Pediatric Neurology

Creatine and Creatine Deficiency Syndromes: Biochemical and Clinical Aspects

Fahmi Nasrallah, Moncef Feki, Naziha Kaabachi — 2010-03-01

Creatine deficiency syndromes, which have only recently been described, represent a group of inborn errors of creatine synthesis (l-arginine-glycine amidinotransferase deficiency and guanidinoacetate methyltransferase deficiency) and transport (creatine transporter deficiency). Patients with creatine deficiency syndromes present with mental retardation expressive speech and language delay, and epilepsy. Patients with guanidinoacetate methyltransferase deficiency or creatine transporter deficiency may exhibit autistic behavior. The common denominator of these disorders is the depletion of the brain creatine pool, as demonstrated by in vivo proton magnetic resonance spectroscopy. For diagnosis, laboratory investigations start with analysis of guanidinoacetate, creatine, and creatinine in plasma and urine. Based on these findings, enzyme assays or DNA mutation analysis may be performed. The creatine deficiency syndromes are underdiagnosed, so the possibility should be considered in all children affected by unexplained mental retardation, seizures, and speech delay. Guanidinoacetate methyltransferase deficiency and arginine-glycine amidinotransferase deficiency are treatable by oral creatine supplementation, but patients with creatine transporter deficiency do not respond to this type of treatment.

Correlation Between Magnetic Resonance Imaging and Histopathologic Grades in Rasmussen Syndrome

Sun Jun Kim, Yong D. Park, Richard Hessler, Mark R. Lee, Joseph R. Smith — 2010-03-01

The aim of this study was to investigate the correlation between magnetic resonance imaging (MRI) and histopathologic findings in Rasmussen syndrome. Serial MRIs were obtained for five patients who had histologically proven Rasmussen syndrome. The histopathologic grades of the lesions were subdivided into phases: active 1-3, resolving 1-3, and chronic inflammatory. The images were then correlated with histopathologic findings. Neuropathologic findings in the central areas on MRI demonstrated only the chronic and resolving grades, but active inflammatory abnormalities were present not only at the margins of the lesions, but also in areas of subtle signal abnormality on MRI. Atrophic areas on MRI exhibited all grades of histopathologic abnormalities, but chronic and resolving grades were predominant. Seizure duration of less than 6 months was associated with very active grades, duration of 1-2 years with variable grades, and duration greater than 6 years with chronic and resolving grades only. The MRI images correlated highly with histopathologic analysis. These findings suggest that the lesions initially arise from one site in the brain, and so support the centrifugal spreading theory of this disease. Findings also suggest that the margin rather than the center of the MRI abnormality may be the most ideal site for biopsy.

CP or Not CP? A Review of Diagnoses in a Cerebral Palsy Register

2010-03-01

The purpose of this study was to document the inaccuracy rate of diagnosis of cerebral palsy recorded on the South Australian Cerebral Palsy Register. A total of 402 children born in South Australia from 1993 to 2002 and notified to the Register as having cerebral palsy were identified through the Register database, and 21 children (5.2%) were later identified to have a noncerebral palsy diagnosis. Of these, 5 had either a metabolic or a neurodegenerative disorder and 2 had a syndromic disorder (1 Joubert syndrome and 1 Sotos syndrome); the remaining 14 children had one of the following final diagnoses: developmental delay, gross motor delay, perinatal myositis, spinal subdural and subarachnoid arteriovenous malformation, and Erb's palsy. In 16 of 21 children (76%), the diagnosis was changed at 5 years of age or older. Studies based on population registers may need to take into account the possibility of misclassification, estimated to be at least 5.2% in this study. A complete clinical assessment at the time of diagnosis followed by regular reassessment would enable the clinician to exclude children with alternative diagnoses, which has important implications for clinical management and research based on cerebral palsy registers.

