Split calvarial fracture: A rare cause of hypovolemic shock in an infant
Journal of Pediatric Neurosciences 2015 10(3):264-265
The present report describes a rare type split fracture of a calvarial bone, causing hypovolemic shock in an infant. The infant responded well to resuscitative measures. The authors discuss the possible mechanisms behind such a calvarial fracture.
Fatal cerebellar hemorrhage as an initial presentation of medulloblastoma in a child
Guner Menekse, Yurdal Gezercan, Pelin Demirturk, Ismail Uysal, Ali Ihsan Okten
Journal of Pediatric Neurosciences 2015 10(3):287-289
Children with medulloblastomas most commonly present with signs and symptoms of elevated intracranial pressure due to obstructive hydrocephalus, especially headaches and vomiting. However, some pediatric patients present with sudden neurological deterioration due to intracerebellar hemorrhage associated with medulloblastoma, although very few reports exist that document this phenomenon. An 8-year-old girl was admitted to our emergency department who presented with sudden loss of consciousness, vomiting, and bradycardia. The neuroradiological evaluation revealed a hemorrhagic mass lesion in the posterior fossa. Urgent evacuation of the hematoma was performed. The postoperative course was uneventful, and the postoperative histopathological examination revealed the lesion to be a medulloblastoma. This report presents an unusual case of a medulloblastoma presenting with fatal intracranial hemorrhage in a child. The clinical features and intraoperative and pathologic findings of the case are discussed.
Childhood-onset (Juvenile) Huntington's disease: A rare case report
Kailash Chandra Patra, Mukund Sudhir Shirolkar
Journal of Pediatric Neurosciences 2015 10(3):276-279
Huntington's disease (HD) is a rare dominantly inherited neurodegenerative disorder characterized clinically by a combination of abnormal involuntary (choreic) movements, neuropsychiatric manifestations, and dementia. It is caused by an unstable CAG repeat expansion in the gene IT15 which encodes a Huntingtin protein. We present a case of a 9 year old boy who had developmental regression starting from the age of 8 years of age along with resistant seizures and signs of cerebellar involvement with absence of chorea and is on anticonvulsants, baclofen, and tetrabenzine. As is expected in a case of childhood-onset HD, our patient is rapidly deteriorating and is currently in the terminal phase of his illness along with resistant convulsions.
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.
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.
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.
Dystrophinopathies and Limb-Girdle Muscular Dystrophies
Muscular dystrophies are a heterogeneous group of inherited diseases. The natural history of these disorders along with their management have changed mainly due to a better understanding of their pathophysiology, the evolution of standards of care, and new treatment options. Dystrophinopathies include both Duchenne's and Becker's muscular dystrophies, but in reality they are a spectrum of muscle diseases caused by mutations in the gene that encodes the protein dystrophin. Duchenne's muscular dystrophy is the most common form of inherited muscle disease of childhood. The current standards of care considerably prolong independent ambulation and survival. Several therapeutic options either aiming at substituting/correcting the primary protein defect or limiting the progression of the dystrophic process are currently being explored in clinical trials.Limb-girdle muscular dystrophies (LGMDs) are rare and heterogeneous conditions, characterized by weakness and wasting of the pelvic and shoulder girdle muscles. Originally classified into dominant and recessive, > 30 genetic forms of LGMDs are currently recognized. Further understanding of the pathogenic mechanisms of LGMD will help identifying novel therapeutic approaches that can be tested in clinical trials.
Vitamin B6–Responsive Epilepsy due to a Novel KCNQ2 Mutation
Mutations in KCNQ2, encoding for subunits of potassium channels, are known to cause neonatal epileptic encephalopathy (NEE). Therapeutic options for these children are often limited. Recently, there are indications that some patients with KCNQ2 NEE show seizure response to vitamin B6 (VB6) therapy. We present a young infant with severe KCNQ2 encephalopathy resulting from a novel de novo mutation (c.1023G>C; p.(Gln341His)). In our patient, VB6 responsiveness could be demonstrated clearly by remarkable seizure-response to VB6 therapy and seizure exacerbation to discontinuation of VB6 therapy. The pathophysiology of VB6 response in potassium channel mutations is not understood. Some hypothetical mechanisms are currently in discussion. To identify the group of patients who benefits from VB6 therapy, further investigations are necessary.
Novel STAC3 Mutations in the First Non-Amerindian Patient with Native American Myopathy
Native American myopathy (NAM) is an autosomal recessive congenital myopathy, up till now exclusively described in Lumbee Indians who harbor one single homozygous mutation (c.1046G>C, pW284S) in the STAC3 gene, encoding a protein important for proper excitation–contraction coupling in muscle. Here, we report the first non-Amerindian patient of Turkish ancestry, being compound heterozygous for the mutations c.862A>T (p.K288*) and c.432+4A>T (aberrant splicing with skipping of exon 4). Symptoms in NAM include congenital muscle weakness and contractures, progressive scoliosis, early ventilatory failure, a peculiar facial gestalt with mild ptosis and downturned corners of the mouth, short stature, and marked susceptibility to malignant hyperthermia. This case shows that NAM should also be considered in non-Indian patients with congenital myopathy, and suggests that STAC3 mutations should be taken into account as a potential cause of malignant hyperthermia.
Inherited and Acquired Muscle Weakness: A Moving Target for Diagnostic Muscle Biopsy
Inherited and acquired muscular weakness is caused by multiple conditions. While the inherited ones are mostly caused by mutations in genes coding for myopathic or neurogenic diseases, the acquired ones occur due to inflammatory, endocrine, or toxic etiologies. Precise diagnosis of a specific disease may be challenging and may require a multidisciplinary approach. What is the current place for a diagnostic biopsy of skeletal muscle? Diagnostic muscle biopsy lost in this context its first-tier place in the primary diagnostic workup for some diseases, but it is still mandatory for others. We here summarize conditions in which we believe a diagnostic sample is most relevant and mention those in which a biopsy may be secondary or can even be left out. We would like to stress that muscle biopsy nowadays has a new important place in description and definition of new diseases, for example, discovered by modern genetic approaches.
Autosomal Recessive Primary Microcephaly (MCPH): An Update
Autosomal recessive primary microcephaly (MCPH; MicroCephaly Primary Hereditary) is a genetically heterogeneous neurodevelopmental disorder characterized by a significantly reduced head circumference present already at birth and intellectual disability. Inconsistent features include hyperactivity, an expressive speech disorder, and epilepsy. Here, we provide a brief overview on this rare disorder pertinent for clinicians.
Congenital Glioblastoma Multiforme: An Unusual and Challenging Tumor
Congenital glioblastoma multiforme is a rare tumor of the central nervous system with unique features. The existing evidence on its pathogenesis, genetic and molecular profile, special characteristics, treatment, and prognosis is reviewed. An increased number of antenatal diagnoses and prolonged survival for those individuals who can tolerate combined surgical resection and chemotherapy has been noted. The overall prognosis, however, remains poor. A better understanding of this unusual entity is important. Further research is needed to discern tumor's pathogenesis and natural history. This will likely lead to the development and implementation of treatment strategies that may decrease mortality and morbidity in these patients.
