K Santosh Mohan Rao, Chidambaram Balasubramaniam, K Subramaniam
Journal of Pediatric Neurosciences 2015 10(3):240-243
Syringohydromyelia is a frequent finding in cases of tethered cord syndrome. The classical teaching is that the development and progression of a syrinx is a chronic process. We present a case report of an acute onset syringomyelia in an infant, who underwent an excision of a lumbosacral transitional lipoma and detethering of the cord. Immediately after recovery, the infant was found to have flaccid paraplegia. An emergency magnetic resonance imaging revealed a large acute onset syringomyelia for which he underwent an emergency midline myelotomy and release of fluid from the syrinx. Though the eventual recovery was good, this made us re-visit our understanding of the concept of syringohydromyelia. The case details and a plausible hypothesis for the rapid development of the syrinx are presented.
Linear undisplaced fracture of temporoparietal bone acting as spontaneous early decompressive craniotomy in a neonate
Siddharth Vankipuram, Srikant Balasubramanium, Devendra K Tyagi, HV Savant
Journal of Pediatric Neurosciences 2015 10(3):261-263
Decompressive craniotomy (DC) is used to treat intracranial hypertension associated with traumatic brain injury. Early DC is associated with better outcomes. We present a neonate with a history of fall with computed tomography scan showing a large frontoparietal contusion and associated parietal and temporal bone fracture. This acted as a spontaneous DC causing bony segment to separate due to which the edematous brain could be accommodated. Despite the presence of a large contusion, the child was neurologically intact and medically managed. The neonate presented with a posttraumatic leptomeningeal cyst 2 months later, which had to be repaired surgically. We discuss how a linear undisplaced fracture acts as spontaneous DC and the role of early DC in improving outcomes.
Diastematomyelia with hemimyelomeningocele: An exceptional and complex spinal dysraphism
Neha Singh, Deepak Kumar Singh, Rakesh Kumar
Journal of Pediatric Neurosciences 2015 10(3):237-239
Variations in split cord malformation (SCM) have been described earlier. However, a true hemimyelomeningocele (HMM) as only congenital malformation is extremely rare and is reported infrequently in published literature. We are reporting the case of a 3-month-old girl child who presented with a swelling on the lower back since birth. Magnetic resonance imaging revealed a type 1 SCM with right hemicord forming a HMM. Precise diagnosis and thorough anatomical detail of dysraphism is essential for optimal, individualized neurosurgical management.
Journal of Pediatric Neurosciences 2015 10(3):282-284
Brain abscesses occur as an uncommon complication of bacterial meningitis in the neonatal period. A 34 weeks preterm at-risk neonate presented with abnormal breathing pattern and inability to maintain the oxygen saturation in room air. Magnetic resonance imaging (MRI) study revealed intra-parenchymal brain abscesses in the left basal ganglion and bilateral fronto-parietal regions. Intravenous piperacillin - tazobactam was commenced and continued for 6 weeks in Neonatal Intensive Care Unit. No surgical intervention was required. The patient responded to the medical management and was discharged after the documentation of radiological clearance in repeat MRI study. No complications were recorded. An appropriate neuro-developmental outcome was observed on follow-up. Brain abscesses may not be preceded by meningitis in all neonates. A strong clinical suspicion is required for the diagnosis especially in cases with atypical presentation.
Journal of Pediatric Neurosciences 2015 10(3):294-296
Acquired Dyke-Davidoff-Masson syndrome, also known as hemispheric atrophy, is characterized by loss of volume of one cerebral hemisphere from an insult in early life. Crossed cerebellar diaschisis refers to dysfunction/atrophy of cerebellar hemisphere which is secondary to contralateral supratentorial insult. We describe magnetic resonance imaging findings in two cases of acquired Dyke-Davidoff-Masson syndrome with crossed cerebro-cerebellar diaschisis.
Journal of Pediatric Neurosciences 2015 10(3):270-272
Extradural hematoma (EDH) occurs in approximately 2% of all patients with head injuries. Bilateral EDHs account for 2-10% of all acute EDHs in adults but are exceedingly rare in children. Posterior fossa EDHs occurs in 5% of all cases of EDHs. EDHs in children are more frequently venous (from tears of a dural sinus or diploic veins) and consequently have a better prognosis than EDHs in adults. Once the diagnosis of BEH is confirmed, urgent surgical treatment should be considered. We are reporting such rare form of injury as bilateral occipital EDH with supratentorial extension in 12 years child following road traffic accident.
Health-Related Quality of Life of Children/Adolescents with Vertigo: Retrospective Study from the German Center of Vertigo and Balance Disorders
Purpose To assess the impact of vertigo on health-related quality of life (HrQoL) of children/adolescents and to assess if the impact on HrQoL varies by age group, gender, and type of vertigo diagnoses.
Methods A retrospective analysis was performed on the clinical and HrQoL data of children and adolescents referred to the German Center of Vertigo and Balance Disorders (n = 32; male = 17; female = 15; age range: 8–18 years), using the KIDSCREEN-52 questionnaire. For each scale, means of the Z-scores with 95% confidence intervals of the study and norm sample were compared. By nonparametric Kruskal–Wallis statistics differences between diagnostic groups were assessed. To assess the gender- and age-specific impact of vertigo on quality of life, Wilcoxon signed-rank test was used.
Results The means of the physical well-being, psychological well-being, autonomy scale, and the general HrQoL index of patients were considerably lower than the means of the norm sample. The physical well-being seemed to be most affected by vertigo. The reduction of HrQoL was not related to gender and vertigo types but seemed to be higher in children suffering from vertigo aged 12 to 18 years than children aged 8 to 11 years.
Conclusion These are the first data to demonstrate impaired HrQoL in children with chronic vertigo.
Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency
GM2 gangliosidosis, AB variant, is a very rare form of GM2 gangliosidosis due to a deficiency of GM2 activator protein. We report on two patients with typical clinical features suggestive of GM2 gangliosidosis, but normal results for hexosaminidase A and hexosaminidase B as well as their corresponding genes. Genetic analysis of the gene encoding the activator protein, the GM2A gene, elucidated the cause of the disease, adding a novel mutation to the spectrum of GM2 AB variant. This report points out that in typical clinical constellations with normal enzyme results, genetic diagnostic for activator protein defects should be performed.
Auditory Processing in Children with Migraine: A Controlled Study
Background This study aimed to investigate central auditory processing performance in children with migraine and compared with controls without headache.
Methods Twenty-eight children of both sexes, aged between 8 and 12 years, diagnosed with migraine with and without aura, and a control group of the same age range and with no headache history, were included. Gaps-in-noise (GIN), duration pattern test (DPT), synthetic sentence identification (SSI) test, and nonverbal dichotic test (NVDT) were used to assess central auditory processing performance.
Results Children with migraine performed significantly worse in DPT, SSI test, and NVDT when compared with controls without headache; however, no significant differences were found in the GIN test.
Conclusions Children with migraine demonstrate impairment in the physiologic mechanism of temporal processing and selective auditory attention. In our short communication, migraine could be related to impaired central auditory processing in children.
Recurrence of Epileptic Spasms as Reflex Seizures Induced by Eating: A Case Report and Literature Review
Background Eating epilepsy (EE) is a rare form of reflex epilepsy in which seizures are induced by eating. It is known that most patients with eating seizures, in fact, suffer from symptomatic temporal lobe epilepsy (TLE), whereas only a few patients with epileptic spasms induced by eating (E-ES) have been reported.
Patient Description The patient was an 8-year-old girl whose magnetic resonance imaging (MRI) of the head detected dysgenesis of the corpus callosum, cerebellar hypogenesis, marked cerebral asymmetry, broad polymicrogyria, periventricular heterotopia, and closed lip-type schizencephaly. She experienced E-ES as the second form of recurrent seizures after the first recurrence of spontaneous ES. After E-ES occurred, the EEG findings in the right hemisphere, predominantly over the right centrotemporal region, were clearly exacerbated, although the interictal EEG originally showed left-side–dominant asymmetric hypsarrhythmia. The ictal EEG of the E-ES showed diffuse large triphasic (negative-positive-negative) potentials, predominantly over the right centrotemporoparietal region.
