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.
The Increasing Genetic and Phenotypical Diversity of Congenital Myasthenic Syndromes
The congenital myasthenic syndromes (CMS) are a diverse group of diseases, which result in an increasing range of phenotypes, but which are all due to inherited defects at the neuromuscular junction (NMJ). Although some patients remain genetically undiagnosed, our ability to identify the causative genes has shed new light on the role of previous uncharacterized proteins at the NMJ. Securing the genetic diagnosis can be challenging, but it is of critical importance to allow rational therapeutic intervention. In this review, we summarize the key clinical and pathologic features of the CMS subtypes, outline diagnostic clues, and challenges, and describe the recent advances that have highlighted the overlap between CMS and the muscular dystrophies and peripheral neuropathies.
MEGDEL Syndrome: Expanding the Phenotype and New Mutations
3-MEthylGlutaconic aciduria, Deafness, Encephalopathy, neuroradiological evidence of Leigh-like disease (MEGDEL syndrome) was initially described in four children with additional features of defective oxidative phosphorylation. Loss of functional variants in the SERAC1 gene was later reported in relation with this disorder of phospholipid remodeling. We describe a girl born after a pregnancy complicated by intrauterine growth retardation. In the neonatal period, she presented hypotonia, lethargy, weak reflexes, transient hypoglycemia, and elevated transaminases. Magnetic resonance imaging (MRI) performed at 12 days of life showed bilateral basal ganglia alterations suggestive of Leigh syndrome. She progressed with failure to thrive, severe delay of developmental milestones, axial hypotonia, spastic tetraparesis and dystonic movements. Investigations disclosed hyperlactacidemia, and the urinary organic acids revealed high levels mainly of 3-methylglutaconic acid. Muscle biopsy showed decreased activity of several complexes of the respiratory chain. Compound heterozygosity for two previously unreported variants in SERAC1 leads to the diagnosis of MEGDEL syndrome. Unlike other patients, this child presents very early MRI alterations and manifests no deafness.
Novel RRM2B Mutation and Severe Mitochondrial DNA Depletion: Report of 2 Cases and Review of the Literature
Purpose To describe the clinical presentation and implications of mitochondrial DNA depletion disorder of two siblings with early fatal encephalomyopathy and a novel mutation in the RRM2B gene. The relevant literature is reviewed.
Methods We describe two brothers aged 2.5 months and 1 month, respectively, who were hospitalized in a tertiary pediatric medical center for evaluation of focal seizures, hypotonia, poor feeding, failure to thrive, lactic acidosis, and developmental delay. The older brother also had seizures, and the younger had severe bilateral neurosensory deafness.
Results Genetic sequencing of the RRM2B gene revealed the same novel mutation in both the siblings. Both children died due to respiratory failure at ages 3 and 2.5 months, respectively.
Conclusion The combination of neonatal hypotonia, developmental delay, and lactic acidosis should raise a clinician's suspicion of a mitochondrial depletion disorder and prompt further genetic studies.
The Genetic Approach: Next-Generation Sequencing-Based Diagnosis of Congenital and Infantile Myopathies/Muscle Dystrophies
The practical basis for massive parallel sequencing is described to help clinicians in choosing the most adequate diagnostic approach for childhood myopathies. The key quality feature for massive parallel sequencing is the sequence depth (coverage) as a prerequisite for variant identification and quantification of sequence copy numbers. Our experience with a next-generation sequencing gene panel for the analysis of muscular dystrophies/myopathies with infantile or juvenile onset resulted in the identification of pathogenic or likely pathogenic mutations in approximately 41% (of 141 patients), thus leading to a definitive diagnosis. A subset of patients shows an accumulation of “excess” heterozygous variants that may act as modifiers of the phenotype. Massive parallel sequencing has become a reliable and cost-effective method, but it requires exact clinical, bioptic, and/or radiologic information to evaluate the clinical relevance of possibly pathologic variants.
Atypical presentation of a progressive and treatable encephalopathy in an older child with gelastic and dacrystic seizures
Publication date: Available online 23 May 2017 Source:Seminars in Pediatric Neurology Author(s): Jorge Vidaurre, Sunjay Nunley We discuss an unusual case of a teenage boy who presented with waxing and waning cognitive decline and gelastic - dacrystic seizures, evolving later into a rapidly progressive encephalopathy with status epilepticus. Extensive genetic and metabolic testing did not lead to a specific diagnosis. CSF studies performed during admission to the intensive care unit provided the information needed to establish a diagnosis. After implementation of specific treatment his seizures stopped and his background EEG returned to normal. He has remained largely seizure free experiencing a significant cognitive recovery. This case illustrates the importance of performing CSF analysis in patient with refractory seizures and cognitive decline of unknown etiology.
Focal epilepsy in a teenager with facial atrophy and hair loss
Publication date: Available online 2 April 2017 Source:Seminars in Pediatric Neurology Author(s): Stephen W. English, Mai Lan Ho, Megha M. Tollefson, Lily C. Wong-Kisiel There is increasing evidence to demonstrate that Parry-Romberg syndrome and linear scleroderma en coup de sabre are both forms of linear scleroderma, representing localized autoimmune conditions affecting the skin, eyes, brain, and surrounding tissues. We present a case highlighting the clinical presentation of a 12-year-old boy with focal seizures and physical exam findings of facial atrophy and hair loss. This paper reviews the literature related to the presentation, epidemiology, diagnosis and treatment of Parry-Romberg syndrome and linear scleroderma en coupe de sabre with focus on the significant correlation with neurologic disease, particularly seizures.
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.
Publication date: May 2017 Source:Brain and Development, Volume 39, Issue 5 Author(s): Hiroshi Yamaguchi, Tsukasa Tanaka, Daisaku Toyoshima, Azusa Maruyama, Akihiro Ichinose, Hiroaki Nagase In adults, aponeurotic blepharoptosis is the most common type of ptosis. However, myogenic ptosis is the predominant cause, and bilateral aponeurotic ptosis is very rare among children. Here, we report a previously healthy 10-year-old Japanese girl with bilateral aponeurotic blepharoptosis who presented initially with bilateral blepharoptosis for about 4years. This case report shows that history taking and careful observation of the patient lead to an accurate diagnosis, and aponeurotic ptosis should be considered in the differential diagnosis of bilateral blepharoptosis among children.
