Brain and Development - Articles in Press

Magnetic resonance imaging in neonates with total asphyxia - Corrected Proof

2012-05-14

Abstract: Magnetic resonance (MR) findings in cases of total asphyxia, whose lesions are mainly in the brainstem and deep nuclei, have not been clarified. In this study, we investigated MR images in neonates with total asphyxia. MR images of six infants (three males and three females; gestational age, 35–39weeks; birth weights, 1880–3572g) with total asphyxia were examined. In all subjects, neonatal cortical MR lesions were limited to the hippocampus with highlighting on T1-weighted imaging (T1-WI). The neonatal MR lesions of the cerebral white matter were limited to the white matter between the insula and putamen in four infants, and were diffusely involved in two infants. The ventral lateral nucleus of the thalamus was hyperintense on T1-WI in all of the subjects. Other nuclei in the thalamus, the globus pallidus and the putamen were involved in neonatal MR images of all subjects. High intensity areas on T2- weighted imaging were observed at the dorsal areas in the midbrain, pons and medulla oblongata in all or most of the subjects at the neonatal period. Also, high intensity areas on T1-WI were observed in the tegmentum of the pons and the midbrain in five cases. Neonates with total asphyxia had lesions mainly in the tegmentem of the brainstem, thalamus, putamen and globus palludus. Some of the infants had extensive lesions of the white matter.

Open study of pranlukast add-on therapy in intractable partial epilepsy - Corrected Proof

2012-05-09

Abstract: Innovative treatments of epileptic seizures are needed to improve the outcome of epilepsy. We studied the effect of pranlukast on seizure outcome in patients with intractable partial epilepsy. An open study was conducted to evaluate the clinical efficacy of 24-week pranlukast add-on therapy in 50 patients with intractable partial seizures. Serum concentrations of matrix metalloproteinase (MMP)-9 were determined using Biotrak Activity Assay System. Cytokines in cerebrospinal fluid (CSF) were measured by the BioPlex (BioRad) system and soluble TNF receptor1 (sTNFR1) in CSF was measured by the ELISA. Surface markers of lymphocytes in CSF were examined by cell-sorter. Seizure-free rate (SFR) was 13.6%, responder rate (RR) was 47.7%, and aggravation rate (AR) was 18.2% at the 13–24week period after starting pranlukast. In patients with increased serum MMP-9 before pranlukast therapy (baseline), comparison of paired serum levels showed a significant decrease after pranlukast therapy. Baseline CSF levels of IL-1β and IL-6 were elevated in patients compared with disease controls. Of four patients with paired data, three (including a responder to pranlukast) showed decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and four showed decreased sTNFR1, after pranlukast treatment, and only a responder had markedly decreased frequency of CD8+ T cells in CSF. Pranlukast reduces seizure frequencies probably by pleiotropic effects including normalization of MMP-9 in sera, reduced leakage of pro-inflammatory cytokines into CNS, and inhibition of extravasation of leucocytes from brain capillaries. Further investigations by double-blind control study and animal models are warranted.

Acute limbic encephalitis with focal hyperperfusion on single photon emission computed tomography - Corrected Proof

2012-05-03

Abstract: Here we report an 11-year-old boy with acute encephalopathy with neuropsychiatric symptoms. The patient had mildly decreased consciousness, delirious behavior, and affective changes next day of fever onset. Hematologic, biochemical, and metabolic examinations were unremarkable. CSF analysis revealed cell counts of 278cells/mm3 and a protein level of 87mg/dL. Although MRI revealed no abnormal findings, an increase in regional cerebral blood flow was present in the bilateral frontal lobes, mesial temporal lobes, and basal ganglia on single photon emission computed tomography. The measurement of the concentrations of biomarkers such as cytokines in the patient’s serum and cerebrospinal fluid revealed elevated levels of IL-4 and TNF-α in the cerebrospinal fluid. Immunohistochemical studies applying control human brain sections did not demonstrate the presence of autoantibodies. We considered that innate immunity rather than autoantibody response may have contributed to the neuropsychiatric symptoms of our patient. These results suggest heterogeneity of patients with acute encephalopathy with neuropsychiatric symptoms.

Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum - Corrected Proof

2012-04-27

Abstract: Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis.

Pharmacotherapy of autism spectrum disorders - Corrected Proof

Arianna Benvenuto, Barbara Battan, Maria Cristina Porfirio, Paolo Curatolo — 2012-04-27

Abstract: Although no pharmacological or behavioral therapy has currently proven effective for treating all core symptoms of autism, many dysfunctional behaviors may be treated pharmacologically. Drug treatments should always be part of a comprehensive management plan that includes behavioral and educational interventions, and should be focused on specific targets. Several classes of psychotropic medications have been used to decrease the wide range of “maladaptive” or “interfering” behaviors and associated medical problems that can interfere with relationships and physical health and hinder the implementation of various non-pharmacological interventions. Atypical neuroleptics have been shown to be useful in the treatment of behavioral symptoms in autism. Attention deficit and hyperactivity disorder medications may be effective for counteracting the additional features of hyperactivity and short attention span. Antiepileptic drugs and selective serotonin reuptake inhibitors have shown promising results, but there are no specific indications for them as of yet. With respect to potential drug targets, some clinical features are caused by a dysfunction in neurochemical signaling systems, and thus may improve with selective pharmacological interventions acting on specific abnormal neurobiological pathways. Recent animal studies can be useful models for understanding the common pathogenic pathways leading to autism spectrum disorders (ASDs), and have the potential to offer new biologically focused treatment options.

Extrauterine environment influences spontaneous low-frequency oscillations in the preterm brain - Corrected Proof

2012-04-25

Abstract: Low-frequency oscillations in cerebral blood flow that are suggestive of resting-state brain activity have recently been reported, but no study on the development of resting-state brain activity in preterm infants has been performed. The objective of this study was to measure the cerebral blood flow oscillations, which are assumed to represent brain function in the resting state, in preterm and term infants of the same postconceptional age. The subjects were 9 preterm infants who had reached full term (gestational age (GA): 23–34weeks, postconceptional age: 37–46weeks) and 10 term infants (GA: 37–40weeks, postconceptional age: 37–41weeks). Their changes in concentration of oxyhemoglobin ([oxyHb]) and deoxyhemoglobin ([deoxyHb]) were measured in the parieto-temporal region during quiet sleep using multi-channel near-infrared spectroscopy, and the power spectral densities (PSD) of the oscillations in the concentrations of these molecules were analyzed and compared. The preterm infants displayed a higher proportion of 0.06–0.10Hz low frequency oscillations of [oxyHb] and [deoxyHb] than the term infants, and the gestational age and the proportion of low frequency oscillations were inversely correlated. These findings suggest that resting-state cerebral blood flow oscillations differ between preterm and term infants, and that the development of circulatory regulation and nerve activity in preterm infants are influenced by the extrauterine environment.