Conclusions This is a unique case because the E-ES were recurrent ES, although the previous ES were spontaneous, which may provide insight into the mechanism of E-ES.
Is Tadpole Pupil in an Adolescent Girl Caused by Denervation Hypersensitivity?
Tadpole pupil is a rarely encountered phenomenon caused by episodic, segmental iris dilator muscle spasm of short duration (2–15 minutes), occurring in clusters without a known precipitating factor. It has most commonly been described in women aged 28 to 48 years. A few hypotheses on pathogenesis have been discussed but none has been proved. Here, we present an adolescent girl with bilateral tadpole pupil that appeared during physical exercise. This is the first pediatric case of tadpole pupil, not caused by preceding surgery, to be published. Based on (1) this case in which tadpole pupil developed when the norepinephrine level rose during exercise, (2) the high ratio of patients with tadpole pupil who concurrently have or later develop Horner syndrome, in which denervation hypersensitivity is well described, (3) a previous report of a patient with both tadpole pupil and Horner syndrome who had denervation hypersensitivity on pharmacological testing, (4) a 29-year-old man with unilateral tadpole pupil induced by exercise, and (5) a 19-year-old man with bilateral tadpole pupil and possible autonomic neuropathy, we suggest denervation hypersensitivity as a probable pathogenic mechanism causing tadpole pupil. In addition, a suggestion for investigations to be performed in future pediatric cases is provided.
Publication date: Available online 26 December 2016 Source:Seminars in Pediatric Neurology Author(s): Karen S. Carvalho, Tal Grunwald, Francesco De Luca The Endocrine system is a complex group of organs and glands that relates to multiple other organs and systems in the body with the ultimate goal of maintaining homeostasis. This complex network functions through hormones excreted by several glands and released in the blood, ultimately targeting different body tissues and modulating their function. Any primary disorders affecting the endocrine glands and altering the amount of hormones synthesized and released will lead to disruption in the functions of multiple organs. The central nervous system of a developing child is particularly sensitive to endocrine disorders. A variety of neurological manifestations have been described as features of several endocrine diseases in childhood. Knowledge of these manifestations may contribute to an early diagnosis of an endocrine disorder, especially when more typical features of that disorder have not manifested yet. In this review, we will discuss specific neurologic manifestations found in various endocrine disorders in children.
Publication date: Available online 16 January 2017 Source:Seminars in Pediatric Neurology Author(s): Nandini Madan, Karen S. Carvalho This article focuses on the complex interactions between the cardiovascular and neurological systems. Initially we focus on neurological complications in children with Congenital Heart Disease both secondary to the underlying cardiac disease or complications of interventions. We discuss diagnosis and management of common syncope syndromes with emphases in Vasovagal Syncope. We review the diagnosis, classification and management of children and adolescents with Postural Orthostatic Tachycardia Syndrome. Last we discuss Long QT Syndrome and SUDEP, reviewing advance in genetics and current knowledge of pathophysiology of these conditions. This article attempts to provide an overview of these disorders with focus on pathophysiology, advances in molecular genetics and current medical interventions.
Neurological Manifestations of Rheumatic disorders
Publication date: Available online 23 December 2016 Source:Seminars in Pediatric Neurology Author(s): Svetlana Lvovich, Donald P. Goldsmith Rheumatologic disorders represent a broad spectrum of systemic conditions manifested by multisystem involvement and mediated by autoimmunity and inflammation. Neurologic manifestations of these disorders may occur at any point in the disease process and are diagnostically challenging. For years CNS was considered a system uniquely protected from effects of the immune system because of the blood brain barrier (BBB). Indeed, under physiologic conditions immune access to CNS is tightly regulated. Over the past decade, new scientific discoveries highlighted pathways by which immune and neurologic systems interact, including variety of mechanisms controlling permeability of BBB, specific roles CD4+ and CD8+ T-lymphocytes play in initiation of specific adaptive immune response to neural antigens leading to release of proinflammatory cytokines ( IL-1, IL-6 and TNF-α). In addition B-cells, involved in CNS inflammation produce antibodies against membrane bound and soluble antigens. This review article describes specific neurologic manifestations of most common autoimmune disorders.
Pediatric Epileptic Encephalopathies: Pathophysiology and Animal Models
Publication date: May 2016 Source:Seminars in Pediatric Neurology, Volume 23, Issue 2 Author(s): Li-Rong Shao, Carl E. Stafstrom Epileptic encephalopathies are syndromes in which seizures or interictal epileptiform activity contribute to or exacerbate brain function, beyond that caused by the underlying pathology. These severe epilepsies begin early in life, are associated with poor lifelong outcome, and are resistant to most treatments. Therefore, they represent an immense challenge for families and the medical care system. Furthermore, the pathogenic mechanisms underlying the epileptic encephalopathies are poorly understood, hampering attempts to devise novel treatments. This article reviews animal models of the three classic epileptic encephalopathies—West syndrome (infantile spasms), Lennox-Gastaut syndrome, and continuous spike waves during sleep or Landau-Kleffner syndrome—with discussion of how animal models are revealing underlying pathophysiological mechanisms that might be amenable to targeted therapy.
Publication date: Available online 23 December 2016 Source:Seminars in Pediatric Neurology Author(s): Lauren Weaver, Ayman Samkari Though the treatment of pediatric cancers has come a long way, acute and chronic effects of cancer are still impacting the life of many children. These effects may be caused not only by the malignancy itself but also by the interventions employed for the purpose of treatment. This review focuses primarily on the indirect effects of pediatric cancers and their treatment on the central and peripheral nervous system. Chemotherapy, radiation, and stem cell transplantation cause an immune compromised state and place the patient at risk of infection, the leading cause of mortality in pediatric cancer. The underlying cancer and the treatments also cause neurovascular changes that may lead to neurological sequelae immediately or many years in the future. Chemotherapy and radiation have both immediate and long-term neurotoxic effects on the central and peripheral nervous system. Cancers may also trigger an immune response that damages nervous system components, leading to altered mental status, seizures, abnormal movements, and even psychosis. Knowledge of these effects can help the practitioner be more vigilant for the signs and symptoms of potential complications during the management of pediatric cancers.
The Neurological Manifestations of Gastrointestinal Disease
Publication date: Available online 4 February 2017 Source:Seminars in Pediatric Neurology Author(s): Melissa Shapiro, David A. Blanco There is a growing interest in the extra-intestinal manifestations of common pediatric gastrointestinal diseases such as IBD and celiac disease. This chapter specifically focuses on the neurological symptoms that manifest as a result of these disorders and their treatments. Many neurologic symptoms have been reported in association with these diseases, including neuropathy, myopathy, ataxia, headache and seizure, among others. It is currently believed that these neurologic symptoms are largely overlooked by practitioners and could be of potential use for earlier diagnosis of disease. However, additional research, especially in the pediatric population, is warranted to further elaborate on the causality and pathophysiology of these neurologic symptoms.