Publication date: May 2017 Source:Brain and Development, Volume 39, Issue 5 Author(s): Shingo Numoto, Hirokazu Kurahashi, Yoshiteru Azuma, Atsushi Numaguchi, Kozaburo Nakahara, Takahisa Tainaka, Michihiko Takasu, Kiyoshi Yamakawa, Nozomi Nago, Taichiro Muto, Yoshiro Kitagawa, Akihisa Okumura Fournier’s gangrene is an infectious necrotizing fasciitis of the perineal, genital, or perianal regions and is uncommon in children. Adrenocorticotropic hormone (ACTH) is effective for the treatment of infantile spasms; however, suppression of immune function is one of the major adverse effects of this approach. We encountered a 2-month-old boy with infantile spasms that had been treated with ACTH and had developed complicating Fournier’s gangrene. Strangulation of a right inguinal hernia was observed after ACTH treatment. Although surgical repair was successful and no intestinal injuries were detected, swelling and discoloration of the right scrotum developed in association with pyrexia and a severe inflammatory response. A scrotal incision revealed pus with a putrid smell. The patient was subsequently diagnosed with Fournier’s gangrene complicated by septic shock and disseminated intravascular coagulation. Extensive debridement and intensive care was performed. Enterobactor aerogenes, methicillin-resistant Staphylococcus aureus, and Enterococcus faecalis were isolated from the pus. Meropenem, teicoplanin, and clindamycin were administered to control the bacterial infection. The patient was discharged from the intensive care unit without any obvious neurological sequelae. Suppression of immune function associated with ACTH therapy may have been related to the development of Fournier’s gangrene in this case.
Electro-clinical-etiological associations of epilepsia partialis continua in 57 Chinese children
Publication date: June 2017 Source:Brain and Development, Volume 39, Issue 6 Author(s): Hui Li, Jiao Xue, Ping Qian, Yuehua Zhang, Xinhua Bao, Xiaoyan Liu, Zhixian Yang ObjectiveEpilepsia partialis continua (EPC) was one type of focal status epilepticus. The aim of this study was to analyze the clinical and electroencephalography (EEG) characteristics, and outcome of 57 child-onset patients with EPC according to different etiologies, and further explore the electro-clinical-etiological associations.MethodsWe retrospectively reviewed 57 children diagnosed with EPC in our department over last ten years. Etiology, clinical and EEG data, and outcome were categorized and analyzed.ResultsFor the 57 child-onset patients, EPC was caused by different etiologies, including immune-related disease (43.9%), focal lesions (17.5%), inborn errors of metabolism (24.6%), and unknown (14.0%). EEG background abnormalities showed generalized slowing in 45 patients (78.9%) and focal slowing in two patients (3.5%). Nineteen patients (33.3%) presented clear correlation of ictal EEG/EMG and the remaining 38 patients (66.7%) showed no clear correlation of ictal EEG/EMG. Both EEG background activity and ictal EEG/EMG correspondence among different etiologies had statistical significance (P<0.05). The ictal patterns without clear EEG/EMG correspondence in immune-related disease and the ictal patterns with clear EEG/EMG correspondence in focal lesions were more prominent (P<0.05).ConclusionThis is the first study of child-onset EPC with a large series in a pediatric epilepsy center in China. The most common cause for EPC was immune-related disease. The EEG background activity and the EEG/EMG correspondence might be influenced by the etiologies of EPC to some degree. These findings might guide the direction of EPC diagnosis in conjunction with other examinations.
Alice in Wonderland Syndrome: A real life version of Lewis Carroll’s novel
Publication date: June 2017 Source:Brain and Development, Volume 39, Issue 6 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.
Relationship between the change of language symptoms and the change of regional cerebral blood flow in the recovery process of two children with acquired aphasia
Publication date: June 2017 Source:Brain and Development, Volume 39, Issue 6 Author(s): Junko Kozuka, Akira Uno, Hiroshi Matsuda, Yoshiya Toyoshima, Shin-ichiro Hamano ObjectiveThis study aimed to investigate the relationship between the change of language symptoms and the change of regional cerebral blood flow (rCBF) in the recovery process of two children with acquired aphasia caused by infarctions from Moyamoya disease with an onset age of 8years.MethodsWe compared the results for the Standard Language Test of Aphasia (SLTA) with rCBF changes in 7 language regions in the left hemisphere and their homologous regions in the right hemisphere at 4 time points from 3weeks for up to 5years after the onset of aphasia, while controlling for the effect of age.ResultsIn both cases, strong correlations were seen within a hemisphere between adjacent regions or regions that are connected by neuronal fibers, and between some language regions in the left hemisphere and their homologous regions in the right hemisphere. Conversely, there were differences between the two cases in the time course of rCBF changes during their recovery process.ConclusionConsistent with previous studies, the current study suggested that both hemispheres were involved in the long-term recovery of language symptoms in children with acquired aphasia. We suggest that the differences between both cases during their recovery process might be influenced by the brain states before aphasia, by which hemisphere was affected, and by the timing of the surgical revascularization procedure. However, the changes were observed in the data obtained for rCBF with strong correlations with the changes in language performance, so it is possible that rCBF could be used as a biomarker for language symptom changes.
