Brain and Development - Articles in Press

Subacute sclerosing panencephalitis (SSPE) the story of a vanishing disease - Corrected Proof

Natan Gadoth — 2012-01-27

Abstract: Subacute sclerosing panencephalitis (SSPE), is a devastating “slow virus” brain disease which affects young children who had measles some 6–7years earlier.Although, the pandemic of SSPE during 1960–1980’s was almost eradicated due to mass immunization, the disease is still taking the life of young children in countries where measles immunization is incomplete and in world regions where genetic polymorphism to this particular infection is present. The present review was written for the fortunate young generation of pediatricians and pediatric neurologists who probably have not seen a case of SSPE during their career, and for those who work in counties where the disease has not been eradicated. It is also a reminder that with full coverage of measles immunization this devastating disease can be fully eradicated.

Molecular diagnostic dilemmas in Rett syndrome - Corrected Proof

2012-01-25

Abstract: Rett syndrome (OMIM 312750) is a progressive, X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene located on chromosome Xq28. The disorder is characterized by a period of normal development during the first 6–18months of life, followed by gradual loss of skills already gained, such as speech and purposeful movement of the hands. The majority of cases are sporadic and represent “de novo” mutations.In this study we summarize the results of diagnostic testing of 30 patients with Rett syndrome (RTT) or mental retardation of unknown etiology using bidirectional sequencing of the open reading frame of the MECP2 gene. Twenty different variants were identified in those patients including 12 missense (R133C, P152R, T158M, V300I, I303M, R306C, T311M, R344W, A358T, P384L, A443T, V481M), four nonsense (R168X, K192X, R255X, R270X), two deletion (E137_L386del, I293_S350del), and two frameshift (S291QfsX26, G343AfsX6) mutations. Seven of the twenty variants identified were novel mutations (E137_L386del, K192X, S291QfsX26, G343AfsX6, I293_S350del, P384L, and A443T). In the cases with novel or non-recurrent missense mutations, family studies were performed to investigate genotype–phenotype correlations. Our results demonstrate the importance of family studies and highlight the complexity of interpretation of MECP2 alterations, which may or may not be disease-associated.

Childhood-onset anti-MuSK antibody positive myasthenia gravis demonstrates a distinct clinical course - Corrected Proof

2012-01-25

Abstract: Anti-muscle-specific tyrosine kinase antibody (MuSK-Ab) is the second most frequent autoantibody identified in adult patients with myasthenia gravis (MG). Adult patients with MuSK-Ab demonstrate characteristic clinical features but very little information is available for childhood-onset patients with MuSK-positive MG. We report a childhood-onset female patient with MuSK-positive MG. This patient showed basic clinical features compatible with adult-onset MuSK-positive MG, but some features, including spontaneous improvement, are distinct from those in adult patients. Serial examination of MuSK-Ab titers revealed a gross correlation with clinical severity despite significantly high titers throughout the clinical course. Therefore, childhood-onset MuSK-positive MG may demonstrate a distinct clinical characteristics in the early period of illness.

An immunologic case study of acute encephalitis with refractory, repetitive partial seizures - Corrected Proof

2012-01-24

Abstract: Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is a neurologic syndrome characterized by extraordinarily frequent and refractory partial seizures, which immediately evolve into refractory epilepsy. To elucidate the pathophysiology of AERRPS, we performed an immunologic study of an affected boy, revealing decreased natural killer (NK) cell activity in the peripheral blood mononuclear cells. IgG antibodies against the glutamate receptor (GluR)ε2, ζ1, and δ2 subunits were all positive in both the serum and cerebrospinal fluid (CSF). There were raised plasma concentrations of interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ as well as an extremely elevated CSF level of IL-6. These findings suggest that AERRPS is immune-mediated encephalitis, in which both autoimmunity and exaggerated cytokine production are involved. NK cell dysfunction may be the underlying abnormality in this AERRPS case, which might have contributed to the production of GluR autoantibodies.

Development of the human abducens nucleus: A morphometric study - Corrected Proof

Katsuyuki Yamaguchi, Koichi Honma — 2012-01-24

Abstract: Background: The abducens nucleus directly innervates the lateral rectus muscle and plays a role in controlling conjugate horizontal eye movements. Although the neuronal cytoarchitecture of the abducens nucleus has been extensively investigated in various species of vertebrates, few studies have been undertaken in humans, especially in fetuses or neonates. Design/Subjects: We examined 12 human brains from preterm infants aged 20–43postmenstrual weeks to document the histology and morphometry of the abducens nucleus. The brain was processed into celloidin-embedded serial sections stained with the Klüver–Barrera and other conventional methods. Results: The nucleus was identified as a mass of cells as early as 20weeks. Its neurons were clearly distinguished from glial cells due to droplet-like, clear nuclei containing prominent nucleoli and surrounded by a basophilic perikaryon. Neurons of various sizes and shapes were intermingled within the nucleus, although larger neurons were located towards the center of the nucleus. Immature granular or reticular Nissl bodies were seen at 20–21weeks. Tigroid, coarse Nissl bodies appeared around 28–29weeks in larger neurons, although in smaller neurons Nissl bodies were dispersed or concentrated peripherally. Morphometric results were: (1) the nuclear volume exponentially increased with age between 20 and 43weeks; (2) the histograms of neuronal profile areas showed a non-normal distribution trailing toward the right and widening with age; (3) the geometric average of neuronal profile areas increased linearly with age. Conclusion: Our study suggests that the human abducens nucleus enlarges more quickly toward the end of gestation, and comprises heterogeneous groups of neurons.

Novel AGTR2 missense mutation in a Japanese boy with severe mental retardation, pervasive developmental disorder, and epilepsy - Corrected Proof

Eri Takeshita, Eiji Nakagawa, Katsutoshi Nakatani, Masayuki Sasaki, Yu-ichi Goto — 2012-01-24

Abstract: Angiotensin II type-2 receptor gene (AGTR2) mutations have been recently detected in patients with mental retardation. AGTR2 plays a role in central nervous system development and cognitive functions. We identified a novel missense mutation of c.572G>A (p.G191E) in a 6-year-old boy showing severe mental retardation, pervasive developmental disorder, and epilepsy. This is the first report on AGTR2 mutation in a Japanese boy with mental retardation.

Hypoyelination in I-cell disease; MRI, MR spectroscopy and neuropathological correlation - Corrected Proof

2012-01-24

Abstract: MRI of a female patient with genetically diagnosed I-cell disease at 2weeks, 4 and 8months revealed delayed myelination or hypomyelination with decreased choline on MR spectroscopy. Brain autopsy was performed 2h after death at 14-month-old. Immunoreactivities for myelin basic protein and proteolipid proteins, markers for mature myelin sheath, were reduced in the myelinated fibers and oligodendrocytes in the white matter, indicating the hypomyelination in the central nervous system. I-Cell disease should be added to the list of delayed or hypomyelination conditions, and this neuroimaging finding could be a key for differentiating I-cell disease from the clinically similar disorder of Hurler syndrome characterized by perivascular lacunation.