Association Between Prenatal Stress and Infantile Spasms: A Case-Control Study in China

Ning-Xiu Shang, Li-Ping Zou, Jian-Bo Zhao, Feng Zhang, Hua Li — 2010-03-01

The present study investigated a possible correlation between prenatal stress and the onset of infantile spasms. A total of 120 infants (60 cases, 30 positive controls, and 30 negative controls) went through routine etiologic screening. The Pregnant Woman Life Event Scale was used to investigate and evaluate the degree of prenatal stress of the mothers in the three infant groups. Etiologic analyses indicated no statistical difference between the infantile spasms group and the other epilepsy control group. There was a significant difference in the degree of prenatal stress among mothers of the three infant groups, with higher maternal prenatal stress levels in the infantile spasms group than in the other epilepsy group (positive control) or the normal control group (P < 0.05). Regression analysis with the dummy variable indicated that the onset risk of infantile spasms correspondingly increased with the degree of maternal prenatal stress for stress levels 1-3 (out of four levels) (P < 0.05). Within a certain range, the onset risk of infantile spasms increases with the degree of prenatal stress.

Cognitive Effects of Topiramate in Migraine Patients Aged 12 Through 17 Years

2010-03-01

Neuropsychologic data are presented from a randomized, double-blind, placebo-controlled, multicenter study with placebo, topiramate 50 mg/day, and topiramate 100 mg/day. The Cambridge Neuropsychological Test Automated Battery (CANTAB) and cognitive adverse events were used to evaluate neurocognitive effects of topiramate. Topiramate 100 mg/day vs placebo was associated with slight statistically significant score increases, indicating slowing, from baseline vs placebo in three CANTAB measures: five-choice reaction time (P = 0.028), pattern recognition memory mean correct latency (P = 0.027), and rapid visual information processing mean latency (P = 0.040). No other patterns related to topiramate treatment were observed in measurements of learning, memory, and visual information processing, except for potential improvement with topiramate 100 mg/day vs placebo in spatial span total errors (accuracy test) (P = 0.040). The most common cognitive and neuropsychiatric adverse events with a higher incidence in the topiramate 50 and 100 mg/day groups vs placebo were anorexia (9% and 11% vs 3%), insomnia (9% and 3% vs 3%), fatigue (6% and 9% vs 6%), and dizziness (6% and 9% vs 0%). Thus, topiramate 100 mg/day was associated with modest increases in psychomotor reaction times. Learning, memory, and executive function were unchanged. The tolerability profile, including cognitive adverse events, appeared to be acceptable.

Value of Brain Magnetic Resonance Imaging in Mitochondrial Respiratory Chain Disorders

2010-03-01

Mitochondrial respiratory chain (MRC) disorders have variable clinical manifestations which are mainly neurologic. Diagnosis in children is more complex than in adults because the classic phenotype, ragged red fibers, and mtDNA mutations are rarely seen in children. Moreover, clinical manifestations of disease in developing brains are less explicit. Although not specific, neuroimaging may be contributory to the diagnosis of these disorders in pediatric patients. Brain magnetic resonance images were reviewed for 133 pediatric patients investigated for a MRC disorder at a single center over a period of 10 years (1997-2006), in an attempt to identify distinctive neuroimaging features of MRC defects. Patients fit into four groups, according to the Bernier criteria: definite (63 cases), probable (53 cases), possible (7 cases) and unlikely diagnosis (10 cases). Brain atrophy (41 cases), supratentorial white matter lesions (14 cases), basal ganglia involvement (9 cases), and delayed myelination (9 cases) were the most frequent anomalies in the definite group, and 8 patients presented Leigh syndrome. Neuroimaging findings of the 63 children in the definite group were compared with the remainder and with those in the possible and unlikely groups. There were no significant differences in brain images between the groups analyzed, and therefore no distinctive brain imaging features were identified specific for MRC disorders.