Developmental changes in autonomic emotional response during an executive functional task: A pupillometric study during Wisconsin card sorting test
Publication date: March 2017 Source:Brain and Development, Volume 39, Issue 3 Author(s): Tetsuo Ohyama, Yoshimi Kaga, Yusuke Goto, Kakuro Aoyagi, Sayaka Ishii, Hideaki Kanemura, Kanji Sugita, Masao Aihara ObjectiveThe autonomic nervous system has a deep relationship with the cognitive network when performing cognitive tasks. We hypothesize that autonomic emotional responses can affect cognitive function, especially executive function. The aim of this study was to clarify the involvement of the autonomic system during an executive functional task via developmental changes assessed using pupillometry.Subjects and methodsSubjects were 16 healthy children and 9 healthy adults. Children were divided into 3 groups (Group A, 7–9years; Group B, 10–14years; Group C, 15–17years). Pupil diameter was recorded using an eye mark recorder during cognitive shift (CS) during the Wisconsin card sorting test (WCST). The rate of pupil variations was integrated and compared within each group, focusing on performance during CS.ResultsCategories achieved (CA) in the behavioral results of WCST increased with age, with significant differences between Group A and other groups. The change of pupillary diameter was increased with CS and decreased at the correct answers after CS in adults. Changes of pupillary diameter with CS showed a linear increase with age, and the pattern of the pupillary response at the age of 10–14years was comparable to adults. The integrated rate of pupil diameter with CS increased with age, and there was a significant difference between Group A and adults. In addition, the degree of mydriasis correlated with the number of CA.ConclusionThese findings suggest that autonomic emotional response play an important role as a part of the process for executive function.
Neurodevelopmental outcome of term infants with perinatal asphyxia with hypoxic ischemic encephalopathy stage II
Publication date: February 2017 Source:Brain and Development, Volume 39, Issue 2 Author(s): Sudhir Adhikari, Kalipatnam Seshagiri Rao BackgroundPerinatal asphyxia with hypoxic ischemic encephalopathy (HIE) causes significant mortality and morbidity in developing countries. There is limited information about long term neurodevelopmental outcome of infants with neonatal encephalopathy.MethodsTerm infants with the diagnosis of perinatal asphyxia were followed up in neurodevelopmental clinics of Manipal Teaching hospital, Nepal. Study design was prospective mixed longitudinal study. Prematurity, major congenital malformations, other intracranial pathology, birth weight <2500g and chromosomal abnormalities were excluded. After consent and enrollment their detailed perinatal history, Apgar score, resuscitation measures and outcome parameters were recorded on a predesigned proforma. Developmental assessment was done with Denver Developmental Screening Tool 2nd edition (DDST 2) at the age of 3months, 6months, 9months, 1year, 18months and 2years.ResultsTotal 187 assessments done in the age group of 3months to 2years among HIE stage 2 patients. Impaired hearing and vision was noted in 5.3% while language delay was observed in 19.2% of infants. Abnormal tone and deep tendon reflexes were noted in 46.2% infants at 3months. Abnormal tone and reflexes were noted only in 18.8% and 9.4% respectively at the age of 2years. Overall, gross motor delay was noted in 55(29.4%) of patient, 34(18.2%) showed fine motor delay and 17.1% social delay. Seizures were persistent in 15.6% patients at 2years age.ConclusionInfants affected with HIE have delay in all sectors of developmental milestones. Motor abnormalities are common and tend to improve with advancing age.
Spectral characteristics of intracranial electroencephalographic activity in patients with Lennox–Gastaut syndrome
Publication date: February 2017 Source:Brain and Development, Volume 39, Issue 2 Author(s): Dongpyo Lee, Junge Liang, Yun Jung Hur, Nam-Young Kim, Heung Dong Kim ObjectiveThe purpose of the current study was to characterize the frequency profiles of epileptogenic regions, independent of visible epileptiform discharges, in intracranial EEG (iEEG) recordings of Lennox–Gastaut syndrome (LGS) patients.MethodsWe selected eight LGS patients who underwent resective surgery in the absence of definite neuroimaging findings. We calculated the absolute and relative band powers of continuous spike-free iEEG data and compared the characteristics of the resected and remaining regions.ResultsFor absolute band powers, there was a trend for higher absolute gamma band power in the remaining brain section. We also found that the absolute delta power in the resected area was higher than that in the remaining area. However, this trend was not statistically different in all patients. For relative band powers, we found decreased relative band power in the beta and gamma band ranges within the areas defined by the surgical margins. Delta, theta, and alpha relative band power differences between the resected and remaining areas were inconsistent between the subjects.ConclusionsOur results showed systematic relative beta and gamma band power variation in the resected areas of LGS patients.
Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis
Publication date: February 2017 Source:Brain and Development, Volume 39, Issue 2 Author(s): Alessandro Iodice, Carlotta Spagnoli, Grazia Gabriella Salerno, Daniele Frattini, Gianna Bertani, Patrizia Bergonzini, Francesco Pisani, Carlo Fusco Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.
A magnetic resonance imaging finding in children with cerebral palsy: Symmetrical central tegmental tract hyperintensity
Publication date: March 2017 Source:Brain and Development, Volume 39, Issue 3 Author(s): Betul Emine Derinkuyu, Evrim Ozmen, Havva Akmaz-Unlu, Namik Kemal Altinbas, Esra Gurkas, Oznur Boyunaga BackgroundCentral tegmental tract is an extrapyramidal tract between red nucleus and inferior olivary nucleus which is located in the tegmentum pontis bilaterally and symmetrically. The etiology of the presence of central tegmental tract hyperintensity on MRI is unclear.PurposeIn this study our aim is to evaluate the frequency of central tegmental tract lesions in patients with cerebral palsy and control group, as well as to determine whether there is an association between central tegmental tract lesions and cerebral palsy types.Materials and methodsClinical and MRI data of 200 patients with cerebral palsy in study group (87 female, 113 male; mean age, 5.81years; range, 0–16years) and 258 patients in control group (114 female, 144 male; mean age, 6.28years; range, 0–16years) were independently evaluated by two reader for presence of central tegmental tract hyperintensity and other associated abnormalities.ResultsCentral tegmental tract hyperintensities on T2WI were detected in 19% of the study group (38/200) and 3.5% of the control group (9/258) (p<0.0001). Among the total of 38 central tegmental tract lesions in study group, the frequency of central tegmental tract hyperintensity was 16% (24/150) in spastic cerebral palsy and 35% (14/40) in dyskinetic cerebral palsy (p=0.0131).ConclusionThe prevalence of central tegmental tract hyperintensity is higher in patients with cerebral palsy particularly in dyskinetic type. We suggest that there is an increased association of the tegmental lesions with dyskinetic CP. Patients with cerebral palsy and ischemic changes were more likely to have central tegmental tract lesions. According to our results we advocate that an ischemic process may have a role in the etiopathogenesis.
Temporal brain metabolite changes in preterm infants with normal development
Publication date: March 2017 Source:Brain and Development, Volume 39, Issue 3 Author(s): Sachiko Tanifuji, Manami Akasaka, Atsushi Kamei, Nami Araya, Maya Asami, Atsushi Matsumoto, Genichiro Sotodate, Yu Konishi, Satoko Shirasawa, Yukiko Toya, Syuji Kusano, Shoichi Chida, Makoto Sasaki, Tsuyoshi Matsuda ObjectivePreterm infants are at high risk for developmental delay, epilepsy, and autism spectrum disorders. Some reports have described associations between these conditions and gamma-aminobutyric acid (GABA) dysfunction; however, no study has evaluated temporal changes in GABA in preterm infants. Therefore, we assessed temporal changes in brain metabolites including GABA using single-voxel 3-Tesla (T) proton magnetic resonance spectroscopy (1H-MRS) in preterm infants with normal development.MethodsWe performed 3T 1H-MRS at 37–46 postmenstrual weeks (PMWs, period A) and 64–73PMWs (period B). GABA was assessed with the MEGA-PRESS method. N-acetyl aspartate (NAA), glutamate–glutamine complex (Glx), creatine (Cr), choline (Cho), and myo-inositol (Ins) were assessed with the PRESS method. Metabolite concentrations were automatically calculated using LCModel.ResultsData were collected from 20 preterm infants for periods A and B (medians [ranges], 30 [24–34] gestational weeks, 1281 [486–2030]g birth weight). GABA/Cr ratio decreased significantly in period B (p=0.03), but there was no significant difference in GABA/Cho ratios (p=0.58) between the two periods. In period B, NAA/Cr, Glx/Cr, NAA/Cho, and Glx/Cho ratios were significantly increased (p<0.01), whereas Cho/Cr, Ins/Cr, and Ins/Cho ratios were significantly decreased (p<0.01). There was no significant difference for GABA or Cho concentrations (p=0.52, p=0.22, respectively). NAA, Glx, and Cr concentrations were significantly increased (p<0.01), whereas Ins was significantly decreased (p<0.01).ConclusionsOur results provide new information on normative values of brain metabolites in preterm infants.