Clinical study in Chinese patients with late-infantile form neuronal ceroid lipofuscinoses - Corrected Proof

2012-01-16

Abstract: Clinical findings, pathological features and tripeptidyl peptidase 1 (TPP1) activity and genetic mutation analysis data of nine patients affected with the late-infantile form of neuronal ceroid lipofuscinoses (LINCL) in China are systematically reviewed with long-term follow-up. The patients were enrolled if curvilinear bodies were found on lymphocyte, skin or muscle specimens’ examination, and/or reduction of tripeptidyl peptidase 1 (TPP1) activity were detected. CLN2 gene mutation were tested in five patients. The patients have onset age of 2–3.5years, and most of them initially present partial seizure, and then progressed to deteriorated mental function, refractory myoclonic seizures, impaired vision, and ataxia with cerebellar atrophy. Discrete small vacuolated lymphocytes are found in 5–10% lymphocytes in 5 patients examined. Curvilinear bodies were found in vacuolated lymphocytes, in skin and muscle tissues. Tripeptidyl peptidase 1 (TPP1) activities are reduced in 5 patients with different CLN2 gene mutation. Detection of vacuolated lymphocytes may be a screen method for LINCL, ultrastructural examination of lymphocytes, combined with TPP1 activity assay, allowing for a definite and faster diagnosis and classification with minimal invasion.

Comments on the article by Pavlou E. et al. entitled “facial nerve palsy in childhood” - Corrected Proof

N. Gadoth — 2012-01-11

The review by Pavlou et al. on facial nerve palsy in childhood , is timely and will certainly contribute to the understanding and workup of this common mononeuropathy by both pediatricians and child neurologists.

Transient reduced diffusion in the cortex in a child with prolonged febrile seizures - Corrected Proof

Toru Kato, Akihisa Okumura, Fumio Hayakawa, Takeshi Tsuji, Jun Natsume — 2012-01-11

Abstract: We report on a 4-year-old boy with transient reduced diffusion in the cortex, thalamus, and hippocampus on diffusion-weighted imaging (DWI) performed after prolonged febrile seizures (PFS). He had experienced intermittent right hemiconvulsions lasting about 90min during the febrile illness, but his neurological symptom resolved completely after several hours. DWI performed immediately after the PFS showed abnormally high signal intensities in the left extended cortex and pulvinar of the ipsilateral thalamus. Two days later, these DWI lesions resolved completely, but abnormally high signal intensities were observed in the left hippocampus. Three months later, the DWI was normal, and no atrophy or gliosis was seen. This patient had unique lesions on DWI after PFS, but it is nevertheless important to attend to such lesions on the DWI of patients with PFS.

Facial nerve palsy in childhood - Corrected Proof

Evangelos Pavlou, Anastasia Gkampeta, Maria Arampatzi — 2012-01-09

We appreciate the comments by Dr. Natan Gadoth on our article entitled “Facial nerve palsy in childhood” which was published in Brain Dev 2011;33:644–50. Concerning the list of infectious causes of facial nerve palsy in childhood, we would like to add the following, taking into consideration the comments by Dr. Gadoth: (a) poliovirus infection can be a cause of facial nerve palsy, especially in polio-endemic countries . (b) Facial palsy can also be caused by varicella-zoster virus (VZV) infection. Besides, VZV reactivation is an important cause of acute peripheral facial palsy in children, especially those between 6 and 15years of age . (c) Either initial infection or reactivation of HSV can be the cause of facial palsy in childhood, as several studies mention . (d) Less than 1% of people infected with West Nile Virus develop central nervous system disease such as meningitis or encephalitis, and severe neurologic disease is more common among adults than children. The neurologic manifestations of West Nile Virus infection include myoclonus, parkinsonian dyskinesias, seizures, polyradiculitis, optic neuritis, and other cranial neuropathies . (e) HIV-1 infection is associated with multiple sensory and motor neuropathies, in spite of the fact that HIV-1 does not replicate especially well in neurons. It has been suggested that the interaction of viral proteins, glia, and cytokines/chemokines may partially mediate viral effects on neuronal function. Neurologic and neurobehavioral deficits are common in children with HIV-1 infection. Children with severe immunosuppression, who do not receive antiretroviral therapy, are at greatest risk for developing neurologic complications .

Shigehiko Kamoshita (1934–2011) - Corrected Proof

Yukio Fukuyama — 2012-01-09

A man who has been one of the founders and a trustful backbone of the Japanese Society of Child Neurology (JSCN) and thus the most esteemed collaborator and friend of mine, Professor Shigehiko Kamoshita (Professor Emeritus, the University of Tokyo; Professor Emeritus, Jichi Medical University; Honorary President, National Center for Global Health and Medicine) passed away suddenly on November 10th, 2011, from prostate cancer at his age of 77. Just four days before that, I had received an e-mail from him in which he sounded pretty positive, so the news was a great shock.

Focal EEG abnormalities might reflect neuropathological characteristics of pervasive developmental disorder and attention-deficit/hyperactivity disorder - Corrected Proof

2012-01-06

Abstract: Neurophysiological characteristics in electroencephalograms (EEG) were investigated for patients with pervasive developmental disorder (PDD) and for patients with attention-deficit/hyperactivity disorder (AD/HD). This study examined 64 PDD children and 22 AD/HD children with no history of epilepsy or progressive neurological or psychiatric disorder. We used multivariate analysis to compare EEG abnormalities, clinical symptoms, and intelligence levels between PDD and AD/AD patient groups. Paroxysmal discharges at the frontopolar–frontal (Fp–F) brain regions and background EEG abnormalities tended to be detected preferentially in the PDD group, although paroxysmal discharges at central–temporal (C–T) regions tended to be detected preferentially in the AD/HD group. The paroxysmal discharges observed in patients expressing persistence and impulsivity are apparently localized respectively in the Fp–F and C–T regions. A combination of EEG abnormalities, including background EEG abnormalities and paroxysmal discharges at Fp–F and C–T regions, might be useful diagnostic hallmarks to distinguish PDD with AD/HD from AD/HD alone using a logistic regression model. The dysfunction of specific brain areas associated with EEG abnormalities might explain characteristics of clinical symptoms observed in PDD and AD/HD patients.

Ring chromosome 21 in the differential diagnosis of waddling gait - Corrected Proof

2011-12-30

Abstract: Ring chromosome 21 syndrome is a rare clinical condition. Most of the patients have a recognizable phenotype and multisystem involvement is described. Structural neurologic anomalies have also been described, but waddling gait due to lower motor neuron involvement has not been previously reported in association with ring 21.

On the likelihood of SCN1A microdeletions or duplications in Dravet syndrome with missense mutation - Corrected Proof

2011-12-29

Abstract: This study examines whether microdeletions and duplications of the gene encoding α1 subunit of the sodium channel (SCN1A) are underlying causes in Dravet syndrome (DS) with SCN1A missense mutation. Multiple exonic deletions were identified in 8/84 patients without mutation and 0/41 patients with missense mutations. Our findings indicate that while microdeletions are not rare in SCN1A-negative patients, they are not likely to be present simultaneously with other SCN1A mutations.

