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.
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.
Determination of restless legs syndrome prevalence in children aged 13–16years in the provincial center of Kayseri
Publication date: February 2017 Source:Brain and Development, Volume 39, Issue 2 Author(s): Huseyin Per, Neslihan Gunay, Sevda Ismailogullari, Didem Behice Oztop, Osman Gunay ObjectiveThis study was conducted to determine the prevalence rate of restless legs syndrome (RLS) and associated factors in adolescents aged 13–16years in the provincial center of Kayseri.Materials and methodsThe study sample included 5720 adolescents who were selected from among 74,421 grade 7–10 students aged 13–16years in the provincial center of Kayseri. Overall, datas from 4792 subjects were included into analysis. Data were collected by using a self reported questionnaire and the Epworth Sleepiness Scale (ESS). The prevalence rate of RLS was determined by questionnaire datas and phone interviews. The effects of age, gender, economical status and body weight on RLS prevalence rate were analyzed. Mean ESS score was calculated. The effect of RLS on academic success, as measured by grade point average, was also assessed. The subjects were stratified as underweight, normal, overweight and obese according to the body mass index and the RLS prevalence rate was compared among groups.ResultsThe RLS prevalence rate was determined to be 2.9% among adolescents aged 13–16years in the study group. It was found that gender and economical status had no significant effect on RLS prevalence. Mean age at symptom onset was 11.4years of age. There was a positive family history in 11.3% of subjects. Mean body mass index (BMI) was found to be significantly higher in subjects with RLS (21.5±3.8 vs. 20.5±3.2). Academic success (72.0±11.2 vs. 77.0±12.0) was found to be poorer and daytime sleepiness level, as measured by ESS (11.4±3.9 vs. 6.3±4.0), was found to be higher in subjects with RLS.ConclusionThe RLS prevalence rate was 2.9% in the study sample while gender and economical status had no significant effect on prevalence rate. The RLS, which results in decreased sleep quality and academic success, is an important disorder with a considerable prevalence in the population.
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.
Alice in Wonderland Syndrome: A real life version of Lewis Carroll’s novel
Publication date: Available online 8 February 2017 Source:Brain and Development Author(s): Patrick O'Toole, Edward Justin Modestino Alice in Wonderland Syndrome was originally coined by Dr. John Todd in 1955. The syndrome is named after the sensations experienced by the character Alice in Lewis Carroll’s novel Alice’s Adventures in Wonderland. Alice in Wonderland Syndrome consists of metamorphopsia (seeing something in a distorted fashion), bizarre distortions of their body image, and bizarre perceptual distortions of form, size, movement or color. Additionally, patients with Alice in Wonderland Syndrome can experience auditory hallucinations and changes in their perception of time. Currently, there is no known specific cause of Alice in Wonderland Syndrome. However, theories point to infections such as the Epstein–Barr virus, medications such as topiramate and associated migraines. Neuroimaging studies have revealed brain regions involved with the manifestation of symptoms. These include the temporo-parietal junction within the temporal lobe and the visual pathway, specifically the occipital lobe. There are no current treatments for Alice in Wonderland Syndrome. Further research is needed to find better treatments for Alice in Wonderland Syndrome and to elucidate the exact cause or causes of Alice in Wonderland Syndrome.
Life course health development of individuals with neurodevelopmental conditions
The life course health development (LCHD) model by Halfon et al. conceptualizes health development occurring through person–environment transactions that enable well-being and participation in desired social roles throughout life, areas that have not received adequate attention in healthcare. The aim of this ‘perspectives’ paper is to apply the six core tenets of the LCHD model and the concept of health development trajectories to individuals with lifelong neurodevelopmental conditions. We share the perspective that modifiable aspects of the environment often restrict health development; we then advocate that children, beginning at a young age, should engage in ‘real-world’ experiences that prepare them for current and future social roles. LCHD encourages future planning from the outset, continuity of care between pediatric and adult systems, and coordination of services and supports. We believe LCHD can be transformative in enabling healthy living of individuals with neurodevelopmental conditions.
Inter- and intrarater clinician agreement on joint motion patterns during gait in children with cerebral palsy
This study aimed to quantify the inter- and intrarater clinician agreement on joint motion patterns in children with spastic cerebral palsy (CP), which were recently specified by a Delphi consensus study. It also examined whether experience with three-dimensional gait analysis (3DGA) is a prerequisite for using the patterns.
