDs used by more than 20 patients, the incidence of sleepiness was high for clonazepam (30.4%) and phenytoin (25.8%). IgG, protein, and albumin levels in cerebrospinal fluid were significantly higher in patients affected by sleepiness than in those not affected. IL-8 in cerebrospinal fluid was significantly higher in the group with sleepiness compared to that without. Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels were not different between the two groups.

Conclusion: Long-lasting blood-brain barrier dysfunction and proliferation of immature vessels induced by IL-8 may contribute to the occurrence of sleepiness as an adverse effect of AEDs in patients with EAE. We recommend to assess for blood-brain barrier dysfunction when choosing AEDs for treating patients with intractable EAE.
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November 2012

Self-induced seizures presumably by peri-orbital somatosensory self-stimulation: a report of two cases.

Brain Dev 2012 Sep 7;34(8):685-90. Epub 2011 Dec 7.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Aoiku, Shizuoka, Japan.

Self-induced seizures by somatosensory stimulation are rare. We describe two epileptic patients with self-induced seizures presumably by peri-orbital somatosensory stimulation. Two infants with severely delayed psychomotor development and poor visual acuity after acute subdural hemorrhage in early infancy had been diagnosed as having West syndrome. They evolutionally became to show serial self-induced seizures preceded by rubbing eye with finger in one case and touching right eyebrow with the back of left hand in the other case. Video-electroencephalography (EEG) monitoring was useful to confirm self-induced seizure by peri-orbital self-stimulation. In patients with serial seizures preceded by peculiar behaviors, we need to consider the possibility of self-induced seizures, even if they have a history of West syndrome and severe psychomotor retardation.
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http://dx.doi.org/10.1016/j.braindev.2011.11.004DOI Listing
September 2012

Cutaneous adverse drug reaction in patients with epilepsy after acute encephalitis.

Brain Dev 2012 Jun 11;34(6):496-503. Epub 2011 Oct 11.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan.

Patients with epilepsy after encephalitis/encephalopathy (EAE) often have refractory seizures, resulting in polytherapy with the risk of adverse reactions due to anti-epileptic drugs (AEDs). We focused on the characteristics of cutaneous adverse reaction (CAR). In this retrospective study, the medical records of 67 patients who were diagnosed as having EAE in our hospital were reviewed and the clinical characteristics were analyzed. Immunological biomarkers including cytokines, chemokines, granzyme B, soluble tumor necrosis factor receptor 1 (s-TNFR 1), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured in 22 patients. CARs attributed to AEDs were observed in 16 of 67 EAE patients (23.9%) (CAR group). High CAR rates were observed with phenytoin, lamotrigine, phenobarbital, and carbamazepine. Severe CARs were found in three of 67 patients (4.5%). The frequencies of CARs were significantly higher in patients with encephalitis onset older than five years of age. CAR occurred only in patients who had onset of EAE within 6 months after encephalitis. The durations from acute encephalitis to CARs were within one year for almost all AEDs, except lamotrigine. The proportion of patients with serumregulated on activation normal T cell expressed and secreted (RANTES) levels higher than the upper limit of normal range was significantly higher in CAR group than in non-CAR group. Patients in the early stage of EAE and patients with encephalitis onset older than five years of age may be at higher risk of CARs to AEDs, especially to phenytoin, lamotrigine, phenobarbital, and carbamazepine. RANTES may be a biomarker for susceptibility to CARs in EAE patients.
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http://dx.doi.org/10.1016/j.braindev.2011.09.003DOI Listing
June 2012

Lamotrigine is favourable for startle-induced seizures.

Epileptic Disord 2011 Sep;13(3):277-83

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.

Falling due to startle-induced seizures (SISs) often leads to injury. The triggers of SIS are mostly unexpected auditory stimuli, which are too common to avoid in daily life. As SISs are often refractory to conventional medications, effective therapeutic options have to be established. We report a small series of six patients treated with lamotrigine (LTG) as add-on therapy. Seizure control was improved greatly in three of the six patients, resulting in less restricted daily life, but no effect was observed in two and a skin rash developed in one. Patient 1 was a 19-year-old man. His seizure comprised of a sudden tonic extension of the extremities induced by auditory or visual stimulus. He fell down due to SISs, five to ten times a day, with frequent injuries. After adding LTG to treatment with valproate (VPA) and clobazam (CLB), SISs were reduced to once a month. Patient 2 was a 51-year-old woman. Sudden tonic extension of all limbs induced by unexpected sounds frequently threw her down onto the floor. Addition of LTG to treatment with CLB, zonisamide and phenytoin reduced her SISs from several to less than once a day. Patient 3 was a seven-year-old girl with post-encephalitic epilepsy. After adjunctive treatment of LTG to VPA, the severity of SISs became milder thus avoiding injury, although seizure frequency did not decrease. LTG is potentially effective for the treatment of SISs and may prevent falling. The addition of LTG treatment dramatically improved the lives of the patients presented here and should be considered as an option for startle-induced seizures.
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http://dx.doi.org/10.1684/epd.2011.0458DOI Listing
September 2011

[Remarkable effect of a modified ketogenic diet in a boy with focal seizures followed by epileptic spasms in a cluster].