Non-protein-bound iron and 4-hydroxynonenal protein adducts in classic autism - Corrected Proof

2012-04-25

Abstract: A link between oxidative stress and autism spectrum disorders (ASDs) remains controversial with opposing views on its role in the pathogenesis of the disease. We investigated for the first time the levels of non-protein-bound iron (NPBI), a pro-oxidant factor, and 4-hydroxynonenal protein adducts (4-HNE PAs), as a marker of lipid peroxidation-induced protein damage, in classic autism. Patients with classic autism (n=20, mean age 12.0±6.2years) and healthy controls (n=18, mean age 11.7±6.5years) were examined. Intraerythrocyte and plasma NPBI were measured by high performance liquid chromatography (HPLC), and 4-HNE PAs in erythrocyte membranes and plasma were detected by Western blotting. The antioxidant defences were evaluated as erythrocyte glutathione (GSH) levels using a spectrophotometric assay. Intraerythrocyte and plasma NPBI levels were significantly increased (1.98- and 3.56-folds) in autistic patients, as compared to controls (p=0.0019 and p<0.0001, respectively); likewise, 4-HNE PAs were significantly higher in erythrocyte membranes and in plasma (1.58- and 1.6-folds, respectively) from autistic patients than controls (p=0.0043 and p=0.0001, respectively). Erythrocyte GSH was slightly decreased (−10.34%) in patients compared to controls (p=0.0215). Our findings indicate an impairment of the redox status in classic autism patients, with a consequent imbalance between oxidative stress and antioxidant defences. Increased levels of NPBI could contribute to lipid peroxidation and, consequently, to increased plasma and erythrocyte membranes 4-HNE PAs thus amplifying the oxidative damage, potentially contributing to the autistic phenotype.

Quantitative computed tomography for enzyme replacement therapy in Pompe disease - Corrected Proof

2012-04-23

Abstract: Objective: Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme, acid alpha-glucosidase (GAA). To the best of our knowledge, no studies have reported the results of systematic and sequential CT analyses before and during ERT. In this study we have treated three patients with late onset Pompe disease by ERT, and investigated the efficacy of treatment by computed tomography number. Methods: We measured the serial changes in the computed tomography (CT) number of multiple organs in three patients with late onset of Pompe disease during 24months of enzyme replacement therapy (ERT). Results: Before treatment, the liver and muscle CT numbers were higher in these patients than in the controls. The liver CT number decreased after performing ERT. Furthermore, the urinary glucose tetrasaccharide levels, a biomarker of glycogen accumulation, were elevated before ERT and reduced thereafter. Conclusions: The findings in these cases suggest that the elevation of the liver CT number represents glycogen accumulation in the liver and that the analysis of the liver CT number is therefore a useful tool for assessing the efficacy of ERT.

Effects of lamotrigine on cognition and behavior compared to carbamazepine as monotherapy for children with partial epilepsy - Corrected Proof

2012-04-23

Abstract: To compare the cognitive and behavioral effects of lamotrigine (LTG) to carbamazepine (CBZ) as monotherapy for pediatric epilepsy. A multicenter, randomized, open-label, parallel-group clinical trial was conducted in children with partial-onset seizures. LTG or CBZ was prescribed as monotherapy for previously untreated children and titrated over 8weeks, followed by maintenance for 24weeks. Outcome measures were change in cognition and behavior in a combined analysis of standardized measures from screening to the end of the maintenance phase, as well as antiepileptic efficacy and tolerability. A total of 67 children completed the study, including 32 of 43 (74.4%) treated with LTG and 35 of 41 (85.4%) treated with CBZ. Seizure-free outcomes did not differ between the intent-to-treat populations (53.5% LTG, 56.1% CBZ; p=0.81). There were no statistically significant differences in the intelligence of the two groups after treatment. Externalizing behavior problems improved in the CBZ group (p<0.05). However, there were no significant differences between the two groups in terms of externalizing behavior. The parents’ report on the Conner scale showed an improvement in the CBZ group compared to the LTG group (p<0.05). LTG and CBZ showed similar efficacy and cognitive effects in treating childhood partial epilepsy. However, CBZ showed more benefits in improving externalizing behaviors.

Aicardi–Goutières syndrome with systemic lupus erythematosus and hypothyroidism - Corrected Proof

Atsushi Kamei, Manami Akasaka, Nami Soga, Yu Suzuki, Mare Uchide, Shoichi Chida — 2012-04-23

Abstract: We report a case of Aicardi–Goutières syndrome with systemic lupus erythematosus and hypothyroidism. A 3-year-old girl, diagnosed with Aicardi–Goutières syndrome at 9months, was transferred to our hospital for fever of unknown origin. Severe spasticity with dystonic posturing and flexion contracture of the limbs were noted. Interstitial pneumonia with pleural effusion was evident. Immunological investigations revealed positive antinuclear antibodies and reduced thyroid function. Prompt treatment with steroids, cyclophosphamide, and levothyroxine sodium hydrate elicited a good response. It is necessary to emphasize that its possible relationship between Aicardi–Goutières syndrome and systemic lupus erythematosus and/or hypothyroidism.

Malignant migrating partial seizures of infancy controlled by stiripentol and clonazepam - Corrected Proof

2012-04-23

Abstract: The syndrome of malignant migrating partial seizures of infancy (MMPSI) is characterized by early onset of multiple seizure types and overall poor prognosis. Seizures are markedly drug resistant and few reports have suggested the efficacy of some antiepileptic drugs. We report one case of MMPSI in which prolonged seizure control is obtained with an association of clonazepam, levetiracetam and stiripentol, confirming thus the possibility of complete sustained seizure control in this epileptic syndrome. Of more than 60 cases reported to date, ours is the forth in which sustained complete control of seizures was obtained.