Efficacy and tolerance of gastrostomy feeding in Japanese muscular dystrophy patients - Corrected Proof

2011-12-28

Abstract: Although muscular dystrophy patients often have feeding difficulty and need long-term enteral nutrition, only a few reports have described gastrostomy feeding in these patients. This study was designed to evaluate the efficacy and tolerance of gastrostomy feeding in patients with muscular dystrophy. We performed a retrospective, multicenter study on 144 patients with muscular dystrophy who received gastrostomy feeding between 2007 and 2009 in 25 neuromuscular centers in Japan. There were 77 Duchenne muscular dystrophy (median age at gastrostomy placement 26years, range 13–47years), 40 myotonic dystrophy (median age 54.5years, range 13–70years), 11 Fukuyama congenital muscular dystrophy (median age 22years, range 13–29years), 5 limb girdle muscular dystrophy (median age 62years, range 43–78years), and 5 facioscapulohumeral muscular dystrophy (median age 52years, range 28–67years) patients. Many benefits including amelioration of malnutrition, swallowing difficulty and respiratory status were observed after the introduction of gastrostomy feeding. Especially in patients with Duchenne muscular dystrophy, mean body weight significantly increased after gastrostomy placement. Although most complications, which are commonly observed in other populations, were tolerable, respiratory failure and peritonitis were important concerns. These findings suggest that gastrostomy placement at an appropriate time is advisable in patients with muscular dystrophy.

Amplitude-integrated electroencephalogram 1h after birth in a preterm infant with cystic periventricular leukomalacia - Corrected Proof

2011-12-26

Abstract: We report a preterm infant, who showed abnormal amplitude-integrated electroencephalogram (aEEG) findings 1h after birth and later developed cystic periventricular leukomalacia (PVL). The patient was a girl with a gestational age of 29weeks. She was delivered by emergency cesarean section because of placental abruption and intrauterine co-twin demise. Artificial ventilation and administration of surfactant were needed to treat respiratory distress syndrome. Her cardiovascular condition was stable with artificial ventilation. Cranial ultrasonography showed extended cystic PVL after 11days of age. aEEG 1h after birth showed a consistently inactive pattern that resolved completely 28h after birth. The neurophysiological findings of this patient suggest that aEEG findings during the very early period after birth provide significant information for predicting PVL.

A case of malignant migrating partial seizures in infancy as a continuum of infantile epileptic encephalopathy - Corrected Proof

Eun Hye Lee, Mi-Sun Yum, Min-Hee Jeong, Kyung Yeon Lee, Tae-Sung Ko — 2011-12-26

Abstract: The syndrome of malignant migrating partial seizures in infancy (MMPSI) is characterized by onset before the age of 6months, nearly continuous electrographic seizures involving multiple independent areas of onset in both hemispheres, and poor developmental outcome. This report presents a case involving a patient with MMPSI, who later developed West syndrome. At the age of 2months old, he showed multifocal partial seizures, which were refractory to antiepileptic drugs. His electroencephalogram (EEG) revealed characteristic migrating multifocal epileptiform activities and neuroimaging finding was normal. The focal seizures were refractory to antiepileptic drugs and ketogenic diet. When he was 9months old, epilepic spasms were observed with hypsarrhythmia on EEG. He also showed severe developmental delay. MMPSI may be a continuum of infantile epileptic encephalpathy and could evolve to West syndrome.

Safety and role of ketogenic parenteral nutrition for intractable childhood epilepsy - Corrected Proof

Da Eun Jung, Hoon-Chul Kang, Joon Soo Lee, Eun Joo Lee, Heung Dong Kim — 2011-12-22

Abstract: To retrospectively evaluate the safety and role of ketogenic parenteral nutrition in patients with intractable childhood epilepsy. The ketogenic parenteral nutrition was given to 10 patients who were unable to absorb nutrients through the intestinal tract because of various gastrointestinal disorders and required complete bowel rest. This nutrition consisted of conventional intravenous fat emulsion (20% Lipision) plus dextrose and amino acid (6% Trophamine) hyperalimentation in a 4:1 (or 3:1) lipid to non-lipid ratio, infused during the bowel rest. If the ketogenic parenteral nutrition allowed normal daily functioning or resolved the underlying problems, we soon changed it to the enteral ketogenic diet (KD). The mean (±SD) duration of the ketogenic parenteral nutrition was 4.1 (±1.5) days. Although a brief span of several days, all patients could maintain ketosis and the efficacy of the previous enteral KD during the ketogenic parenteral nutrition. Complications included elevated aspartate aminotransferase and/or alanine aminotransferase in one patient. Amylase and lipase increased in one patient. Serum triglyceride level increased to the level of 1885mg/dl in one patient, but normalized in one week after discontinuation of the ketogenic parenteral nutrition and resuming of the enteral KD. Nine patients (90%) remained on the enteral KD after the ketogenic parenteral nutrition (the mean follow-up period was 9months), including 2 patients who successfully completed the diet with seizure free state. Only one patient discontinued the ketogenic parenteral nutrition because of persistent increase of the amylase and lipase levels. The ketogenic parenteral nutrition proved to be a relatively safe short-term method of continuing KD to maintain ketosis for seizure control, while patients were unable to absorb nutrients through their intestinal tract.

Searching for Potocki–Lupski syndrome phenotype: A patient with language impairment and no autism - Corrected Proof

2011-12-19

Abstract: Potocki–Lupski syndrome (PTLS; OMIM 610883) is a genomic syndrome that arises as a result of a duplication of 17p11.2. Although numerous cases of individuals with PTLS have been presented in the literature, its behavioral characterization is still ambiguous. We present a male child with a de novo dup(17)(p11.2p11.2) and he does not possess any autistic features, but is characterized by severe speech and language impairment. In the context of the analyses of this patient and other cases of PTLS, we argue that the central feature of the syndrome appears to be related to diminished speech and language capacity, rather than the specific social deficits central to autism.

Long term clinical course of Tourette syndrome - Corrected Proof

Renata Rizzo, Mariangela Gulisano, Paola Valeria Calì, Paolo Curatolo — 2011-12-19

Abstract: Background: Recent studies using cluster analysis and factor analysis have suggested that Tourette Syndrome (TS) should no longer be considered a unitary condition. Material and methods: We retrospectively studied the long term clinical course of 100 TS patients. The patients were assessed at the onset and after 10years follow-up to evaluate the severity of tic, the Obsessive Compulsive Disorder (OCD), the Attention Deficit Hyperactivity Disorder (ADHD) and the presence of anxiety and depression, rage attacks, self injuries behavior. Moreover at the follow-up they completed an evaluation scale on quality of life to assess the impairment in everyday life after 10years of illness. Results: The “pure TS” clinical group (38 subjects) showed after 10years follow-up that 58% carried on with the same clinical phenotype, whereas 42% changed in “TS+OCD” phenotype. Fifty-five percentage required pharmacological treatment. All the “TS+ADHD” clinical group (48 subjects) showed after 10years follow-up a different clinical phenotype: 62% “TS pure” phenotype, 35% “TS+OCD” phenotype, 2% “TS+ADHD+OCD” phenotype. Sixty-five percentage of the subject required pharmacological treatment. The “TS+ADHD+OCD” clinical group (14 subjects) after 10years follow-up showed that 14% carried on with the same clinical phenotype, whereas 8.3% presented “TS pure” phenotype and 92% presented “TS+OCD” phenotype. Seventy-one percentage were in need of therapy. With regards to quality of life, patients presented widespread impairment correlated to the presence of comorbid conditions. Conclusion: Our findings suggest that pure TS has quite a good long-term clinical course. By contrast, those who presented comorbid condition at the onset showed a more severe prognosis.

