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.
Facial Weakness and Ophthalmoplegia in a 4-Day-Old Infant
Publication date: Available online 2 April 2017 Source:Seminars in Pediatric Neurology Author(s): Ioanna Kouri, Katherine Mathews, Charuta Joshi We present a neonate with neurologic deficits recognized at 4 days of age. A male infant was born at term via emergency cesarian section due to failure to progress and fetal decelerations. He underwent therapeutic hypothermia for hypoxic ischemic encephalopathy. Upon completion of rewarming, he was noted to have left facial palsy, abduction deficit on the left eye past the midline, and nystagmus involving the right eye. Brain magnetic resonance imaging showed a pontine stroke, and computed tomography angiogram revealed basilar artery thrombosis. He was treated with enoxaparin for 3 months, followed by low-dose aspirin. The mechanism of the stroke remains unclear, and there is limited evidence to guide management.
The characteristics of salivary pepsin in patients with severe motor and intellectual disabilities
Publication date: Available online 8 May 2017 Source:Brain and Development Author(s): Naoki Hashizume, Suguru Fukahori, Kimio Asagiri, Shinji Ishii, Nobuyuki Saikusa, Naruki Higashidate, Motomu Yoshida, Daisuke Masui, Saki Sakamoto, Yoshiaki Tanaka, Minoru Yagi, Yushiro Yamashita PurposeThe aim of the present study was to determine the utility of measuring the salivary pepsin level (SPL) as an objective assessment of gastroesophageal reflux disease (GERD) in severe motor and intellectual disabilities (SMID) patients.Subjects and methodsThis prospective study included 26 SMID patients who underwent simultaneous 24-h multichannel intraluminal impedance pH measurement (pH/MII) and SPL evaluation. The enrolled patients were divided into GERD (+) or GERD (−) groups according to the pH/MII findings. The age, gender and pH/MII parameters were compared between the two groups. A correlation analysis was also conducted for the SPL following early-morning fasting and post-enteral feeding and the age, gender, presence of gastrostomy and tracheostomy and pH/MII parameters. The SPL was compared between the two sampling groups.ResultsFifteen patients were classified as GERD (+), and 11 patients were classified as GERD (−). The mean SPL following early-morning fasting and post-enteral feeding among all patients were 104.3 (median: 38, 25th and 75th percentile: 12, 361) ng/ml and 222.2 (median: 152:0, 500) ng/ml, respectively. Regarding positivity, 76.9% and 73.1% of SPL values in early-morning fasting and post-enteral feeding SMID patients, respectively, were positive (≧16ng/ml). The SPL following early-morning fasting demonstrated a weak but significant positive correlation with age. In contrast, we noted no correlation between the pH/MII parameters and the SPL for either the early-morning fasting or post-enteral feeding patients, and no significant difference in the SPL was observed between the GERD (+) and (−) patients.ConclusionsThe present study showed that a high proportion of SMID patients had a relatively high SPL, regardless of the presence of GERD. The SPL in SMID patients might be affected by several distinctive factors in addition to gastroesophageal reflux.
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.
Electrical status epilepticus during sleep in Mowat–Wilson syndrome
Publication date: Available online 10 May 2017 Source:Brain and Development Author(s): Paolo Bonanni, Susanna Negrin, Anna Volzone, Nicoletta Zanotta, Roberta Epifanio, Claudio Zucca, Elisa Osanni, Elisa Petacchi, Franco Fabbro AimMowat–Wilson Syndrome (MWS) is a genetic rare disease. Epilepsy is present in 70–75% of Patients and an age-dependent electroclinical pattern has been described. Up to date, there are studies with overnight sleep EEGs, probably because of the severe intellectual disability (ID) and hyperactivity of these Patients.Our purpose was to verify the hypothesis that MWS Patients might have electrical status epilepticus in slow wave sleep (ESES pattern).MethodsA retrospective analysis of anamnestic and electrographic data was performed on 7 consecutive MWS Patients followed between 2007 and 2016. Only Patients with at least one overnight sleep EEG were included in the study.ResultsFive out of 7 Patients had overnight sleep EEG studies and were included in this study. All of them had an anterior ESES pattern with spike-and-wave index>85%. The architecture of sleep was abnormal. An ESES related regression of cognitive and motor functions with impact on daily activities (ESES-related syndrome) was demonstrated in 3 out of 5 (60%) Patients. In two Patients marked improvement of cognitive and motor performances was observed when the epileptiform activity during sleep was successfully controlled or it was spontaneously reduced.ConclusionsThe clinical significance of the ESES pattern is hard to assess in MWS Patients due to severe ID, but changing in behaviour or in motor and cognitive functions should mandate sleep EEG investigation and, if ESES is present, an appropriate treatment should be tried. Furthermore, overnight sleep EEG recordings, if regularly performed in the follow up, might help to understand if ESES pattern hampers the cognitive and communicative profile in MWS.