Passive toothbrushing-induced seizures: Report of a severely disabled girl - Corrected Proof

2012-04-20

Abstract: Toothbrushing-induced seizures are rare reflex seizures triggered by the brushing of one’s own teeth. We encountered an 11-year-old girl with severe mental retardation, hypotonic cerebral palsy and epilepsy who presented with toothbrushing-induced seizures. She had had spontaneous brief tonic seizures several times a day since the age of 1year and 2months and started presenting with the same type of seizures induced by toothbrushing from the age of 8years. As she could not brush her teeth by herself due to her disabilities, her mother brushed her teeth daily for her. The interictal EEG showed spike-and-wave complexes in the frontal regions bilaterally. The [Tc-99m]HMPAO-SPECT at the time of the seizure induced by toothbrushing suggested that the seizures originated from the left perisylvian cortex. This is the first report of toothbrushing-induced seizures triggered by the brushing of the patient’s teeth by another person (‘passive toothbrushing’).

Perfusion status of the stroke-like lesion at the hyperacute stage in MELAS - Corrected Proof

2012-04-20

Abstract: Hypoperfusion on single-photon emission computed tomography (SPECT) of the stroke-like lesion (SLL) at the hyperacute stage of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is considered to be a supportive evidence of the mitochondrial angiopathy theory. Our objectives were to examine whether other neuroimages, especially transcranial color-coded sonography (TCCS), done at the hyperacute stage of stroke-like episode (SLE) is consistent with hypoperfusion of the SLL. We reviewed the magnetic resonance imaging (MRI), SPECT, cerebral angiography, and TCCS of a patient with MELAS syndrome, all of which were performed at the hyperacute stage of one SLE. MRI on the 1st day post SLE showed right temporoparietal lesion with vasogenic edema. SPECT on the 2nd day showed focal decreased uptake of technetium-99m hexamethylpropyleneamine oxime (99mTc-HMPAO) in the same region, but cerebral angiography and TCCS on the 3rd day showed increased regional cerebral blood flow (rCBF) and distal arteriole dilation in the same region. TCCS can delineate increased rCBF of the SLL at the hyperacute stage of SLE. We propose that the discrepancy between the decreased 99mTc-HMPAO uptake and increased rCBF might be caused by mitochondrial dysfunction. The phenomenon of “hypoperfusion” on SPECT might be caused by cell dysfunction but not decreased rCBF. We suggest that SPECT can be complemented by angiography and TCCS in future studies to delineate the perfusion status of SLLs.

Peripheral nerve abnormalities in pediatric patients with spinal muscular atrophy - Corrected Proof

Takahiro Yonekawa, Hirofumi Komaki, Yuko Saito, Kenji Sugai, Masayuki Sasaki — 2012-04-18

Abstract: We examined the specific nerve conduction deficits distinguishing spinal muscular atrophy (SMA) subtypes I and II. Five SMA I patients (age, 0.2–1.1years) and 10 SMA II patients (age, 1.0–2.8years) were examined. Patients were compared to age-matched controls for motor and sensory conduction velocity (MCV and SCV) changes, compound muscle and sensory nerve action potential amplitudes (CMAP and SNAP), and F-wave occurrence (FO). Slower MCVs were found in three of five SMA I patients; all five exhibited markedly decreased CMAP amplitudes. Tibial nerve CMAP amplitudes significantly reduced in SMA II patients (p<0.01). Slower SCVs and decreased SNAP amplitudes were observed in three of five SMA I patients but not in SMA II patients. Although FOs were reduced in both extremities of SMA I patients, the reduction was prominent in the tibial nerve of SMA II patients (p=0.031). Loss of motor units may be widespread in the early stage of SMA I, while specific to the legs in young SMA II patients. SMA I showed sensory nerve degeneration, especially of large myelinated fibers. SMA II showed no sensory nerve abnormalities.

Behavioral assessment of Japanese children with epilepsy using SDQ (strengths and difficulties questionnaire) - Corrected Proof

2012-04-11

Abstract: The aim of this study was to elucidate the availability of the strengths and difficulties questionnaire (SDQ) as a screening tool for identifying behavioral problems in Japanese children with epilepsy. Methods: Eighty-three 4–16year-old epileptic patients, followed at Tanabe-Kadobayashi Children’s Clinic, were studied. Children with severe mental or physical disability were excluded. The Japanese version of the SDQ was used, and scores were compared to the Japanese standard. Results: ‘Hyperactivity’ was the SDQ category with the most striking differences from normal: a significant numbers of children had scores above the clinically normal range and only a small proportion were within the normal range (p<0.0001). The rates of epilepsy patients with scores above normal range were also significantly higher for ‘peer problems’ and ‘conduct problems’ (p<0.0001 and p<0.01). The rates of epilepsy patients with scores within the normal range was significantly lower for ‘emotional symptoms’ than in normal controls (p<0.001). On the other hand, the ‘pro-social behavior’ score did not differ significantly from the Japanese standard. As for clinical factors, patients with symptomatic localization-related epilepsy and focal electroencephalographic abnormalities had significantly higher scores for some SDQ items. Age at epilepsy onset correlated negatively with scores for ‘total difficulties’ and ‘hyperactivity’, suggesting early onset to be a risk factor for poor SDQ scores. Conclusions: These findings confirm that higher rates of psychiatric comorbidity in Japanese children with epilepsy may be diagnosed using SDQ in Japanese children with epilepsy. These problems should be addressed in the early phase of epilepsy management in order to preserve health-related quality of life for affected patients.

