Pediatric Neurology

Role of Cochrane Reviews in Pediatric Neurology

2012-02-01

Abstract: Evidence-based medicine in pediatric neurology is considered an important contributor to the best quality of care. We performed a literature review of all Cochrane reviews from 1996-2010 in pediatric neurology. Some reviews concluded that a certain intervention provided benefits, some concluded that certain interventions should not be performed, and some concluded that the current level of evidence was inconclusive. One hundred and twelve reviews were enrolled; only 17 exclusively involved children. In 33/112, a clear recommendation in favor of a certain intervention was given, 11/112 issued a conditionally positive recommendation, and 32/112 concluded that certain interventions should not be performed. Six concluded that no differences were evident between different therapeutic/treatment options. Thirty were inconclusive. The proportion of inconclusive reviews increased during three a priori defined time intervals. Common criticisms regarding quality of enrolled studies included heterogeneous study populations (49/112), a small number of participants (48/112), and a lack of comparability of studies (40/112). An ongoing need exists for high-quality research to reduce the proportion of inconclusive meta-analyses. Further randomized, controlled trials should involve only pediatric populations.

Diurnal Melatonin Patterns in Children: Ready to Apply in Clinical Practice?

2012-02-01

Abstract: Experimental and clinical studies suggest that endogenous melatonin plays an important role in pediatric sleep regulation. This finding led to the introduction of exogenous melatonin to treat sleep disturbances. Optimizing the treatment algorithm involves a review of melatonin measurements and interpretations in clinical practice. Diurnal patterns of salivary melatonin and urinary metabolite 6-sulfatoxymelatonin were investigated in 29 children and adolescents (age, 5.5-17.3 years) by measuring concentrations every 3 hours. Relationships between melatonin parameters (peak concentrations and area under the time curve) and anthropometric measures (height, weight, and body mass index), age, and sleep scores (Sleep Disturbance Scale for Children) were investigated. High interindividual variability was evident in melatonin diurnal profiles. Melatonin production (adjusted to body weight) decreased with age and sexual maturation (P < 0.00). Both salivary melatonin and its urinary metabolite measurements can be used to evaluate the melatonin system in children. However, the high interindividual variability of diurnal melatonin concentrations challenges clinical applications in regard to diagnostic purposes and the criteria for initiating exogenous melatonin therapy. Further investigations and the development of criteria for clinical evaluations of the pediatric melatonin system are needed.

Tyrosine Hydroxylase Deficiency in Taiwanese Infants

Ching-Shiang Chi, Hsiu-Fen Lee, Chi-Ren Tsai — 2012-02-01

Abstract: We analyzed the clinical manifestations, genetic mutations, treatment responses to l-dopa, and long-term neurologic outcomes in Taiwanese infants with tyrosine hydroxylase deficiency. From 1999 to May 2011, we enrolled six infants who had been diagnosed with tyrosine hydroxylase deficiency by identifying point mutations on the tyrosine hydroxylase gene. Two patients manifested fetal distress during the perinatal period. Four patients exhibited generalized tremor as their first observed neurologic sign at age 3 months. All presented brisk reflexes, hypokinesia, rigidity, distal chorea, and athetosis. We identified a novel missense mutation, I382T, and report on the first patient, to the best of our knowledge, with a homozygous R153X nonsense mutation. Five of six patients responded to l-dopa at a dose of 4.2-34.7 mg/kg/day combined with biperiden or selegiline or both. Long-term neurologic outcomes (median follow-up, 5 years and 10.5 months) revealed two patients demonstrated slightly low intelligence quotients, three demonstrated mild to moderate psychomotor retardation, and one died of respiratory failure. A higher dose of l-dopa, together with alternative therapies, may lead to improvements in motor function. However, several years of observation may be needed to reach definitive conclusions about neurologic outcomes.