Prognostic factors in acute encephalopathy with reduced subcortical diffusion - Corrected Proof

2011-12-19

Abstract: Objectives: Acute encephalopathy with reduced subcortical diffusion (AED) covers a spectrum including not only typical acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) but also atypical AESD with monophasic clinical course, or more severe subtypes. Aim of this study is to analyze prognostic factors of AED. Materials & methods: We recruited 33 children with AED, that is, widespread diffusion restriction in cortical and subcortical structures. Their clinical courses, laboratory data, MRI, and the efficacy of treatment were analyzed retrospectively. Results: Of the 33 children, 20 were males and the mean age at diagnosis was 22months. Eighteen children had good outcome and 15 had poor outcome. Univariate analysis showed loss of consciousness 24h after the onset, prolonged seizure at the onset, and mechanical ventilation to be weak predictors of poor outcome. Maximal aspartate aminotransferase, alanine aminotransferase, and creatinine kinase levels were significantly higher in the poor outcome group. Multivariate analysis showed loss of consciousness 24h after the onset and prolonged seizure at the onset to be poor predictors of AED. Treatment with steroids and/or immunoglobulins did not result in better outcome. Conclusion: Prolonged seizure at the onset and loss of consciousness 24h after the onset were seen at early stages of severe AED. Using these features, a prospective study of early intervention in AED should be conducted to further analyze the efficacy of its treatment.

Consequences of nicotine exposure during different phases of rat brain development - Corrected Proof

Pooja Khanna Sood, Sonika Sharma, Bimla Nehru — 2011-12-12

Abstract: Nicotine is a psychoactive drug whose intensity of the addiction is so tremendous that it is now the fastest growing public health hazard in the world. The present study was designed to study the toxic effects of nicotine during different phases of rat brain development. The study is extended through adult brain designated as group A, that received nicotine at the dosage of 5mg/kg of b.wt. for 21days and were sacrificed following 21days of recovery. In the second group P, pups in different gestational phases (P2–P4) were given maternal nicotine exposures for only a period of 7days followed by recovery till they had achieved the age of 40days. A significant decrease in long term memory was observed in adult rats which correlated well with a significant decrease in the acetylcholine esterase activity. Simultaneously a significant decrease in the total glutathione, GSH content and catalase activity was observed which could account for the increase in peroxidation of lipids as evaluated by malondialdehyde (MDA) content in the nicotine exposed adult rats. The consequences of maternal nicotine exposure were different during different exposures regimes the alterations were least during the early gestation period, i.e. P2 (2–9days of their gestation period) as compared to P3 (7–14days of their gestation period) and P4 (21days of their weanling period). The study indicates that the consequences of nicotine exposure are varied during different stages of brain development.

Self-induced seizures presumably by peri-orbital somatosensory self-stimulation: A report of two cases - Corrected Proof

2011-12-09

Abstract: 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.

Cerebral hemispherectomy: Sensory scores before and after intensive mobility training - Corrected Proof

Stella de Bode, Stacy Fritz, Gary W. Mathern — 2011-12-05

Abstract: Purpose: It is unclear whether sensory modalities can be modified by rehabilitation and if sensory functions vary on the affected side many years after cerebral hemispherectomy. This pilot, proof-of-concept study assessed light touch and proprioception before and after 10days of intensive mobility training in individuals after hemispherectomy. Methods: Light touch and proprioception of the upper and lower extremity was measured using the Fugl-Meyer sensory subtest on the paretic side in 18 individuals with hemispherectomy before and after mobility training. Sensory scores and differences related to mobility training were compared with clinical variables. Results: Patients were 7.1±5.7years from time of surgery to sensory assessment and mobility training. Light touch scores were 81±22% and proprioception values were 64±23% of normal (p=0.0022). Light touch did not correlate with proprioception scores, and differences comparing after with before mobility training did not correlate. In multivariate analysis, younger age at seizure onset correlated with better light touch scores, and older age at onset correlated with improvements in light touch scores with mobility training. By comparison, proprioception scores were better in individuals with perinatal infarcts compared with Rasmussen encephalitis and Sturge-Weber. Post-training, proprioception scores were better in Sturge-Weber cases. Conclusion: Light touch was less affected than proprioception on the paretic side after cerebral hemispherectomy. Improvements with mobility training correlated with older age at seizure onset and etiology. These findings suggest that many years after epilepsy surgery sensory functions are not static supporting the notion of existing developmental neuroplasticity of the remaining cerebral cortex along with brain stem and spinal cord pathways.

Sporadic hemiplegic migraine presenting as acute encephalopathy - Corrected Proof

2011-12-02

Abstract: A 10-year-old boy with psychomotor developmental delay and cerebellar vermis atrophy developed right hemiplegia with vomiting, unconsciousness, convulsions, and late-onset fever. Slow delta activity was noted over the left hemisphere on electroencephalography, and neuroimaging revealed swelling of the left temporo-occipital cerebral cortex with restricted diffusivity, successive transient cortical atrophy, and hyperperfusion over the left cerebral hemisphere. Interleukin-6 was elevated in the cerebrospinal fluid. The acute symptoms resolved completely within 3weeks after onset, but hypoperfusion persisted in the left posterior cortex thereafter. Another episode with transient left hemiplegia appeared 7months later, followed by recurrence of migraine attacks. Analysis of the CACNA1A gene revealed a mutation of c.1997 C>T (p.T666M). None of his family members had migraine. This case represents an unusual evolution of sporadic hemiplegic migraine with manifestations of acute encephalopathy, for which the role of migraine-related inflammatory process is assumed.

Involvement of SHP2 in focal adhesion, migration and differentiation of neural stem cells - Corrected Proof

2011-11-28

Abstract: Objectives: SHP2 (Src-homology-2 domain-containing protein tyrosine phosphatase) plays an important role in cell adhesion, migration and cell signaling. However, its role in focal adhesion, differentiation and migration of neural stem cells is still unclear.Methods: In this study, rat neurospheres were cultured in suspension and differentiated neural stem cells were cultured on collagen-coated surfaces.Results: The results showed that p-SHP2 co-localized with focal adhesion kinase (FAK) and paxillin in neurospheres and in differentiated neural precursor cells, astrocytes, neurons, and oligodendrocytes. Suppression of SHP2 activity by PTP4 or siRNA-mediated SHP2 silencing caused reduction in the cell migration and neurite outgrowth, and thinning of glial cell processes. Differentiation-induced activation of FAK, Src, paxillin, ERK1/2, and RhoA was decreased by SHP2 inactivation.Conclusions: These results indicate that SHP2 is recruited in focal adhesions of neural stem cells and regulates focal adhesion formation. SHP2-mediated regulation of neural differentiation and migration may be related to formation of focal adhesions and RhoA and ERK1/2 activation.