Quantification of walking-based physical activity and sedentary time in individuals with Rett syndrome
To quantify, in individuals with Rett syndrome with the capacity to walk, walking-based activity and sedentary time, and to analyse the influences of age, walking ability, scoliosis, and the severity of epilepsy.
Sixty-four participants with a mean age of 17 years and 7 months (standard deviation [SD] 9y) were recruited from the Australian Rett Syndrome Database for this cross-sectional study. Each participant wore a StepWatch Activity Monitor for at least 4 days. Linear regression models were used to assess relationships between daily step count and the proportion of waking hours spent in sedentary time with the covariates of age group, walking ability, presence of scoliosis, and frequency of seizures.
On average, 62% (SD 19%) of waking hours were sedentary and 20% (SD 8%) was at cadences lower than or equal to 20 steps in a minute. The median daily steps count was 5093 (interquartile range 2026–8602). Compared with females younger than 13 years of age and accounting for the effects of covariates, adults took fewer steps, and both adolescents and adults had more sedentary time.
Adolescents and adults led the least active lives and would appear to be in particular need of interventions aiming to optimize slow walking-based physical activity and reduce sedentary time.
Event-related potential measures of executive functioning from preschool to adolescence
Executive functions are a collection of cognitive abilities necessary for behavioural control and regulation, and are important for school success. Executive deficits are common across acquired and developmental disorders in childhood and beyond. This review aims to summarize how studies using event-related potential (ERP) can provide insight into mechanisms underpinning how executive functions develop in children from preschool to adolescence. We specifically focus on ERP components that are considered to be well-established markers of executive functioning, including the ability to resist distraction (inhibition, N200), hold scenes in mind (visuospatial working memory, contralateral delay activity), attend to specific stimuli (information processing, P300), follow rules (response monitoring, error-related negativity [ERN], and error-related positivity [Pe]), and adjust to feedback (outcome monitoring, feedback-related negativity). All of these components show developmental changes from preschool to adolescence, in line with behavioural and neuroimaging findings. These ERP markers also show altered developmental trajectories in the context of atypical executive functions. As an example, deficits in executive function are prominently implicated in attention-deficit–hyperactivity disorder. Therefore, this review highlights ERP studies that have investigated the above ERP components in this population. Overall, ERPs provide a useful marker for the development and dysfunction of executive skills, and provide insight into their neurophysiological basis.
Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway
To investigate the cognitive and behavioural phenotype in rare disorders of the Ras/MAPK pathway, namely Noonan, cardiofaciocutaneous (CFC), and Costello syndromes, particularly prevalence of autism spectrum disorder (ASD) and attention-deficit–hyperactivity disorder (ADHD).
Fifty children were recruited over 10 months through the regional genetics service and advertisements. A range of parent, child, and observational measures were administered including Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Scale.
Using the Collaborative Programme for Excellence in Autism criteria, 12 out of 40 children with Noonan syndrome (30%) showed ASD, and 12 out of 40 (30%) with partial ASD features and 16 out of 40 (40%) showed non-ASD. The Noonan syndrome ASD group showed male dominance in a ratio of 5:1. In the CFC group, eight out of nine children met the criteria for ASD, with equal sex distribution. Additionally 19 out of 40 (48%) of the Noonan syndrome group and eight out of nine (88.9%) of the CFC group scored met clinical criteria for ADHD. Only one child was in the Costello syndrome group.
This is the first systematic study to suggest a high prevalence of ASD in Noonan and CFC syndromes, and thus offers crucial evidence to support the importance of the Ras/MAPK pathway in the aetiology of ASD. Limitations include the inevitable possibility of a sampling bias in a rare disorder study of this kind.
A randomized controlled trial of lacosamide versus sodium valproate in status epilepticus
To compare the efficacy and safety of lacosamide (LCM) and sodium valproate (SVA) in lorazepam (LOR)–resistant status epilepticus (SE).
Patients with LOR-resistant SE were randomized to intravenous LCM 400 mg at a rate of 60 mg/kg/min or SVA 30 mg/kg at a rate of 100 mg/min. The SE severity score (STESS), duration of SE and its etiology, and magnetic resonance imaging (MRI) findings were noted. Primary outcome was seizure cessation for 1 h, and secondary outcomes were 24 h seizure remission, in hospital death and severe adverse events (SAEs).
Sixty-six patients were included, and their median age was 40 (range 18–90) years. Thirty-three patients each received LCM and SVA. Their demographic, clinical, STESS, etiology, and MRI findings were not significantly different. One hour seizure remission was not significantly different between LCM and SVA groups (66.7% vs. 69.7%; p = 0.79). Twenty-four hour seizure freedom was higher in SVA (20, 66.6%) compared with LCM group (15, 45.5%), but this difference was not statistically significant. Death (10 vs. 12) and composite side effects (4 vs. 6) were also not significantly different in LCM and SVA groups. LCM was associated with hypotension and bradycardia (one patient), and SVA with liver dysfunction (six patients).
In LOR-resistant SE patients, both LCM and SVA have comparable efficacy and safety. SVA resulted in slightly better 24 h seizure remission.
Characterization of focal cortical dysplasia with balloon cells by layer-specific markers: Evidence for differential vulnerability of interneurons
Focal cortical dysplasia (FCD) is a major cause of pharmacoresistant focal epilepsy. Little is known about the pathomechanisms underlying the characteristic cytoarchitectural abnormalities associated with FCD. In the present study, a broad panel of markers identifying layer-specific neuron subpopulations was applied to characterize dyslamination and structural alterations in FCD with balloon cells (FCD 2b).
Pan-neuronal neuronal nuclei (NeuN) and layer-specific protein expression (Reelin, Calbindin, Calretinin, SMI32 (nonphosphorylated neurofilament H), Parvalbumin, transducin-like enhancer protein 4 (TLE4), and Vimentin) was studied by immunohistochemistry on paraffin sections of FCD2b cases (n = 22) and was compared to two control groups with (n = 7) or without epilepsy (n = 4 postmortem cases). Total and layer-specific neuron densities were systematically quantified by cell counting considering age at surgery and brain region.
We show that in FCD2b total neuron densities across all six cortical layers were not significantly different from controls. In addition, we present evidence that a basic laminar arrangement of layer-specific neuron subtypes was preserved despite the severe disturbance of cortical structure. SMI32-positive pyramidal neurons showed no significant difference in total numbers, but a reduction in layers III and V. The densities of supragranular Calbindin- and Calretinin-positive interneurons in layers II and III were not different from controls, whereas Parvalbumin-expressing interneurons, primarily located in layer IV, were significantly reduced in numbers when compared to control cases without epilepsy. In layer VI, the density of TLE4-positive projection neurons was significantly increased. Altogether, these data show that changes in cellular composition mainly affect deep cortical layers in FCD2b.
The application of a broad panel of markers defining layer-specific neuronal subpopulations revealed that in FCD2b neuronal diversity and a basic laminar arrangement are maintained despite the severe disturbance of cytoarchitecture. Moreover, it showed that Parvalbumin-positive, inhibitory interneurons are highly vulnerable in contrast to other interneuron subtypes, possibly related to the epileptic condition.
Overexpression of pregnane X and glucocorticoid receptors and the regulation of cytochrome P450 in human epileptic brain endothelial cells
Recent evidence suggests a metabolic contribution of cytochrome P450 enzymes (CYPs) to the drug-resistant phenotype in human epilepsy. However, the upstream molecular regulators of CYP in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic (PXR) and glucocorticoid (GR) nuclear receptors in endothelial cells established from post-epilepsy surgery brain samples.