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.
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.
Genotype–phenotype relationship in mucopolysaccharidosis II: predictive power of IDS variants for the neuronopathic phenotype
Mucopolysaccharidosis type II (MPS II) is caused by variants in the iduronate-2-sulphatase gene (IDS). Patients can be either neuronopathic with intellectual disability, or non-neuronopathic. Few studies have reported on the IDS genotype–phenotype relationship and on the molecular effects involved. We addressed this in a cohort study of Dutch patients with MPS II.
Intellectual performance was assessed for school performance, behaviour, and intelligence. Urinary glycosaminoglycans were quantified by mass spectrometry. IDS variants were analysed in expression studies for enzymatic activity and processing by immunoblotting.
Six patients had a non-neuronopathic phenotype and 11 a neuronopathic phenotype, three of whom had epilepsy. Total deletion of IDS invariably resulted in the neuronopathic phenotype. Phenotypes of seven known IDS variants were consistent with the literature. Expression studies of nine variants were novel and showed impaired IDS enzymatic activity, aberrant intracellular processing, and elevated urinary excretion of heparan sulphate and dermatan sulphate irrespective of the MPS II phenotype.
We speculate that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype of MPS II. Whereas the molecular effects of IDS variants do not distinguish between MPS II phenotypes, the IDS genotype is a strong predictor.
Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5
To characterize the phenotypic profile of a cohort of children affected with CLN5, a rare form of neuronal ceroid-lipofuscinosis (NCL), and to trace the features of the natural history of the disease.
Records of 15 children (nine males, six females) were obtained from the data sets of the DEM-CHILD International NCL Registry. Disease progression was measured by rating six functional domains at different time points along the disease course. All patients underwent mutation analysis of the CLN5 gene and ultrastructural investigations of peripheral tissues. Expression of the gene product, pCLN5, was characterized in vitro in six patients.
Disease onset was at 2 to 7 years 6 months of age: impaired learning and cognition were the most common early symptoms. Seizures occurred relatively late (median age 8y) and were the presenting symptoms in two children. Nine mutations were detected in 30 alleles, including six mutations predicting a truncated protein. Mixed cytosomes were observed by electron microscopy. Differences of disease progression were observed in two groups of patients and could be related to their genetic profile.
Clinical features in a multicentre cohort of patients with CLN5 confirm that cognitive difficulties are early clinical markers of this condition. Severe mutations were associated with a more rapid decline of neurological function.
Motor function domains in alternating hemiplegia of childhood
To characterize motor function profiles in alternating hemiplegia of childhood, and to investigate interrelationships between these domains and with age.
We studied a cohort of 23 patients (9 males, 14 females; mean age 9y 4mo, range 4mo–43y) who underwent standardized tests to assess gross motor, upper extremity motor control, motor speech, and dysphagia functions.
Gross Motor Function Classification System (GMFCS), Gross Motor Function Measure-88 (GMFM-88), Manual Ability Classification System (MACS), and Revised Melbourne Assessment (MA2) scales manifested predominantly mild impairments; motor speech, moderate to severe; Modified Dysphagia Outcome and Severity Scale (M-DOSS), mild-to moderate deficits. GMFCS correlated with GMFM-88 scores (Pearson's correlation, p=0.002), MACS (p=0.038), and MA2 fluency (p=0.005) and accuracy (p=0.038) scores. GMFCS did not correlate with motor speech (p=0.399), MA2 dexterity (p=0.247), range of motion (p=0.063), or M-DOSS (p=0.856). Motor speech was more severely impaired than the GMFCS (p<0.013). There was no correlation between any of the assessment tools and age (p=0.210-0.798).
Our data establish a detailed profile of motor function in alternating hemiplegia of childhood, argue against the presence of worse motor function in older patients, identify tools helpful in evaluating this population, and identify oropharyngeal function as the more severely affected domain, suggesting that brain areas controlling this function are more affected than others.