Genetics of temporal lobe epilepsy - Corrected Proof

Su-Kyeong Hwang, Shinichi Hirose — 2011-11-21

Abstract: The most common partial epilepsy, temporal lobe epilepsy (TLE) consists of a heterogeneous group of seizure disorders originating in the temporal lobe. TLE had been thought to develop as a result of acquired structural problems in the temporal lobe. During the past two decades, there has been growing evidence of the important influence of genetic factors, and familial and non-lesional TLE have been increasingly described. Here, we focus on the genetics of TLE and review related genes which have been studied recently. Although its molecular mechanisms are still poorly understood, TLE genetics is a fertile field, awaiting more research.

Maturation of visual evoked potentials across adolescence - Corrected Proof

Yatin Mahajan, Genevieve McArthur — 2011-11-21

Abstract: Adolescence represents the period of transition from childhood to adulthood and is characterized by significant changes in brain structure and function. We studied changes in the functional visual processing in the brain across adolescence. Visual evoked potentials (VEPs) to three types of pattern reversal checkerboard stimuli were measured in 90 adolescents (10–18years) and 10 adults. Across adolescence, the N75 and P100 VEP peaks decreased in size while the N135 peak increased slightly in size. The latency of VEP peaks showed no reliable change across adolescence. The results suggest that even very basic visual sensory function continues to develop throughout adolescence. The results indicate significant changes in visual parvocellular and magnocellular pathways across adolescence.

Psychophysiological mechanisms underlying spatial attention in children with primary headache - Corrected Proof

2011-11-18

Abstract: Objective: Neurophysiological studies to evaluate spatial attention in children with primary headache are lacking. Tactile spatial attention modulates the N140 somatosensory evoked potential (SEP) amplitude.The aims of the study are: (1) to investigate the effect of spatial attention on the N140 amplitude in children with migraine and tension-type headache (TTH) and in healthy children, and (2) to correlate the neurophysiological results with a neuropsychological test for spatial attention.Methods: We studied 16 patients with migraine without aura (MoA), 12 TTH children and 10 healthy subjects. “Deux Barrage” test for spatial attention was administered. SEPs were recorded in a neutral condition (NC) and in a spatial attention condition (SAC).Results: No significant differences in neuropsychological measures were found between MoA, TTH and healthy subjects. The N140 amplitude increase during SAC, as compared to NC, was significantly higher in patients than in healthy controls. Migraineurs showed a positive correlation between the N140 amplitude increase during SAC and their neuropsychological performance.Conclusions: Although spatial attention performances in children with headache are as good as in controls, the N140 amplitude increase during SAC in headache patients suggests that the psychophysiological mechanisms subtending spatial attention are different from those in healthy children.

Evaluation of the GABAergic nervous system in autistic brain: 123I-iomazenil SPECT study - Corrected Proof

2011-11-18

Abstract: Purpose: To evaluate the GABAA receptor in the autistic brain, we performed 123I-IMZ SPECT in patients with ASD. We compared 123I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings.Subjects and methods: The subjects consisted of 24 patients with ASD (mean age, 7.3±3.5years), including 9 with autistic disorder (mean age, 7.0±3.7years) and 15 with Asperger’s disorder (mean age, 7.5±3.2years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8±3.6years) without intellectual delay as a control group.For an objective evaluation of the 123I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically.Results: In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of 123I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings.Conclusion: The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of 123I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind).

Early predictors of short term neurodevelopmental outcome in asphyxiated cooled infants. A combined brain amplitude integrated electroencephalography and near infrared spectroscopy study - Corrected Proof

2011-11-15

Abstract: Background: Brain Cooling (BC) represents the elective treatment in asphyxiated newborns. Amplitude Integrated Electroencephalography (aEEG) and Near Infrared Spectroscopy (NIRS) monitoring may help to evaluate changes in cerebral electrical activity and cerebral hemodynamics during hypothermia. Objectives: To evaluate the prognostic value of aEEG time course and NIRS data in asphyxiated cooled infants. Methods: Twelve term neonates admitted to our NICU with moderate-severe Hypoxic-Ischemic Encephalopathy (HIE) underwent selective BC. aEEG and NIRS monitoring were started as soon as possible and maintained during the whole hypothermic treatment. Follow-up was scheduled at regular intervals; adverse outcome was defined as death, cerebral palsy (CP) or global quotient <88.7 at Griffiths’ Scale. Results: 2/12 Infants died, 2 developed CP, 1 was normal at 6months of age and then lost at follow-up and 7 showed a normal outcome at least at 1year of age. The aEEG background pattern at 24h of life was abnormal in 10 newborns; only 4 of them developed an adverse outcome, whereas the 2 infants with a normal aEEG developed normally. In infants with adverse outcome NIRS showed a higher Tissue Oxygenation Index (TOI) than those with normal outcome (80.0±10.5% vs 66.9±7.0%, p=0.057; 79.7±9.4% vs 67.1±7.9%, p=0.034; 80.2±8.8% vs 71.6±5.9%, p=0.069 at 6, 12 and 24h of life, respectively). Conclusions: The aEEG background pattern at 24h of life loses its positive predictive value after BC implementation; TOI could be useful to predict early on infants that may benefit from other innovative therapies.

Corrected Proof

Norio Sakai — 2011-11-14

This is a unique textbook that comprehensively describes the basic physiology of normal myelination and the pathophysiology of representative diseases that manifest as leukodystrophies. The book was planned as the latest in the International Review of Child Neurology Series from Mac Keith Press. It is dedicated to the memory of Hugo Moser, who guided so many medical scientists in the field of white matter disorders.