A severe form of epidermal nevus syndrome associated with brainstem and cerebellar malformations and neonatal medulloblastoma - Corrected Proof

2012-04-09

Abstract: Here we report a boy with epidermal nevus syndrome associated with brainstem and cerebellar malformations and neonatal medulloblastoma. The patient had epidermal nevi and complicated brain malformations including macrocephaly with polymicrogyria, dysmorphic and enlarged midbrain tectum, enlarged cerebellar hemispheres with small and maloriented folia. The patient died after surgical resection of medulloblastoma which was newly recognized on MRI at 51days of age. Postmortem pathological examinations showed very unique and bizarre malformation of the midbrain and hindbrain. The cerebellar cortex exhibited a coarse, irregular and bumpy surface, blurred border between the Purkinje cell layer and internal granule cell layer, and many foci of heterotopia in the cerebellar white matter. The brainstem showed multiple anomalies, including enlargement of superior colliculi, hypoplasia of pyramidal tracts and dysplasia of inferior olivary nuclei. The unusual constellation of brain malformations of our patient will widen the spectrum of epidermal nevus syndrome.

Antiamnesic activity of Syzygium cumini against scopolamine induced spatial memory impairments in rats - Corrected Proof

2012-04-04

Abstract: We evaluated the Antiamnesic effects of methanolic extract of Syzygium cumini (MESC) on spatial memory impairments induced by scopolamine (1mg/kg, i.p.), a muscarinic antagonist, using the Radial arm maze, Morris water maze, learned helpless ness tests. Effect of MESC was evaluated and compared to standard drug, piracetam (200mg/kg, i.p.). The MESC significantly (p<0.05) improved the impairment of short term or working memory induced by scopolamine in the Radial arm maze test, and significantly (p<0.05) reversed cognitive impairments in rats as measured by the learned helplessness test. In addition, MESC decreased escape latencies in the Morris water maze test. The activity of acetylcholinesterase in the brain was inhibited significantly (p<0.05) by treatment with MESC to a level similar to that observed in rats treated with piracetam. Moreover treatment with MESC (200 and 400mg/kg, p.o.) to scopolamine induced rats significantly (p<0.05) decreased TBARS levels which was accompanied by an increase in the activities of SOD and Catalase. MESC has dose dependent effect and 400mg/kg dose shown more prominent results when compared to 200mg/kg dose of MESC. These results indicate that MESC may exert anti-amnesic activity via inhibition of acetylcholinesterase and antioxidant mechanisms in the brain.

An atypical patient with Cowden syndrome and PTEN gene mutation presenting with cortical malformation and focal epilepsy - Corrected Proof

2012-04-02

Abstract: We report the case of a girl with Cowden syndrome (CS) presenting with unilateral perisylvian dysplasia and with drug resistant focal seizures carrying a novel missense mutation 385G>A (G129R) in the PTEN gene. CS has been rarely reported in association with a cortical malformation or epilepsy. These cases suggest that cortical dysplasia needs to be suspected when a CS patient presents with drug-resistant seizures.

EEG characteristics and visual cognitive function of children with attention deficit hyperactivity disorder (ADHD) - Corrected Proof

2012-03-29

Abstract: Using visual and auditory continuous performance tests (CPT) and EEG, cognitive function and EEG power were investigated in patients with attention deficit hyperactivity disorder (ADHD). CPT and EEG were conducted for 44 ADHD children and 44 healthy controls of comparable age and sex. The EEG power tests include relative power of theta, alpha, and beta, and theta/beta and theta/alpha ratios. ADHD patients showed significantly higher theta relative power, lower beta relative power, and higher theta/beta ratio (p<0.05). ADHD patients showed a significantly lower score of auditory CPT (p<0.05). The EEG power characteristics were correlated significantly with the visual attention function in ADHD children (p<0.01). Higher-order level cognitive dysfunction affects ADHD pathogenesis. Cortical hypoarousal effects on several mechanisms including the fronto-striatal circuitry may be implicated in the inhibition of prepotent and premature responses.

Attention and executive functions profile in childhood absence epilepsy - Corrected Proof

2012-03-29

Abstract: Childhood absence epilepsy (CAE) has been associated with executive functions and attention deficits. To clarify the issue of neurocognitive impairments in CAE, we investigated whether specific executive functions and attention deficit patterns were present in a well-defined group of children with CAE who were taking valproic acid. Participants included 15 children with CAE and 15 healthy controls aged 8–15years and matched for sex, age and IQ. We compared the performances of the two groups in the following neuropsychological domains: planning and problem solving (TOL), verbal fluency (FAS and CAT), verbal short-term memory (DSF), verbal working memory (DSB), visuospatial memory (Corsi Block Tapping Test) and sustained and divided attention (TMT-A and TMT-B). No differences were found between the two groups on measures of intellectual functioning, verbal short-term memory and visuospatial memory. By contrast, significant differences were found in total time of planning task, phonological and category fluency and sustained and divided attention. Future studies that systematically examine different aspects of attention and executive functions are needed to outline a clear and specific neuropsychological profile in CAE.

Pulmonary hypertension in a child with mitochondrial A3243G point mutation - Corrected Proof

Po-Cheng Hung, Huei-Shyong Wang, Hung-Tao Chung, Mao-Sheng Hwang, Long-Sun Ro — 2012-03-28

Abstract: Mitochondrial diseases are a group of disorders caused by pathologic dysfunction of the mitochondrial respiratory chain that present with a wide range of clinical expression. Cardiorespiratory complications have previously been described in association with mitochondrial disease; however, pulmonary hypertension has rarely been reported. Pulmonary hypertension is characterized by elevated pulmonary arterial pressure and secondary right ventricular failure. It is a life-threatening condition with a poor prognosis if untreated. We report a case of 3-year-4-month-old boy who had mitochondrial A3243G point mutation with pulmonary hypertension. The unusual features of our case strengthen the concepts of pulmonary hypertension should be considered as another potential manifestation of mitochondrial disease.

Lateral medullary syndrome in a boy with hereditary dysfibrinogenemia - Corrected Proof

Tetsuya Kibe, Manae Ikeya, Kenji Yokochi, Nobuo Okumura — 2012-03-27

Abstract: A 9-year-old boy presented with sudden onset of nausea, vomiting and unsteady gait after a bread-eating game, which possibly caused neck hyperextension. Neurological examination revealed hemisensory loss of pain and temperature sensation in the right trunk and limbs along with left Horner’s syndrome, suggesting lateral medullary syndrome (LMS). Magnetic resonance (MR) imaging of the brain revealed infarction at the left lateral medulla. MR angiography showed no sign of arterial dissection and no occlusion or stenosis of the intracranial, basilar or vertebral arteries or their branches. No evidence of cardioemboli or systemic inflammation was apparent. Repeated blood examination revealed low activity of fibrinogen. Genetic testing confirmed the presence of hereditary dysfibrinogenemia with a mutation in the FGB gene (BβGly15Cys). This fibrinogen variant has previously been found in Japanese patients with atherosclerosis obliterans or no symptoms. Under conservative treatment without anticoagulation and aspirin, the patient made a good recovery within a few months. We presume that microthrombosis may have been deposited within the vertebral system as a result of extension and rotation of the neck during sports activity, with a contribution from hereditary dysfibrinogenemia.

