Journal of Child Neurology recent issues

Child Neurologists Should Be Interested In Brain Tumors!

Brumback, R. A. — Mon, 19 Oct 2009 13:48:07 PDT

Introduction to a Special Issue on Pediatric Neuro-Oncology

Fangusaro, J., Chi, S. — Mon, 19 Oct 2009 13:48:07 PDT

Neuroimaging of Pediatric Brain Tumors: From Basic to Advanced Magnetic Resonance Imaging (MRI)

Panigrahy, A., Bluml, S. — Mon, 19 Oct 2009 13:48:07 PDT

In this review, the basic magnetic resonance concepts used in the imaging approach of a pediatric brain tumor are described with respect to different factors including understanding the significance of the patient’s age. Also discussed are other factors directly related to the magnetic resonance scan itself including evaluating the location of the tumor, determining if the lesion is extra-axial or intra-axial, and evaluating the contrast characteristics of the lesion. Of note, there are key imaging features of pediatric brain tumors, which can give information about the cellularity of the lesion, which can then be confirmed with advanced magnetic resonance imaging (MRI) techniques. The second part of this review will provide an overview of the major advanced MRI techniques used in pediatric imaging, particularly, magnetic resonance diffusion, magnetic resonance spectroscopy, and magnetic resonance perfusion. The last part of the review will provide more specific information about the use of advanced magnetic resonance techniques in the evaluation of pediatric brain tumors.

The Evolving Role of Surgery in the Management of Pediatric Brain Tumors

Souweidane, M. M. — Mon, 19 Oct 2009 13:48:07 PDT

Surgery is an integral component and typically the first line of therapy for children with central nervous system tumors. The outcome with regard to surgical morbidity and disease control can be greatly influenced by the initial care that these children receive. Conventional aims of neurosurgery including tumor removal, management of hydrocephalus, and diagnostic sampling have been radically modified with innovative technologies such as navigational guidance, functional mapping, endoscopic surgery, second-look surgery, and physiologic imaging. The overall role of the pediatric neurosurgeon in caring for children with nervous system tumors is also expanding to include unconventional responsibilities including disease staging, tissue procurement, and drug delivery. It is thus anticipated that the pediatric neurosurgeon will be increasingly relied upon for oncologic therapeutic strategies and should thus remain abreast of forthcoming information and technologies.

Histology and Molecular Pathology of Pediatric Brain Tumors

Pfister, S., Hartmann, C., Korshunov, A. — Mon, 19 Oct 2009 13:48:07 PDT

In recent years, brain tumors have become the single most frequent cause of cancer-related mortality in children, although their frequency is approximately 50% less than leukemia. According to the classification of the World Health Organization, histopathological diagnosis is of paramount importance for clinicians to choose the most appropriate treatment option and tailor treatment intensity to disease risk. However, histopathological assessment is often difficult, and adding molecular information to classic neuropathological analyses may help ensure diagnostic accuracy, improve risk stratification of patients within a given tumor entity, and help in identifying novel therapeutic targets for an individualized treatment approach. Therefore, this review focuses both on established histopathology as well as on molecular features in the most important brain tumors in children.

Radiation Therapy for Pediatric Central Nervous System Tumors

Hoffman, K. E., Yock, T. I. — Mon, 19 Oct 2009 13:48:07 PDT

Radiation therapy is an important component of treatment of many pediatric central nervous system tumors. The radiation treatment target is determined by tumor histology, extent of disease, anticipated pattern of spread, and expected pattern of failure. Children cured of their tumors live to experience the long-term sequelae of radiation treatment, including developmental, neurocognitive, neuroendocrine, and hearing late effects. The development of more conformal radiation techniques has decreased inadvertent radiation dose to normal tissues and should decrease long-term treatment sequelae that are the result of normal tissue radiation. Intensity-modulated radiation therapy improves treatment conformity and decreases high dose to nearby normal tissues; however, it delivers a larger volume of low- and intermediate-dose radiation. Proton radiation eliminates exit dose to normal tissues, thereby eliminating approximately 50% of unnecessary radiation to normal tissues. The long-term clinical benefits of proton radiation in the pediatric population are just beginning to be reported in the literature.