Vigabatrin for Childhood Partial-Onset Epilepsies

2012-02-01

Abstract: To determine vigabatrin’s effectiveness and the prevalence of symptomatic visual impairment (i.e., impairment affecting the ability to perform everyday activities) associated with its therapy in pediatric epilepsy, we retrospectively reviewed medical records of 156 patients receiving vigabatrin at Cincinnati Children’s Medical Center from 1998-2010. In addition to demographics and vigabatrin dosing information, data included seizure type/frequency at presentation and subsequent follow-up. Of 156 patients, we excluded 35 because their medical records were insufficient to permit verification of the exact duration or timing of vigabatrin treatment. To evaluate efficacy (n = 121/135), we used a 5-point scale (0-4) to compare seizure frequency at several time points. To evaluate visual impairment (n = 63), we reviewed serial ophthalmologic evaluations at baseline and during treatment for patients in whom they were clinically indicated. Mean age at treatment initiation was 1.8 years (range, 0.1-29.2 years). Treatment duration ranged from 0.7-101.0 months, with an estimated average daily dose of 79 mg/kg/day. Tuberous sclerosis complex was the commonest seizure etiology (83%). Partial-onset seizure, alone or with infantile spasms, was the commonest seizure type (84%). Seizure frequency decreased from 3.7 ± 0.6 S.D. at baseline to 1.8 ± 1.7 S.D. at 6 months (P < 0.001). Responses to vigabatrin did not differ by tuberous sclerosis complex or nontuberous sclerosis complex etiology, and were sustained for 5 years. Sixty-three patients (∼50% of all patients evaluated) underwent clinically indicated ophthalmologic assessments during the review period. In our clinical judgment, no cases of clinically relevant vigabatrin-associated visual impairment occurred. Vigabatrin was effective for refractory childhood partial-onset epilepsy, and was not associated with symptomatic vision loss.

Novel Mutation of GLRA1 in Omani Families With Hyperekplexia and Mild Mental Retardation

2012-02-01

Abstract: Hyperekplexia is characterized by neonatal hypertonia and exaggerated startle reflex in response to loud noise or tactile stimuli. Mutations in patients with hyperekplexia were evident in several genes encoding proteins involved in glycinergic neurotransmission, i.e., glycine receptor α and β subunits, collybistin, gephyrin, and glycine transporter 2. We clinically and genetically characterized two large, unrelated consanguineous families with hyperekplexia. Affected members of the two families manifested hyperekplexia with mild mental retardation. Patients exhibited a novel homozygote c.593G>C missense mutation in GLRA1, resulting in amino acid substitution p.W170S in the corresponding mature glycine receptor α1 subunit. This mutation was absent in 400 randomly selected chromosomes in the same population. In conclusion, a novel p.W170S mutation in the extracellular ligand binding domain of glycine receptor α1 subunit was detected in patients with hyperekplexia and mild mental retardation.

Functional Magnetic Resonance Imaging Study Comparing Rhythmic Finger Tapping in Children and Adults

2012-02-01

Abstract: This study compared brain activation during unpaced rhythmic finger tapping in 12-year-old children with that of adults. Subjects pressed a button at a pace initially indicated by a metronome (12 consecutive tones), and then continued for 16 seconds of unpaced tapping to provide an assessment of their ability to maintain a steady rhythm. These analyses focused on the superior vermis of the cerebellum, which is known to play a key role in timing. Twelve adults and 12 children performed this rhythmic finger tapping task in a 3 T scanner. Whole-brain analyses were performed in Brain Voyager, with a random-effects analysis of variance using a general linear model. A dedicated cerebellar atlas was used to localize cerebellar activations. As in adults, unpaced rhythmic finger tapping in children demonstrated activations in the primary motor cortex, premotor cortex, and cerebellum. However, overall activation was different, in that adults demonstrated much more deactivation in response to the task, particularly in the occipital and frontal cortices. The other main differences involved the additional recruitment of motor and premotor areas in children compared with adults, and increased activity in the vermal region of the cerebellum. These findings suggest that the timing component of the unpaced rhythmic finger tapping task is less efficient and automatic in children, who need to recruit the superior vermis more intensively to maintain the rhythm, although they performed somewhat more poorly than adults.