Focal cortical myoclonus in rolandic cortical dysplasia presenting as hemifacial twitching - Corrected Proof

2012-03-27

Abstract: A 2-year-old girl presented with brief episodes of left hemifacial twitching. On ictal electroencephalography, repetitive focal spike discharges appeared at the right fronto-centro-temporal regions; these discharges preceded the onset of each twitch by 12ms. Magnetic resonance imaging showed a linear abnormal signal intensity in the subcortical white matter at the right postcentral gyrus, where a cluster of dipole sources was detected by magnetoencephalography. These findings suggested that the patient had focal cortical myoclonus due to rolandic focal cortical dysplasia.

Nonconvulsive status epilepticus due to drug induced neurotoxicity in chronically ill children - Corrected Proof

2012-03-23

Abstract: Nonconvulsive status epilepticus (NCSE) is a specific form of status epilepticus and is defined as epileptic activity on an EEG without seizures and as an alteration in mental status lasting more than 30min. NCSE may be caused by drugs, cerebrovascular events, metabolic disorders or toxins. Herein, we present four cases of patients with drug-induced NCSE who were chronically ill due to renal failure or childhood leukemia. NCSE should be suspected in patients with an altered mental status without clinical seizures who are being treated with multiple drugs.

A pediatric patient with myopathy associated with antibodies to a signal recognition particle - Corrected Proof

2012-03-21

Abstract: We report the case of a 15-year-old Japanese girl with myopathy associated with antibodies to a signal recognition particle (anti-SRP myopathy). The patient presented with progressive symmetrical proximal muscle weakness that caused difficulty in walking within 3months, and marked elevation of the serum creatine kinase levels. A skeletal muscle biopsy revealed active necrotic and regenerating processes, with mild inflammatory changes. Based on the above findings, the patient was diagnosed as having anti-SRP myopathy. Only a limited number of pediatric patients with anti-SRP myopathy has been reported previously, with usually a poor prognosis. Early diagnosis is important for obtaining a better prognosis in patients with anti-SRP myopathy.

Two Japanese patients with Leigh syndrome caused by novel SURF1 mutations - Corrected Proof

2012-03-14

Abstract: We report two patients with Leigh syndrome that showed a combination of facial dysmorphism and MRI imaging indicating an SURF1 deficiency, which was confirmed by sequence analysis. Case 1 is a 3-year-old girl with failure to thrive and developmental delay. She presented with tachypnea at rest and displayed facial dysmorphism including frontal bossing, lateral displacement of inner canthi, esotropia, maxillary hypoplasia, slightly upturned nostril, and hypertrichosis dominant on the forehead and extremities. Case 2 is an 8-year-old boy with respiratory failure. He had been diagnosed as selective complex IV deficiency. Case 2 displayed facial dysmorphism and hypertrichosis. Since both patients displayed characteristic facial dysmorphism and MRI findings, we sequenced the SURF1 gene and identified two heterozygous mutations; c.49+1 G>T and c.752_753del in Case 1, and homozygous c.743 C>A in Case 2. For patients with Leigh syndrome showing these facial dysmorphism and hypertrichosis, sequence analysis of the SURF1 gene may be useful.

Abnormalities of joint mobility and gait in children with autism spectrum disorders - Corrected Proof

Maya Shetreat-Klein, Shlomo Shinnar, Isabelle Rapin — 2012-03-09

Abstract: Aims: Abnormalities of gross motor function in children with autism are well known to clinicians but have not received much empirical documentation and, with the exception of stereotypies, are not among its diagnostic criteria. We recorded the characteristics of gait and prevalence of toe walking, the range of passive joint mobility, and age at walking in children with DSM IV autism spectrum disorders (ASDs) and in age- and gender-matched typically developing peers (mean age 4years 6months, range 22months–10years 9months). Methods: We evaluated maximum range of mobility at the elbow, wrist, metacarpo–phalangeal, and ankle joints and videoed children walking and running. Two neurologists blind to diagnosis independently scored features of gait clinically. Results: Children with ASDs had significantly greater joint mobility (p<.002), more gait abnormalities (p<.0001), and on average walked 1.6months later than their non-autistic peers. Interpretation: This study indicates that attention should be directed to motor abnormalities as well as sociability, communication, and restricted and repetitive behaviors in individuals with ASDs. Motor deficits add to children’s other handicaps. They indicate that ASDs affect a broader range of central nervous system circuitry than often appreciated.

Clinical and genetic characterization of a 2-year-old boy with complete PLP1 deletion - Corrected Proof

2012-03-09

Abstract: We report herein a case of 2-year-old boy diagnosed with a mild form of Pelizaeus–Merzbacher disease due to deletion of the entire proteolipid protein 1 (PLP1) gene. The patient demonstrated spastic quadriplegia, mental retardation, and microcephaly. He exhibited brainstem auditory evoked potentials with prolonged interpeak latencies and magnetic resonance imaging characteristics suggestive of hypomyelination in most areas of the brain with the exception of the brainstem, cerebellar peduncles, corpus callosum, and the posterior limbs of the internal capsules. Proton magnetic resonance spectroscopy revealed a mildly reduced ratio of N-acetyl aspartate to creatine levels in the white matter, suggesting axonal involvement. Additionally, nerve conduction velocity of the lower extremities was mildly decreased. Genetic analysis showed a deletion of PLP1 in this patient. Further genome mapping followed by sequence analysis of the deletion breakpoints revealed that a genomic region, about 73kb in length, including the entire PLP1 and RAB9B, was deleted. The size of the deletion was the smallest among those previously reported in this region. Except for the 1-base pair microhomology, there were no homologous sequences between the regions around the distal and proximal breakpoints, which suggests that the deletion occurred by nonhomologous end joining.