Pediatric Low-Grade Gliomas

Sievert, A. J., Fisher, M. J. — Mon, 19 Oct 2009 13:48:07 PDT

Pediatric low-grade gliomas encompass a heterogeneous set of tumors of different histologies. Cerebellar pilocytic astrocytomas occur most frequently followed by supratentorial diffuse fibrillary astrocytomas. Recent research has implicated activation of the RAS/RAF/MEK pathway in tumorigenesis of these tumors. Surgery is the mainstay of therapy. Overall survival rates for patients whose tumors are completely resected are 90% or greater, 10 years from diagnosis. Conversely, most optic pathway/hypothalamic, deep midline, and brain stem gliomas have minimal potential for resection; these tumors can be difficult to treat and deserve special attention. Combination chemotherapy is currently recommended as front-line adjuvant treatment for progressive or recurrent tumors. Second-line radiotherapy can also improve overall survival but is associated with more frequent and significant neurocognitive, endocrine, and other long-term toxicities.

Pediatric High-Grade Gliomas and Diffuse Intrinsic Pontine Gliomas

Fangusaro, J. — Mon, 19 Oct 2009 13:48:07 PDT

Pediatric high-grade gliomas represent approximately 10% of all pediatric brain tumors. Similar to adult high-grade gliomas, they behave very aggressively, and these children have a very poor prognosis despite a variety of therapies that include chemotherapy and radiotherapy. In this review, we present an overview of both pediatric high-grade gliomas and diffuse intrinsic pontine gliomas with a focus on their epidemiology, etiology, presentation, prognostic factors, biology, treatment modalities, outcomes, and future research directions.

Medulloblastoma

Dhall, G. — Mon, 19 Oct 2009 13:48:07 PDT

Medulloblastoma is the most common malignant brain tumor in children. Patients with medulloblastoma are stratified into ‘‘standard’’ and ‘‘high’’ risk categories based on age at diagnosis, degree of surgical resection, and disease spread. In children older than 3 years of age, the long-term survival can be achieved in approximately 85% of standard risk patients and 70% of high risk patients with a combination of chemotherapy and irradiation. Younger children, particularly infants, are at a significantly higher risk of side-effects of treatment. Despite tremendous progress in the field of molecular biology of medulloblastoma, much remains to be achieved in understanding the pathogenesis, critical pathways responsible for medulloblastoma, and molecular risk stratification, and in devising treatment strategies with even better survival and less long-term sequelae.

Ependymoma: An Update

Zacharoulis, S., Moreno, L. — Mon, 19 Oct 2009 13:48:07 PDT

The authors provide an update on most issues related to biology, diagnosis, and treatment of children with ependymoma based on a literature review. Ependymoma is the third most common brain tumor in children and overall survival ranges from 24% to 75% at 5 years. The extent of surgical resection remains the principal risk factor that clearly influences outcome. The influence of age, location, grade, or stage has proved to be more controversial. Current standard therapy includes surgical resection and radiotherapy. Chemotherapy has a role in infants to avoid/delay radiotherapy and can be helpful to improve resectability. About half of patients will experience relapse, and outcome is dismal. New radiation modalities, reirradiation, chemotherapy, or targeted agents have been tested with promising results. Results of multi-institutional clinical trials are awaited to determine the best first-line treatment, while results of early phase I/ II trials will explore directed therapies based on new biologic factors.

Central Nervous System Germ Cell Tumors: Classification, Clinical Features, and Treatment With a Historical Overview

Fujimaki, T. — Mon, 19 Oct 2009 13:48:07 PDT

Central nervous system germ cell tumors are neoplasms that affect children and young adults. They are subclassified into germinoma and nongerminomatous germ cell tumors. The latter include teratoma (mature teratoma, immature teratoma, teratoma with malignant transformation), choriocarcinoma, embryonal carcinoma, yolk sac tumors, and mixtures of these entities. Germinoma with syncytiotrophoblastic giant cells is a variant of germinoma. Germinomas respond well to radiation therapy, but late sequelae due to irradiation have been reported. The results of radiation treatment alone for nongerminomatous germ cell tumor are not satisfactory. Combination radiochemotherapy has been applied, and this yields a good outcome with less toxicity for germinomas and better survival of nongerminomatous germ cell tumors. This article also discusses other issues, including the controversy regarding spinal irradiation and the treatment of recurrent disease.