Cardiac Arrhythmias and Ictal Events Within an Epilepsy Monitoring Unit

Shannon M. Standridge, Katherine D. Holland, Paul S. Horn — 2010-03-01

The aim of this study was to determine the incidence and describe the factors influencing ictal cardiac arrhythmias in children with epilepsy. A 2-year review within a pediatric epilepsy monitoring unit revealed 2066 electrographically confirmed seizures in 139 patients. Demographic, seizure, and cardiac variables were collected for each patient. Fisher's exact test, Wilcoxon rank-sum test, and Spearman's rank correlation coefficient were used to identify significant differences and associations at the seizure and patient levels. In 244 seizures meeting inclusion criteria, ictal cardiac arrhythmias were seen in 45% of the seizures (40% of the patients). The most common arrhythmia was benign respiratory sinus arrhythmia (78% of seizures with arrhythmias, 70% of patients with arrhythmias). Potentially serious arrhythmias included irregular variable arrhythmias, and abnormal QRS intervals were seen in 12% of all the patients. In seizures with ictal arrhythmias, 64% occurred in male patients (P = 0.016) and 78% occurred in white patients (P = 0.013). This study estimates the incidence of ictal arrhythmias within the pediatric population that need further medical attention and management.

Paralytic Syndromes in Children: Epidemiology and Relationship to Vaccination

2010-03-01

Acute flaccid paralysis is a standard outcome for detection of poliomyelitis globally and an ongoing potential vaccine-associated adverse event concern for polio, influenza, and meningococcal vaccines. No systematic population-based data on the epidemiologic and clinical features of this condition, or its potential association with immunization, have been reported from the United States. The present retrospective cohort study of acute flaccid paralysis in the Southern and Northern California Kaiser Permanente Health Care Plans was conducted using computerized diagnosis data and medical record review of potential cases among children aged 1 month to <15 years and diagnosed from January 1, 1992 through December 31, 1998. In all, 3297 potential cases were identified; of these, 2682 cases (81%) did not meet the case definition, and of the remaining 615 cases, 245 (7% of the total) were included. The incidence of disease was 1.4 per 100,000 children/year (95% confidence interval = 1.2–1.6); predicting approximately 844 children/year in the United States. Disease incidence did not vary with season or sex, varied inversely with age, and declined 28% during the study period. No cases of vaccine-associated acute flaccid paralysis were identified. In nonendemic countries, ongoing acute flaccid paralysis surveillance is often conducted, because of the risk of poliovirus importation, but this practice may be difficult to justify, given low disease incidence and breadth of clinical presentation.

Anti-N-Methyl-d-Aspartate Receptor Encephalitis: Early Treatment is Beneficial

2010-03-01

Anti-N-methyl-d-aspartate receptor antibody has been associated with a severe stereotypic form of subacute encephalitis, often found in women with ovarian teratoma. Reported here is the diagnosis of anti-N-methyl-d-aspartate receptor encephalitis in a 5-year-old girl who presented with subacute encephalopathy and movement disorder without evidence of malignancy. Early diagnosis and treatment with immune globulin and steroids resulted in near-complete recovery.

Persistent Focal Seizures After Cat Scratch Encephalopathy

Pue Farooque, Divya S. Khurana, Joseph J. Melvin — 2010-03-01

This report describes a 9-year-old child with status epilepticus and cat scratch disease. This patient's focal seizures and electroencephalographic changes persisted for 18 months after status epilepticus. This patient represents the third reported case of persistent focal seizures or electroencephalographic changes after status epilepticus secondary to cat scratch disease. This finding suggests that cat scratch encephalopathy may be a cause of localization-related epilepsy, and should be investigated when evaluating a patient with new-onset partial seizures.