PXR/GR localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug-resistant seizures. We used primary cultures of endothelial cells obtained from epileptic brain tissues (EPI-ECs; n = 8), commercially available human brain microvascular endothelial cells (HBMECs; n = 8), and human hepatocytes (n = 3). PXR/GR messenger RNA (mRNA) levels in brain ECs was initially determined by complementary DNA (cDNA) microarrays. The expression of PXR/GR proteins was quantified by Western blot. PXR and GR silencing was performed in EPI-ECs (n = 4), and the impact on downstream CYP expression was determined.
PXR/GR expression was detected by immunofluorescence in ECs and neurons in the human temporal lobe samples analyzed. Elevated mRNA and protein levels of PXR and GR were found in EPI-ECs versus control HBMECs. Hepatocytes, used as a positive control, displayed the highest levels of PXR/GR expression. We confirmed expression of PXR/GR in cytoplasmic-nuclear subcellular fractions, with a significant increase of PXR/GR in EPI-ECs versus controls. CYP3A4, CYP2C9, and CYP2E1 were overexpressed in EPI-ECs versus control, whereas CYP2D6 and CYP2C19 were downregulated or absent in EPI-ECs. GR silencing in EPI-ECs led to decreased CYP3A4, CYP2C9, and PXR expression. PXR silencing in EPI-ECs resulted in the specific downregulation of CYP3A4 expression.
Our results indicate increased PXR and GR in primary ECs derived from human epileptic brains. PXR or GR may be responsible for a local drug brain metabolism sustained by abnormal CYP regulation.
Validating the shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) in a sample of children with drug-resistant epilepsy
The aim of this study was to validate the newly developed shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) in a sample of children with drug-resistant epilepsy.
Data came from 136 children enrolled in the Impact of Pediatric Epilepsy Surgery on Health-Related Quality of Life Study (PEPSQOL), a multicenter prospective cohort study. Confirmatory factor analysis was used to assess the higher-order factor structure of the QOLCE-55. Convergent and divergent validity was assessed by correlating subscales of the KIDSCREEN-27 with the QOLCE-55. Measurement equivalence of the QOLCE-55 was evaluated using multiple-group confirmatory factor analysis of children with drug-resistant epilepsy from PEPSQOL versus children with new-onset epilepsy from HERQULES (Health-Related Quality of Life in Children with Epilepsy Study).
The higher-order factor structure of the QOLCE-55 demonstrated adequate fit: Comparative Fit Index (CFI) = 0.948; Tucker-Lewis Index (TLI) = 0.946; Root Mean Square of Approximation (RMSEA) = 0.060 (90% confidence interval [CI] 0.054–0.065); Weighted Root Mean Square Residuals (WRMR) = 1.247. Higher-order factor loadings were strong, ranging from λ = 0.74 to 0.81. Internal consistency reliability was excellent (α = 0.97, subscales α > 0.82). QOLCE-55 subscales demonstrated moderate to strong correlations with similar subscales of the KIDSCREEN-27 (ρ = 0.43–0.75) and weak to moderate correlations with dissimilar subscales (ρ = 0.25–0.42). The QOLCE-55 demonstrated partial measurement equivalence at the level of strict invariance – χ2 (2,823) = 3,727.9, CFI = 0.961, TLI = 0.962, RMSEA = 0.049 (0.044, 0.053), WRMR = 1.834.
The findings provide support for the factor structure of the QOLCE-55 and contribute to its robust psychometric profile as a reliable and valid measure. Researchers and health practitioners should consider the QOLCE-55 as a viable option for reducing respondent burden when assessing health-related quality of life in children with epilepsy.
Accuracy of claims-based algorithms for epilepsy research: Revealing the unseen performance of claims-based studies
To evaluate published algorithms for the identification of epilepsy cases in medical claims data using a unique linked dataset with both clinical and claims data.
Using data from a large, regional health delivery system, we identified all patients contributing biologic samples to the health system's Biobank (n = 36K). We identified all subjects with at least one diagnosis potentially consistent with epilepsy, for example, epilepsy, convulsions, syncope, or collapse, between 2014 and 2015, or who were seen at the epilepsy clinic (n = 1,217), plus a random sample of subjects with neither claims nor clinic visits (n = 435); we then performed a medical chart review in a random subsample of 1,377 to assess the epilepsy diagnosis status. Using the chart review as the reference standard, we evaluated the test characteristics of six published algorithms.
The best-performing algorithm used diagnostic and prescription drug data (sensitivity = 70%, 95% confidence interval [CI] 66–73%; specificity = 77%, 95% CI 73–81%; and area under the curve [AUC] = 0.73, 95%CI 0.71–0.76) when applied to patients age 18 years or older. Restricting the sample to adults aged 18–64 years resulted in a mild improvement in accuracy (AUC = 0.75,95%CI 0.73–0.78). Adding information about current antiepileptic drug use to the algorithm increased test performance (AUC = 0.78, 95%CI 0.76–0.80). Other algorithms varied in their included data types and performed worse.
Current approaches for identifying patients with epilepsy in insurance claims have important limitations when applied to the general population. Approaches incorporating a range of information, for example, diagnoses, treatments, and site of care/specialty of physician, improve the performance of identification and could be useful in epilepsy studies using large datasets.
Ca2+-permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma
Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+-permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+-permeable AMPA receptors due to dislocation of ADAR2.
Reduced local input to fast-spiking interneurons in the somatosensory cortex in the GABAA γ2 R43Q mouse model of absence epilepsy
Absence seizures in childhood absence epilepsy are initiated in the thalamocortical (TC) system. We investigated if these seizures result from altered development of the TC system before the appearance of seizures in mice containing a point mutation in γ-aminobutyric acid A (GABAA) receptor γ2 subunits linked to childhood absence epilepsy (R43Q). Findings from conditional mutant mice indicate that expression of normal γ2 subunits during preseizure ages protect from later seizures. This indicates that altered development in the presence of the R43Q mutation is a key contributor to the R43Q phenotype. We sought to identify the cellular processes affected by the R43Q mutation during these preseizure ages.
We examined landmarks of synaptic development at the end of the critical period for somatosensory TC plasticity using electrophysiologic recordings in TC brain slices from wild-type mice and R43Q mice.
We found that the level of TC connectivity to layer 4 (L4) principal cells and the properties of TC synapses were unaltered in R43Q mice. Furthermore, we show that, although TC feedforward inhibition and the total level of GABAergic inhibition were normal, there was a reduction in the local connectivity to cortical interneurons. This reduction leads to altered inhibition during bursts of cortical activity.
This altered inhibition demonstrates that alterations in cortical circuitry precede the onset of seizures by more than a week.
“For Whom the Bell Tolls”: Blockade of Toll-Like Receptors May Regulate Seizure Occurrence
Toll-Like Receptor 4 and High-Mobility Group Box-1 Are Involved in Ictogenesis and Can Be Targeted to Reduce Seizures. Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M, Casalgrandi M, Manfredi AA, Bianchi ME, Vezzani A. Nat Med 2010;16(4):413–419. Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1β (IL-1β), are partly mediated by ifenprodil-sensitive N-methyl-D-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs.
Intractable Epilepsy: Relapsing, Remitting, or Progressive?