Neuroimaging, cardiovascular physiology, and functional outcomes in infants with congenital heart disease
This review integrates data on brain dysmaturation and acquired brain injury using fetal and neonatal magnetic resonance imaging (MRI), including the contribution of cardiovascular physiology to differences in brain development, and the relationship between brain abnormalities and subsequent neurological impairments in infants with congenital heart disease (CHD). The antenatal and neonatal period are critical for optimal brain development; the developing brain is particularly vulnerable to haemodynamic disturbances during this time. Altered cerebral perfusion and decreased cerebral oxygen delivery in the antenatal period can affect functional and structural brain development, while postnatal haemodynamic fluctuations may cause additional injury. In critical CHD, brain dysmaturation and acquired brain injury result from a combination of underlying cardiovascular pathology and surgery performed in the neonatal period. MRI findings in infants with CHD can be used to evaluate potential clinical risk factors for brain abnormalities, and aid prediction of functional outcomes at an early stage. In addition, information on timing of brain dysmaturation and acquired brain injury in CHD has the potential to be used when developing strategies to optimize neurodevelopment.
Use of active video gaming in children with neuromotor dysfunction: a systematic review
To examine current evidence on use of active video gaming (AVG) to improve motor function in children with movement disorders including cerebral palsy, developmental coordination disorder, and Down syndrome.
Scopus, MEDLINE, Cochrane Library, EMBASE, and CINAHL were searched. Included papers studied the use of AVG for improving movement-related outcomes in these populations. Parameters studied included health condition, strength of evidence, AVG delivery methods, capacity for individualizing play, outcomes addressed, effectiveness for achieving outcomes, and challenges/limitations.
The 20 extracted articles varied in quality. Studies involved children with six different conditions using AVG in clinical, home, or school settings for 49 different motor outcomes. Dosage varied in frequency and duration. Choice of games played and difficulty level were therapist determined (n=6) or child controlled (n=14). The most common study limitations were small sample sizes and difficulty individualizing treatment. All articles showed improvement in outcomes with AVG, although differences were not consistently significant compared with conventional therapy.
Heterogeneity of measurement tools and target outcomes prevented meta-analysis or development of formal recommendations. However, AVG is feasible and shows potential for improving outcomes in this population. Additional investigations of dosing variables, utility as a home supplement to clinical care, and outcomes with larger sample sizes are merited.
Mental health outcomes of developmental coordination disorder in late adolescence
To assess the relationship between developmental coordination disorder (DCD) and mental health outcomes in late adolescence.
Data were analyzed from the Avon Longitudinal Study of Parents and Children. Moderate-to-severe DCD was defined at 7 to 8 years according to the DSM-IV-TR criteria. Mental health was assessed at 16 to 18 years using self-reported questionnaires: Strengths and Difficulties Questionnaire, Short Moods and Feelings Questionnaire, and the Warwick–Edinburgh Mental Well-being Scale. Logistic and linear regressions assessed the associations between DCD and mental health, using multiple imputation to account for missing data. Adjustments were made for socio-economic status, IQ, and social communication difficulties.
Adolescents with DCD (n=168) had an increased risk of mental health difficulties (total Strengths and Difficulties Questionnaire score) than their peers (n=3750) (odds ratio 1.78, 95% confidence interval 1.12–2.83, adjusted for socio-economic status and IQ). This was, in part, mediated through poor social communication skills. Adolescent females with DCD (n=59) were more prone to mental health difficulties than males. Greater mental well-being was associated with better self-esteem (β 0.82, p<0.001).
Individuals with DCD, particularly females, had increased risk of mental health difficulties in late adolescence. Interventions that aim to promote resilience in DCD should involve improving social communication skills and self-esteem.
Variations in Duchenne muscular dystrophy course in a multi-ethnic UK population: potential influence of socio-economic factors
To explore variation in clinical course and steroid treatment in Duchenne muscular dystrophy (DMD) by ethnic origin and socio-economic status.
In this longitudinal cohort study, clinical outcome was defined as age at loss of ambulation (LOA). Ages are presented as months for accurate calculation. Steroid use was reviewed against national guidelines. Kaplan–Meier survival analysis was used to determine probabilities over time of LOA. Log-rank test was used to evaluate comparisons between ethnic and socio-economic groups.
From 2005 to 2014, 71 children were newly diagnosed with DMD. Complete data were available on 69, including 33 of white British heritage and 23 of South Asian heritage. Mean age at diagnosis (without known family history) was 45.7 months; white British ethnicity 42.1 months (range 14–86mo), South Asian ethnicity 50.2 months (range 5–98mo). Twenty-four males lost ambulation. Those of South Asian heritage lost ambulation earlier (mean LOA 105.8mo [8y 10mo]) than those of white British heritage (mean LOA 117.8mo [9y 10mo]): log-rank test score 0.012 (p<0.05). Those most deprived did worse: mean age at LOA 130.0 months (10y 10mo) for the top 20 per cent and 102.5 months (8y 6mo) in the lower 20 per cent: log-rank test score 0.035 (p<0.05). The most socially deprived were diagnosed earlier and started steroids earlier. Of those of South Asian heritage, 18 per cent declined steroids, compared with 9 per cent of white British heritage. Also, 44 per cent of those of South Asian heritage stopped steroids compared with 17 per cent of those of white British heritage.
Patients from South Asian and deprived backgrounds had earlier LOA. Genetic disease modifiers are likely to be implicated, but social and cultural factors influence access to treatment.
Assessments of pain in children and adolescents with cerebral palsy: a retrospective population-based registry study
To explore pain screening in CPUP, a follow-up surveillance programme for people with cerebral palsy (CP), specifically to describe reported pain prevalence, localizations, patterns of distribution; to compare with studies using psychometrically sound assessment instruments; and to assess agreement between pain documented in CPUP and medical records.
Registry study of a population with CP, born 1993 to 2008, living in Skåne, Sweden in 2013. Descriptive data, cross-tabulations, and chi-square tests to characterize and compare the study groups. Kappa analysis to test the concordance between register and medical record reports on pain.
Pain was reported by 185 out of 497 children (37%; females 40%, males 35%). Level V in both Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) was associated with highest prevalence of pain (50% and 54%), and level I with lowest prevalence of pain (30% and 32%). Pain was most frequent in dyskinetic CP (46%) and least frequent in unilateral spastic CP (33%). Feet and knees were the dominant localizations. Fair–moderate agreement (kappa 0.37, prevalence-adjusted bias-adjusted kappa [PABAK] 0.44) was found between documented pain in CPUP and medical records, although more seldom recognized in medical records.