Neurologic Sequelae of Brain Tumors in Children

Ullrich, N. J. — Mon, 19 Oct 2009 13:48:07 PDT

Neurologic signs and symptoms are often the initial presenting features of a primary brain tumor and may also emerge during the course of therapy or as late effects of the tumor and its treatment. Variables that influence the development of such neurologic complications include the type, size, and location of the tumor, the patient’s age at diagnosis, and the treatment modalities used. Heightened surveillance and improved neuroimaging modalities have been instrumental in detecting and addressing such complications, which are often not appreciated until many years after completion of therapy. As current brain tumor therapies are continually refined and newer targeted therapies are developed, it will be important for future cooperative group studies to include systematic assessments to determine the incidence of neurologic complications and to provide a framework for the development of novel strategies for prevention and intervention.

Late Effects of Therapy for Pediatric Brain Tumor Survivors

Turner, C. D., Rey-Casserly, C., Liptak, C. C., Chordas, C. — Mon, 19 Oct 2009 13:48:07 PDT

Approximately 2 of every 3 of all pediatric patients with brain tumors will be long-term survivors. However, there is a steep cost for pediatric brain tumor survivors, and the group as a whole faces significantly more late effects than many other survivors of pediatric cancers. Most of these effects can be attributed to direct neurologic damage to the developing brain caused by the tumor and its removal, the long-term toxicity of chemotherapy, or the effects of irradiation on the central nervous system. The late effects experienced by childhood brain tumor survivors involve multiple domains. This article will review the significant late effects that occur within the medical, neurocognitive, psychosocial, and economic domains of the survivorship experience. We conclude by discussing how the late effects in different domains often coexist and can create a complex set of obstacles that pose significant challenges for a survivor of a pediatric brain tumor on a daily basis.

Diagnosis and Treatment of Childhood Brain Tumors: Current Perspectives

Pollack, I. F. — Mon, 19 Oct 2009 13:48:07 PDT

JCN Calendar of Events

Mon, 19 Oct 2009 13:48:07 PDT

Pediatric Constraint-Induced Movement Therapy Is Associated With Increased Contralateral Cortical Activity on Functional Magnetic Resonance Imaging

Sutcliffe, T. L., Logan, W. J., Fehlings, D. L. — Mon, 05 Oct 2009 16:39:18 PDT

The mechanism behind constraint-induced movement therapy (constraint therapy) success is unknown. Study objectives were to evaluate cortical change after modified constraint therapy and explore a novel approach to quantify developmental disregard. Five participants underwent modified constraint therapy. Functional magnetic resonance imaging (MRI) and clinical measures were done pretreatment and posttreatment. Developmental disregard indices were calculated. Four participants showed clinical improvement posttreatment. Functional MRI laterality indices were variable pretreatment and exclusively contralateral among participants posttreatment. The disregard index range was —12.9 to 62.6 among participants. Disregard indices were correlated with change scores after treatment on the Pediatric Motor Activity Log amount of use domain (r = .93, P = .02), Assisting Hand Assessment (r = .93, P = .02), and grip strength (r = .92, P = .03). Study results suggest that a shift to or persistence of contralateral cortical activity for affected hand movement is important for constraint therapy mechanism of action; and developmental disregard may be a predictor of positive response to treatment.

Neurologic Outcome in Neonatal Temporal Lobe Hemorrhagic Venous Infarcts

Slaughter, L., Egelhoff, J., Balmakund, T. — Mon, 05 Oct 2009 16:39:18 PDT

Consequences of neonatal cerebral venous infarct can be severe. However, we have identified a series of neonates with unilateral temporal lobe infarcts, suspected to be secondary to superficial cortical venous thrombosis, who have had relatively normal outcomes. Medical records were reviewed retrospectively. History, relevant studies, and outcomes for 7 patients are described. Most patients presented with neonatal seizures. Neuroimaging showed unilateral temporal lobe hemorrhage and surrounding ischemic change, which was initially attributed to thrombosis of the vein of Labbe; however, magnetic resonance venogram findings suggest that thrombosis of other superficial temporal lobe veins may also be involved. Seizure control was achieved in all cases. Development and neurologic examination at follow-up were usually normal. We conclude that neonatal temporal lobe hemorrhagic infarct secondary to suspected superficial temporal venous thrombosis appears to have a good clinical outcome. This is surprising, given the dramatic imaging and clinical presentations.