A perfusion-metabolic mismatch in Sturge-Weber syndrome: A multimodality imaging study - Corrected Proof

2011-11-10

Abstract: Objective: We combined perfusion weighted imaging (PWI) with 2-deoxy-2[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) to study the relationship between regional metabolic and perfusion abnormalities and their clinical correlates in children with Sturge-Weber syndrome (SWS). Methods: Fifteen children (age: 0.9–10years) with unilateral SWS underwent high-resolution PWI and FDG PET prospectively. Regional (lobar) asymmetry indices (AIs) of subcortical white matter (WM) cerebral blood flow (CBF) were correlated with corresponding cortical FDG uptake asymmetries, extent of leptomeningeal vascular malformation and clinical seizure variables. Results: Abnormal cortical glucose metabolism and/or subcortical WM CBF were seen in all lobes affected by vascular malformation and extended to lobes not affected by abnormal pial vessels in 6 patients. Lower CBF was associated with lower cortical glucose metabolism in the temporal, parietal and occipital lobes (p⩽0.02). While decreased perfusion was associated with hypometabolism in most cases, increased regional CBF (found in 6 patients) was commonly associated with relatively mild or no hypometabolism. Ten of 24 cerebral lobes with normal glucose metabolism in the affected hemisphere showed abnormal perfusion. High seizure frequency was associated with severe parieto-occipital hypoperfusion (p⩽0.03), while long duration of epilepsy was related to frontal lobe hypometabolism (p=0.015). Conclusions: Regional perfusion and cortical metabolic abnormalities can extend beyond lobes affected by leptomeningeal vascular malformations and are related to epilepsy in SWS. Despite a general correlation between perfusion and metabolism, increased WM perfusion with preserved cortical metabolism in overlying cortex is a common pattern of a perfusion/metabolic mismatch. This may represent a disease stage where cortical function is preserved while increased WM perfusion provides collateral drainage of cortex via the deep vein system.

Clinical spectrum of SCN2A mutations - Corrected Proof

2011-10-26

Abstract: Mutations in SCN2A, the gene encoding α2 subunit of the neuronal sodium channel, are associated with a variety of epilepsies: benign familial neonatal–infantile seizures (BFNIS); genetic epilepsy with febrile seizures plus (GEFS+); Dravet syndrome (DS); and some intractable childhood epilepsies. More than 10 new mutations have been identified in BFNIS, all of them are missense. To date, only one nonsense mutation has been found in a patient with intractable childhood epilepsy and severe mental decline. Recently, microduplication of chromosome 2q24.3 (containing eight genes including SCN2A, SCN3A, and the 3′ end of SCN1A) was reported in a family with dominantly inherited neonatal seizures and intellectual disability. Functional studies of SCN2A mutations show that they can cause divergent biophysical defects in NaV1.2 and impair cell surface expressions. There is no consistent relationship between genotype and phenotype.

Aberrant high-gamma oscillations in the somatosensory cortex of children with cerebral palsy: A meg study - Corrected Proof

2011-10-24

Abstract: Objective: Our study is to investigate somatosensory dysfunction in children with spastic cerebral palsy (CP) using magnetoencephalography (MEG) and synthetic aperture magnetometry (SAM). Methods: Six children with spastic CP and six age- and gender-matched typically developing children were studied using a 275-channel MEG system while their left and right index fingers were stimulated in random order. The latency and amplitude of somatosensory evoked magnetic fields were analyzed at sensor level. The patterns of high-gamma oscillations were investigated with SAM at source level. Results: In comparison to the children with typical development, the latency of the first response of somatosensory evoked magnetic fields (SEFs) in the children with spastic CP was significantly delayed (p<0.05). High-gamma oscillations were identified in the somatosensory cortex in both children with CP and typical developing children. Interestingly, children with spastic CP had significantly higher incidence of ipsilateral activation in the somatosensory cortex following right and left finger stimulation, compared to typically developing children (p=0.05). Conclusion: The results suggest that children with spastic CP have a measurable delay of SEFs and high-gamma oscillations. The high rates of ipsilateral cortical activation imply the impairments of functional lateralization in the developing brain. This is the first MEG study to demonstrate abnormal high-gamma oscillations of somatosensory cortices representing the finger in children with spastic CP.

Kawasaki disease-associated MERS: Pathological insights from SPECT findings - Corrected Proof

2011-10-24

Abstract: We report for the first time the single photon emission computed tomography (SPECT) findings of a patient with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with Kawasaki disease, which showed hypoperfusion of the bilateral cingulate gyri, thalamus, basal ganglia, brainstem, and cortex of the frontal lobes. These findings indicate that the pathogenesis of MERS is based on cerebral hypoperfusion due to vasculitis or cerebrovascular dehydration.

The differences in epileptic characteristics in patients with porencephaly and schizencephaly - Corrected Proof

Miki Shimizu, Tomoki Maeda, Tatsuro Izumi — 2011-10-24

Abstract: The epileptic characteristics and their differences in patients with porencephaly and schizencephaly were, respectively, evaluated. Eleven patients with porencephaly and eight patients with schizencephaly were retrospectively enrolled in this study. Five of the six patients with extensive porencephaly and all five patients with open-lip schizencephaly had been suffering from various types of epileptic seizures. Three patients with extensive porencephaly and all five patients with open-lip schizencephaly had presented with early onset seizures before 9months of age. Two patients with extensive porencephaly and three patients with open-lip schizencephaly had presented with West syndrome. These two groups of patients with epileptic seizures showed generalized epilepsy or generalized epilepsy with unilateral dominancy at the onset, and then developed localization-related epilepsy or unilateral seizures with increasing age. The epileptic paroxysms showed multifocal independent spikes, which were not always localized in the defect or cleft sites at the last examination. Polytherapy or synergistic combinations were eventually introduced for these intractable seizures in both groups for patients without any evidence of efficacy. In the porencephaly patients, four of five patients achieved good seizure control with appropriate monotherapy or two-drug therapy including valproate. All five patients with schizencephaly had been treated by polytherapy, and three of them had persistent intractable seizures in spite of trying rational monotherapy or two-drug therapy. The epileptic intractability associated with open-lip schizencephaly might be related to the epileptogenesis of these extensive and widespread defective lesions, which were commonly associated with cortical dysplasia. A trial of rational monotherapy or two-drug therapy may be effective, rather than larger-number polytherapy in many cases, more in porencephaly than schizencephaly.

Do the eyes have it? Extraction of identity and positive expression from another’s eyes in autism, probed using “Bubbles” - Corrected Proof

Yongning Song, Takahiro Kawabe, Yuji Hakoda, Xiaoxin Du — 2011-10-17

Abstract: Background: It has been debated whether attending to a particular facial region, such as the eyes, is impaired in children with autism. The purpose of this study was to verify the poor eye gaze hypothesis postulating that children with High-Functioning Autism (HFA)/AS are impaired in their ability to attend to another’s eyes. Methods: Our study used the “Bubbles” method. A group with ASD (n=15) and a paired non-ASD group (n=18) completed an identity judgment task requiring a binary judgment of the identity of a person in an image, and an emotion judgment task requiring perception of expressed happiness in a facial image. Results: Results indicated that similar to non-ASD individuals, ASD individuals used information from other people’s eyes to judge identity as well as emotion, and performed as successfully as the non-ASD group both in identity and emotion judgment tasks. The results challenge the conventional hypothesis that individuals with ASD cannot attend to or derive information from another’s eyes. Conclusion: Our findings combined with the results of poor eye gaze to expressions of fear in previous studies suggest that ASD individuals can derive information pertaining to positive emotion, but cannot sufficiently extract information pertaining to negative emotion from another’s eyes.