Developmental change of visuo-spatial working memory in children: Quantitative evaluation through an Advanced Trail Making Test - Corrected Proof

2012-03-07

Abstract: Aim: The present study aimed to investigate the developmental change in Visuo-Spatial Working Memory (VSWM) in typically developed children using a specially designed Advanced Trail Making Test for children (ATMT-C). Methods: We developed a new method for evaluating VSWM efficiency in children using a modified version ATMT to suit their shorter sustained attention. The ATMT-C consists of two parts; a number-based ATMT and a hiragana (Japanese phonogram)-based ATMT, both employing symbols familiar to young children. A total of 94 healthy participants (6–28years of age) were enrolled in this study. Results: A non-linear developmental change of VSWM efficiency was observed in the results from the ATMT-C. In the number-based ATMT, children under 8years of age showed a relatively rapid increase in VSWM efficiency while older children (9–12years) had a more gradual increase in VSWM efficiency. Results from the hiragana-based ATMT-C showed a slightly delayed increase pattern in VSWM efficiency compared to the pattern from the number-based ATMT. There were no significant differences in VSWM efficiency for gender, handedness and test order. Interpretation: VSWM in children gradually matures in a non steady-state manner and there is an important stage for VSWM maturation before reaching 12years of age. VSWM efficiency may also vary depending on developmental condition of its cognitive subsystems.

Benign myoclonic epilepsy in infancy with preceding afebrile generalized tonic–clonic seizures in Japan - Corrected Proof

Susumu Ito, Hirokazu Oguni, Makiko Osawa — 2012-03-05

Abstract: Benign myoclonic epilepsy in infancy (BMEI) is the youngest form of idiopathic generalized epilepsy, characterized by myoclonic seizures (MS) in the first three years of life in otherwise normal infants, and the lack of other seizure types except for rare simple febrile seizures. Although afebrile generalized tonic–clonic seizures (GTCS) have been described to develop later in the clinical course of BMEI, mostly during adolescence, an association with GTCS in the early stage of BMEI has never been recognized. We herein report seven children who satisfied the criteria of BMEI except for the recurrence of GTCS before the onset of MS. The age of onset and ictal video-polygraphic features of MS, as well as the long-term seizure and developmental outcome in these children were similar to those of children with typical BMEI. Furthermore, these GTCS mostly disappeared within several months and were replaced by MS. Our study indicates that these children may constitute a BMEI subgroup, expanding the spectrum of BMEI.

Reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage - Corrected Proof

2012-03-02

Abstract: We described a 7-year-old girl with reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. She initially presented with high fever and pancytopenia, leading to a diagnosis of most severe type aplastic anemia. We treated her with cyclosporine, methylprednisolone and anti-thymocyte globulin. Thereafter she recurrently complained of a very severe headache called as thunderclap, and finally exhibited loss of consciousness. Brain imaging revealed massive parenchymal hemorrhage between the left occipital and parietal lobes on computed tomography, and diffuse cerebral vasoconstriction on magnetic resonance angiography. The cerebral vasoconstriction resolved within two months, and thus we diagnosed her as having reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. This syndrome has been frequently reported in adult females, but rarely in children. However, even in children, a so called thunderclap headache may become a clue for the diagnosis of reversible cerebral vasoconstriction syndrome, especially in cases taking immunosuppressive agents. Immediate magnetic resonance angiography is essential to diagnose this syndrome, and a prompt application of calcium channel inhibitors should be considered to resolve constriction of the vessels and to prevent subsequent brain damage.

Complex malformation (Ruggieri–Happle) phenotype with “cutis tricolor” in a 10-year-old girl - Corrected Proof

2012-02-27

Abstract: The term cutis tricolor describes the combination of congenital hyper- and hypo-pigmented skin lesions in close proximity to each other in a background of normal complexion. It is currently regarded as a twin-spotting phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far: (a) as an isolated skin manifestation; (b) as a part of a complex malformation syndrome (Ruggieri–Happle syndrome – RHS); (c) as a distinct phenotype [cutis tricolor parvimaculata]; (d) in association with other (e.g., vascular) skin disturbances. We report a novel case of cutis tricolor in a 10-year-old girl who had dysmorphic facial features [alike those seen in cases with syndromic (RHS) cutis tricolor], overall overgrowth [weight, length, and head circumference were >90th percentile; there was increased bone age], mild cognitive delay (current IQ=55), behavioural disturbances, febrile seizures and (later) partial complex epilepsy (currently under good control), and skeletal defects [i.e., posterior scalloping of the lumbar vertebrae]. We discuss the main similarities and differences between the various phenotypes in the spectrum of cutis tricolor and with other conditions sharing features with the present case.

Congenital abnormalities in Japanese patients with Menkes disease - Corrected Proof

Yan-Hong Gu, Hiroko Kodama, Tadaaki Kato — 2012-02-23

Abstract: Menkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK is 2.8 per million live births in Japan. The aim of this study was to observe congenital malformations (CMs) in MNK patients. Subjects comprised 35 Japanese male patients with classical MNK who received copper histidine treatment. Patient clinical data were obtained anonymously from medical records or medical record summaries by pediatrician’s retrospective review through a survey. We observed 21 different CMs in 14 patients. Eight of these had a single CM, while six had multiple CMs. The most frequent CM was higher arched palate with other CMs found in five patients. There was no relationship between CMs and mutations in the ATP7A gene. Using Mann–Whitney U tests, age at death was also significantly lower in MNK patients with CMs (P<0.05), compared to those without CMs, even though there was no significant difference of age onset, age at diagnosis and age at start of treatment with copper histidine between both groups of patients. Sudden death occurred in three MNK patients with CMs only: two with congenital heart disease, and one with microphallus.