No To Hattatsu 2011 Jul;43(4):305-8

National Epilepsy Center Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka.

A modified ketogenic diet was demonstrated to be remarkably effective in a child with intractable symptomatic focal epilepsy with combined seizures of focal seizures and epileptic spasms (ES) in a cluster (ESC). ES started at 8 months of age and disappeared with ACTH therapy. At the age of 13 months, the child began to have intractable focal seizures that, later, were followed by ESC 10 times a day. Brain MRI showed only a non-specific diffuse cerebral atrophy. Interictal EEG showed high amplitude diffuse disorganized slow waves with prominent sharp waves predominant over the bilateral occipital region. We started a modified ketogenic diet (mKD) treatment without fasting or a water/calorie limitation. Since the 20th day of mKD, the patient has been seizure free (6 months) without adverse effects. EEG showed remarkable improvement and he has some improvement in the developmental milestones. A modified ketogenic diet is easier to start and continue compared to the classic ketogenic diet, and should be tried in intractable epilepsies that are not treatable surgically early in life from the developmental prognosis point of view.
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July 2011

CDKL5 alterations lead to early epileptic encephalopathy in both genders.

Epilepsia 2011 Oct 19;52(10):1835-42. Epub 2011 Jul 19.

Tokyo Women's Medical University Institute for Integrated Medical Sciences, Shinjuku-ward, Tokyo, Japan.

Purpose: Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders.

Methods: A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations.

Key Findings: One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features.

Significance: We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.
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http://dx.doi.org/10.1111/j.1528-1167.2011.03174.xDOI Listing
October 2011

Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy.

J Hum Genet 2011 Aug 2;56(8):561-5. Epub 2011 Jun 2.

Tokyo Women's Medical University Institute for Integrated Medical Sciences, 8-1 Kawada-cho, Shinjuku, Tokyo, Japan.

Microarray-based comparative genomic hybridization analysis identified a 737-kb microdeletion of Xq11.1, including the cell division cycle 42 guanine nucleotide exchange factor (GEF)-9 gene (ARHGEF9), encoding collybistin, which has a pivotal role in formation of postsynaptic glycine and γ-aminobutyric acid receptor clusters, in a male patient with severe mental retardation and epilepsy. No overlapping deletion with this was identified in the database of genomic copy number variations. A cohort study of ARHGEF9 nucleotide sequence identified a nonsense mutation in another male patient with severe mental retardation and epilepsy. This mutation affects one of the three transcript variants of ARHGEF9, which was confirmed to be expressed in the brain by reverse transcription-PCR. Although this nonsense mutation was shared with the patient's mother, it was not observed in 100 normal individuals. Both male patients suffered epileptic seizures after 1 year of age. Brain magnetic resonance imaging revealed mild frontal atrophy in the first patient and right frontal polymicrogyria in the second patient. Three previously reported mutations of ARHGEF9 consisted of a missense mutation in a male patient with hyperekplexia and two chromosomal disruptions in two female patients. The common phenotypic effects of all ARHGEF9 mutations were mental retardation and epilepsy. Therefore, ARHGEF9 is likely to be responsible for syndromic X-linked mental retardation associated with epilepsy.
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http://dx.doi.org/10.1038/jhg.2011.58DOI Listing
August 2011

Schinzel-Giedion syndrome: a further cause of early myoclonic encephalopathy and vacuolating myelinopathy.

Brain Dev 2012 Feb 19;34(2):151-5. Epub 2011 Apr 19.

Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Taihakuku, Sendai, Japan.

Here, we report a male child with Schinzel-Giedion syndrome associated with intramyelinic edema detected on brain magnetic resonance imaging (MRI) and persistent suppression-burst pattern on electroencephalography (EEG) with erratic myoclonus of the extremities and face. Similar to nonketotic hyperglycinemia, Schinzel-Giedion syndrome may be recognized as another causative genetic disease of early myoclonic encephalopathy and vacuolating myelinopathy.
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http://dx.doi.org/10.1016/j.braindev.2011.03.010DOI Listing
February 2012