Early-onset neurodegeneration with brain iron accumulation due to PANK2 mutation - Corrected Proof

2011-10-17

Abstract: Background: Pantothenate kinase-associated neurodegeneration (PKAN) is a neurodegenerative disorder caused by pantothenate kinase (PANK2) gene mutations. Brain magnetic resonance imaging (MRI) typically shows the “eye-of-the-tiger” sign, i.e. bilateral pallidal T2 hypointensity with a small central region of T2-hyperintensity. Aims: To describe clinical and MRI findings of a boy with early-onset neurodegeneration with brain iron accumulation due to PANK2 mutation. Methods: Clinical, neuroradiological and molecular investigations have been performed. Results: At first observation (2years and 10months) the boy presented only with developmental delay and toe-walking and isolated T2 hyperintensity within globi pallidi on brain MRI. One year later, small rounded areas of markedly low signal within the globi pallidi on T2∗- weighted images appeared in association with mild dystonia. PANK2 gene homozygous mutation confirmed the diagnosis of PKAN. Conclusions: In young children, PKAN should be suspected also before clinical and neuroradiological picture is fully indicative, to avoid delayed diagnosis of a genetic disease for which therapeutical options could be potentially useful if administered in paucisymptomatic subjects.

Bilateral spinal neurofibromas in patients with neurofibromatosis 1 - Corrected Proof

2011-10-17

Abstract: Neurofibromatosis 1 (NF1) is a neurocutaneous syndrome that can be inherited as autosomal dominant or may appear due to a de novo mutation. We present 8 patients (5 M and 3 F) with sporadic or non-familial spinal neurofibromatosis 1 (non-FSNF1) associated with bilateral spinal neurofibromas involving all of the paraspinal nerves. To our knowledge, this is the first series of such association described in the literature. Their ages ranged from 6months to 20years (average 9.8years) at the time of radiological diagnosis. This presentation appears to be earlier than in familial spinal neurofibromas in NF1 (FSNF1). Predisposition to malignancy probably is greater in the non-FSNF1 type. MRI studies were performed routinely in all patients with NF1 and these were complemented with MRI enhanced with gadolinium and repeated at different ages in cases with paraspinal tumors. Coronal views provided the best evidence for the presence of neurofibromas in every spinal nerve. The size of the tumors and the clinical complications increased with advancing age in most patients. Giant plexiform tumors were often seen in the cervico-thoracic region. Malignant peripheral nerve sheath tumors (MPNST) were found in one patient with a sciatic tumor and another patient died suddenly at home without necropsy or pathological study. Voluminous paraspinal neurofibromas can be at risk for malignancy. More frequent neuroimaging studies may be necessary for an earlier detection. Early surgical treatment to anticipate the occurrence of MPNST during surveillance could be an option. Bilateral spinal neurofibromas are found in both patients who inherited the NF1 and in those due to de novo mutations.

Various indications for a modified Atkins diet in intractable childhood epilepsy - Corrected Proof

2011-10-17

Abstract: Purpose: We reviewed retrospectively our experiences with children with intractable epilepsy who were indicated for a modified Atkins diet (MAD). Methods: Twenty children (8 female, 12 male) who were aged 2–17years with intractable epilepsy and tried the MAD between September 2008 and December 2010 were enrolled. Outcome measures included seizure frequency, adverse reactions and tolerability of the diet. Results: Finally 9 patients maintained the MAD with favorable seizure outcomes (a reduction of seizure frequency by over 50%) or successfully completed the diet therapy. Two patients who required a long-term trial of the diet therapy respectively due to Leigh’s syndrome and uncategorized mitochondrial cytopathy derived from cytochrome c oxidase defect, respectively, successfully maintained the diet treatment without any significant complications. In 7 patients, the ketogenic diet (KD) was not only effective but also too restrictive or caused serious unwanted events. Five of them maintained the seizure outcome previously achieved by the KD with the MAD. Ten patients began the MAD because they were reluctant to start the KD. Unfortunately, only 2 patients maintained the MAD with favorable seizure outcomes. One patient who chose the MAD to bridge the KD and complete discontinuation of the treatment successfully completed the diet therapy. Conclusion: A long-term treatment with the MAD was well tolerated. Moreover, the MAD can successfully substitute the classic KD in patients who showed improvement in seizure outcomes by the KD but could not tolerate it.

Congenital variant of Rett syndrome due to an intragenic large deletion in MECP2 - Corrected Proof

Yu Kobayashi, Tsukasa Ohashi, Noriyuki Akasaka, Jun Tohyama — 2011-10-17

Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder that is one of the most common causes of mental retardation in females. RTT diagnosis is based on distinct clinical criteria. We describe here a female patient with severe phenotype of congenital variant RTT. The patient originally presented with severe developmental delay prior to the age of 6months and later exhibited characteristic features of RTT that included air swallowing, bruxism, and hand stereotypies. Results of an array-based comparative genomic hybridization analysis indicated there was a very small microdeletion in Xq28. Multiplex ligation-dependent probe amplification analysis further confirmed there were heterozygous deletions of intron 2, exon 3, intron 3, and part of exon 4 in MECP2. Findings in the present patient confirm the view that large MECP2 deletions are an important cause of severe congenital variant RTT. To ensure an accurate diagnosis of congenital variant RTT, a multiplex ligation-dependent probe amplification analysis of MECP2 should be performed in patients suspected of having this disorder.

Cutaneous adverse drug reaction in patients with epilepsy after acute encephalitis - Corrected Proof

2011-10-13

Abstract: 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.

An investigation into kana reading development in normal and dyslexic Japanese children using length and lexicality effects - Corrected Proof

2011-10-13

Abstract: This is the first study to report differences between Japanese children with and without dyslexia in the way string-length and lexicality effects are manifested when reading Japanese kana. These children were asked to read kana words and non-words consisting of either two or five kana characters. The results showed that the error rates of the normal Preschoolers and Primary-School children with dyslexia were higher than those of the normal Primary-School children. Further, the reading latencies of the normal Preschoolers, First-graders and dyslexics were significantly longer than those of the normal Second, Third and Fifth/Sixth graders. Moreover, reading latencies became shorter as the age of the participants increased. Both normal and dyslexic children showed significant effects of length and lexicality on reading latencies. However, the interaction between the length and lexicality was only seen in normal children from the Second-grade onwards. These results suggest that (1) normal First-graders reach a ceiling in terms of reading accuracy and that (2) as Japanese normal children become older, they become better at lexical reading processes, which leads to fluent kana reading, but that (3) the dyslexics, even at Fifth/Sixth grades, have not developed sufficient lexical reading processes.