The experimental group consisted of 82 patients with CP (57 males, 25 females; uni-/bilateral CP [n=27/55]; Gross Motor Function Classification System levels I to III; mean age 9y 5mo [range 4y–18y]). Thirty-two clinicians were split into ‘experienced’ and ‘inexperienced’ rater groups. Each rater was asked to classify 3DGA reports of 27 or 28 patients twice. Inter- and intrarater agreement on 49 joint motion patterns was estimated using percentage of agreement and kappa statistics.
Twenty-eight raters completed both classification rounds. Intrarater agreement was ‘substantial’ to ‘almost perfect’ for all joints (0.64<ĸ<0.91). Interrater agreement reached similar results (0.63<ĸ<0.86), except for the knee patterns during stance (ĸ=0.49, ‘moderate agreement’). Experienced raters performed significantly better on patterns of the knee during stance and ankle during swing.
Apart from some specific knee patterns during stance and ankle patterns during swing, the results suggested that clinicians could use predefined joint motion patterns in CP with good confidence, even in case of limited experience with 3DGA.
Single-subject research designs in pediatric rehabilitation: a valuable step towards knowledge translation
Knowledge translation may be particularly challenging in pediatric rehabilitation, where study findings are often ambiguous owing to low statistical power or inconsistent responses to intervention. Disconnection between research protocols and clinical practicality, as well as variability of responsiveness in heterogeneous pediatric populations, may further impede integration of research findings into everyday practice. Use of single-subject research designs (SSRDs) may bridge the gap between research and practice, with robust design options that better identify and preserve patterns of responsiveness to specific interventions and offer protocols that are more readily implemented in practice settings than can be done in traditional randomized controlled trials. This review defines SSRD, provides examples of research questions that can be answered using SSRD, details the experimental designs that can be used and the level of evidence of each design, and describes statistical analysis approaches and clinical application. This analysis will aid researchers, reviewers, clinicians, and others in better understanding SSRD methodology and its application in everyday practice.
Carisbamate blockade of T-type voltage-gated calcium channels
Carisbamate (CRS) is a novel monocarbamate compound that possesses antiseizure and neuroprotective properties. However, the mechanisms underlying these actions remain unclear. Here, we tested both direct and indirect effects of CRS on several cellular systems that regulate intracellular calcium concentration [Ca2+]i.
We used a combination of cellular electrophysiologic techniques, as well as cell viability, Store Overload-Induced Calcium Release (SOICR), and mitochondrial functional assays to determine whether CRS might affect [Ca2+]i levels through actions on the endoplasmic reticulum (ER), mitochondria, and/or T-type voltage-gated Ca2+ channels.
In CA3 pyramidal neurons, kainic acid induced significant elevations in [Ca2+]i and long-lasting neuronal hyperexcitability, both of which were reversed in a dose-dependent manner by CRS. Similarly, CRS suppressed spontaneous rhythmic epileptiform activity in hippocampal slices exposed to zero-Mg2+ or 4-aminopyridine. Treatment with CRS also protected murine hippocampal HT-22 cells against excitotoxic injury with glutamate, and this was accompanied by a reduction in [Ca2+]i. Neither kainic acid nor CRS alone altered the mitochondrial membrane potential (ΔΨ) in intact, acutely isolated mitochondria. In addition, CRS did not affect mitochondrial respiratory chain activity, Ca2+-induced mitochondrial permeability transition, and Ca2+ release from the ER. However, CRS significantly decreased Ca2+ flux in human embryonic kidney tsA-201 cells transfected with Cav3.1 (voltage-dependent T-type Ca2+) channels.
Our data indicate that the neuroprotective and antiseizure activity of CRS likely results in part from decreased [Ca2+]i accumulation through blockade of T-type Ca2+ channels.
Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent
Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible—and largely asymptomatic—signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena.
Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure.
We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the limited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumulative) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039).
We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy.
Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies
This study aimed at defining clinical predictors of drug resistance in adults with genetic generalized epilepsy (GGE) who were treated with a broad spectrum of antiepileptic drugs. Of a cohort of 137 unselected adult GGE patients with long-term follow up, clinical and demographic data, putative prognostic factors (e.g., psychiatric comorbidities, electroencephalography [EEG]), treatment response, and data indicative of social status were collected. Fifty-eight patients had seizures within the past year. Thirty-three patients met the definition of “drug-resistant epilepsy” according to the International League Against Epilepsy (ILAE) definition. Psychiatric comorbidities, age at first diagnosis, and absences were associated with worse seizure control, whereas focal changes in EEG remained without prognostic impact. Resistance to valproic acid was the most important prognostic factor for refractory seizures. Resistance to valproic acid had a specificity of 100% to identify patients with drug resistance and correlated strongly with bad social outcome and seizure burden. Conversely, 21.2% of all patients with refractory seizures according to the ILAE definition later became seizure free (mainly with valproic acid). Our data suggest that “drug resistant GGE” must not be declared unless patients were adequately treated with valproic acid, and advocate resistance to valproic acid as a new clinical biomarker for drug-resistant GGE.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Randomized, double-blind, placebo-controlled phase 2 study of ganaxolone as add-on therapy in adults with uncontrolled partial-onset seizures
To evaluate the efficacy and safety of ganaxolone as adjunctive therapy in adults with uncontrolled partial-onset seizures despite taking up to three concomitant antiepileptic drugs (AEDs).
Adults aged 18–69 years and refractory to conventional AEDs were enrolled in a multicenter, double-blind, placebo-controlled trial. After an 8-week baseline period, patients were randomized 2:1 to ganaxolone 1,500 mg/day or placebo for a 10-week treatment period (2-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. The primary endpoint was mean weekly seizure frequency. Secondary endpoints included the proportion of patients experiencing ≥50% reduction in seizure frequency (responder rate), percent change in mean weekly seizure frequency, seizure-free days, and quality of life. Safety and tolerability assessments included adverse events (AEs), treatment discontinuation, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population.
Of 147 randomized patients (98 ganaxolone, 49 placebo), 131 completed the study; 95% of participants titrated up to 1,500 mg/day and 78% maintained this dose. From baseline to endpoint, mean weekly seizure frequency decreased with ganaxolone (6.5–5.2) versus placebo (9.2–10.8), representing an 11.4% decrease versus placebo (p = 0.0489, analysis of covariance [ANCOVA]). Mean percent change from baseline was −17.6% with ganaxolone versus 2.0% with placebo (p = 0.0144, Kruskal-Wallis test). Responder rates were 24% with ganaxolone versus 15% with placebo (p = 0.19). Discontinuation due to adverse events was similar with ganaxolone (7.1%) and placebo (6.1%). Common adverse events were mild to moderate in severity and included dizziness (16.3% vs. 8.2%), fatigue (16.3% vs. 8.2%), and somnolence (13.3% vs. 2.0%).
Ganaxolone 1,500 mg/day reduced partial-onset seizure frequency and was generally safe and well tolerated in this phase 2 study. These results support continued development of ganaxolone for adult patients with refractory partial-onset seizures.
Modified Atkins diet is an effective treatment for children with Doose syndrome
Children with myoclonic astatic epilepsy (MAE; Doose syndrome) whose seizures do not respond immediately to standard antiepileptic drugs (AEDs) are at high risk of developing an epileptic encephalopathy with cognitive decline. A classic ketogenic diet (KD) is a highly effective alternative to AEDs. To date, there are only limited data on the effectiveness of the modified Atkins diet (MAD), which is less restrictive and more compatible with daily life. We report findings from a retrospective study on 30 MAE patients treated with MAD.
Four participating centers retrospectively identified all patients with MAE in whom a MAD had been started before June 2015. Seven children were recruited from a cohort included in an open prospective controlled trial. A retrospective review of all available charts was performed in the other patients.
Thirty patients (24 boys) were included. Mean age at epilepsy onset was 3.1 years (range 1.5–5.6). MAD was started at a mean age of 4.5 years (range 2.2–9.1) after the children had received an average of six different AEDs (range 2–15). Mean MAD observation time was 18.7 months (range 1.5–61.5). Twenty of 30 patients were still on MAD at the end of study (duration range 1.5–61.5, mean 18.5 months). MAD was stopped without relapse in three patients after sustained seizure freedom for >2 years. For the other seven cases, ineffectiveness (three patients), loss of efficacy (two), or noncompliance (two) led to termination. No severe adverse effects were noted. By the end of the observation period, 25 (83%) of 30 patients experienced a seizure reduction by ≥50% and 14 (47%) of 30 were seizure-free. None of the evaluated factors differed significantly between the groups of seizure-free and non–seizure-free children.
MAD is an effective treatment for MAE. It should be considered as an alternative to AEDs or the more restrictive classic ketogenic diet.