Exacerbation of idiopathic paroxysmal kinesigenic dyskinesia in remission state caused by secondary hypoparathyroidism with hypocalcemia after thyroidectomy: Evidence for ion channelopathy - Corrected Proof

2012-02-23

Abstract: Most reported cases of paroxysmal kinesigenic dyskinesia (PKD) are idiopathic or familial; however, hypoparathyroidism is another unusual cause of secondary PKD. The pathomechanism of PKD remains poorly understood, and the association between idiopathic and secondary PKD remains an enigma, and has yet to be clearly elucidated. We recently encountered a patient with idiopathic PKD whose symptoms were aggravated by secondary hypoparathyroidism with hypocalcemia after having undergone a thyroidectomy. The patient’s paroxysms were ameliorated by the normalization of serum calcium levels. The results discussed herein may provide support for the hypothesis that PKD is associated with neuronal ion regulation.

Corrected Proof

Hidenobu Ohta, Shohei Ohgi — 2012-02-20

This is the latest update of the Neonatal Behavioral Assessment Scale (NBAS) manual, the previous (3rd) edition of which was published in 1995. The NBAS has been widely used for almost four decades internationally as a standard tool for research into the behavior of term and preterm infants. The scale has also enabled academic and clinical professionals to demonstrate to parents the remarkable abilities of newborns to communicate behaviorally and has helped researchers and clinicians objectively describe the neurobehavioral characteristics of newborns.

Amplitude spectral analyses of disorganized patterns on electroencephalograms in preterm infants - Corrected Proof

2012-02-20

Abstract: The aim of this study is to clarify the differences of EEG activities according to the presence or absence of disorganized patterns using amplitude spectral analysis. We compared EEGs of 17 preterm infants with disorganized patterns with those of 34 matched controls. Amplitude was defined as a square root of EEG power analyzed by fast Fourier transform algorithm, and was calculated in the 9 frequency bands. Six EEG segments of 10s were collected from the part of EEG with continuous high voltage slow waves in the absence of artifacts. The results were separately evaluated according to the post-conceptional age at EEG recordings. In patients with disorganized patterns, reduced amplitude of delta waves in the central areas and increased amplitude of beta waves in the occipital areas were observed at 29–30weeks of post-conceptional age. The results were almost similar at 31–32weeks of post-conceptional age. Amplitude in theta or alpha frequency bands was not different between those with and without disorganized patterns either at 29–30 or 31–32weeks of post-conceptional age. Amplitude spectral analyses will contribute to objective evaluation of disorganized patterns.

Identification of fetal precentral gyrus on diffusion weighted MRI - Corrected Proof

Umit Aksoy Ozcan, Ugur Işik, Alp Dincer, Canan Erzen — 2012-02-17

Abstract: To investigate the association of the diffusion-weighted MR imaging characteristics of fetal preCG and gestational age. Forty-four fetuses with normal brain MRI findings were included in the study. Gestational ages ranged from 18 to 36weeks (mean 25.2weeks). All exams were performed with a 1.5-T scanner using a body array coil during free maternal breathing without sedation. Precentral gyrus was defined as the hyperintense strip anterior to the central sulcus, on the superior section of axial brain images at the level of superior frontal cortex. The presence of preCG hyperintensity was noted as observed/subtle/not observed at different b values (500, 1000s/mm2) and on apparent diffusion coefficient (ADC) maps and compared to the imaging characteristics of the superior frontal cortex. Precentral gyrus was first detected at 25weeks as a hyperintense strip on DWI and hypointense strip on ADC maps. Display of preCG b 1000s/mm2 images were better than b 500s/mm2. Between 25 and 27weeks, in 40% of fetuses preCG was observed on one hemisphere, and it was evident bilaterally in 60% of cases. Starting from the 28th week, preCG was observed on both hemispheres in 100% of cases. Diffusion weighted imaging helps better understanding of the evolution of fetal preCG. The hyperintense preCG strip starts to appear at 25weeks, and when interpreting fetal DWI after 28weeks this may be a sign to be sought for in all fetuses and an indicator for normal development.

Long-term developmental outcome in patients with West syndrome after epilepsy surgery - Corrected Proof

2012-02-15

Abstract: It has been hypothesized that early seizure control may prevent children with intractable epileptic spasms (ES) from developmental regression and may contribute to better developmental outcome. The effectiveness of surgery for ES has been reported. We investigated long-term post-operative outcomes of seizure control and development in patients with symptomatic West syndrome (S-WS) who underwent epilepsy surgery. Six children who underwent surgical intervention for intractable ES were retrospectively investigated. Cortical malformations were observed on pre-operative MRI in all patients, with hemispheric or multilobar involvement in four children and focal lesions in two. Following surgery, we measured motor function, developmental age (DA), language skills, and sociopsychological function for up to 7years (mean, 4.9years). Post-operative seizure outcome was Engel Class I (n=4) or III (n=2). Motor function and DA was increased following surgery in six and five patients, respectively. Two patients started to speak in sentences following focal resection. Autistic features were noted in four of the five examined patients post-operatively. None of the patients showed developmental regression following surgery. Epilepsy surgery for S-WS with ES may result in good seizure control and improvement in motor development. Improvement in cognitive function was modest in this small cohort of children and autistic features were noted post-operatively in a substantial proportion of the children. While seizure control can be obtained by epilepsy surgery, early intervention for sociopsychological comorbidities may be warranted in children with S-WS.

Neuroprotective effect of human placental extract on hypoxic–ischemic brain injury in neonatal rats - Corrected Proof

2012-02-15

Abstract: We investigated the neuroprotective effects of human placental extracts (HPE) and the effects of HPE on recovery of cognitive and behavioral function on hypoxic–ischemic brain injury in the newborn rat. The right common carotid arteries of 7-day-old rats were coagulated, and rats were then exposed to 8% oxygen. Immediately before and again at three times after the hypoxia–ischemia (pre-treatment group), and immediately after and three times again after hypoxia–ischemia (post-treatment group), the rats were intraperitoneally injected with HPE (0.1, 0.25, or 0.5mL/10g/dose). No-treatment rats received saline only. On postnatal day 12, brains were removed and gross morphological damage was evaluated. To quantify the severity of brain injury, bilateral cross-sectional areas of the anterior commissural and posterior hippocampal levels were analyzed with NIH Image. Assessments of the open field activity levels at 2, 4, 6 and 8week and, the Morris water maze test at 8weeks after hypoxia–ischemia were carried out according to standard methods. HPE pre-treatment decreased the incidence of liquefactive cerebral infarction, at an optimally neuroprotective dose of 0.5mL/10g/dose (P<0.05). In the Morris water maze test, the group injected with HPE at 0.5mL/10g/dose concentration showed shorter escape latencies than the no-treatment group (P<0.05). These findings support a protective effect of the HPE treatment on neuronal integrity and cognitive function following hypoxic–ischemic brain injury. Injected at an appropriate dose prior to exposure, HPE may significantly reduce or prevent hypoxic–ischemic injury in the immature brain.