A Profile of Adolescent-Onset Epilepsy

Simard-Tremblay, E., Shevell, M. — Mon, 05 Oct 2009 16:39:18 PDT

To describe the profile of children with adolescent-onset epilepsy and to determine factors predictive of outcome. A database was searched for all patients with a first seizure between the age of 12 and 16 years. Sixty-five adolescents met inclusion criteria. Ten patients needed at least two medications to control seizures, 36 remained on medication at their last visit and 12 patients had at least 1 seizure in the year preceding. A diagnosis of juvenile myoclonic epilepsy, the presence of coexisting seizures, coexisting myoclonic seizures, age ≤14.5 years at initial diagnosis, and the presence of compliance issues were significantly associated with the need for medication at last visit. Female gender and the presence of compliance issues were associated with the occurrence of at least 1 seizure in the year preceding last visit. A good outcome for adolescent-onset epilepsy can generally be expected in the short term.

Low Detection Rate of Craniocervical Arterial Dissection in Children Using Time-of-Flight Magnetic Resonance Angiography: Causes and Strategies to Improve Diagnosis

Tan, M. A., deVeber, G., Kirton, A., Vidarsson, L., MacGregor, D., Shroff, M. — Mon, 05 Oct 2009 16:39:18 PDT

Craniocervical arterial dissection is a frequent cause of childhood arterial ischemic stroke requiring prompt diagnosis and treatment. However, there is no universal guideline for diagnostic cerebrovascular imaging in children. We assessed the role of time-of-flight magnetic resonance angiography in diagnosing craniocervical arterial dissection. We included children (1 month to 18 years) with craniocervical arterial dissection and ischemic stroke from January 1998 to June 2007. Institutional protocol required magnetic resonance imaging (MRI)/ magnetic resonance angiography for all ischemic stroke cases and conventional cerebral angiography if magnetic resonance angiography showed any arteriopathy. Among 233 ischemic stroke cases, craniocervical arterial dissection was diagnosed in 13 patients (5.6%; 10 males), with a mean age of 7.5 years. Initial time-of-flight magnetic resonance angiography missed dissection in 8 patients (61.5%) because the neck vessels were not scanned (n = 2), of suboptimal technique (n = 3), and of diagnostic error (n = 3). T1 fat-saturated MRI and contrast-enhanced magnetic resonance angiography were not performed in 12 patients. If suspicion for arterial dissection is high, T1 fat-saturated neck imaging and contrast-enhanced magnetic resonance angiography should be considered to maximize detection.

Association of Y Chromosome Haplotypes With Autism

Serajee, F. J., Mahbubul Huq, A.H.M. — Mon, 05 Oct 2009 16:39:18 PDT

There is significant male excess in autism. In this study, we investigated a possible Y chromosome effect by haplotype analysis. We investigated 12 single-nucleotide polymorphisms in Y-linked neuroligin 4, transducin β-like 1, and eukaryotic translation initiation factor 1a genes in 146 autistic participants and 102 control participants of European American origin. The set of 12 single-nucleotide polymorphisms defined 9 Y chromosome haplotypes in autistic and control participants. Although the 2 most frequent haplotypes were equally distributed in the autistic and control participants, some haplotypes were overrepresented or underrepresented in autistic participants. The distribution of haplotypes between the autistic and control groups, as determined by Monte Carlo tests with Clump software, was significantly different (P = .0001 with 100 000 simulations). Our results are suggestive of a Y chromosome effect in autism.