Dominios de la función motora en la hemiplejia alterna de la infancia
Caracterizar los perfiles de la función motora en la hemiplejia alterna de la infancia e investigar las interrelaciones entre estos dominios y la edad.
Estudiamos una cohorte de 23 pacientes (9 masculinos, 14 femeninas, con una media de edad de 9 años y 4 meses, entre un rango de 4 meses–44 años) quienes se sometieron a una evaluación estandarizada para valorar la función motora gruesa, el control motor de las extremidades superiores, el control motor del habla y la disfagia.
Las siguientes escalas: Sistema de Clasificación de la Función Motora Gruesa (GMFCS), la Medida de la Función Motora Gruesa-88 (GMFM-88), el Sistema de la Clasificación de la Capacidad Manual (MACS), y la Evaluación Melbourne-2 (MA2), demostraron deterioros predominantemente leves. El control motor del habla mostro un compromiso moderado a severo, la Escala de gravedad de la disfagia modificada evidencio un compromiso leve a moderado. Los niveles GMFCS se correlacionaron con el GMFM-88 (coeficiente de correlación de Pearson, p=0.002, MACS (p=0.027), y las puntuaciones de precisión (p=0.038) y fluidez (p=0.005) de MA2. El GMFCS no se correlaciono con el control motor del habla (p=0.321), la MA2 destreza, o el rango de movimiento (p=0.063), o M-DOSS (p=0.856), el control motor del habla se encontró más severamente comprometido que la función motora gruesa GMFCS (p<0.013). No hubo correlación entre ninguna herramienta de evaluación y la edad (p=0.071–0.798).
Nuestros datos establecieron un perfil detallado de la función motora en la hemiplejia alterna de la infancia, además estos datos argumentan en contra de la presencia de una función motora deteriorada en pacientes de edad mayores, identifican herramientas útiles para la evaluación de esta población, y finalmente identifican a la función orofaríngea como el dominio más severamente comprometido, sugiriendo que las áreas del cerebro que controlan esta función se encuentran mas comprometidas que otras áreas.
Domínios da função motora na hemiplegia alternante da infância
Caracterizar perfis de alteração motora na hemiplegia alternante da infância e investigar se há relação entre estes domínios e faixa etária.
Foi estudada uma coorte de 23 pacientes (9 do sexo masculino, 14 do sexo feminino, média de idade de 9 anos e 4 meses, numa faixa de 4 meses a 44 anos). Todos passaram por testes padronizados de avaliação das funções motora grossa, controle motor de membros superiores, controle motor da fala e disfagia.
As escalas Sistema de classificação motora grossa (GMFCS), Medida da função motora grossa-88 (GMFM-88), Sistema de classificação das habilidades manuais (MACS) e Avaliação de Melbourne-2 (MA2) evidenciaram deficiências leves; controle motor da fala, deficiências de moderadas a severas; déficits leves a moderados na Escala modificada de severidade da disfagia (M-DOSS). A GMFCS correlacionou-se com os escores da GMFM-88 (correlação de Pearson; p=0.002, MACS (p=0.0027) e escores de acurácia (p=0.038) e fluência (p=0.005) do MA2. A GMFCS não se correlacionou com o controle motor da fala (p=0.321), destreza no MA2, amplitude de movimento (p=0.063), ou M-DOSS (p=0.856), com a articulação da linguagem sendo mais severamente afetada que a GMFCS (p<0.013). Não houve correlação entre nenhum dos instrumentos com a idade (p=0.071–0.798).
Nossos dados estabelecem um perfil detalhado da função motora na hemiplegia alternante da infância, e contrariam a idéia de pior função motora em pacientes mais velhos; identifica instrumentos úteis na avaliação desta população, e identifica a função orofaríngea como o domínio mais afetado, sugerindo que áreas cerebrais que controlam esta função são mais afetadas que outras.
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.
Circadian clustering of spontaneous epileptic seizures emerges after pilocarpine-induced status epilepticus
Seizures in mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis are thought to develop with various latency intervals after an initial transient brain insult. To study seizure dynamics after an initial transient precipitating insult in a systematic fashion, we utilized continuous video–electroencephalography (EEG) monitoring after the induction of status epilepticus (SE) in a mouse MTLE model.