MECP2 mutations and clinical correlations in Greek children with Rett syndrome and associated neurodevelopmental disorders - Corrected Proof

2011-10-10

Abstract: Background: Mutations in the MECP2 gene (methyl-CpG-binding protein-2) are responsible for 60–95% of cases of Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder affecting mostly girls. Classic RTT is characterized by normal early development followed by psychomotor regression and onset of microcephaly, although variant forms are also observed. MECP2 has also been implicated in variable mental retardation (MR) phenotypes, including X-linked Mental Retardation (XLMR), Fragile-X-like Syndrome (FXS) and Angelman-like (AS) phenotypes. Aim: The aim of the study was: (a) to evaluate the incidence and spectrum of MECP2 mutations in children with RTT and variant MR; (b) to evaluate phenotype-genotype correlations. Methods: Exons 3–4 were analyzed for mutations in 281 MR patients (aged 13months–27years old, 144 males–137 females) consisting of 88 patients referred for RTT and 193 patients referred for AS-like and FXS-like types of MR. Statistical analysis included correlation between classic MECP2-positive and MECP2-negative and variant RTT patients, and frequency of MECP2 mutations in the various categories. Results: Mutations were detected in ≈70% of classic and ≈21% of variant RTT, respectively. Amongst MR cases, 2.1% carried MECP2 mutations. MECP2-positive females had more problems in ambulation, muscle tone, tremor and ataxia, respiratory disturbances, head growth, hand use and stereotypies. Classic RTT-positive versus negative had significant respiratory and sitting problems and versus variant RTT-positive females ambulatory, hand and stereotypies problems. Conclusion: The analysis of the MECP2 gene could provide a diagnostic tool for RTT and non-specific MR research.

A novel mutation in an atypical presentation of the rare infantile Farber disease - Corrected Proof

Fatma Al Jasmi — 2011-10-10

Abstract: Background: Farber disease (MIM 228000) is a rare autosomal recessive condition caused by deficiency of lysosomal acid ceramidase (EC 3.5.1.23). The disease presents classically during the infantile period with a characteristic triad of clinical manifestations: (a) painful joints, (b) subcutaneous nodules, and (c) progressive hoarseness due to laryngeal involvement. All cases reported in the literature to date have presented with the above features, except for the neonatal-visceral subtype. Methods: Here we describe a 2-year-old female, a product of a non-consanguineous Emirati union, who was quite well until 8months of age when presented with failure to thrive, developmental delay with relative sparing of cognitive function, cherry-red spot, painful joint, progressive limitation of joint movement, and hoarseness of voice. The sibling of patient died with similar presentation and the nerve biopsy of deceased sibling showed features consistent with Farber disease. Results: Gene sequencing of the ASAHI gene confirmed the diagnosis of Farber disease. Our patient has two heterozygous novel mutations, one in exon 8 (c.533 T>C) and the other in exon 13 (c.1144 A>C). The carrier status of the parents was confirmed. Conclusions: Farber disease is well known for its striking unique triad of symptoms. This study demonstrates that not all the cases essentially present with subcutaneous nodules which is considered a hallmark of the disease.

Atonic variant of benign childhood epilepsy with centrotemporal spikes (atonic-BECTS): A distinct electro-clinical syndrome - Corrected Proof

2011-10-10

Abstract: Purpose: To describe the clinical and electroencephalographic features, treatment strategies and outcome in a series of children with the atonic variant of benign childhood epilepsy with centrotemporal spikes (atonic-BECTS).Material and methods: Out of the 148 patients with BECTS reviewed from January 2005 to June 2010 in our Institute, there were seven (5%) with atonic-BECTS. All underwent video EEG, high-resolution magnetic resonance imaging (MRI), neuropsychological evaluation and language assessment. Their progress was followed. In addition to sodium valproate, three were treated with steroids, followed by intravenous immunoglobulin (IVIG) when the seizures relapsed while tapering or after stopping the steroids.Results: All of the children had earlier onset (mean=2.4years), increased frequency and increased duration of focal seizures compared to typical BECTS. Head drop and truncal sway due to axial or axiorhizomelic atonia occurring several times per day or week was the key manifestation. The atonic seizures worsened with carbamazepine in three, clonazepam in two and clobazam in one. When the atypical seizures commenced, some children developed one or more of the following problems: hyperactivity, attention deficit, clumsy gait, and mild cognitive or language dysfunction. Three children became seizure free, one on steroids and the other two on IVIG.Conclusions: BECTS in children with an early age of onset and frequent and prolonged seizures is more likely to evolve into atonic-BECTS. Carbamazepine and some benzodiazepines may worsen these seizures. Three children became seizure free with immunomodulatory therapy, one on steroids and the other two on IVIG, and had complete resolution of the transient motor and cognitive impairment. Atonic-BECTS needs to be differentiated from Lennox–Gastaut syndrome since it is potentially treatable and children recover with no sequel. Although all the children in this series continued to be on treatment with sodium valproate it is currently undetermined whether they would have required to do so if followed up for an extended period of time.

Ohtahara syndrome with emphasis on recent genetic discovery - Corrected Proof

Piero Pavone, Alberto Spalice, Agata Polizzi, Pasquale Parisi, Martino Ruggieri — 2011-10-04

Abstract: Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with Suppression-Burst, is the most severe and the earliest developing age-related epileptic encephalopathy. Clinically, the syndrome is characterized by early onset tonic spasms associated with a severe and continuous pattern of burst activity. It is a debilitating and early progressive neurological disorder, resulting in intractable seizures and severe mental retardation. Specific mutations in at least four genes (whose protein products are essential in lower brain’s neuronal and interneuronal functions, including mitochondrial respiratory chains have been identified in unrelated individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at 9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship between early myoclonic encephalopathy (EME–ErbB4 mutations) versus the EIEE spectrum of disorders.

EEG characteristics predict subsequent epilepsy in children with febrile seizure - Corrected Proof

Hideaki Kanemura, Sonoko Mizorogi, Kakuro Aoyagi, Kanji Sugita, Masao Aihara — 2011-09-28

Abstract: The role of electroencephalography (EEG) in the work-up of febrile seizure (FS) remains controversial. We investigated the importance of EEG characteristics, especially the localizations of paroxysmal discharges, as predictors for subsequent epilepsy. Patients were referred from the outpatient department for EEG within 7–20days after the seizure. EEGs were classified as paroxysmally abnormal based on the presence of spikes, sharp waves, or spike–wave complexes, whether focal or generalized, that were considered abnormal for age and state. Of 119 patients with FS, 26 (21.8%) revealed paroxysmal abnormality on EEG and 9 (7.6%) developed epilepsy. Of nine patients with later epilepsy, 6 (66.7%) revealed paroxysmal EEG abnormality. Of 26 patients with paroxysmal abnormality, 6 (23.1%) developed epilepsy. Of 10 patients with generalized paroxysmal spike and wave activity, one (10%) developed epilepsy. Of seven patients with rolandic discharge (RD), two (28.5%) developed epilepsy. Of four patients with paroxysms in the frontal region, three (75%) developed epilepsy. Of five patients with paroxysms in the occipital region, none developed epilepsy. Compared with generalized EEG foci, the relative risk (RR) for patients with frontal EEG foci was 27.0. Patients with frontal EEG paroxysms had a significantly higher risk of developing epilepsy than those with paroxysms in other regions of EEG foci (p=0.035). These findings suggest that patients with FS presenting with frontal paroxysmal EEG abnormalities may be at risk for epilepsy. In patients with frontal paroxysmal EEG abnormalities, serial EEG should be performed, even though it does not contribute to treatment.