The distribution of pain between CP subtypes, functional levels, sex, and age in CPUP is concordant with previous population-based studies, indicating the validity of the CPUP pain screening. Despite this, further clinical evaluation with extended pain assessments and pain management were largely neglected in children reporting chronic pain.
A systematic review of scales to measure dystonia and choreoathetosis in children with dyskinetic cerebral palsy
To identify and systematically review the psychometric properties and clinical utility of dystonia and choreoathetosis scales reported for children with cerebral palsy (CP).
Six electronic databases were searched for dystonia and choreoathetosis scales with original psychometric data for children with CP aged 0 to 18 years.
Thirty-four papers met the inclusion criteria, which contained six scales purported to measure dystonia and/or choreoathetosis in children with CP: the Burke–Fahn–Marsden Dystonia Rating Scale; Barry–Albright Dystonia Scale; Unified Dystonia Rating Scale; Movement Disorder-Childhood Rating Scale; Movement Disorder-Childhood Rating Scale 0–3 Years; and the Dyskinesia Impairment Scale.
Each scale provides useful information about dyskinesia, with most focusing on dystonia. The Barry–Albright Dystonia Scale, which was designed for CP, is the most commonly reported scale and least complex to use clinically. The Dyskinesia Impairment Scale is the only tool to consider both dystonia and choreoathetosis in CP. All tools are designed to classify movement disorders at the level of body functions and structures, rather than activity limitations or participation restrictions, although many provide some insight into the impact of dystonia on activities. Further studies are required to fully examine the validity, reliability, responsiveness, and clinical utility of each scale specifically for children with CP.
Revisão sistemática de escalas para medir distonia e coreoatetose em crianças com paralisia cerebral discinética
Identificar e revisar sistematicamente as propriedades psicométricas e a utilidade clínica das escalas de distonia e coreoatetose para crianças com paralisia cerebral (PC).
Seis bases de dados eletrônicas foram pesquisadas para verificar os dados psicométricos originais das escalas de distonia e coreoatetose para crianças com PC de 0 a 18 anos de idade.
Trinta e quatro artigos foram selecionados de acordo com os critérios de inclusão, os quais continham seis escalas que pretendiam medir distonia e/ou coreoatetose em crianças com PC: Escala de Avaliação da Distonia Burke-Fahn-Marsden; Escala da Distonia de Barry-Albright; Escala Unificada de Avaliação da Distonia; Escala de Avaliação do Distúrbio do Movimento Infantil; Escala de Avaliação do Distúrbio do Movimento - Infantil 0-3 Anos; e a Escala de Disfunção da Discinesia [Burke–Fahn–Marsden Dystonia Rating Scale; Barry–Albright Dystonia Scale; Unified Dystonia Rating Scale; Movement Disorder–Childhood Rating Scale; Movement Disorder-Childhood Rating Scale 0–3 Years; Dyskinesia Impairment Scale].
Cada escala fornece informações úteis sobre a discinesia, a maioria com foco na distonia. A Escala da Distonia de Barry–Albright, a qual foi elaborada para PC, é a escala mais comumente relatada e a menos complexa de ser utilizada clinicamente. A Escala de Disfunção da Discinesia é o único instrumento que considerou tanto a distonia quanto a coreoatetose na PC. Todos os instrumentos são elaborados para classificar os distúrbios do movimento ao nível das estruturas e funções do corpo, ao invés das limitações na atividade ou restrições na participação, embora muitos forneçam alguma ideia sobre o impacto da distonia nas atividades. Estudos adicionais são necessários para analisar completamente a validade, confiabilidade, responsividade e utilidade clínica de cada escala especificamente para crianças com PC.
Revisión sistemática de escalas de medición de distonía y coreoatetosis en niños con diagnóstico de parálisis cerebral disquinética
Identificar y hacer una revisión sistemática de las propiedades psicométricas y de la utilidad clínica de las escalas de distonía y coreoatetosis reportadas en niños con parálisis cerebral (PC).
Fueron buscadas escalas para distonía y coreoatetosis, con datos psicométricos originales en niños con PC entre 0 y 18 años de edad, en seis bases de datos electrónicas.
Treinta y cuatro trabajos cumplieron los criterios de inclusión, los cuales contenían seis escalas dirigidas a medir distonía y/o coreoatetosis en niños con PC: la escala de valoración de distonía Burke-Fahn-Marsden; la escala de distonía Barry-Albright; la escala unificada de valoración de distonía; la escala de valoración de desorden de movimiento infantil; la escala de valoración de desorden de movimiento infantil entre 0 y 3 años; la escala de deterioro de disquinesia [Burke–Fahn–Marsden Dystonia Rating Scale; Barry–Albright Dystonia Scale; Unified Dystonia Rating Scale; Movement Disorder-Childhood Rating Scale; Movement Disorder-Childhood Rating Scale 0–3 Years; Dyskinesia Impairment Scale].
Cada escala brinda información útil sobre la disquinesia, con la mayoría centrándose en la distonía. La escala de distonía Barry-Albright, la cual fue diseñada para PC, es la mas comúnmente reportada y la menos compleja para utilizar clínicamente. La escala de deterioro de disquinesia es la única que considera tanto distonía como coreoatetosis en PC. Todas las herramientas fueron diseñadas para clasificar los desordenes de movimientos al nivel de las estructuras y funciones corporales, en lugar de limitaciones de actividades o restricciones en la participación, aunque muchas proporcionan información sobre el impacto de la distonía en las actividades. Se requieren más estudios para examinar dtalladamente la validez, confiabilidad, sensibilidad y utilidad clínica de cada escala específicamente para niños con PC
Psychological well-being and independent living of young adults with childhood-onset craniopharyngioma
To assess the psychological well-being and social integration of adults with craniopharyngioma diagnosed in childhood.