Pseudobulbar Affect in Survivors of Extreme Prematurity With Cerebellar Injury: Support for the Cerebellar Link in Pathological Laughter and Crying
Publication date: Available online 2 April 2017 Source:Seminars in Pediatric Neurology Author(s): John B. Bodensteiner Pseudo-bulbar affect (PBA), ie. pathological laughter and crying is being increasingly recognized in adults and is seen in association with a number of diseases like Parkinson disease, dementia, traumatic encephalopathy and others but has not previously been described in children with cerebral palsy CP. The condition (PBA) may be due to lesions in (or degeneration of) the cerebro-ponto-cerebellar pathways. Here we report two children with CP who have structural cerebellar injury as a result of their being born extremely premature who have pathological crying and probably laughter.
Aspartylglucosaminuria caused by a novel homozygous mutation in the AGA gene was identified by an exome-first approach in a patient from Japan
Publication date: May 2017 Source:Brain and Development, Volume 39, Issue 5 Author(s): Toshiyuki Yamamoto, Keiko Shimojima, Mayumi Matsufuji, Ryuichi Mashima, Eri Sakai, Torayuki Okuyama BackgroundAspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the lysosomal enzyme, aspartylglucosaminidase (AGA). This disorder is rare in the general population except in Finland. Since the most characteristic feature of this disorder is a progressive developmental regression, patients often show no specific symptoms in the initial stages, and thus early diagnosis is often challenging.Case reportWe encountered a 16-year-old boy who began to show difficulties in his speech at the age of 6years. Due to a mild regression in his development, he gradually lost common daily abilities. His diagnosis was first obtained through exome sequencing that identified a novel homozygous mutation in the AGA gene. This result was reasonable because of parental consanguinity. Reduced enzymatic activity of AGA was then confirmed. His urine was retrospectively screened by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and a specific pattern of abnormal metabolites was identified.ConclusionsBecause both exome sequencing and MALDI-TOF-MS screening are adaptable and comprehensive, future combinatory use of these methods would be useful for diagnosis of rare inborn errors of metabolism such as AGU.
Publication date: Available online 20 April 2017 Source:Brain and Development Author(s): Natan Gadoth, Arie Oksenberg Since 1962, when Critchley and Hoffman coined the term Kleine–Levin Syndrome (KLS) for the triad of hypersomnia, excessive eating and “often abnormal behavior” which they have observed in 11 adolescent boys, the number of patients recognized with this rare syndrome expanded, the spectrum of the clinical presentation, disease course, prognosis, gender specificity and the presence of familial cases were established. However, in spite of the progress made in neuroscience, the search for the cause, neuroanatomy, pathophysiology and drug treatment of KLS is still ongoing. In this mini-review we will describe in some detail the scientific efforts made to understand in depth the complex symptomatology of KLS and refer also to updated findings reached up till now.
The AAV-mediated and RNA-guided CRISPR/Cas9 system for gene therapy of DMD and BMD
Publication date: Available online 5 April 2017 Source:Brain and Development Author(s): Jing-Zhang Wang, Peng Wu, Zhi-Min Shi, Yan-Li Xu, Zhi-Jun Liu Mutations in the dystrophin gene (Dmd) result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which afflict many newborn boys. In 2016, Brain and Development published several interesting articles on DMD treatment with antisense oligonucleotide, kinase inhibitor, and prednisolone. Even more strikingly, three articles in the issue 6271 of Science in 2016 provide new insights into gene therapy of DMD and BMD via the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). In brief, adeno-associated virus (AAV) vectors transport guided RNAs (gRNAs) and Cas9 into mdx mouse model, gRNAs recognize the mutated Dmd exon 23 (having a stop codon), and Cas9 cut the mutated exon 23 off the Dmd gene. These manipulations restored expression of truncated but partially functional dystrophin, improved skeletal and cardiac muscle function, and increased survival of mdx mice significantly. This review concisely summarized the related advancements and discussed their primary implications in the future gene therapy of DMD, including AAV-vector selection, gRNA designing, Cas9 optimization, dystrophin-restoration efficiency, administration routes, and systemic and long-term therapeutic efficacy. Future orientations, including off-target effects, safety concerns, immune responses, precision medicine, and Dmd-editing in the brain (potentially blocked by the blood–brain barrier) were also elucidated briefly. Collectively, the AAV-mediated and RNA-guided CRISPR/Cas9 system has major superiorities compared with traditional gene therapy, and might contribute to the treatment of DMD and BMD substantially in the near future.
Heparan sulfate storage in the cardiac conduction system triggers atrioventricular block
Publication date: May 2017 Source:Brain and Development, Volume 39, Issue 5 Author(s): Rie Kato, Hiroaki Miyahara, Tatsuya Kawano, Atsuko Matsuzuka, Kimiko Noda, Tatsuro Izumi ObjectiveTo elucidate the novel biological functions of heparan sulfate (HS) by clinic-pathologically studying a patient with paroxysmal atrioventricular (AV) block.PatientA long-surviving male patient with Sanfilippo syndrome type A presented with paroxysmal AV block at age 33years. He then survived another 2.5years after the onset of paroxysmal AV block and pacemaker implantation.Methods and resultsHis cardiac histopathological examination at autopsy showed HS storage in the cardiac conduction system (CCS), especially in the atrioventricular node (AVN)-His bundle branches.ConclusionHS storage in the CCS might trigger AV block, arising from below the AVN-His bundle branches. This is the first description to indicate that HS might be an essential constituent of life-long CCS plasticity and that its storage in the CCS results in AV block.
Low glycemic index treatment in patients with drug-resistant epilepsy
Publication date: Available online 18 April 2017 Source:Brain and Development Author(s): Se Hee Kim, Hoon-Chul Kang, Eun Joo Lee, Joon Soo Lee, Heung Dong Kim ObjectiveLow glycemic index treatment (LGIT) is a newly developed dietary therapeutic option for epilepsy that is less restrictive than the ketogenic diet (KD). Our objective was to determine the efficacy and tolerability of LGIT.MethodsFrom March 2014 to February 2015, 36 patients received LGIT at Severance Children’s Hospital. One-year seizure outcomes and side effects were evaluated.ResultsA total of 36 patients were assessed. Fourteen were female. Common diagnoses were Lennox-Gastaut syndrome (33%, 12/36) and Dravet syndrome (14%, 5/36). The median age at the initiation of the LGIT was 12.6years (min.=1.5, max.=28, interquartile range (IQR) 8–17). After 3months of therapy, 20 (56%) patients experienced a 50% or greater reduction in seizure frequency, which was maintained in 19 (53%) patients for 1year. Two (6%) patients became seizure-free after 3months of LGIT; they remained seizure-free for 1year. These two had Dravet syndrome and generalized epilepsy. Only three (8%) patients discontinued treatment within 1year. Adverse events were rare, and two patients (6%) reported transient diarrhea.ConclusionsLGIT effectively reduced seizure frequency in the present study, although seizure freedom was infrequently achieved. LGIT may be considered as a therapeutic option for patients with drug-resistant epilepsy, particularly those who find KD effective but intolerable.