Seizure Remission and Relapse in Adults with Intractable Epilepsy: A Cohort Study. Choi H, Heiman G, Pandis D, Cantero J, Resor SR, Gilliam FG, Hauser WA. Epilepsia 2008;49(8):1440–1445. PURPOSE: To investigate the cumulative probabilities of ≥12 month seizure remission and seizure relapse following remission, and to test the associations of clinical characteristics with these two study end points in a prevalence cohort of intractable adult epilepsy patients during medical management. METHODS: A retrospective cohort study of intractable epilepsy patients seen in 2001 at a single center was conducted. Kaplan–Meier analysis was used to estimate the cumulative probabilities of seizure remission and subsequent seizure relapse. Cox proportional hazards models were used to estimate the association (1) between clinical factors and ≥12 month seizure remission and (2) between clinical factors and seizure relapse following remission. RESULTS: One hundred eighty-seven subjects met the eligibility criteria for intractable epilepsy. The estimate of probability of remission was about 4% per year. Seizure remission was temporary for some individuals, as 5 out of 20 subjects with remission ultimately relapsed. No clinical factors predicted the likelihood of achieving ≥12 month seizure remission or subsequent seizure relapse. DISCUSSION: Some people with intractable epilepsy achieve ≥12 month seizure remission during medical treatment. Remission, however, is only temporary for some individuals. We were unable to identify clear predictors for remission.Quantifying the Response to Antiepileptic Drugs: Effect of Past Treatment History. Schiller Y, Najjar Y. Neurology 2008;70(1):54–65. OBJECTIVE: To quantify the response to treatment with antiepileptic drugs (AEDs) as a function of the past treatment history and identify additional prognostic factors for predicting the response to newly administered AED treatments. METHODS: A cohort of 478 consecutive patients who received newly administered AED treatments between January 1999 and December 2004 and were followed prospectively for 1.5 to 7.5 years in a single epilepsy clinic. RESULTS: The response to newly administered AED treatments was highly dependent on the past treatment history. The seizure-free rates decreased from 61.8% for the first AED to 41.7%, 16.6%, and 0% after one, two to five, and six to seven past AEDs proved inefficient. This response curve corresponded to a mono-exponential function with a maximal response of 61.8% and half-decay constant of 1.5 AEDs. Likewise the response curve describing a greater than 50% reduction in seizure frequency corresponded to a mono-exponential function with a maximal response of 85.3% and half-decay constant of two AEDs. Three additional independent prognostic factors for predicting the response to AEDs were identified: type of epilepsy, duration of epilepsy, and number of seizures in the 3 months prior to AED initiation. CONCLUSION: Drug resistance is a graded process that follows a mono-exponential course with a half-decay constant of 1.5 to two antiepileptic drugs (AEDs). Although relative drug-resistant epilepsy can be diagnosed after failure of two past AEDs, absolute drug resistance requires failure of six AEDs, as a significant minority of patients (16.6%) is rendered seizure-free by addition of newly administered AEDs even after failure of two to five past antiepileptic drugs.
Predicting the Unpredictable: Stereotactic Radiosurgery and Temporal Lobe Epilepsy
Predictors of Efficacy After Stereotactic Radiosurgery for Medial Temporal Lobe Epilepsy. Chang EF, Quigg M, Oh MC, Dillon WP, Ward MM, Laxer KD, Broshek DK, Barbaro NM; Epilepsy Radiosurgery Study Group. Neurology 2010;74(2):165–172. BACKGROUND: Stereotactic radiosurgery (RS) is a promising treatment for intractable medial temporal lobe epilepsy (MTLE). However, the basis of its efficacy is not well understood. METHODS: Thirty patients with MTLE were prospectively randomized to receive 20 or 24 Gy 50% isodose RS centered at the amygdala, 2 cm of the anterior hippocampus, and the parahippocampal gyrus. Posttreatment MRI was evaluated quantitatively for abnormal T2 hyperintensity and contrast enhancement, mass effect, and qualitatively for spectroscopic and diffusion changes. MRI findings were analyzed for potential association with radiation dose and seizure remission (Engel Ib or better outcome). RESULTS: Despite highly standardized dose targeting, RS produced variable MRI alterations. In patients with multiple serial imaging, the appearance of vasogenic edema occurred approximately 9–12 months after RS and correlated with onset of seizure remission. Diffusion and spectroscopy-detected alterations were consistent with a mechanism of temporal lobe radiation injury mediated by local vascular insult and neuronal loss. The degree of these early alterations at the peak of radiographic response was dose-dependent and predicted long-term seizure remission in the third year of follow-up. Radiographic changes were not associated with neurocognitive impairments. CONCLUSIONS: Temporal lobe stereotactic radiosurgery resulted in significant seizure reduction in a delayed fashion which appeared to be well-correlated with structural and biochemical alterations observed on neuroimaging. Early detected changes may offer prognostic information for guiding management.
How Does Altered Metabolism Lead to Seizure Control? Partially Filling the Knowledge Gap
Metabolic Autocrine Regulation of Neurons Involves Cooperation Among Pannexin Hemichannels, Adenosine Receptors, and KATP Channels. Kawamura M, Jr., Ruskin DN, Masino SA. J Neurosci 2010;30(11):3886–3895. Metabolic perturbations that decrease or limit blood glucose—such as fasting or adhering to a ketogenic diet—reduce epileptic seizures significantly. To date, the critical links between altered metabolism and decreased neuronal activity remain unknown. More generally, metabolic changes accompany numerous CNS disorders, and the purines ATP and its core molecule adenosine are poised to translate cell energy into altered neuronal activity. Here we show that nonpathological changes in metabolism induce a purinergic autoregulation of hippocampal CA3 pyramidal neuron excitability. During conditions of sufficient intracellular ATP, reducing extracellular glucose induces pannexin-1 hemichannel-mediated ATP release directly from CA3 neurons. This extracellular ATP is dephosphorylated to adenosine, activates neuronal adenosine A1 receptors, and, unexpectedly, hyperpolarizes neuronal membrane potential via ATP-sensitive K+ channels. Together, these data delineate an autocrine regulation of neuronal excitability via ATP and adenosine in a seizure-prone subregion of the hippocampus and offer new mechanistic insight into the relationship between decreased glucose and increased seizure threshold. By establishing neuronal ATP release via pannexin hemichannels, and hippocampal adenosine A1 receptors coupled to ATP-sensitive K+ channels, we reveal detailed information regarding the relationship between metabolism and neuronal activity and new strategies for adenosine-based therapies in the CNS.
Epilepsy Treatment Stimulus Package? Deep Brain Stimulation in Treatment-Resistant Focal Epilepsy
Electrical Stimulation of the Anterior Nucleus of Thalamus for Treatment of Refractory Epilepsy. Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Epilepsia 2010;51(5):899–908. PURPOSE: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. METHODS: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. RESULTS: One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model ( p= 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and “most severe” seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. DISCUSSION: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.
An Update on Antiepileptic Drugs and Suicide: Are There Definitive Answers Yet?
In 2008, the Food and Drug Administration (FDA) issued a warning that any and all antiepileptic drugs (AEDs) might increase the risk of suicidal ideation, suicide attempt, and completed suicide. Considerable confusion and concern followed regarding the use of these drugs, in general, and specifically for people with epilepsy. Recently, four publications examined suicidality and AED use among several databases and illustrated how biases affect the findings. None of the studies was able to control completely for the indication for which the AEDs were prescribed or to account for the varying intensities with which different specialists monitoring patients for suicidality. Though multiple analyses were conducted for many AEDs, no study controlled for the numerous comparisons made. The result is a multitude of contradictions in the findings across studies and even within studies, with no study providing clear or convincing support for the FDA conclusions. This review attempts to clarify the methodological issues in assessing potential associations between AED use and suicidality.
Neurosteroids on the Epilepsy Chessboard—Keeping Seizures in Check
Endogenous Neurosteroid Synthesis Modulates Seizure Frequency. Lawrence C, Martin BS, Sun C, Williamson J, Kapur J. Ann Neurol 2010;67(5):689–693. Inhibitory neurosteroids, molecules generated in glia from circulating steroid hormones and de novo from cholesterol, keep seizures in check in epileptic animals. They can enhance inhibitory transmission mediated by γ-aminobutyric acid receptors and have anticonvulsant action.
How might a genetic diagnosis benefit children with dystonia?
Dystonia is a common presentation to the paediatric neurology clinic, and can be caused by a broad range of disease processes and disorders of brain development, much like the childhood epilepsies. Childhood dystonia is most commonly a symptomatic condition, arising due to damage to the developing motor system, e.g. as a consequence of hypoxic ischaemic encephalopathy.1 For a subset of children, dystonia arises as an isolated disorder, with no sign of structural abnormality on conventional magnetic resonance neuroimaging.