A cross-sectional study of a nationwide cohort of young adults with craniopharyngioma in Germany was performed. A structured questionnaire covered the sociodemographic, clinical data, and subjective effects of the condition on social integration. Psychological well-being was assessed using the Hospital Anxiety and Depression Scale (HADS). Results were compared to young adults with type 1 diabetes mellitus (T1DM).
The study included 59 participants (29 females, 30 males; mean age 25y 2mo [SD 5y 10mo]), mean age at first surgery 10y 2mo [SD 3y 7mo]. Compared to the T1DM group, significantly more young people with craniopharyngioma aged 25 to 35 years lived at their parents’ homes (craniopharyngioma 43.34%; T1DM 13.7%; χ2=4.14, p=0.049), and fewer lived in a relationship (craniopharyngioma 8.69%; T1DM 54.7%; χ2=15.74, p<0.001). The HADS revealed a score for depression above the cut-off in 20.69 per cent of young adults with craniopharyngioma and in 6 per cent of young adults with T1DM (χ2=13.42, p<0.001).
Young adults with craniopharyngioma reported subjective disadvantages in professional and social integration. Further, they presented with reduced well-being and increased depression rates. Better psychosocial support and self-management education might reduce the long-term burden of the disease.
Bienestar psicológico y vida independiente en adultos jóvenes con craneofaringioma de inicio en la infancia
Evaluar el bienestar psicológico e integración social en adultos con craneofaringioma diagnosticado en la infancia.
Se realizó un estudio transversal de cohorte en todo el país de Alemania de adultos jóvenes con diagnóstico de craneofaringioma. Se diseñó un cuestionario cubriendo aspectos sociodemográficos, datos clínicos así como los efectos subjetivos de la enfermedad en cuanto a integración social. Para evaluar el bienestar psicológico se utilizó la Escala de Ansiedad Hospitalaria y Depresión (HADS – Hospital Anxiety and Depression Scale). Se compararon los resultados con jóvenes adultos con Diabetes Mellitus tipo I (DMT1).
En el estudio se incluyeron 59 participantes (29 mujeres, 30 varones; edad promedio 25 años y 2 meses (D.S. 5 años 10 meses), edad promedio a la primera cirugía 10 años 2 meses (D.S. 3 años 7 meses). Al comparar con el grupo de DMT1, se observó un número significativamente mayor de jóvenes con craneofaringioma, de 25 a 35 años de edad, que vivían en sus hogares parentales (craneofaringioma 43.34%; DMT1 13.7%; v2=4.14, p=0.049), y un número menor que vivían en una relación, (craneofaringioma 8.69%; DMT1 54.7%; v2=15.74, p<0.001). La escala HADS reveló un puntaje para depresión por arriba del punto de corte en el 20.69% de los jóvenes adultos con craneofaringioma y en el 6% de los jóvenes adultos con DMT1 (v2=13.42, p<0.001).
Los adultos jóvenes con diagnóstico de craneofaringioma reportaron desventajas subjetivas en la integración profesional y social. Además, el grupo mostró un bienestar reducido e índices de depresión incrementados. Un mejor apoyo psicosocial y una mejor educación en cuanto a autogestión podría reducir la carga que significa a largo plazo esta enfermedad.
Bem-estar psicológico e vida independente de adultos jovens com craniofaringioma de início da infância
Avaliar o bem-estar psicológico e a integração social de adultos com craniofaringioma diagnosticado na infância.
Foi realizado um estudo transversal de uma coorte nacional de adultos jovens com craniofaringioma na Alemanha. Um questionário estruturado abordou características sociodemográficas, dados clínicos e efeitos subjetivos da doença na integração social. O bem-estar psicológico foi avaliado utilizando a Escala Hospitalar de Ansiedade e Depressão (HADS – Hospital Anxiety and Depression Scale). Os resultados foram comparados com adultos jovens com diabetes mellitus tipo 1 (DMT1).
O estudo incluiu 59 participantes (29 do sexo feminino, 30 do sexo masculino; média de idade de 25 anos e 2 meses [DP 5 anos e 10 meses]), idade média na primeira cirurgia de 10 anos e 2 meses [DP 3 anos e 7 meses]. Em comparação ao grupo DMT1, houve um número significativamente maior de jovens com craniofaringioma com idades entre 25 e 35 anos que viviam na casa de seus pais (craniofaringioma 43.34%; DMT1 13.7%; v2=4.14, p=0.049) e menos jovens com craniofaringioma que viviam em uma relação (craniofaringioma 8.69%; DMT1 54.7%; v2=15.74, p<0.001). A HADS evidenciou pontuação para a depressão acima do ponto de corto em 20.69% dos adultos jovens com craniofaringioma e em 6% dos adultos jovens com DMT1 (v2=13.42, p<0.001).
Adultos jovens com craniofaringioma relataram desvantagens subjetivas na integração profissional e social. Além disso, eles apresentaram bem-estar reduzido e taxas de depressão elevadas. Melhorias no apoio psicossocial e na educação de auto-gestão poderiam reduzir o fardo da doença a longo prazo.
Defining epileptogenic networks: Contribution of SEEG and signal analysis
Epileptogenic networks are defined by the brain regions involved in the production and propagation of epileptic activities. In this review we describe the historical, methodologic, and conceptual bases of this model in the analysis of electrophysiologic intracerebral recordings. In the context of epilepsy surgery, the determination of cerebral regions producing seizures (i.e., the “epileptogenic zone”) is a crucial objective. In contrast with a traditional focal vision of focal drug-resistant epilepsies, the concept of epileptogenic networks has been progressively introduced as a model better able to describe the complexity of seizure dynamics and realistically describe the distribution of epileptogenic anomalies in the brain. The concept of epileptogenic networks is historically linked to the development of the stereoelectroencephalography (SEEG) method and subsequent introduction of means of quantifying the recorded signals. Seizures, and preictal and interictal discharges produce clear patterns on SEEG. These patterns can be analyzed utilizing signal analysis methods that quantify high-frequency oscillations or changes in functional connectivity. Dramatic changes in SEEG brain connectivity can be described during seizure genesis and propagation within cortical and subcortical regions, associated with the production of different patterns of seizure semiology. The interictal state is characterized by networks generating abnormal activities (interictal spikes) and also by modified functional properties. The introduction of novel approaches to large-scale modeling of these networks offers new methods in the goal of better predicting the effects of epilepsy surgery. The epileptogenic network concept is a key factor in identifying the anatomic distribution of the epileptogenic process, which is particularly important in the context of epilepsy surgery.