Publication date: April 2017 Source:Brain and Development, Volume 39, Issue 4 Author(s): Salvatore Grosso, Silvia Ferranti, Carla Gaggiano, Elisabetta Grande, Barbara Loi, Rosanna Di Bartolo Lamotrigine (LTG) represents the most commonly prescribed of the so-called new generation antiepileptic drugs. We describe a child who was admitted to the emergency room because of generalized tonic–clonic status epilepticus followed by a complex neurological picture with hyperkinesia and acute ataxia as a result of a LTG intoxication. The experience on acute LTG intoxication is very limited in pediatrics. The present case provides information on the clinical picture related to LTG overdose and confirms that drug intoxications should be considered in the differential diagnosis strategy when severe and polymorphic neurological symptoms occur acutely.
Neural alterations in ADHD children as indicated by voxel-based cortical thickness and morphometry analysis
Publication date: May 2017 Source:Brain and Development, Volume 39, Issue 5 Author(s): Uttam Kumar, Amit Arya, Vivek Agarwal PurposeNeuroimaging studies provide vital information related to the neurobiology of ADHD, but there still exists a wide gap in relevant information. The present study aimed to elucidate the neuroanatomical alteration in Attention deficit hyperactivity disorder (ADHD) children/adolescents.MethodsVoxel-based cortical thickness (VBCT) and voxel-based morphometry (VBM) was performed to examine neuroanatomic distinctions in 18 children/adolescents aged 7.5–13years diagnosed with DSM-IV TR as ADHD (non-medicated). They were compared with 18 healthy matched controls.ResultsVBCT findings in ADHD children/adolescents revealed reduced cortical thickness in the left superior frontal, left orbito-frontal and left dorsal anterior cingulate cortex. VBM findings confirmed decreased gray matter volume in the left orbito frontal, left middle frontal/dorsolateral prefrontal, left middle temporal and left cerebellum in comparison to control group. A decrease in white matter volume was also observed in the left inferior frontal and left calcarine of ADHD children/adolescents.ConclusionResults reflect possible abnormal neuroanatomical development patterns in ADHD children.
Herpes simplex virus-induced anti-N-methyl-D-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases
To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.
We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar's test, Fisher's test, and Wilcoxon rank sum test were used (two-tailed significance level set at 5%).
Forty-three patients with biphasic disease were identified (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs 40.5d; p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% vs 75% respectively; p<0.001), and significantly lower rate of seizures (70% vs 30% respectively; p=0.001). Compared with adults, during anti-NMDAR encephalitis children had significantly more movement disorders (86.7% children vs 40% adults; p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults; p=0.025), and a slightly higher median modified Rankin Scale score (5 in children vs 4 in adults; p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for ≤7d in 22.7%; long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal fluid HSV polymerase chain reaction (median follow-up 7mo).
Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV-induced anti-NMDAR encephalitis does not predispose patients to HSE recurrence.
Prevalence and characteristics of autism spectrum disorders in children with cerebral palsy
To evaluate the prevalence of co-occurring autism spectrum disorders (ASDs) among children with cerebral palsy (CP), and to describe their characteristics.
The data of 1225 CP cases from four population-based registers (Iceland, Sweden, and two in France) and one population-based surveillance programme (North East England, UK) participating in the Surveillance of Cerebral Palsy in Europe Network (SCPE) were analysed. The ASD diagnoses were systematically recorded using category F84 of the International Classification of Diseases, 10th Revision. The registers provided data on children born between 1995 and 2006, while the cross-sectional survey in the UK concerned children aged 0 to 19 years, registered in 2010.
Among the children with CP, 107 had an associated diagnosis of ASD – i.e., 8.7% of the study population (95% confidence interval 7.2–10.5). This proportion varied across centres from 4.0% to 16.7% but was independent of CP prevalence. Male sex, co-occurring epilepsy, intellectual disability, and better walking ability were associated with the coexistence of ASD.
Our findings support the need for a multidisciplinary approach to management of children with CP to adequately identify and address all facets of presentation, including ASD.
Prevalencia y características de los trastornos del espectro autista en niños con parálisis cerebral
Evaluar la prevalencia de trastornos del espectro autista (TEA) en niños con parálisis cerebral (PC) y describir sus características.
Se analizaron los datos de 1225 casos de CP de cuatro registros poblacionales (Islandia, Suecia y dos en Francia) y un programa de vigilancia poblacional (Inglaterra, Reino Unido) que participaban en la Red de Parálisis Cerebral en Europa (SCPE). Los diagnósticos de TEA fueron sistemáticamente registrados utilizando la categoría F84 de la Clasificación Internacional de Enfermedades-10 (ICD-10). Los registros proporcionaron datos sobre los niños nacidos entre 1995 y 2006, mientras que la encuesta transversal en el Reino Unido se refería a niños de 0 a 19 años, registrados en 2010.
Entre los niños con CP, 107 tuvieron un diagnóstico asociado de TEA, es decir, el 8,7% de la población estudiada (intervalo de confianza del 95% [IC] 7,2-10,5). Esta proporción varió entre los centros de 4,0% a 16,7%, pero fue independiente de la prevalencia de CP. El sexo masculino, la epilepsia coexistente, la discapacidad intelectual y una mejor capacidad para caminar se asociaron con la coexistencia de TEA.
Nuestros hallazgos apoyan la necesidad de un enfoque multidisciplinario del manejo de los niños con CP para identificar adecuadamente y abordar todas las facetas de la presentación, incluyendo ASD.
Prevalência e características do transtorno do espectro autista em crianças com paralisia cerebral
Avaliar a prevalência do transtorno do espectro autista (TEA) como comorbidade em crianças com paralisia cerebral (PC) e descrever as suas características.
Foram analisados os dados de 1225 casos de PC de quatro registros populacionais (Islândia, Suécia e dois na França) e de um programa de vigilância populacional (Inglaterra, Reino Unido) que participam da Rede de Vigilância da Paralisia Cerebral na Europa. Os diagnósticos de TEA foram registrados sistematicamente utilizando a categoria F84 da Classificação Internacional de Doenças-10 (ICD-10). Os registros forneceram dados sobre crianças nascidas entre 1995 e 2006, enquanto que a pesquisa transversal no Reino Unido englobou crianças com idades compreendidas entre 0 e 19 anos registradas em 2010.
Entre as crianças com PC, 107 tiveram um diagnóstico associado de TEA – isto representa 8,7% da população estudada (intervalo de confiança de 95% [IC] 7,2-10,5). Esta proporção variou de 4,0% a 16,7% entre os centros, mas foi independente da prevalência de PC. Gênero masculino, epilepsia comórbida, deficiência intelectual e uma melhor capacidade de marcha foram associados com TEA coexistente.
Os nossos resultados apoiam a necessidade de uma abordagem multidisciplinar no manejo de crianças com PC, para identificar e abordar adequadamente todas as facetas de apresentação, incluindo TEA.
Functional vision and cognition in infants with congenital disorders of the peripheral visual system
To investigate how vision relates to early development by studying vision and cognition in a national cohort of 1-year-old infants with congenital disorders of the peripheral visual system and visual impairment.
This was a cross-sectional observational investigation of a nationally recruited cohort of infants with ‘simple’ and ‘complex’ congenital disorders of the peripheral visual system. Entry age was 8 to 16 months. Vision level (Near Detection Scale) and non-verbal cognition (sensorimotor understanding, Reynell Zinkin Scales) were assessed. Parents completed demographic questionnaires.