Presurgical language localization with visual naming associated ECoG high- gamma modulation in pediatric drug-resistant epilepsy
This prospective study compared presurgical language localization with visual naming–associated high-γ modulation (HGM) and conventional electrical cortical stimulation (ECS) in children with intracranial electrodes.
Patients with drug-resistant epilepsy who were undergoing intracranial monitoring were included if able to name pictures. Electrocorticography (ECoG) signals were recorded during picture naming (overt and covert) and quiet baseline. For each electrode the likelihood of high-γ (70–116 Hz) power modulation during naming task relative to the baseline was estimated. Electrodes with significant HGM were plotted on a three-dimensional (3D) cortical surface model. Sensitivity, specificity, and accuracy were calculated compared to clinical ECS.
Seventeen patients with mean age of 11.3 years (range 4–19) were included. In patients with left hemisphere electrodes (n = 10), HGM during overt naming showed high specificity (0.81, 95% confidence interval [CI] 0.78–0.85), and accuracy (0.71, 95% CI 0.66–0.75, p < 0.001), but modest sensitivity (0.47) when ECS interference with naming (aphasia or paraphasic errors) and/or oral motor function was regarded as the gold standard. Similar results were reproduced by comparing covert naming-associated HGM with ECS naming sites. With right hemisphere electrodes (n = 7), no ECS-naming deficits were seen without interference with oral-motor function. HGM mapping showed a high specificity (0.81, 95% CI 0.78–0.84), and accuracy (0.76, 95% CI 0.71–0.81, p = 0.006), but modest sensitivity (0.44) compared to ECS interference with oral-motor function. Naming-associated ECoG HGM was consistently observed over Broca's area (left posterior inferior-frontal gyrus), bilateral oral/facial motor cortex, and sometimes over the temporal pole.
This study supports the use of ECoG HGM mapping in children in whom adverse events preclude ECS, or as a screening method to prioritize electrodes for ECS testing.
Treatment of experimental status epilepticus with synergistic drug combinations
During status epilepticus (SE), synaptic γ-aminobutyric acid A receptors (GABAARs) become internalized and inactive, whereas spare N-methyl-d-aspartate receptors (NMDARs) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABAARs is drastically reduced, and a GABAA agonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABAARs), ketamine (to mitigate the effect of the NMDAR increase), and valproate (to enhance inhibition at a nonbenzodiazepine site) to treat seizures in a model of severe cholinergic SE. High doses of diazepam failed to stop electrographic SE, showing that benzodiazepine pharmacoresistance had developed. The diazepam-ketamine-valproate combination was far more effective in stopping SE than triple-dose monotherapy using the same individual drugs. Isobolograms showed that this drug combination's therapeutic actions were synergistic, with positive cooperativity between drugs, whereas drug toxicity was simply additive, without positive or negative cooperativity. As a result, the therapeutic index was improved by this drug combination compared to monotherapy. These results suggest that synergistic drug combinations that target receptor changes can control benzodiazepine-refractory SE.
“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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[Correspondence] Dementia research priorities—2 – Author's 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.
[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.
[Correspondence] Dementia research priorities—2 – Authors' reply
David Smith and colleagues have rightly emphasised the need to contextualise the research priorities that we identified in the dementia research prioritisation exercise. We agree that the present conflicting evidence between the two existing long-term randomised clinical trials on secondary prevention of dementia should be further investigated.
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.
[Articles] Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial
In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention.
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.
Electroencephalogram Coherence Patterns in Autism: An Updated Review
Publication date: February 2017 Source:Pediatric Neurology, Volume 67 Author(s): Sophie Schwartz, Riley Kessler, Thomas Gaughan, Ashura W. Buckley Electrophysiologic studies suggest that autism spectrum disorder is characterized by aberrant anatomic and functional neural circuitry. During normal brain development, pruning and synaptogenesis facilitate ongoing changes in both short- and long-range neural wiring. In developmental disorders such as autism, this process may be perturbed and lead to abnormal neural connectivity. Careful analysis of electrophysiologic connectivity patterns using EEG coherence may provide a way to probe the resulting differences in neurological function between people with and without autism. There is general consensus that electroencephalogram coherence patterns differ between individuals with and without autism spectrum disorders; however, the exact nature of the differences and their clinical significance remain unclear. Here we review recent literature comparing electroencephalogram coherence patterns between patients with autism spectrum disorders or at high risk for autism and their nonautistic or low-risk for autism peers.