Historic, Clinical, and Prognostic Features of Epileptic Encephalopathies Caused by CDKL5 Mutations

Brian D. Moseley, Radhika Dhamija, Elaine C. Wirrell, Katherine C. Nickels — 2012-02-01

Abstract: Mutations within the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are important causes of early-onset epileptic encephalopathies. We sought to determine the historic, clinical, and prognostic features of epilepsy secondary to CDKL5 mutations. We performed retrospective chart reviews of children at our institution with epilepsy and CDKL5 mutations. Six children were identified. One manifested a deletion in exons 10-15 of the CDKL5 gene, another manifested a single base-pair duplication in exon 3, and the rest manifested base-pair exchanges. The mean age of seizure onset was 1.8 months (range, 1-3 months). Although the majority (4/6, 67%) presented with partial-onset seizures, all children developed infantile spasms. All children demonstrated developmental delay and visual impairment. Although such mutations are X-linked, two children were boys. They did not present with more severe phenotypes than their female counterparts. Despite trials of antiepileptic drugs (mean, 5; range, 3-7), steroids/adrenocorticotropic hormone (4/6; 67%), and the ketogenic diet (6/6; 100%), all children manifested refractory seizures at last follow-up. Although no treatment eliminated seizures, topiramate, vigabatrin, and the ketogenic diet were most helpful at reducing seizure frequency.

Changing Pattern of Perinatal Brain Injury in Term Infants in Recent Years

2012-02-01

Abstract: Perinatal brain injury in term infants remains a significant clinical problem. Recently a change appears to have occurred in the pattern of such injuries. We sought to characterize the incidence, etiology, clinical manifestations, and outcomes of these injuries. A retrospective chart review identified clinical characteristics of neuroimaging, electroencephalography, and placental pathologic findings. Perinatal depression was defined as hypotonia and the need for respiratory support. From January 2004-December 2009, 29,597 term deliveries occurred. Brain injuries in 33 infants (live term births) included hypoxic-ischemic encephalopathy (n = 8; 0.27/1000), subdural hemorrhage (n = 10; 0.34/1000), intraventricular/intraparenchymal hemorrhage (n = 5; 0.17/1000), and focal cerebral infarctions (n = 4; 0.14/1000). Thirteen of 33 infants (39%) were triaged to a regular nursery. Delayed presentations included apnea (n = 6), desaturation episodes (n = 3), and seizures (n = 4). Twenty of 33 (61%) were admitted directly to the neonatal intensive care unit because of perinatal depression or evolving hypoxic-ischemic encephalopathy. Clinical signs included seizures (n = 12) and apnea (n = 2). Nine of 19 manifested electroencephalographic seizures. Pathology included chorioamnionitis (n = 7) and fetal thrombotic vasculopathy (n = 5). The latter was associated with focal cerebral infarctions in 3/4 cases. Most cases attributable to perinatal brain injury, except for evolving hypoxic-ischemic encephalopathy, are not identified according to any perinatal characteristics until the onset of signs, limiting opportunities for prevention.