Of 90 infants (49 males, 41 females; mean 13mo, standard deviation [SD] 2.5mo; range 7–17mo); 25 (28%) had profound visual impairment (light perception at best) and 65 (72%) had severe visual impairment (basic ‘form’ vision). The Near Detection Scale correlated significantly with sensorimotor understanding developmental quotients in the ‘total’, ‘simple’, and ‘complex’ groups (all p<0.001). Age and vision accounted for 48% of sensorimotor understanding variance. Infants with profound visual impairment, especially in the ‘complex’ group with congenital disorders of the peripheral visual system with known brain involvement, showed the greatest cognitive delay.
Lack of vision is associated with delayed early-object manipulative abilities and concepts; ‘form’ vision appeared to support early developmental advance. This paper provides baseline characteristics for cross-sectional and longitudinal follow-up investigations in progress. A methodological strength of the study was the representativeness of the cohort according to national epidemiological and population census data.
Visión funcional y función cognitiva en lactantes con desórdenes congénitos del sistema visual periférico
Investigar cómo se relaciona la visión con ell desarrollo temprano mediante el estudio de la visión y de las habilidades cognitivas en una cohorte de lactantes de un año de edad
Este fue un estudio transversal observacional de una cohorte nacional de lactantes con desórdenes congénitos “simples y complejos” del sistema visual periférico. La edad de los lactantes de ingreso al estudio fue de 8 a 16 meses. Se determinaron los niveles de visión (mediante la Escala de Visión cercana [Near Detection Scale]) y habilidades cognitivas no verbales (comprensión sensorimotora, Escala de Reynell Zinkin). Los padres completaron cuestionarios sobre características demográficas.
De 90 niños (49 masculinos, 41 femeninos; edad promedio 13 meses, desviación estándar [DS] 2.5 m; rango 7-17 meses); 25 (28%) presentaron limitación visual profunda (solo percepción de luz) y 65 (72%) presentaron limitación visual severa (visión básica – “contornos/formas”). La Escala de Visión Cercana se correlaciono significativamente con el cociente de desarrollo de la comprensión sensorimotora en todos los grupos de lactantes “total” y en los grupos con desordenes “simples y complejos” ( p<0.001 en todos). La edad del los lactantes y el déficit visual explicaron el 48% de la variabilidad de la comprensión sensorimotara. Lactantes con limitación visual profunda, especialmente en el grupo de desórdenes “complejos” del sistema visual periférico, con compromiso cerebral confirmado, mostraron el mayor retraso cognitivo.
El déficit visual está asociado con el retraso temprano de la manipulación de objetos y conceptos; la visión básica de “formas” sustenta el avance en el desarrollo temprano. La presente publicación sirve como una referencia para investigaciones transversales y longitudinales de seguimiento - en curso. Una fortaleza metodológica del presente estudio fue el poder contar con una cohorte representativa según datos epidemiológicos nacionales y censo poblacional.
Visão funcional e cognição em lactentes com desordens congênitas do sistema visual periférico
Investigar como a visão se relaciona com o desenvolvimento precoce por meio do estudo da visão e da cognição em uma coorte nacional de lactentes de 1 ano de idade com desordens congênitas do sistema visual periférico e com deficiência visual.
Esta foi uma investigação transversal observacional de uma coorte nacionalmente recrutada de lactentes com desordens congênitas do sistema visual periférico “simples” e “complexas”. A idade de entrada foi de 8 a 16 meses. O nível de visão (Escala de detecção próxima [Near Detection Scale]) e a cognição não verbal (compreensão sensório-motora, Escalas Reynell Zinkin) foram avaliados. Os pais completaram questionários demográficos.
De 90 lactentes (49 do sexo masculino, 41 do sexo feminino; média 13 meses, desvio-padrão [DP] 2,5 meses; variação de 7 a 17 meses); 25 (28%) tinham deficiência visual profunda (no máximo percepção de luminosidade) e 65 (72%) tinham deficiência visual severa (visão básica de formas). A escala de detecção próxima se correlacionou significantemente como os quocientes desenvolvimentais de compreensão sensório-motora nos grupos “total”, “simples” e “complexo” (todos com p<0,001). A idade e a visão responderam por 48% da variância da compreensão sensóriomotora. Lactentes com deficiência visual profunda, especialmente no grupo “complexo” com desordens congênitas do sistema visual periférico com envolvimento cerebral conhecido, mostraram o maior atraso cognitivo.
A falta de visão está associada com atraso em habilidades manipulativas e conceituais sobre objetos precoces; a visão de formas pareceu dar suporte ao avanço desenvolvimental precoce. Este artigo fornece características de base para investigações transversais e acompanhamento longitudinal em andamento. Uma vantagem metodológica do estudo foi a representatividade da coorte de acordo com dados epidemiológicos e censo populacional.
Cerebrospinal fluid cyto-/chemokine profile during acute herpes simplex virus induced anti-N-Methyl-d-aspartate receptor encephalitis and in chronic neurological sequelae
To examine the cytokine/chemokine profile of cerebrospinal fluid (CSF) during acute herpes simplex virus-induced N-methyl-d-aspartate receptor (NMDAR) autoimmunity and in chronic/relapsing post-herpes simplex virus encephalitis (HSE) neurological syndromes.
We measured longitudinal serial CSF cyto-/chemokines (n=34) and a glial marker (calcium-binding astroglial protein, S100B) in one patient during acute HSE and subsequent anti-NMDAR encephalitis, and compared the results with those from two patients with anti-NMDAR encephalitis without preceding HSE. We also compared cyto-/chemokines in cross-sectional CSF samples from three children with previous HSE who had ongoing chronic or relapsing neurological symptoms (2yr 9 mo–16y after HSE) with those in a group of children having non-inflammatory neurological conditions (n=20).
Acute HSE showed elevation of a broad range of all T-helper-subset-related cyto-/chemokines and S100B whereas the post-HSE anti-NMDAR encephalitis phase showed persistent elevation of two of five T-helper-1 (chemokine [C-X-C motif] ligand 9 [CXCL9], CXCL10), three of five predominantly B-cell (CXCL13, CCL19, a proliferation-inducing ligand [APRIL])-mediated cyto-/chemokines, and interferon-α. The post-HSE anti-NMDAR encephalitis inflammatory response was more pronounced than anti-NMDAR encephalitis. All three chronic post-HSE cases showed persistent elevation of CXCL9, CXCL10, and interferon-α, and there was histopathological evidence of chronic lymphocytic inflammation in one biopsied case 7 years after HSE. Two of three chronic cases showed a modest response to immune therapy.
HSE-induced anti-NMDAR encephalitis is a complex and pronounced inflammatory syndrome. There is persistent CSF upregulation of cyto-/chemokines in chronic or relapsing post-HSE neurological symptoms, which may be modifiable with immune therapy. The elevated cyto-/chemokines may be targets of monoclonal therapies.
Perfil de Citoquinas/Quimiocinas en líquido cefalorraquídeo durante la encefalitis inducida por anticuerpos contra el receptor anti-N-Metil-D-Aspartato en la infección por el virus herpes simple y en las secuelas neurológicas crónicas
Examinar el perfil de Citoquinas/Quimiocinas en líquido cefalorraquídeo (LCR) durante la encefalitis autoinmunide contra el receptor N-Metil-D-Aspartato (NMDAR), inducida por la infección del virus del herpes simple, y en los síndromes neurológicos crónicos/recurrentes posteriores a la encefalitis por herpes simple (EHS).