Intracerebral Blood and MRS in Neonatal Nonketotic Hyperglycinemia

Brett J. Manley, Jenni Sokol, Jeanie L.Y. Cheong — 2010-03-01

Nonketotic hyperglycinemia is an inborn error of glycine metabolism leading to the accumulation of glycine in the brain. The neonatal form presents in the first days after birth with encephalopathy, seizures. and characteristic “hiccups.” Rapid progression can lead to intractable seizures, coma, and respiratory failure. The outcome is invariably poor, and many die before age 1 year. The diagnosis of nonketotic hyperglycinemia is traditionally based on the finding of a raised cerebrospinal fluid-to-plasma-glycine ratio. An elevated glycine peak, using long echo time proton magnetic resonance spectroscopy, is also specific to nonketotic hyperglycinemia. The presence of blood in a cerebrospinal fluid sample is known to render the glycine level uninterpretable. However, there have been no reports of intracerebral blood confounding the cerebral glycine detected on long echo time proton magnetic resonance spectroscopy. We report on an infant who presented with neonatal encephalopathy and imaging findings consistent with hypoxic-ischemic encephalopathy, as well as intracerebral hemorrhage and an abnormal glycine peak on spectroscopy. The source of the abnormal glycine on long echo time proton magnetic resonance spectroscopy was intracerebral blood, highlighting an important confounder in the interpretation of long echo time proton magnetic resonance spectroscopy in suspected nonketotic hyperglycinemia.

Mucolipidosis Type IV: A Subtle Pediatric Neurodegenerative Disorder

Joseph S. Geer, Steve A. Skinner, Ehud Goldin, Kenton R. Holden — 2010-03-01

The mucolipidoses are a heterogeneous group of autosomal recessive neurodegenerative lysosomal storage disorders. Mucolipidosis type IV is rare; it is seen predominantly in the Ashkenazi Jewish population and usually presents with global neurodevelopmental delays in infancy, subtle corneal opacifications or clouding, and very slowly progressive neurodegeneration over many years. Elevation of serum gastrin is reported; findings from x-rays of bone and joints and lysosomal studies are normal. Reported here are two cases of mucolipidosis type IV in children not of Ashkenazi Jewish origin who presented during infancy with nonspecific global psychomotor delays, generalized hypotonia, and mild corneal abnormalities, but remained undiagnosed for years. A rare gene mutation in MCOLN1 was confirmed in one of the two patients, in addition to abnormal serum gastrin levels. More striking was the length of time that these children eluded detection of their final diagnosis.

A Novel Mutation in the SCO2 Gene in a Neonate With Early-Onset Cardioencephalomyopathy

2010-03-01

Mutations in the SCO2 gene [SCO cytochrome oxidase deficient homolog 2 (yeast)] causing cytochrome c oxidase deficiency have been reported in at least in 26 patients with fatal infantile cardioencephalomyopathy. Mutation 1541G > A affecting protein stability is associated with the majority of cases, and the other 11 described mutations have more serious deleterious structural consequences for the protein product. Reported here is a novel case caused by compound heterozygosity of SCO2. The child presented at the age of 3 weeks with failure-to-thrive, muscular hypotonia, hypertrophic cardiomyopathy, and lactic acidemia. Leigh syndrome was diagnosed based on magnetic resonance imaging findings. Immunohistochemical and enzymatic investigations on muscle indicated totally absent cytochrome c oxidase activity. Both parents had mild mental retardation. Sequence analysis in the patient and in his parents revealed heterozygous mutation c.418G > A in exon 2 inherited from the father and maternally inherited heterozygous insertion of 19bp at position 17 in the coding region of the SCO2 gene. Respiratory chain enzyme activity measurements indicated normal activity in both parents, although the mother's cytochrome c oxidase activity was lower. This gene may be involved in the etiology of the mother's mental retardation.

Grade IV Fetal Intracranial Hemorrhage With Good Cognitive Function

Erica T. Ting, Meredith R. Golomb — 2010-03-01

Fewer than 200 cases of prenatally diagnosed magnetic resonance imaging-confirmed fetal intracranial hemorrhage have been reported. Children surviving grade IV fetal intracranial hemorrhage usually manifest severe impairments, including mental retardation. We report on a child with a grade IV intracranial hemorrhage diagnosed by in utero ultrasound at 28 weeks of gestation, and confirmed by fetal magnetic resonance imaging at 29 weeks of gestation. At age 27 months, she has a ventriculoperitoneal shunt and exhibits hemiplegic cerebral palsy, but without seizures, and with normal cognitive function and excellent verbal ability. We discuss how perinatal care may have contributed to her good outcome.