A developmental change of the visual behavior of the face recognition in the early infancy - Corrected Proof

2012-02-10

Abstract: The purpose of this study was to examine developmental changes in visuocognitive function, particularly face recognition, in early infancy. In this study, we measured eye movement in healthy infants with a preference gaze problem, particularly eye movement between two face stimulations. We used the eye tracker system (Tobii1750, Tobii Technologies, Sweden) to measure eye movement in infants. Subjects were 17 3-month-old infants and 16 4-month-old infants. The subjects looked two types of face stimulation (upright face/scrambled face) at the same time and we measured their visual behavior (preference/looking/eye movement). Our results showed that 4-month-old infants looked at an upright face longer than 3-month infants, and exploratory behavior while comparing two face stimulations significantly increased. In this study, 4-month-old infants showed a preference towards an upright face. The numbers of eye movements between two face stimuli significantly increased in 4-month-old infants. These results suggest that eye movements may be an important index in face cognitive function during early infancy.

Ultrasound evaluation of fetal brain dysfunction based on behavioral patterns - Corrected Proof

2012-02-10

Abstract: To identify fetuses at high risk of poor neurological outcomes using a novel ultrasound evaluation system. We assessed an ultrasound evaluation system based on our previous findings, consisting of screening for decreased or lack of fetal movements, abnormal patterns of fetal heart rate, congenital CNS malformations, polyhydramnios of unknown cause, and a “brief ultrasound evaluation” of fetal brain functions, including movement of extremities, breathing movements, ultradian rhythm, REM period, and NREM period. We then assessed the correlation between fetal brain functions and neurological outcomes in infancy (MR, CP, and low Developmental Quotient). During screening, we prospectively evaluated 4978 fetuses receiving prenatal and intrapartum management between January 2000 and December 2009 in our hospital that were later delivered between 32 and 41weeks’ gestation and identified 93 cases as suspicious for impairment. Of the 93 fetuses, 26 underwent the second step of brief ultrasound examination at 35–40weeks’ gestation. Our findings revealed that this method was adequately sensitive (80%) and specific (88%) in identifying neurological impairment. We concluded that this method was mainly useful in the clinical setting for establishing the first indication for fetal CNS examination for functional impairment, rendering it suitable for clinical application.

A case of bulbar type cerebral palsy: Representative symptoms of dorsal brainstem syndrome - Corrected Proof

2012-02-06

Abstract: In this study, we present the case of a 2-year-old boy who exhibited facial and bulbar paralysis since birth, severe dysphagia, signs of oculomotor disturbance, jaw jerks, pyramidal signs on both toes, intellectual disability, and severe gastroesophageal reflux. His blink reflex and auditory/somatosensory evoked potentials suggested abnormalities in the lower brainstem, and magnetic resonance imaging showed a T2 hyperintense area in the pontine tegmentum. These findings combined with the patient’s symptoms suggested “dorsal brainstem syndrome” and indicated a possibility of prenatal asphyxia in this patient. Nosologic issues regarding this subgroup of cerebral palsy are discussed here.

Gray matter volumetric MRI differences late-preterm and term infants - Corrected Proof

2012-01-30

Abstract: Gray matter develops rapidly during the third trimester of pregnancy, which is a critical period for lipid deposition. We measured brain volume in term and late-preterm infants to determine if it is related to disabilities in late-preterm infants. In addition, we measured serum lipid concentrations to investigate the relationship between brain volume and lipid nutrition. Magnetic resonance imaging scans were obtained in 16 late-preterm and 13 term infants. We measured cerebrum, gray matter, and white matter volumes. We performed serum cholesterol, triglyceride (TG), and lipoprotein analyses in cord blood by high-performance liquid chromatography using gel permeation columns to assess lipid nutritional levels. The gray matter volume and percent cerebrum volume of gray matter were significantly smaller in late-preterm infants (p<0.001). Head circumference and cerebrum and white matter volume did not differ between the two groups. Gray matter volume correlated positively with gestational age (r=0.647, p<0.001), head circumference (r=0.688, p<0.001), and high-density lipoprotein (HDL)-TG levels (r=0.496, p=0.006). Late-preterm infants had a normal head circumference and a lower gray matter volume than term infants. Gestational age and head circumference were significantly associated with gray matter volume. Only HDL-TG levels were significantly associated with gray matter volume. HDL-TG might contribute to the transport of fatty acids and gray matter development during the postnatal period. Thus, delayed gray matter development may partly contribute to neurodevelopmental disabilities in late-preterm infants.

A pediatric case of reversible cerebral vasoconstriction syndrome with cortical subarachnoid hemorrhage - Corrected Proof

Seiichiro Yoshioka, Tomoyuki Takano, Fukiko Ryujin, Yoshihiro Takeuchi — 2012-01-30

Abstract: Reversible cerebral vasoconstriction syndrome (RCVS) is a rare disorder characterized by acute onset, severe headache, with reversible vasoconstriction of cerebral arteries often accompanied by additional neurological symptoms. This syndrome is seen mainly in middle-aged adults, predominantly women. Herein, we report on a pediatric case of RCVS with cortical subarachnoid hemorrhage (SAH). A 12-year-old boy developed acute, severe headache with paralysis of lower extremities causing gait disturbance after administration of eletriptan. Brain magnetic resonance angiography (MRA) revealed multifocal narrowing of the cerebral arteries, whereas magnetic resonance imaging (MRI) demonstrated sulcal hyperintensity on fluid-attenuated inversion recovery, consistent with cortical SAH. The patient’s clinical symptoms resolved spontaneously after a few days and the MRI and MRA findings disappeared 3months later, suggesting a diagnosis of RCVS. Eletriptan might cause vasoconstriction of cerebral arteries. Although most patients with RCVS are adults and pediatric cases are rare, RCVS should be considered in a child complaining of severe headache.

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.