Medimos longitudinalmente varios perfiles de Citoquinas/ Quimiocinas (n=34) y un marcador glial (proteína astroglial ligada al calcio, S100B) en un paciente durante un cuadro agudo de EHS y la subsecuente encefalitis anti-NMDAR y se compararon los resultados con aquellos perfiles provenientes de dos pacientes con encefalitis anti NMDAR. También comparamos los perfiles de Citoquinas/ Quimiocinas en muestras transversales de LCR de tres niños con antecedentes de EHS, que tenían síntomas neurológicos crónicos o recurrentes (2 años 6 meses- 17 años, después de EHS) con un grupo de niños que tenían condiciones neurológicas no inflamatorias (n=20).
EHS aguda demostró elevación en un amplio rango de todas las células T-colaboradoras del subtipo relacionado con las Citoquinas/Quimiocinas y S100B, mientras que en la fase de encefalitis anti-NMDAR post EHS mostro elevación persistente de dos de cinco T-colaboradoras-1 (Quimiocina [C-X-C motif] ligando 9[CXCL9], CXCL 10), tres de cinco predominantemente de Células B (CXCL13, CCL19, un ligando inductor de proliferación [APRIL])- mediados por Citoquinas/Quimiocinas, e interferón –a. La respuesta inflamatoria de las post EHS anti-NMDAR fue más elevada que en la encefalitis anti-NMDAR. Los tres casos de síndrome neurológico crónico post EHS mostraron elevación persistente de CXCL9, CXCL10, e interferón-a y hubo evidencia histopatológica de inflamación linfocítica crónica en un caso, en el que se obtuvo una biopsia 7 años después de EHS. Dos de tres casos crónicos mostraron una respuesta modesta a la terapia de modulacion inmune.
La encefalitis anti-NMDAR inducida por EHS es un síndrome inflamatorio complejo y pronunciado. Existe una regulación positiva persistente de las Citoquinas/Quimiocinas en individuos que presentan síntomas neurológicos crónicos o recurrentes después del EHS, que pueden ser modificables con la inmunoterapia. Las Citoquinas/Quimiocinas elevadas pueden ser “blanco molecular” de las terapias monoclonales.
Perfil de citoquinas/quimiocinas no líquor [cerebrospinal fluid] durante encefalite aguda anti- receptor N-metil-D-aspartato induzida pelo vírus herpes simplex e na sequela neurológica crônica
Examinar o perfil de citoquinas/quimiocinas no líquor durante a autoimunidade aguda anti-receptor N-metil-D-aspartato (NMDAR) e nas síndromes neurológicas crônicas/recorrentes pós encefalite por herpes simplex vírus (HSE).
Nós medimos longitudinalmente, de forma seriada, as cito-/quimiocinas (n=34) e um marcador glial (proteína astroglial ligadora de cálcio, S100B) em um paciente durante HSE agudo e encefalite anti-NMDAR subsequente e comparamos esses resultados com os de dois pacientes com encefalite anti-NMDAR. Nós também comparamos transversalmente as cito-/quimiocinas em amostras de líquor de 3 pacientes com HSE prévio que evoluíram com sintomas neurológicos crônicos ou recorrentes (2 anos e 6 meses – 17 anos após HSE) com amostras de um grupo de criança com condições neurológicas não inflamatórias.
HSE agudo demonstrou elevação de uma ampla faixa de todos as cito/quimiocinas relacionadas ao subconjunto T-helper e S100B enquanto a encefalite anti-NMDAR pos-HSE demonstrou elevação persistente de dois dos cinco T-helper-1 (quimiocina [C-X-C-motif] ligand 9 [CXCL9], CXCL10), três de cinco células B predominantemente (CXCL13, CCL19, um ligante indutor de proliferação [APRIL]) – mediadas por cito/quimiocinas, e interferon-a. A resposta inflamatória na encefalite anti-NMDAR pos-HSE foi mais pronunciada do que na encefalite anti-NMDAR. Todos os três casos de pós-HSE crônica demonstraram elevação persistente do CXCL9, CXCL10 e inteferon-a, e houve evidência histopatológica de inflamação linfocítica crônica em um caso biopsiado 7 anos após HSE. Dois de três casos crônicos mostraram uma resposta modesta a terapia imune.
A encefalite anti-NMDAR induzida pelo HSE é uma síndrome inflamatória complexa e pronunciada. Há uma persistente regulação ascendente de cito/quimiocinas no líquor em sintomas neurológicos crônicos ou recorrentes pós-HSE, que podem ser modificáveis com imunoterapia. As elevadas cito/quimiocinas podem ser o alvo das terapias monoclonais.
Development and pharmacologic characterization of the rat 6 Hz model of partial seizures
The mouse 6 Hz model of psychomotor seizures is a well-established and commonly used preclinical model for antiseizure drug (ASD) discovery. Despite its widespread use both in the identification and differentiation of novel ASDs in mice, a corresponding assay in rats has not been developed. We established a method for 6 Hz seizure induction in rats, with seizure behaviors similar to those observed in mice including head nod, jaw clonus, and forelimb clonus.
A convulsive current that elicits these seizure behaviors in 97% of rats (CC97) was determined using a Probit analysis. Numerous prototype ASDs were evaluated in this model using stimulus intensities of 1.5× and 2× the CC97, which is comparable to the approach used in the mouse 6 Hz seizure model (e.g., 32 and 44 mA stimulus intensities). The ASDs evaluated include carbamazepine, clobazam, clonazepam, eslicarbazepine, ethosuximide, ezogabine, gabapentin, lacosamide, lamotrigine, levetiracetam, phenobarbital, phenytoin, rufinamide, tiagabine, topiramate, and sodium valproate. Median effective dose (ED50) and median toxic (motor impairment) dose (TD50) values were obtained for each compound.
Compounds that were effective at the 1.5 × CC97 stimulus intensity at protective index (PI) values >1 included clobazam, ethosuximide, ezogabine, levetiracetam, phenobarbital, and sodium valproate. Compounds that were effective at the 2 × CC97 stimulus intensity at PI values >1 included ezogabine, phenobarbital, and sodium valproate.
In a manner similar to the use of the mouse 6 Hz model, development of a rat 6 Hz test will aid in the differentiation of ASDs, as well as in study design and dose selection for chronic rat models of pharmacoresistant epilepsy. The limited number of established ASDs with demonstrable efficacy at the higher stimulus intensity suggests that, like the mouse 6 Hz 44 mA model, the rat 6 Hz seizure model may be a useful screening tool for pharmacoresistant seizures.
Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury
Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury.
Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE.
Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1β levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1β and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1β, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1β or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17–393) of hippocampal T2 hyperintensity after FSE.
Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).
22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy
Previous studies examining seizures in patients with 22q11.2 deletion syndrome (22q11.2DS) have focused primarily on children and adolescents. In this study we investigated the prevalence and characteristics of seizures and epilepsy in an adult 22q11.2DS population.