Comparison and optimization of in silico algorithms for predicting the pathogenicity of sodium channel variants in epilepsy
Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians’ understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel (SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy.
Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity.
Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52–0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm had an accuracy of 0.90 and a combination of algorithms increased the accuracy to 0.92.
Potentially pathogenic variants are present in population-based sources. Most computational algorithms overestimate pathogenicity; however, a weighted combination of several algorithms increased classification accuracy to >0.90.
BGG492 as an adjunctive treatment in patients with partial-onset seizures: A 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study with an open-label extension
To evaluate dose–response relationship of BGG492 as add-on therapy to 1–3 antiepileptic drugs in patients with partial-onset seizures and to investigate safety and tolerability of BGG492.
This was a 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study (core study) with a 30-week, flexible-dose, open-label extension. In the core study, patients were randomized (1:2) to placebo or BGG492 100 mg t.i.d. in cohort 1, and in cohort 2 patients were randomized (1:4) to placebo or BGG492 150 mg t.i.d. On completion of the core study, eligible patients entered the extension study. Primary outcome measures were total partial seizure frequency per 28 days (core study) and safety and tolerability (extension study).
Overall, 93 patients were randomized (150 mg [n = 44]; 100 mg [n = 24]; placebo [n = 25]), and 81 (87.1%) completed the core study. Fifty-one patients entered and 43 (84.3%) completed the extension study. In the core study, no statistically significant dose–response trend among the BGG492 treatment groups (100 and 150 mg) was observed at the 4-week double-blind maintenance period (weeks 7–10); however, there was higher percent reduction in total partial seizure frequency in the BGG492 150 mg over placebo groups (37.32%; 95% confidence interval [CI] −18.90, 66.95). Dizziness, somnolence, and fatigue were the most common adverse events (AEs), higher in the BGG492 150 mg group than in the 100 mg and placebo groups (dizziness: 14 [31.8%] vs. 3 [12.5%] and 1 [4.0%]; somnolence: 7 [15.9%] vs. 1 [4.2%] and 1 [4.0%]; fatigue: 5 [11.4%] vs. 1 [4.2%] and 1 [4.0%]). During the open-label extension study, 39 (76.5%) patients on BGG492 had AEs, and the most commonly experienced AEs were dizziness (14 [27.5%]) and somnolence (9 [17.6%]).
There was no significant dose–response trend in the BGG492 treatment groups (100 and 150 mg); however, higher percent reduction over placebo was observed in the BGG492 150 mg group. Safety and tolerability data were consistent with the known safety profile for BGG492, and no new safety risks were identified.
Child- and parent-reported quality of life trajectories in children with epilepsy: A prospective cohort study
To describe the developmental trajectories of quality of life (QoL) in a large cohort of children with epilepsy, and to assess the relative contribution of clinical, psychosocial, and sociodemographic variables on QoL trajectories.
Five assessments during a 28-month prospective cohort study were used to model trajectories of QoL. Participants were recruited with their parents from six Canadian tertiary centers. A convenience sample of 506 children aged 8–14 years with epilepsy and without intellectual disability or autism spectrum disorder were enrolled. A total of 894 children were eligible and 330 refused participation. Participating children were, on average, 11.4 years of age, and 49% were female. Nearly one third (32%) had partial seizures. At baseline, 479 and 503 child- and parent-reported questionnaires were completed. In total, 354 children (74%) and 366 parents (73%) completed the 28-month follow-up. QoL was measured using the child- and parent-reported version of the Childhood Epilepsy QoL scale (CHEQOL-25).
Child-reported QoL was fitted best by a six-class model and parent-reported QoL by a five-class model. In both models, trajectories remained either stable or improved over 28 months. Of these children, 62% rated their QoL as high or moderately high, defined as at least one standard deviation above the average CHEQOL-25 score. Greater family, classmate, and peer social support, fewer symptoms of child and parent depression, and higher receptive vocabulary were identified as the most robust predictors of better QoL (all p < 0.001).
Most children with epilepsy and their parents reported relatively good QoL in this first joint self- and proxy-reported trajectory study. Findings confirm the heterogeneous QoL outcomes for children with epilepsy and the primary importance of psychosocial factors rather than seizure and AED-specific factors in influencing QoL. These predictors that are potentially amenable to change should now be the focus of specific intervention studies.
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.
“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.
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.
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.
Arrested Glutamatergic Synapse Development in Human Partial Epilepsy
While studying the brain function of the human partial epilepsy gene, leucine-rich glioma-inactivated 1 (LGI1), a new mechanism of human epileptogenesis was revealed—persistent immaturity of glutamatergic circuitries. LGI1, a novel secreted protein, was found to be increased during the postnatal period; when glutamatergic synapses both downregulate their presynaptic vesicular release probability and reduce their postsynaptic NMDA-receptor subunit NR2B. During this same period, the dendritic arbor and spines are pruned and remodeled. Using bacterial artificial chromosome transgenic mouse techniques, excess wild-type LGI1 was shown to magnify these critical brain developmental events in the hippocampal dentate gyrus; while an epilepsy-associated, truncated, dominant-negative form of LGI1 blocked them. By contrast, the hippocampal dentate granule neuron GABAergic synapses and intrinsic excitability were unaltered. A role for LGI1 in downregulating glutamate synapse function was confirmed by germline gene deletion; this intervention also revealed a selective increase of glutamatergic synaptic transmission with unaltered GABAergic synapses and intrinsic excitability of hippocampal CA1 pyramidal neurons. Interestingly, the role of LGI1 in neurological disease was further expanded when a subset of patients with limbic encephalitis (an autoimmune disorder with memory loss in 100% and seizures in 80% of individuals) were discovered to carry autoantibodies to LGI1.