Cannabidiol Treatment for Refractory Seizures in Sturge-Weber syndrome
Publication date: Available online 22 February 2017 Source:Pediatric Neurology Author(s): Emma H. Kaplan, Elizabeth A. Offermann, Jacqueline W. Sievers, Anne M. Comi BackgroundSturge-Weber syndrome (SWS) results in leptomeningeal vascular malformations, medically-refractory epilepsy, stroke(s), and cognitive impairments. Cannabidiol (CBD), a cannabinoid without psychoactive properties, has been demonstrated in preclinical models to possibly have anticonvulsant, anti-oxidant, and neuroprotective actions.MethodsFive subjects with SWS brain involvement and treatment-resistant epilepsy were enrolled. Motor seizure frequency, quality of life (QoL), and adverse events were recorded from the 8 week pre-treatment period, 8 weeks after starting maintenance dose (Week 14), and most recent visit.ResultsFour subjects had data through Week 14; one of whom initially withdrew for lack of efficacy, but because of other benefits re-enrolled with a lower dose. Two subjects at Week 14 and three bilaterally brain involved subjects at last visit had greater than 50% seizure reduction, reported improved quality of life, and remain on CBD 63 to 80 weeks after starting drug. Three subjects reported mild side effects considered related to CBD.ConclusionThis study suggests that CBD may be well-tolerated as adjunctive medication for seizure management and provides initial data supporting further study of CBD in SWS patients.
A pediatric case of reversible cerebral vasoconstriction syndrome with similar radiographical findings to posterior reversible encephalopathy syndrome
Publication date: Available online 20 February 2017 Source:Pediatric Neurology Author(s): Tomoya Kamide, Taishi Tsutsui, Kouichi Misaki, Hiroki Sano, Masanao Mohri, Naoyuki Uchiyama, Mitsutoshi Nakada BackgroundReversible cerebral vasoconstriction syndrome predominantly occurs in middle-aged women. Only 9 pediatric cases of this syndrome have ever been reported.Case reportHere we present a pediatric case of reversible cerebral vasoconstriction syndrome (RCVS) with similar radiographical findings to posterior reversible encephalopathy syndrome (PRES). A 10-year-old healthy boy developed thunderclap headache with no neurological deficit. Brain magnetic resonance angiography (MRA) revealed multifocal narrowing of the cerebral arteries, while magnetic resonance imaging (MRI) with diffusion-weighted imaging and fluid-attenuated inversion recovery demonstrated hyperintense lesions in the bilateral occipital lobes and the left cerebellum. The patient’s clinical symptoms resolved spontaneously after a few hours and no recurrence was reported thereafter. MRA on the 2nd day showed a complete normalization of the affected arteries and MRI after 1 month demonstrated a significant improvement in the abnormal findings, leading to a diagnosis of RCVS with similar radiographical findings to PRES.ConclusionsThis report suggests that, although rare, RCVS with or without PRES, should be considered in pediatric patients if they present with a thunderclap headache.
Males With MECP2 C-terminal-Related Atypical Rett Syndromes and Their Carrier Mothers
Publication date: February 2017 Source:Pediatric Neurology, Volume 67 Author(s): Gabriel M. Ronen, Lauren I. Brady, Mark A. Tarnopolsky BackgroundThis communication examines the expanding phenotypes of the MECP2 C-terminal atypical Rett syndromes in males and their affected carrier mothers.DescriptionsWe describe three males with normal karyotypes who presented with congenital evolving complex neurodevelopmental encephalopathies with multifaceted symptomatology of hypotonia, epilepsy, ataxia, spasticity, movement disorders, behavioral issues, severe intellectual impairment, and communication skills, and a protracted regression phase followed by stabilization. These phenotypes did not prompt us to identify atypical Rett syndrome early in childhood.ResultsGenetic analysis identified the two brothers with C-terminal truncation and the third male with C-terminal missense mutations. These mutations were inherited from their mothers, both of whom had incompletely characterized modest intellectual, mental health, social, and gastrointestinal impairments. Neither was independently able to care properly for their son(s).ConclusionsMutations of the MECP2 gene should be considered early in males with hypotonia, developmental delay, profound intellectual impairment, and seizures, associated with a mother with psychosocial, cognitive, and gastrointestinal impairments. Counseling and supporting mildly affected mothers requires both medical and social efforts.