The medical records of 202 adult patients with 22q11.2DS were retrospectively reviewed for documentation of seizures, electroencephalography (EEG) reports, and magnetic resonance imaging (MRI) findings. Epilepsy status was assigned in accordance with 2010 International League Against Epilepsy Classification.
Of 202 patients, 32 (15.8%) had a documented history of seizure. Of these 32, 23 (71.8%) had acute symptomatic seizures, usually associated with hypocalcemia and/or antipsychotic or antidepressant use. Nine patients (9/32, 28%; 9/202, 4%) met diagnostic criteria for epilepsy. Two patients had genetic generalized epilepsy; two patients had focal seizures of unknown etiology; two had epilepsy due to malformations of cortical development; in two the epilepsy was due to acquired structural changes; and in one patient the epilepsy could not be further classified.
Similarly to children, the prevalence of epilepsy and acute symptomatic seizures in adults with 22q11.2DS is higher than in the general population. Hypocalcemia continues to be a risk factor for adults, but differently from kids, the main cause of seizures in adults with 22q11.2DS is exposure to antipsychotics and antidepressants. Further prospective studies are warranted to investigate how 22q11.2 microdeletion leads to an overall decreased seizure threshold.
Magnetic resonance imaging connectivity for the prediction of seizure outcome in temporal lobe epilepsy
Currently, approximately 60–70% of patients with unilateral temporal lobe epilepsy (TLE) remain seizure-free 3 years after surgery. The goal of this work was to develop a presurgical connectivity-based biomarker to identify those patients who will have an unfavorable seizure outcome 1-year postsurgery.
Resting-state functional and diffusion-weighted 3T magnetic resonance imaging (MRI) was acquired from 22 unilateral (15 right, 7 left) patients with TLE and 35 healthy controls. A seizure propagation network was identified including ipsilateral (to seizure focus) and contralateral hippocampus, thalamus, and insula, with bilateral midcingulate and precuneus. Between each pair of regions, functional connectivity based on correlations of low frequency functional MRI signals, and structural connectivity based on streamline density of diffusion MRI data were computed and transformed to metrics related to healthy controls of the same age.
A consistent connectivity pattern representing the network expected in patients with seizure-free outcome was identified using eight patients who were seizure-free at 1-year postsurgery. The hypothesis that increased similarity to the model would be associated with better seizure outcome was tested in 14 other patients (Engel class IA, seizure-free: n = 5; Engel class IB-II, favorable: n = 4; Engel class III–IV, unfavorable: n = 5) using two similarity metrics: Pearson correlation and Euclidean distance. The seizure-free connectivity model successfully separated all the patients with unfavorable outcome from the seizure-free and favorable outcome patients (p = 0.0005, two-tailed Fisher's exact test) through the combination of the two similarity metrics with 100% accuracy. No other clinical and demographic predictors were successful in this regard.
This work introduces a methodologic framework to assess individual patients, and demonstrates the ability to use network connectivity as a potential clinical tool for epilepsy surgery outcome prediction after more comprehensive validation.
The epileptology of Koolen-de Vries syndrome: Electro-clinico-radiologic findings in 31 patients
This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1.
We were invited to attend a large gathering of individuals with KdVS and their families. While there, we recruited individuals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure.
Thirty-one individuals were studied, aged 2–35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma.
The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery should be undertaken with care given the widespread neuroanatomic abnormalities; however, tumors are a rare, yet important, occurrence.
Heart-rate variability indices as predictors of the response to vagus nerve stimulation in patients with drug-resistant epilepsy
To assess heart-rate variability (HRV) measures of interictal electrocardiography (ECG) for drug-resistant epilepsy and to relate the findings to the outcome of vagus nerve stimulation (VNS) treatment.
Time-domain, frequency-domain, and nonlinear analyses were used to analyze preoperative HRV measures in 32 patients with drug-resistant epilepsy who had received VNS implants at the same hospital and 32 healthy age- and sex-matched control subjects. HRV measurements based on ambulatory 24 h ECG recordings were analyzed to identify seizure reduction 1 year after VNS treatment. Responders were defined as having at least 50% seizure reduction 1 year after treatment.
Patients with drug-resistant epilepsy had significantly lower time domain (SDNN, RMSSD, pNN50), frequency domain (VLF, LF, HF, TP), and nonlinear (SD1, SD2) HRV measurements than matched healthy controls. None of the analyzed HRV measures of the responders differed significantly from their controls, whereas those of the nonresponders had significantly lower RMSSD, pNN50, HF, and SD1 than the responders.
The preoperative HRV indices demonstrate that nonresponders have more pronounced impairment of their cardiac autonomic function than the responders. Presurgical HRV measurements representing parasympathetic cardiac control or vagal tone were significantly associated with the responsiveness to VNS. Thus the measurements show promise for predicting the reduction of seizure frequency after VNS treatment.
Length of stay for patients undergoing invasive electrode monitoring with stereoelectroencephalography and subdural grids correlates positively with increased institutional profitability
Lowering the length of stay (LOS) is thought to potentially decrease hospital costs and is a metric commonly used to manage capacity. Patients with epilepsy undergoing intracranial electrode monitoring may have longer LOS because the time to seizure is difficult to predict or control. This study investigates the effect of economic implications of increased LOS in patients undergoing invasive electrode monitoring for epilepsy.
We retrospectively collected and analyzed patient data for 76 patients who underwent invasive monitoring with either subdural grid (SDG) implantation or stereoelectroencephalography (SEEG) over 2 years at our institution. Data points collected included invasive electrode type, LOS, profit margin, contribution margins, insurance type, and complication rates.
LOS correlated positively with both profit and contribution margins, meaning that as LOS increased, both the profit and contribution margins rose, and there was a low rate of complications in this patient group. This relationship was seen across a variety of insurance providers.
These data suggest that LOS may not be the best metric to assess invasive monitoring patients (i.e., SEEG or SDG), and increased LOS does not necessarily equate with lower or negative institutional financial gain. Further research into LOS should focus on specific specialties, as each may differ in terms of financial implications.
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.
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.
“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.
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.
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.
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.
Response to “Sleep and executive functions in children with ADHD”
We would like to thank Dr. Mao et al. for their interest in our manuscript “Prevalence of sleep disorders and their relationship with core symptoms inattention and hyperactivity in children with attention deficit/hyperactivity disorder”.1
Vagus nerve stimulation in children: A focus on intellectual disability
Many children suffer from epilepsy from an early age, during rapid brain development when synaptic and neuronal circuit processes are very intensive. In about 2/3, the young patients have their seizures controlled by antiepileptic drugs (AED). However, 20%–30% of children with epilepsy have drug-resistant epilepsy and do not achieve seizure remission despite treatment with several AEDs. Along with seizures, many develop behavioural and cognitive difficulties. However, selected patients benefit from epilepsy surgery, resulting in partial or complete freedom from seizures.
Risk factors for psychiatric and behavioural adverse events associated with antiepileptic drugs in adolescents and children
Chen et al.,1 in this issue, have reported the results of a retrospective, electronic case review study of the psychiatric and behavioural adverse events (which the authors refer to as psychiatric and behavioural side effects: PBSEs) associated with antiepileptic drugs (AEDs) in children and adolescents under 18 years of age. The results they obtained are of considerable interest because this was a large (n = 922) study and provides numerical data together with several statistically significant associations indicating possible risk factors.