As the first Professor of Paediatric Neurology in the UK appointed in 1989, and subsequently the first Professor of Childhood Epilepsy, Brian Neville made a significant contribution to the understanding and care of neurological disease in childhood around the world.
Predicting the IQ of young children from early developmental markers
The article presented by Peyre et al., this edition, addresses the extent to which we can predict the IQ of 5–6 year-old children, an age where in many countries children will enter formal education, from early assessments of developmental milestones. The study uses baseline data from a large population-based sample of French children from the EDEN prospective mother–child cohort study1 and presents data from 1100 children assessed at follow-up aged 5–6 years. The authors use developmental questionnaires completed by parent/carer at 6, 8, 12 and 24 months and use a predictive validity coefficient model to look at correlations with subsequent IQ.
Editorial commentary on ‘Toolbox of multi-item measures aligning with ICF core sets for children and youth with cerebral palsy’
We all know that choosing the most appropriate test from the wide variety of measures devised to assess function and interventional outcomes in children and young people with cerebral palsy can be confusing for both researchers and busy clinicians alike. Dr Schiariti's group has provided a comprehensive and robust overview of the current English Language options in line with the ICF framework. As part of this process they also, appropriately, highlight the important role of using validated measures to help us collaborate on an international perspective.
Comment on How to Create a Website: 10 Easy Steps to Build & Make Your Own Site by Alex Jasin
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Just leave a comment!
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[Review] Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update
Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists.
[Comment] Can natalizumab be beneficial in acute ischaemic stroke?
Experimental and clinical evidence suggests an early activation of the immune system after brain ischaemia, with rapid invasion of ischaemic regions by leucocytes and an increase in complement concentrations in blood.1–3 Natalizumab is a humanised monoclonal antibody against α4 integrin, a glycoprotein that is expressed on the surface of lymphocytes and monocytes and facilitates their adhesion to the endothelial vessel wall; natalizumab was approved for use as monotherapy in relapsing-remitting multiple sclerosis over a decade ago.
Joseph Babinski (1857–1932), a French neurologist of Polish descent, first described the Babinski sign, the best known neurological eponym and one of the most important signs in clinical neurology, in 1896.1 Babinski was the favourite pupil of Jean-Martin Charcot, who markedly influenced Babinski's research. He appears in the famous painting of Charcot's lesson at Salpêtrière hospital (“Une leçon clinique à la Salpêtrière” by Pierre Aristide André Brouillet [1857–1914]), helping to support a patient who was being treated for hysteria.
[Correspondence] Dementia research priorities—1 – Author's reply
Like Emiliano Albanese and colleagues, I'm all for transparency, democracy, and advancing research. The priority-setting group indeed captured the “wisdom of the crowd” in a transparent and structured way, but by means of a constricted democratic process in which the outcomes were predetermined. The crowd here is a select group of stakeholders—mainly contributors to current literature, advocacy, and funding organisations—who provided the questions, consolidated them into themes, and then voted for their selections.
[Editorial] The Human Brain Project: adjusting the flagship's course
The Human Brain Project (HBP), launched in October, 2013, is one of two flagship initiatives for the Future Emerging Technologies (FET) programme of the European Commission (EC), and aims to support brain research. The HBP involves researchers from more than 100 institutions in 19 countries, and is expected to receive around €1 billion over its 10-year course. However, less than a year into its first ramp-up phase, the HBP found itself embroiled in a public dispute with a group of researchers over the scientific scope and governance of the project.
[Review] Mobile stroke units for prehospital thrombolysis, triage, and beyond: benefits and challenges
In acute stroke management, time is brain. Bringing swift treatment to the patient, instead of the conventional approach of awaiting the patient's arrival at the hospital for treatment, is a potential strategy to improve clinical outcomes after stroke. This strategy is based on the use of an ambulance (mobile stroke unit) equipped with an imaging system, a point-of-care laboratory, a telemedicine connection to the hospital, and appropriate medication. Studies of prehospital stroke treatment consistently report a reduction in delays before thrombolysis and cause-based triage in regard to the appropriate target hospital (eg, primary vs comprehensive stroke centre).
[Correspondence] Dementia research priorities—2 – Authors' reply
David Smith and colleagues further illustrate the constraints of WHO's CHNRI process by focusing on the top three prevention research avenues prioritised by majority vote. The three priorities are actually one theme: we should do primary and secondary dementia prevention trials that take into account modifiable and non-modifiable midlife risk factors, and establish the best methods and the effectiveness of the interventions. WHO specifically names the risk factors as gender, genetics, age, physical activity, diet, cognitive stimulation, cognitive activity, education, and nutrition.
Wachter R, Gröschel K, Gelbrich G, et al. Holter-electrocardiogram-monitoring in patients with acute ischaemic stroke (Find-AFRANDOMISED): an open-label randomised controlled trial. Lancet Neurol 2017; published online Feb 7. http://dx.doi.org/10.1016/S1474-4422(17)30002-9—In the discussion of this Article, the penultimate sentence of the second paragraph should read “A more thorough diagnostic work-up before randomisation might have led to a selection bias that could have affected the generalisability of the study results because patients with findings suggestive of a specific stroke cause (eg, hypokinetic left ventricular segment or persistent foramen ovale), but no option might have been excluded before the initiation of an intensified ECG monitoring.” This correction has been made to the online version as of Feb 16, 2017.
[Comment] Selective sodium channel blockers in trigeminal neuralgia
Trigeminal neuralgia (or tic douloureux) is characterised by short-lasting explosive attacks of pain in the facial region, and is often triggered by different stimuli inside or around the mouth and nose.1 The daily occurrence of often unexpected pain paroxysms might disrupt the lives of patients and causes fear. Treatment for trigeminal neuralgia can either be pharmacological or surgical.2 For patients with a vascular compression or distortion of the trigeminal root, surgical intervention with vascular decompression is effective.
[Articles] Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial
The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials.
Fassbender K, Grotta JC, Walter S, Grunwald IQ, Ragoschke-Schumm A, Saver JL. Mobile stroke units for prehospital thrombolysis, triage, and beyond: benefits and challenges. Lancet Neurology 2017; 16: 227–37—In figure 2 of this Review, the first two sentences of the legend should read “Non-contrast CT (A), CT angiography (B), and ASPECTS (C) done in a mobile stroke unit of a 73-year-old woman with acute right hemiparesis. Although the parenchyma shows no signs of infarction (ASPECTS 10), CT angiography allowed prehospital diagnosis of an occlusion of the left middle cerebral artery (B, arrow)”.
[Comment] Approved drugs for multiple sclerosis: the challenge of choice
The expansion of the treatment landscape in multiple sclerosis has increased the complexity of treatment choices. The best evidence for informed and objective clinical decisions should be a collection of large, high-quality, randomised trials that compares all eligible treatments and treatment algorithms. However, because of the absence of such randomised studies, only two strategies can be used to compare treatment efficacy: indirect treatment comparison by combination of the results of randomised trials, or comparative observational studies done in real-life settings.
[Articles] Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study
Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles.
[In Context] Henrik Zetterberg: biomarking neurological disorders
Henrik Zetterberg's steady outlook on life could date back to his tranquil upbringing close to the Gothenburg archipelago in Sweden. His parents inspired his love of nature, which would eventually translate into a love of science and a medical degree. Today, he is Professor of Neurochemistry, senior consultant of clinical chemistry, and head of the Department of Psychiatry and Neurochemistry at the University of Gothenburg (Gothenburg, Sweden), where he is also co-lead of the Clinical Neurochemistry Laboratory with long-time friend Kaj Blennow.