Diaphragmatic Paralysis Associated With Neonatal Brachial Plexus Palsy

Michyla Bowerson, Virginia S. Nelson, Lynda J.-S. Yang — 2010-03-01

Phrenic nerve palsy can occur in the context of neonatal brachial plexus palsy, yet neither outcomes nor definitive treatment guidelines have been established. Diaphragmatic paralysis alone in the newborn results in significant respiratory sequelae and failure to thrive. Reviewing the available literature revealed little information about the incidence of phrenic nerve palsy associated with neonatal brachial plexus palsy, or whether outcomes are associated with the severity of the brachial plexus palsy. Of patients with brachial plexus palsy evaluated during 2005-2009 (n = 166) at our institution, a minority (2.4%; n = 4) had clinically significant diaphragmatic palsy. Of these, a majority (75%; n = 3) manifested respiratory complications sufficient to warrant diaphragmatic plication. The severity of brachial plexus palsy failed to correlate with severity of respiratory consequences. None of the patients underwent nerve repair or reconstruction. We suggest that diaphragmatic paralysis should not be overlooked during a brachial plexus examination, and diaphragmatic paralysis in the very young may require aggressive intervention before the treatment of brachial plexus palsy.

Rolandic Epilepsy

Orvar Eeg-Olofsson — 2010-03-01

To the Editor: Watemberg et al. described five cases with epileptic negative myoclonus as the presenting seizure type in rolandic epilepsy. Rolandic epilepsy occurs in about 15-17% of all childhood epilepsies. A higher prevalence indicates that other disorders, mainly with rolandic discharges in electroencephalograms, but without the typical clinical picture, were included, e.g., syncope, breath-holding spells, vertigo, and behavioral disturbances. The authors wrote in their Abstract that epileptic negative myoclonus (atonic seizures) “has been associated largely with rolandic epilepsy.” This is not correct, and indicates a wrong diagnosis. Unfortunately, rolandic epilepsy has also been diagnosed in children with rolandic discharges and other seizure manifestations as myoclonia, absences, and atonic seizures. A diagnosis of rolandic epilepsy must be accurately addressed, to avoid misconceptions . The typical semiology is very distinct and clearly defined, in contrast with what can be called “atypical semiology” .

Response

Nathan Watemberg, Uri Kramer — 2010-03-01

Dr. Eeg-Olofsson addresses an issue important to physicians caring for pediatric patients with epilepsy, and in particular those children whose electroencephalogram recordings depict centrotemporal spikes. This issue refers to the clinical question of whether a “classic” form of rolandic epilepsy exists, along with atypical presentations of the disease in a continuum , or whether the clinical variants represent different diseases related to specific, though as yet undefined, genetic etiologies, or to anatomic malformations in some cases.

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2010-03-01

Instructions to Contributors

2010-03-01

Pediatric Neurology

Creatine and Creatine Deficiency Syndromes: Biochemical and Clinical Aspects

Correlation Between Magnetic Resonance Imaging and Histopathologic Grades in Rasmussen Syndrome

CP or Not CP? A Review of Diagnoses in a Cerebral Palsy Register

Association Between Prenatal Stress and Infantile Spasms: A Case-Control Study in China

Cognitive Effects of Topiramate in Migraine Patients Aged 12 Through 17 Years

Value of Brain Magnetic Resonance Imaging in Mitochondrial Respiratory Chain Disorders

Cardiac Arrhythmias and Ictal Events Within an Epilepsy Monitoring Unit

Paralytic Syndromes in Children: Epidemiology and Relationship to Vaccination

Anti-N-Methyl-d-Aspartate Receptor Encephalitis: Early Treatment is Beneficial

Persistent Focal Seizures After Cat Scratch Encephalopathy

Intracerebral Blood and MRS in Neonatal Nonketotic Hyperglycinemia

Mucolipidosis Type IV: A Subtle Pediatric Neurodegenerative Disorder

A Novel Mutation in the SCO2 Gene in a Neonate With Early-Onset Cardioencephalomyopathy

Grade IV Fetal Intracranial Hemorrhage With Good Cognitive Function

Diaphragmatic Paralysis Associated With Neonatal Brachial Plexus Palsy

Rolandic Epilepsy

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Instructions to Contributors