Continuous 24/7 video/telemetric hippocampal EEG recordings in the systemic pilocarpine MTLE mouse model.
After SE, we observed emerging seizures interfering with the circadian EEG rhythms. The physiologic circadian EEG pattern of mice was transiently suppressed for 2.9 (mean) ± (SEM) 0.5 days after SE. This period was accompanied predominately by nonconvulsive seizure activity, followed by convulsive seizures at later stages. After the circadian rhythm was restored, spontaneous generalized seizures occurred mainly in a clustered manner in a narrow time window between 4 and 7 p.m. (light cycle 7 a.m./7 p.m.). Moreover, we demonstrate that depth-electrode implantation surgery transiently disturbs the physiologic EEG circadian cycle; variation of the time point of SE induction after electrode insertion surgery revealed a substantial impact on the epilepsy phenotype, which was more severe when SE occurred after postsurgical reappearance of EEG circadian cycling.
These data have several experimental and pathophysiologic implications. The impact of depth-electrode surgery on the phenotype has to be tightly controlled. In mice monitored after pilocarpine-induced SE, the “epileptogenesis” period is characterized by the dynamics of epileptiform activity toward behavioral recurrent seizure patterns. The striking clustering of spontaneous seizures at the transition from sleep to activity stages of mice has to be taken into account for future studies on the model. Improving our understanding of the molecular mechanisms that determine the circadian dynamics of seizure threshold remains an intriguing task for the future.
Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein-bound concentrations
Given that only the free non–protein-bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine-epoxide and N-desmethyl clobazam), using standardized methodology and under set conditions.
The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein-bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.
Gabapentin and pregabalin are non–protein-bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N-desmethyl-clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7–74.8%).
These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine-epoxide and N-desmethyl-clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.
Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy
To ascertain possible determinants of carbamazepine (CBZ)– and oxcarbazepine (OXC)–induced hyponatremia in a large cohort of people with epilepsy.
We collected data on serum sodium levels in people with epilepsy who were attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L and severe hyponatremia as Na+ ≤128 mEq/L.
We identified 1,782 people who had used CBZ (n = 1,424) or OXC (n = 358), of whom 50 were treated with both drugs. Data on sodium level measurements were available in 1,132 on CBZ and in 289 on OXC. Hyponatremia occurred in 26% of those taking CBZ and 46% of those taking OXC. This was severe in 7% in the CBZ group and 22% in the OXC group. Hyponatremia was symptomatic in 48% and led to admissions in 3%. Age over 40 years, high serum levels of CBZ and OXC, and concomitant use of other antiepileptic drugs were the main risk factors for hyponatremia in both treatment groups. Female patients on OXC were at a higher risk than male patients of hyponatremia. The risk of hyponatremia on CBZ was significantly associated with the risk of hyponatremia on OXC within a subgroup that used both drugs consecutively.
Hyponatremia is a common problem in people taking CBZ or OXC. Regular ascertainment of sodium levels in those taking either drug is recommended and results should be acted on.
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.
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.
Reliability and Clinical Correlation of Transcranial Doppler Ultrasound in Sturge-Weber syndrome
Publication date: Available online 8 May 2017 Source:Pediatric Neurology Author(s): Elizabeth A. Offermann, Aditya Sreenivasan, M. Robert DeJong, Doris D.M. Lin, Charles E. McCulloch, Melissa G. Chung, Anne M. Comi BackgroundThe reproducibility of transcranial Doppler (TCD) ultrasound measurements in Sturge-Weber syndrome (SWS) and TCD’s ability to predict neurologic progression is unknown.MethodsIn fourteen SWS patients, TCD measured mean flow velocity, pulsatility index, peak systolic velocity (PSV), and end diastolic velocity (EDV) in the middle (MCA), posterior (PCA) and anterior cerebral arteries (ACA) of the affected and unaffected hemisphere. TCD was performed either once (n=5) or twice in one day (n=9). We assessed the reproducibility of the measurements performed twice on the same day on subjects and compared the TCD measurements to previously published age-matched controls. Clinically obtained neuroimaging was scored for extent and severity of SWS brain involvement. Patients were prospectively assigned SWS neuroscores.ResultsMCA velocity (r=0.79, p=0.04, n=7), PCA velocity (r=0.90, p=0.04, n=5), and ACA pulsatility index (r=0.82, p=0.02, n=7) were reproducible TCD measurements comparing same-day percent side-to-side differences. In subjects with SWS, affected and unaffected mean PSV and EDV velocities in the MCA, PCA, and ACA were globally lower compared to age-matched controls. Subjects with the lowest affected MCA velocity had the greatest worsening in total neurologic score between time 1 and 2 (r=-0.73, p=0.04, n=8) and the most severe MRI involvement of the affected frontal lobe (r=-0.82, p=0.007, n=9).ConclusionsTCD is suggested as a reliable measure with potential clinical value, indicating blood flow may be globally decreased in SWS patients with unilateral brain involvement.