Neonatal Seizures: Treatment Practices Among Term and Preterm Infants

Hannah C. Glass, Jessica Kan, Sonia L. Bonifacio, Donna M. Ferriero — 2012-02-01

Abstract: Neonatal seizures are common clinical conditions in both term and preterm neonates, yet no clinical management guidelines for direct care exist. We surveyed 193 international neurologists, neonatologists, and specialists in neonatal neurology or neonatal neurocritical care to assess management practices for seizures in preterm and term neonates. We found high reported rates of electroencephalogram and amplitude-integrated electroencephalogram (aEEG) monitoring to detect neonatal seizures, prevalent use of older anticonvulsant agents, and high rates of neuroimaging. Overall, responses were similar for term and preterm neonates. However, term neonates were likelier to be more heavily investigated, with higher use of magnetic resonance imaging and of electroencephalogram and aEEG monitoring of at-risk neonates. Continuous monitoring and cranial imaging of neonatal seizures now comprise the standard of care in many centers, although management practices vary widely. Early recognition and management of neonatal seizures and possible underlying injury may lead to increased opportunities for stopping seizures, protecting the brain, and improving developmental outcomes in at-risk neonates. The need for collaboration among neonatologists and neurologists is urgent, to address gaps in knowledge regarding management of neonatal seizures in term and preterm neonates.

Changes of Positron Emission Tomography in Newborn Infants at Different Gestational Ages, and Neonatal Hypoxic-Ischemic Encephalopathy

2012-02-01

Abstract: Cerebral glucose metabolism was measured by 18F-fluorodeoxyglucose position emission tomography in infants at different gestational ages and with neonatal hypoxic-ischemic encephalopathy. Thirty-six preterm and term infants at different gestational ages without brain injury were divided into four subgroups: ≤32 weeks (n = 4), 33-34 weeks (n = 5), 35-36 weeks (n = 12), and ≥37 weeks (n = 15). Twenty-four newborn infants with hypoxic-ischemic encephalopathy were divided into three subgroups: mild (n = 13), moderate (n = 7), and severe (n = 4). Cerebral glucose metabolism manifested a trend toward increase, and the structure of cranial 18F-fluorodeoxyglucose positron emission tomography images became clear with increased gestational age, especially at ≥37 weeks. Uptakes of 18F-fluorodeoxyglucose in the ≥37-week group were significantly higher than in the ≤32-week group (P < 0.01). Cerebral glucose metabolism changed significantly in neonatal hypoxic-ischemic encephalopathy, and was either unbalanced bilaterally or relatively low at all sites. Moreover, uptakes of 18F-fluorodeoxyglucose were significantly lower in severe than in mild and medium hypoxic-ischemic encephalopathy (P < 0.05). Cerebral glucose metabolism, as measured by 18F-fluorodeoxyglucose positron emission tomography, may prove useful for estimating brain development and injury in newborn infants, and its clinical values need further investigation.

Reactivation of Varicella Presenting as Pseudotumor Cerebri: Three Cases and a Review of the Literature

Sarit Ravid, Yael Shachor-Meyouhas, Eli Shahar, Zipi Kra-Oz, Imad Kassis — 2012-02-01

Abstract: The possible association of pseudotumor cerebri and varicella infection was previously mentioned in a few case reports. In those cases, the history and clinical features of active varicella were obvious, and signs were directly related to the varicella infection. We describe three immunocompetent children with pseudotumor cerebri as the only manifestation of Varicella zoster virus reactivation, with a review of the literature. We suggest considering Varicella zoster virus in children with pseudotumor cerebri, even in the absence of a history of recent varicella infection.

TUBA1A Mutation-Associated Lissencephaly: Case Report and Review of the Literature

Aman P.S. Sohal, Tara Montgomery, Dipayan Mitra, Venkateswaran Ramesh — 2012-02-01

Abstract: Lissencephaly is a disorder of neuronal migration resulting in abnormal cerebral cortical sulcation and gyration. Affected children present with microcephaly, developmental delay, and early-onset epileptic seizures. Recently, de novo missense mutations in the tubulin α-1A (TUBA1A) gene were identified as causing a distinctive radiologic phenotype comprising of posteriorly predominant lissencephaly with dysgenetic corpus callosum, cerebellar and brainstem hypoplasia, and more recently, polymicrogyria. We describe a 14-month-old girl with TUBA1A mutation-associated lissencephaly, and summarize the clinical and neuroradiologic findings of 19 cases in the literature.