Heterogeneity of FHF1 related phenotype: novel case with early onset severe attacks of apnea, partial mitochondrial respiratory chain complex II deficiency, neonatal onset seizures without neurodegeneration
We report the case of a child prospectively followed in our institution for a severe, neonatal onset epilepsy presenting with severe attacks of apnea that were not initially recognized as seizure since they were not associated with any abnormal movement and since interictal EEG was normal. Recording of attacks using prolonged video-EEG recording allowed to confirm the diagnosis of epileptic seizures. Using whole exome sequencing we found a de novo heterozygous, missense mutation of FHF1 (p.Arg52His, NM_004113), a mutation that has been very recently described in 7 patients with an early onset epileptic encephalopathy.
Fetal akinesia deformation sequence (FADS) or arthrogryposis multiplex congenita (AMC) is characterized by clinical ambiguity and genetic heterogeneity, hampering genetic diagnosis via traditional sequencing methods. Next generation sequencing (NGS) of all known disease-causing genes offers an elegant solution to identify the genetic etiology of AMC/FADS in a diagnostic setting.
Juvenile myasthenia gravis in Norway: Clinical characteristics, treatment, and long-term outcome in a nationwide population-based cohort
This study aimed to characterize juvenile myasthenia gravis in a national population-based cohort in Norway, and to evaluate long-term outcome and potential differences correlated with prepubertal versus postpubertal disease onset.
[Comment] Disease progression in LRRK2 parkinsonism
Over the past two decades, more than 25 mutant genes have been associated with familial forms of parkinsonism, including the gene encoding leucine-rich repeat kinase 2 (LRRK2).1 Dominantly inherited mutations in LRRK2 are associated with the highest attributable risk in populations with familial and sporadic forms of Parkinson's disease.2 In The Lancet Neurology, Daryl Wile and colleagues3 report results from a dopaminergic and serotonergic PET imaging study in LRRK2 mutation carriers with and without manifest Parkinson's disease, who they assessed in parallel with a cohort of individuals with sporadic Parkinson's disease and healthy controls.
[Correspondence] Membrane damage is at the core of Alzheimer's disease
Evidence from autosomal dominant Alzheimer's disease has convincingly pointed to amyloid deposition as the central event in disease pathogenesis.1 This hypothesis has driven research into treatment of the disease for the past 20 years. However, most cases of Alzheimer's disease are late onset, and the relationship between their pathogenesis and amyloid deposition is much less clear. In the past 10 years, genome wide association studies and exome sequencing have identified many new genetic loci relevant to late onset, sporadic disease in addition to the long established APOE locus.
[Editorial] Vascular disease and neurodegeneration: advancing together
On Feb 19, 2017, immediately before the International Stroke Conference, the MarkVCID consortium held its first meeting in Houston (TX, USA). The focus of this new research consortium is on understanding small vessel disease and its contributions to vascular cognitive impairment and dementia (VCID). For too long, research in dementia has neglected the most common comorbidity in elderly patients: cerebrovascular disease. Funders are now reversing this trend and encouraging research into the role of brain vessels in neurodegeneration, and MarkVCID is a momentous initiative in that direction.
[Policy View] Increasing value and reducing waste in stroke research
Stroke is a major burden to patients and society, and resources spent on stroke research must be used efficiently and produce good value in terms of improvements in human health. However, many instances of poor value from stroke research funding have resulted from the way in which stroke research topics have been chosen and how studies have been designed, conducted, analysed, regulated, managed, disseminated, or reported. A cooperative effort of European stroke researchers aimed to identify sources of inefficiency and waste, recommend approaches to increase value, and highlight examples of best practice in stroke research.
[In Context] Historical landmarks in dementia with Lewy bodies
Fritz Jakob Heinrich Lewy (1885–1950) described the eosinophilic intraneuronal inclusion bodies, later named after him, while studying the neuropathology of Parkinson's disease at Alois Alzheimer's laboratory (Munich, Germany) in 1912.1 In 1962, neuropathologist John Woodard (Camarillo State Hospital, CA, USA) reported neuropsychiatric symptoms and cognitive decline in 27 patients with autopsy-proven Lewy body disease, of whom only about a quarter had parkinsonian symptoms.2 Over the following decades, Kenji Kosaka (Yokohama City University, Yokohama, Japan) and others from Japan reported detailed autopsies of more than 20 patients with a variable distribution of Lewy bodies in their brain stem and cerebral cortex, who clinically presented with varying amounts of cognitive impairment, and neuropsychiatric and motor symptoms.
Edor Kabashi is a tenured Inserm researcher and Principal Investigator at the Brain and Spinal Cord Institute at the Pierre and Marie Curie University in Paris, France, since 2011. He is dedicating his scientific career to the study of amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. He has received numerous awards and honours for his research, including the 2016 International Paulo Gontijo Award in Medicine for developing new laboratory models of ALS to identify shared mechanisms of degeneration.
[Comment] Imaging the ageing brain: identifying early disease or opening Pandora's box?
Increasing age is the biggest risk for Alzheimer's disease, and therefore identification of elderly individuals in the pre-symptomatic stages when disease-modifying therapies might be most beneficial is of interest. A logical approach is to use biomarkers of core Alzheimer's disease pathologies, such as neuronal loss, β-amyloidosis, and hyperphosphorylated tau. Findings from MRI studies1 have shown that increased atrophy occurs years before dementia, and studies using β-amyloid PET tracers have identified that a third or more of cognitively unimpaired individuals older than 70 years have substantial fibrillary β-amyloid accumulation.
[Articles] Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years: a cross-sectional study
Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired.
[Articles] Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study
More frequent use of health care in patients with multiple sclerosis than in controls in the 5 years before a first demyelinating event, according to health administrative data, suggests the existence of a measurable multiple sclerosis prodrome. These findings have clinical and research implications, including the establishment of an earlier window of opportunity to identify and potentially treat multiple sclerosis.
Imagine a book all about hard science, which is littered with metaphors and stories, jokes and quips, ideas and assumptions, and crammed with knowledge. Ransom Stephens delivers this medley and concoction in his latest book, The Left Brain Speaks The Right Brain Laughs. “I want to understand how brains work for the same reason that I want to know how anything works—for the buzz of understanding, and so I can put that understanding to work”, Stephens explains. His supposition is, that through studying neuroscience, we can develop our intuition about what we are capable of, and how we can do better—be better people—”our brains are the only tools we have to create solutions”, he says.
[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.