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.
Early Imaging And Adverse Neurodevelopmental Outcome in Asphyxiated Newborns Treated with Hypothermia
Publication date: Available online 19 May 2017 Source:Pediatric Neurology Author(s): Fatema Al Amrani, Saskia Kwan, Guillaume Gilbert, Christine Saint-Martin, Michael Shevell, Pia Wintermark BackgroundBrain injury can be identified as early as day 2 of life in asphyxiated newborns treated with hypothermia, when using diffusion magnetic resonance imaging (MRI). However, it remains unclear if these diffusion changes can predict future neurodevelopment. This study aimed to determine whether abnormal early diffusion changes in newborns treated with hypothermia are associated with adverse neurodevelopmental outcome at 2 years of age.MethodsAsphyxiated newborns treated with hypothermia were enrolled prospectively. They had magnetic resonance imaging (MRI) at specific time-points over the first month of life, including diffusion-weighted imaging and diffusion-tensor imaging. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured in different regions of interest. Adverse neurodevelopmental outcome was defined as cerebral palsy, global developmental delay, and/or seizure disorder around 2 years of age. ADC and FA values were compared between the newborns developing or not adverse outcome.ResultsTwenty-nine asphyxiated newborns treated with hypothermia were included. Among the newborns developing adverse outcome, ADC values were significantly decreased on days 2–3 of life and increased around day 10 of life in the thalamus, posterior limb of the internal capsule, and the lentiform nucleus. FA values decreased in the same regions around day 30 of life. These newborns also had increased ADC around day 10 of life and around day 30 of life, and decreased FA around day 30 of life in the anterior and posterior white matter.ConclusionDiffusion changes that were evident as early as day 2 of life when the asphyxiated newborns were still treated with hypothermia were associated with later abnormal neurodevelopmental outcome.
Dexamethasone, IVIg, and Rituximab Combination Immunotherapy for Pediatric Opsoclonus-Myoclonus Syndrome
Publication date: Available online 19 May 2017 Source:Pediatric Neurology Author(s): Michael R. Pranzatelli, Elizabeth D. Tate BackgroundAlthough pulse-dose dexamethasone is increasingly favored for treating pediatric opsoclonus-myoclonus syndrome (OMS), and multimodal immunotherapy is associated with improved clinical response, there have been no neuroimmunological studies of dexamethasone-based multimodal disease-modifying therapy.MethodsIn this observational retrospective study, 19 children with OMS (with or without associated neuroblastoma) underwent multi-biomarker evaluation for neuroinflammation. Nine of varying OMS severity, duration, and treatment status were treated empirically with pulse dexamethasone, IVIg, and rituximab combination immunotherapy (DEXIR-CI). Another 10 children on dexamethasone alone or with IVIg at initial evaluation only provided a comparison group. Motor severity (Total Score) was scored blinded from videotapes using the validated OMS Evaluation Scale.ResultsDEXIR-CI was associated with a 69% reduction in group Total Score (P = 0.004), and was well-tolerated clinically. Patients given the dexamethasone combination exhibited significantly lowered B cell frequencies in CSF (-94%) and blood (-76%), normalizing the CSF B cell percentage. The number of patients with positive inflammatory markers dropped 87% (P = 0.002), as did the number of markers. CSF OCB were positive in 4/9 pre- but 0/6 post-treatment. In the comparison group, partial response to dexamethasone alone or with IVIg was associated with multiple positive markers for neuroinflammation despite an average of 7 months of treatment.ConclusionsMulti-mechanistic dexamethasone-based combination immunotherapy increases the therapeutic armamentarium for OMS, providing a viable option for less severe cases. Partial response to dexamethasone with or without IVIg is indicative of ongoing neuroinflammation and should be treated promptly and accordingly.