Hashimoto Encephalopathy Causing Drug-Resistant Status Epilepticus Treated With Plasmapheresis

Ömer Bektas, Arzu Yılmaz, Tanıl Kendirli, Zeynep Sıklar, Gülhis Deda — 2012-02-01

Abstract: Hashimoto encephalopathy is a rare, clinically heterogenous condition. Its treatment is based on corticosteroids. A previously normal 12-year-old boy was admitted to our pediatric emergency department with status epilepticus. He experienced a recurrence of status epilepticus after pentobarbital withdrawal, and required repeated resumptions of drug-induced coma. He manifested acute personality changes. His limbic encephalitis markers were normal, but his level of anti-thyroid peroxidase antibody was high. A diagnosis of Hashimoto encephalopathy was considered. Our patient responded to plasmapheresis instead of corticosteroid treatment. This case report is the first, to the best of our knowledge, of plasmapheresis because of Hashimoto encephalopathy in a child.

Stroke and cerebrovascular disease in childhood

Heather J. Fullerton — 2012-02-01

Cerebrovascular diseases in children are heterogeneous and complex. They can occur either in isolation or as a manifestation of a vast array of genetic, inflammatory, or other systemic diseases. A single disease may also predispose patients to stroke through several mechanisms. Trisomy 21, for example, can predispose patients to stroke because of cardiac defects, moyamoya disease, or arterial dissection secondary to cervical instability. Furthermore, the clinical presentation of cerebrovascular diseases can vary dramatically, depending on the age of the child. The editors of an outstanding new book, Stroke and Cerebrovascular Disease in Childhood, succeed in summarizing these diseases in a single comprehensive text.

Peri-Ictal Magnetic Resonance Imaging Signal Abnormalities: Do They Exist?

Eugenio Grillo — 2012-02-01

In their case report (“Peri-Ictal Imaging in Focal Status Epilepticus”), Malik and Hernandez assume that signal abnormalities observed on magnetic resonance imaging 1 day after a supposed episode of status epilepticus were secondary to injury provoked by the ictal phenomenon itself.

Response:

Saleem I. Malik, Angel W. Hernandez — 2012-02-01

We read with interest Dr. Grillo’s remarks about our report on peri-ictal imaging in focal status epilepticus . We appreciate his insights regarding our report, and agree that obscure etiologies and infectious or immune-mediated encephalopathies can cause changes on magnetic resonance imaging, similar to those in our patient.

Calendar

2012-02-01

Instructions to Contributors

2012-02-01

Pediatric Neurology

Role of Cochrane Reviews in Pediatric Neurology

Diurnal Melatonin Patterns in Children: Ready to Apply in Clinical Practice?

Tyrosine Hydroxylase Deficiency in Taiwanese Infants

Vigabatrin for Childhood Partial-Onset Epilepsies

Novel Mutation of GLRA1 in Omani Families With Hyperekplexia and Mild Mental Retardation

Functional Magnetic Resonance Imaging Study Comparing Rhythmic Finger Tapping in Children and Adults

Historic, Clinical, and Prognostic Features of Epileptic Encephalopathies Caused by CDKL5 Mutations

Changing Pattern of Perinatal Brain Injury in Term Infants in Recent Years

Neonatal Seizures: Treatment Practices Among Term and Preterm Infants

Changes of Positron Emission Tomography in Newborn Infants at Different Gestational Ages, and Neonatal Hypoxic-Ischemic Encephalopathy

Reactivation of Varicella Presenting as Pseudotumor Cerebri: Three Cases and a Review of the Literature

TUBA1A Mutation-Associated Lissencephaly: Case Report and Review of the Literature

Hashimoto Encephalopathy Causing Drug-Resistant Status Epilepticus Treated With Plasmapheresis

Stroke and cerebrovascular disease in childhood

Peri-Ictal Magnetic Resonance Imaging Signal Abnormalities: Do They Exist?

Response:

Calendar

Table of Contents

Instructions to Contributors