Incidence and Demographics of Pediatric Intracranial Hypertension
Publication date: Available online 27 April 2017 Source:Pediatric Neurology Author(s): Natalie Gillson, Charlotte Jones, Rachel E. Reem, David L. Rogers, Nicholas Zumberge, Shawn C. Aylward ObjectiveTo report the incidence and demographic features of pediatric intracranial hypertension.MethodsInpatient and outpatient encounters of children aged 18 years or younger who were diagnosed with primary (idiopathic) or secondary intracranial hypertension between January 2010 and December 2013 were identified. Data was collected from a subspecialty clinic devoted to intracranial hypertension and the sole children’s hospital in a large midwestern city of the United States. Estimated incidence rates were calculated based upon the number of newly diagnosed patients in our hospital’s primary service area which includes seven central Ohio counties. Sex, race, BMI, socioeconomic status, and geographic distribution are also described.ResultsA total of 74 pediatric patients with intracranial hypertension were diagnosed (49 primary/idiopathic and 25 secondary) between January 2010 and December 2013. Using data from the Ohio Hospital Association’s database, we were able to determine the pediatric population in our service area during the 3 year period. The database estimated that 92.3% of patients aged 0-17 years residing in the region sought care at our institution. The estimated annual incidence of primary and secondary intracranial hypertension was calculated at 0.63 and 0.32 per 100,000 children respectively.ConclusionWe found that the estimated annual incidence of pediatric primary intracranial hypertension in our 7 county service area in central Ohio is in line with previous pediatric reports from other countries and is 2/3 that reported in the US adult population.
Clinical Predictors of Attention and Executive Functioning Outcomes in Children After Perinatal Arterial Ischemic Stroke
Publication date: April 2017 Source:Pediatric Neurology, Volume 69 Author(s): Danielle D. Bosenbark, Lauren Krivitzky, Rebecca Ichord, Arastoo Vossough, Aashim Bhatia, Laura E. Jastrzab, Lori Billinghurst BackgroundChildren with perinatal arterial ischemic stroke (PAIS) are at risk for later neurocognitive and behavioral deficits, yet the clinical predictors of these outcomes are understudied. We examined the influence of clinical and infarct characteristics on attention and executive functioning in children following PAIS.MethodsForty children born at term (≥37 weeks' gestation) with PAIS (28 with neonatal arterial ischemic stroke and 12 with presumed PAIS) underwent a comprehensive neuropsychological battery at age three to 16 years (median age 7.2 years; 58% male) to assess attention and executive functioning. Parents also completed questionnaires regarding real-world functioning. Clinical variables including perinatal stroke subtype, infarct characteristics (location, laterality, and volume), and the presence of comorbid epilepsy were ascertained from the medical record.ResultsPresumed PAIS, larger infarct volume, and comorbid epilepsy negatively influenced the performance on attention and executive functioning measures. These clinical variables were also associated with greater functional problems on parent reports, including a higher frequency of attention-deficit/hyperactivity disorder symptoms and greater difficulties in some subdomains of executive functioning. Infarct location and laterality were not associated with performance measures or parental report of functioning.ConclusionAlthough all children with PAIS are at risk for later deficits in attention and executive functioning, those with presumed PAIS, larger infarct size, and comorbid epilepsy appear to be the most vulnerable. As they approach and reach school age, these children should undergo neuropsychological assessment to ensure timely implementation of therapeutic interventions and behavioral strategies.
Epidemiology of Benign External Hydrocephalus in Norway – a population based study
Publication date: Available online 24 April 2017 Source:Pediatric Neurology Author(s): Ulrikke Straume Wiig, Sverre Morten Zahl, Arild Egge, Eirik Helseth, Knut Wester BackgroundBenign external hydrocephalus (BEH) is defined as a rapidly increasing head circumference (Occipitofrontal circumference - OFC) with characteristic radiological findings of increased subarachnoid cerebrospinal fluid (CSF) spaces on neuroimaging. To our knowledge, the incidence of BEH has not been previously reported, and there is no available information on the ratio of BEH in the population of hydrocephalic children.MethodsThis study is retrospective and population-based, geographically covering two health regions in the southern half of Norway with a total mean population of 3.34 million in the ten-year study period, constituting approximately 75 % of the Norwegian population. Children with a head circumference crossing two percentiles, or above the 97.5th percentile, and with typical imaging findings of enlarged frontal subarachnoid spaces with or without enlarged ventricles were included. Children were excluded if they had a history of head trauma, intracranial haemorrhage, CNS infection, other known causes of hydrocephalus, or prematurity defined as birth prior to 37 weeks of gestation.ResultsA total of 176 children fitting the criteria were identified, giving an incidence of 0.4 per 1000 live births. 152 (86.4%) of the patients were male, and mean age at referral was 7.3 months. Increasing head circumference was the main reason for referral in 158 patients (89.8%) and the only finding in 60 patients (34.1%). 37 children (21%) had normal ventricles on imaging, the remainder had increased ventricular size. The incidence of paediatric hydrocephalus in Norway is reported to be 0.75 per 1000 live births, thus BEH accounts for approximately 50% of hydrocephalic conditions in this population.ConclusionsThe incidence of BEH was found to be 0.4 per 1000 live births in this population.
Dyspigmentation of skin as a clue to the diagnosis of dystonia in a 10-year old child
Publication date: Available online 20 April 2017 Source:Pediatric Neurology Author(s): Abhijit Dutta, Sudip Kumar Ghosh, Sagar Basu, Rajesh Kumar Mandal Dyschromatosis symmetrica hereditaria (DSH) is an uncommon pigmentary genodermatosis characterized by the presence of hyper- and hypopigmented macules on the dorsal aspects of the extremities. The association of neurological disorders with DSH have rarely been reported in literature. In this article we describe herein a 10- year-old- girl who presented to us with dystonic features with dyspigmentation of skin, and the diagnosis of DSH was made possible after histopathological examination of the involved skin. In this article we seek to emphasize the importance of neurological evaluation in a patient with pigmentary disorder.
Barriers to Genetic Testing for Pediatric Medicaid Beneficiaries with Epilepsy
Publication date: Available online 20 April 2017 Source:Pediatric Neurology Author(s): Eric J. Kutscher, Sucheta Joshi, Anup D. Patel, Baria Hafeez, Zachary M. Grinspan ObjectiveChildren with public insurance (Medicaid) have increased barriers to specialty care in the United States. For children with epilepsy, the relationship between public insurance and barriers to genetic testing is understudied.MethodsWe surveyed a sample of US child neurology clinicians. We performed quantitative and qualitative analysis of responses.ResultsThere were 302 responses (of 1982 surveyed; response rate 15%) from clinicians from 46 states, the District of Columbia, and Puerto Rico, including board-certified child neurologists (82%), resident physicians (6%), nurses (3%), and nurse practitioners (3%). More clinicians felt it was more difficult to get genetic testing for patients with Medicaid insurance compared to commercial insurance, (43% vs. 12%, p<0.05), though many felt it was about the same degree of difficulty (25%) or were not sure (20%). Increased availability of testing was associated with less complex testing (p<0.001), in-house testing (p<0.001), and no pre-authorization requirements (p<0.001). Qualitative responses described barriers related to cost, clinician familiarity and comfort, commercial laboratories, healthcare organization, payer, and patient concerns. Descriptions of facilitators included lowered cost, availability of clinical genetics expertise, clinician knowledge, commercial laboratory assistance, healthcare organizational changes, improved payer coverage, and increased interest by parents.Significance.Pediatric Medicaid beneficiaries with epilepsy have barriers to genetic testing, compared to children with commercial insurance, particularly for more advanced testing. Potential strategies to improve access include broader coverage, lower co-pays, increased capacity for testing outside of specialty labs, fewer pre-authorization requirements, improved clinician education, ongoing development and dissemination of guidelines, improved availability of clinical genetics services, and continued assistance programs from commercial laboratories.