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.
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.
Association of a synonymous SCN1B variant affecting splicing efficiency with Benign Familial Infantile Epilepsy (BFIE)
Benign familial infantile epilepsy (BFIE) is clinically characterized by clusters of brief partial seizures progressing to secondarily generalized seizures with onset at the age of 3-7 months and with favorable outcome. PRRT2 mutations are the most common cause of BFIE, and found in about 80% of BFIE families. In this study, we analyzed a large multiplex BFIE family by linkage and whole exome sequencing (WES) analyses. Genome-wide linkage analysis revealed significant evidence for linkage in the chromosomal region 19p12-q13 (LOD score 3.48).
Upper limb and hand patterns in cerebral palsy: Reliability of two new classifications
Despite the single, short training session on use of the classifications, agreement between the examiners and the expert examiner was good to high, confirming that these classifications are easy to use and reliable. The classifications proposed here provide homogenous terminology for use in both clinical practice and research, to describe, evaluate and follow-up changes in upper limb and hand patterns in patients with cerebral palsy, particularly those with dyskinesia.
Spasticity, dyskinesia and ataxia in cerebral palsy: Are we sure we can differentiate them?
Cerebral palsy (CP) can be classified as spastic, dyskinetic, ataxic or combined. Correct classification is essential for symptom-targeted treatment. This study aimed to investigate agreement among professionals on the phenotype of children with CP based on standardized videos.
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.
[Editorial] Prepublication and clinical practice: challenges ahead
The timely incorporation of research advances into clinical practice is affected by problems with reproducibility and the retraction of study reports. Thus, approaches to ensure the integrity of research are needed both to protect patients and to move scientific advances forward. With this aim, on April 11, 2017, the USA National Academies of Sciences, Engineering, and Medicine released a new report, Fostering Integrity in Research. The report stresses that “the research enterprise is not broken but it faces serious challenges in creating the appropriate conditions to foster and sustain the highest standards of integrity”.
Jorge Sepulcre is an Associate Professor and Lab Director at the Gordon Center for Medical Imaging, Massachusetts General Hospital, and Harvard Medical School (Boston, MA, USA). Currently, he studies the vulnerability of brain networks to Alzheimer's disease pathology through nuclear and molecular neuroimaging, graph-theory, and other analytical methods.
[Comment] The neurodegenerative prodrome in multiple sclerosis
All neurodegenerative diseases have a preclinical phase during which damage occurs. This phase might be associated with subtle symptoms and signs that do not warrant a diagnosis—ie, a prodrome. Identification of a prodrome is important because it might allow clinicians to diagnose disease earlier. With the emergence of disease-modifying therapies, identification of patients in the preclinical phase of the disease might improve disease outcomes. Additionally, preservation of brain reserve should reduce the effect of normal ageing on the disease outcome.
How do we identify genius? Is the sole indicator of brilliance limited to tangible output, or is it possible to trace this quality back to a tangible output, or do geniuses share neurological characteristics? These are some of the questions the late neuropsychologist Christine Temple explored in Picasso's Brain: The Basis of Creative Genius. Posthumously published, the book is somewhat of a chimera, drawing on biographical, neurological, and psychological sources in a bid to understand the “creative genius” of one of the 20th century's most iconic artists.
[Comment] Detection of neurodegenerative disease using olfaction
Clinical manifestations of cognitive, sensory, or motor impairment detected by a routine examination routinely serve as beacons or pointers that alert and orient neurologists to the possibility of an ongoing and often covert neurodegenerative disease process, and they subsequently assist in differential diagnosis. Many chronic neurological diseases (eg, Parkinson's disease or Alzheimer's disease) are still diagnosed in the same way they were diagnosed a century ago, by carefully listening to and observing patients and their symptoms.
[Series] Severe traumatic brain injury: targeted management in the intensive care unit
Severe traumatic brain injury (TBI) is currently managed in the intensive care unit with a combined medical–surgical approach. Treatment aims to prevent additional brain damage and to optimise conditions for brain recovery. TBI is typically considered and treated as one pathological entity, although in fact it is a syndrome comprising a range of lesions that can require different therapies and physiological goals. Owing to advances in monitoring and imaging, there is now the potential to identify specific mechanisms of brain damage and to better target treatment to individuals or subsets of patients.
[Correspondence] The multiple faces of artwork diagnoses
We read with interest the Focal Point by Raffaella Bianucci and colleagues1 on the diagnosis of a short-statured woman depicted by Andrea Mantegna in the painting at La Camera degli Sposi. However, we disagree with their diagnosis of neurofibromatosis type 1 (NF1) and hypopituitary dwarfism.
Many public awareness campaigns intend to improve society's understanding of dementia, its symptoms, and the difficulties faced by patients. Often less well described are the challenges faced by carers, be they family or professional caregivers. In The Dementia Whisperer: scenes from the frontline of caring by Agnes Juhasz, the reader gains insight into the life of an experienced live-in carer for a person with dementia. The book does not use scientific terminology, nor does it try to introduce and explain the neurological condition.
[Comment] Edaravone: a new treatment for ALS on the horizon?
Despite the urgent, unmet clinical and economic need for treatment of neurodegenerative diseases, trials of disease modifying drugs have produced little success. Amyotrophic lateral sclerosis (ALS), an exemplar of neurodegeneration, is primarily characterised by rapid-onset loss of upper and lower motor neurons that results in patient death from respiratory failure. As with other neurodegenerative diseases, the pathobiology of ALS is not well understood. At least 30 genes of major effect have been reported, and disease models suggest that a number of different but interacting pathogenic processes contribute to disruption of neuronal cell machinery, oxidative stress, and activation of a neuroinflammatory response by microglia and astrocytes.
[Articles] Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial
Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria.