Growth and psychological development in post-operative patients of anterior encephaloceles
Publication date: Available online 8 February 2017 Source:Pediatric Neurology Author(s): Hemonta K. Dutta, C. Wachana Khangkeo, Kaberi Baruah, Debasish Borbora PurposeAnterior encephaloceles are rare malformations frequently associated with other brain anomalies. This study evaluates the growth and psychological development of children following encephalocele repair.Materials & methodsGrowth and psychological assessment was done in 24 children with only encephalocele (group-I), 9 children with encephalocele and hydrocephalus (group-II), 7 children with encephalocele, hydrocephalus and secondary malformations (group-III) and 40 apparently healthy controls. Psychological assessment was done by evaluating intelligence and temperament.ResultsSingle-stage repair was performed in 38 children, 2 underwent multistage repair. Major post-operative complications were noted in 3 patients. The follow-up period ranged from 12 to 168 months, during which the growth velocity declined significantly among group-II and group-III patients when compared to controls. After age-adjusting body mass index (BMI), our data revealed that group-III participants had a significantly (p=0.02) lower BMI than the control group. Group III also had poor indices for intelligence quotient (IQ) (p≤0.01) and temperament (p≤0.01). Female patients had lower temperament indices as compared to unaffected females- approach withdrawal (p≤0.01), mood (p=0.026) and intensity (p=0.03). Overall, increased disease severity adversely affected psychological indices.ConclusionAnterior encephalocele patients without associated intracranial defects had excellent post-operative outcomes in terms of growth and psychological developments. Hydrocephalus and agenesis of corpus callosum had least impact on the psychological development. However the presence of secondary brain defects led to developmental delays. Gender differences in temperament explains the need for distinct treatment regimen to assess psychosocial well-being for male and female cases.
Intracerebroventricular Delivery as a Safe, Long-Term Route of Drug Administration
Publication date: February 2017 Source:Pediatric Neurology, Volume 67 Author(s): Jessica L. Cohen-Pfeffer, Sridharan Gururangan, Thomas Lester, Daniel A. Lim, Adam J. Shaywitz, Manfred Westphal, Irene Slavc Intrathecal delivery methods have been used for many decades to treat a broad range of central nervous system disorders. A literature review demonstrated that intracerebroventricular route is an established and well-tolerated method for prolonged central nervous system drug delivery in pediatric and adult populations. Intracerebroventricular devices were present in patients from one to 7156 days. The number of punctures per device ranged from 2 to 280. Noninfectious complication rates per patient (range, 1.0% to 33.0%) were similar to infectious complication rates (0.0% to 27.0%). Clinician experience and training and the use of strict aseptic techniques have been shown to reduce the frequency of complications.
Early-Onset Parkinsonism: Case Report and Review of the Literature
Publication date: February 2017 Source:Pediatric Neurology, Volume 67 Author(s): Ahmed Al-Rumayyan, Christine Klein, Majid Alfadhel BackgroundEarly-onset parkinsonism can be caused by PTEN-induced putative kinase 1 (PINK1) gene defects and is usually characterized by an age of onset in the fourth decade of life, slow disease progression, resting tremor, rigidity, bradykinesia, postural instability, and levodopa-induced dyskinesia.MethodsWe evaluated a child with early-onset symptoms and performed a literature review for previously reported examples of children aged 18 years or less with PINK1 gene defects.ResultsWe describe a five-year-old boy with autosomal recessive early-onset parkinsonism caused by a homozygous missense mutation in the PINK1 gene. This is the youngest individual yet reported with early-onset parkinsonism.ConclusionPINK1-type of early-onset parkinsonism can occur in very young patients, and phenotypic expression of PINK1 mutations may depend on age of onset and ethnicity.
Clinical Epidemiology and Treatment of Febrile and Afebrile Convulsions With Mild Gastroenteritis: A Multicenter Study
Publication date: February 2017 Source:Pediatric Neurology, Volume 67 Author(s): Yousuke Higuchi, Toshihide Kubo, Toshiharu Mitsuhashi, Naoko Nakamura, Ichiro Yokota, Osamu Komiyama, Isamu Kamimaki, Shigenori Yamamoto, Yasushi Uchida, Kyoko Watanabe, Hironori Yamashita, Shigeki Tanaka, Kosei Iguchi, Ryouji Ichimi, Shinichiro Miyagawa, Toshimitsu Takayanagi, Hiroshi Koga, Akinori Shukuya, Akiko Saito, Keizo Horibe BackgroundWe investigated features and responses to treatment in patients with febrile and afebrile convulsions with mild gastroenteritis and characterized convulsions with rotavirus and norovirus gastroenteritis.MethodsWe conducted a prospective, observational study to evaluate patients with febrile and afebrile convulsions with mild gastroenteritis who were hospitalized between November 2011 and March 2014 at 13 facilities in the National Hospital Organization. We classified the patients into two groups: presence or absence of fever. We investigated the background, clinical and laboratory characteristics, viral antigen in stool, and efficacy of anticonvulsant drugs.ResultsOf 126 patients enrolled in this study, 50 were febrile (Fc group) and 76 were afebrile (aFc group). A family history of febrile seizures was significantly more frequent in the Fc group than in the aFc group (28.0% vs 9.2%, P = 0.005). Clinical characteristics were similar between the rotavirus and norovirus groups, but fever was significantly more frequent in the rotavirus group (46.2% vs 8.3%, P < 0.001). Serum sodium levels were significantly negatively related to the number of seizures in the aFc group (β = −0.13; 95% confidence interval, −0.24, −0.03; P = 0.01). Carbamazepine was significantly more efficacious than diazepam suppositories in the aFc group (odds ratio = 49.3, 95% confidence interval, 2.35, 1037; P = 0.01).ConclusionFebrile convulsions with mild gastroenteritis show characteristics of both febrile seizures and convulsions with mild gastroenteritis. Carbamazepine is optimal for convulsions with mild gastroenteritis. Clinical features of convulsions with rotavirus and norovirus gastroenteritis are similar, except for fever. Serum sodium levels may play a major role in the onset of convulsions with mild gastroenteritis.
Trends in Outcomes and Hospitalization Charges of Infant Botulism in the United States: A Comparative Analysis Between Kids' Inpatient Database and National Inpatient Sample
Publication date: February 2017 Source:Pediatric Neurology, Volume 67 Author(s): Tamara Opila, Asha George, Mohammad El-Ghanem, Nizar Souayah BackgroundNew therapeutic strategies, including immune globulin intravenous, have emerged in the past two decades for the management of botulism. However, impact on outcomes and hospitalization charges among infants (aged ≤1 year) with botulism in the United States is unknown.MethodsWe analyzed the Kids' Inpatient Database (KID) and National Inpatient Sample (NIS) for in-hospital outcomes and charges for infant botulism cases from 1997 to 2009. Demographics, discharge status, mortality, length of stay, and hospitalization charges were reported from the two databases and compared.ResultsBetween 1997 and 2009, 504 infant hospitalizations were captured in KID’, and 340 hospitalizations from NIS, for comparable years. A significant decrease was observed in mean length of stay for ’KID (P < 0.01); a similar decrease was observed for the NIS. The majority of patients were discharged to home. Despite an initial decrease after 1997, an increasing trend was observed for ’KID/NIS mean hospital charges from 2000 to 2009 (from $57,659/$56,309 to $143,171/$106,378; P < 0.001/P < 0.001). A linear increasing trend was evident when examining mean daily hospitalization charges for both databases. In conducting a subgroup analysis of the ’KID database, the youngest patients with infantile botulism (≤1.9 months) displayed the highest average number of procedures during their hospitalization (P < .001) and the highest rate of mechanical ventilation (P < .001), compared with their older counterparts.ConclusionInfant botulism cases have demonstrated a significant increase in hospitalization charges over the years despite reduced length of stay. Additionally, there were significantly higher daily adjusted hospital charges and an increased rate of routine discharges for immune globulin intravenous–treated patients. More controlled studies are needed to define the criteria for cost-effective use of intravenous immune globulin in the population with infant botulism.