Artists' residencies in hospitals could now be considered the rule rather than the exception. These provide opportunities for patients to explore their creative potential and have superseded more craft-based activities to aid rehabilitation therapy or simply to alleviate boredom during hospitalisation. Artists in residence facilitate creative workshops for patients, often with the objective of subsequently exhibiting the participants' works. These projects have proven so popular that cynics might suggest that hospitalisation is a quicker route to securing an exhibition than spending years at art school.
[In Context] Neurons and architecture: from the inside out
Built from the bottom up over thousands of years of evolution, the brain could be the greatest architectural masterpiece of all time. In essence, the brain is similar to a building; each part of the brain has its own function, but overall it must work as a whole. However, what about the building that houses the hub of brain research—does it need to have an architectural vision that aligns with what is actually happening inside? How can science and architecture work together to accelerate and promote discoveries?
[In Context] Minpins and medicine: the life of Roald Dahl
Neurologist Tom Solomon's book, Roald Dahl's Marvellous Medicine, is a unique combination of memoir, popular science, and biography. Solomon was driven to write the book after recording a radio show on Roald Dahl's life, in collaboration with his official biographer Donald Sturrock, for the BBC's Great Lives programme. Solomon realised that although the public was well versed in Dahl's oompa loompas, gremlins, and minpins, they knew little of his interest in, and contributions to, medicine. With this book, Solomon sought to fill that void.
The UK Epilepsy Society is 125 years old. Now a leader in research and patient support, the history of this once ‘home for such epileptic persons as are capable of work’ opens a window onto wider society's changing understanding of, and attitude towards, epilepsy. Adrian Burton investigates.
Cannabidiol Treatment for Refractory Seizures in Sturge-Weber Syndrome
Publication date: June 2017 Source:Pediatric Neurology, Volume 71 Author(s): Emma H. Kaplan, Elizabeth A. Offermann, Jacqueline W. Sievers, Anne M. Comi BackgroundSturge-Weber syndrome results in leptomeningeal vascular malformations, medically refractory epilepsy, stroke(s), and cognitive impairments. Cannabidiol, a cannabinoid without psychoactive properties, has been demonstrated in preclinical models to possibly have anticonvulsant, antioxidant, and neuroprotective actions.MethodsFive subjects with Sturge-Weber syndrome brain involvement and treatment-resistant epilepsy were enrolled. Motor seizure frequency, quality of life, and adverse events were recorded from the eighth week of the pretreatment period, eight weeks after starting maintenance dose (week 14), and the 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 subjects with bilateral brain involvement had at the last visit a greater than 50% seizure reduction, reported an improved quality of life, and remained on cannabidiol 63-80 weeks after starting the drug. Three subjects reported mild side effects considered related to cannabidiol.ConclusionThis study suggests that cannabidiol may be well tolerated as adjunctive medication for seizure management and provides initial data supporting further study of cannabidiol in individuals with Sturge-Weber syndrome.
Cumulative Incidence of Seizures and Epilepsy in 10-Year-old Children Born Before 28 Weeks Gestation
Publication date: Available online 18 May 2017 Source:Pediatric Neurology Author(s): Laurie M. Douglass, Timothy C. Heeren, Carl E. Stafstrom, William DeBassio, Elizabeth N. Allred, Alan Leviton, T. Michael O’Shea, Deborah Hirtz, Julie Rollins, Karl Kuban ObjectiveTo evaluate seizures and epilepsy incidence in the first decade of life among children born extremely premature (< 28 weeks gestation).MethodIn a prospective, multi-center, observational study, 889 of 966 eligible children born 2002-2004 were evaluated at 2 and 10 years for neurological morbidity. Complementing questionnaire data to determine a history of seizures, all caregivers were interviewed retrospectively for post-neonatal seizures using a validated seizure screen followed by a structured clinical interview by a pediatric epileptologist. A second pediatric epileptologist established an independent diagnosis based on recorded responses of the interview. A third epileptologist determined the final diagnosis when evaluators disagreed (3%). Lifetable survival methods were used to estimate seizure incidence through 10 years.ResultsBy age 10 years, 12.2% percent (95% CI: 9.8, 14.5) of children had ≥1 seizure, 7.6% (95% CI 5.7, 9.5) had epilepsy, 3.2% had seizure with fever, and 1.3% had a single, unprovoked seizure. Seizure incidence increased with decreasing gestational age. In more than 75% of children with seizures, onset was after one year of age. Seizure incidence was comparable in both sexes. Two-thirds of those with epilepsy had other neurological disorders. One-third of children with epilepsy were not recorded on the medical history questionnaire.SignificanceThe incidence of epilepsy through 10 years of age among children born extremely premature is approximately 7 to 14-fold higher than the 0.5-1% lifetime incidence reported in the general pediatric population. Seizures in this population are under-recognized, and possibly under-diagnosed, by parents and providers.
Involvement of Cerebellum in Leigh Syndrome: Case report and review of literature
Publication date: Available online 19 May 2017 Source:Pediatric Neurology Author(s): Nitish Chourasia, Rahmat Adejumo, Rajan Patel, Mary Kay Koenig A 6 year old male with Leigh syndrome developed recurrent cerebellar involvement. The patient was diagnosed with Leigh syndrome at 2 years of age with bilateral basal ganglia lesions on brain magnetic resonance imaging (MRI). Genetic testing confirmed a diagnosis of Leigh syndrome secondary to a homoplasmic mitochondrial DNA mutation (m.9176T>C). The patient experienced regressive episodes (ages 5, and 6 years). All the regressive episodes had a similar presentation with worsening of baseline ataxia and dysarthria. The first episode mimicked infectious cerebellitis, with elevated cerebral spinal fluid (CSF) protein and white blood cell count. No organisms were isolated from the CSF/blood during any of the regressive episodes. Brain MRI consistently showed cerebellar lesions, however cerebellar spectroscopy during the second episode found: an elevated lactate peak, a decrease of the N-acetylaspartate peak, and elevation of the choline peak; consistent with an acute exacerbation of Leigh syndrome. We therefore hypothesize that, although rare, Leigh syndrome can present primarily with involvement of the cerebellum and should be considered in the differential diagnosis for acute cerebellitis.