The T Allele of the 677C>T Polymorphism of Methylenetetrahydrofolate Reductase Gene is Associated With an Increased Risk of Ischemic Stroke in Polish Children

Mon, 05 Oct 2009 16:39:19 PDT

Ischemic stroke is a very rare and multifactorial disease in children. The aim of the study was to analyze the relationship between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and stroke in Polish children and to observe whether there is any significant transmission of MTHFR alleles from heterozygous parents to their affected offspring. We analyzed 64 patients with stroke, 122 parents, and 59 healthy children. The MTHFR polymorphism was genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism. The T allele was more frequent in the stroke group (38%) than in controls (25%, P = .029, odds ratio = 1.84). We also found higher frequency of T allele in male patients compared to male controls (46% vs. 25%, P = .009, odds ratio = 2.53). The number of T allele carriers was again more prevalent in boys with stroke (71%) than in healthy boys (45%, P = .023, odds ratio = 3.09). The T allele was significantly transmitted in male patients (P < .019). We conclude that the MTHFR 677C>T polymorphism may be considered as a genetic risk factor of childhood stroke, especially in boys.

Branched Chain Amino Acids as Adjunctive Therapy to Ketogenic Diet in Epilepsy: Pilot Study and Hypothesis

Mon, 05 Oct 2009 16:39:19 PDT

A pilot prospective follow-up study of the role of the branched chain amino acids as additional therapy to the ketogenic diet was carried out in 17 children, aged between 2 and 7 years, with refractory epilepsy. All of these patients were on the ketogenic diet; none of them was seizure free, while only 13 had more or less benefited from the diet. The addition of branched chain amino acids induced a 100% seizure reduction in 3 patients, while a 50% to 90% reduction was noticed in 5. Moreover, in all of the patients, no reduction in ketosis was recorded despite the change in the fat-to-protein ratio from 4:1 to 2.5:1. Although our data are preliminary, we suggest that branched chain amino acids may increase the effectiveness of the ketogenic diet and the diet could be more easily tolerated by the patients because of the change in the ratio of fat to protein.

Neural Correlates of Developmental Coordination Disorder: A Review of Hypotheses

Zwicker, J. G., Missiuna, C., Boyd, L. A. — Mon, 05 Oct 2009 16:39:19 PDT

Affecting 5% to 6% of school-age children, developmental coordination disorder is characterized by a marked impairment of motor coordination that significantly interferes with activities of daily living and academic achievement. Little is known about the etiology of developmental coordination disorder, but the disorder often coexists with attention-deficit hyperactivity disorder (ADHD), speech/language impairment, and/or reading disability. This comprehensive review examines the literature supporting or refuting hypothesized neural correlates of developmental coordination disorder and suggests directions for future research. Potential sources of neuropathology include the cerebellum, parietal lobe, corpus callosum, and basal ganglia. Comorbidities and deficits associated with developmental coordination disorder are highly suggestive of cerebellar dysfunction; yet, given the heterogeneity of this disorder, it is likely that the cerebellum is not the only neural correlate. Neuroimaging studies and behavioral investigations of learning-related change in motor behavior are the next critical step in enhancing our understanding of developmental coordination disorder.

Attention-Deficit Hyperactivity Disorder (ADHD) and Tuberous Sclerosis Complex

D'Agati, E., Moavero, R., Cerminara, C., Curatolo, P. — Mon, 05 Oct 2009 16:39:19 PDT

The neurobiological basis of attention-deficit hyperactivity disorder (ADHD) in tuberous sclerosis complex is still largely unknown. Cortical tubers may disrupt several brain networks that control different types of attention. Frontal lobe dysfunction due to seizures or epileptiform electroencephalographic discharges may perturb the development of brain systems that underpin attentional and hyperactive functions during a critical early stage of brain maturation. Comorbidity of attention-deficit hyperactivity disorder (ADHD) with mental retardation and autism spectrum disorders is frequent in children with tuberous sclerosis. Attention-deficit hyperactivity disorder (ADHD) may also reflect a direct effect of the abnormal genetic program. Treatment of children with tuberous sclerosis complex with combined symptoms of attention-deficit hyperactivity disorder (ADHD) and epilepsy may represent a challenge for clinicians, because antiepileptic therapy and drugs used to treat attention-deficit hyperactivity disorder (ADHD) may aggravate the clinical picture of each other.

Permanent Visual Loss Due to Dietary Vitamin A Deficiency in an Autistic Adolescent

McAbee, G. N., Prieto, D. M., Kirby, J., Santilli, A. M., Setty, R. — Mon, 05 Oct 2009 16:39:19 PDT

Children with autism often have restrictive diets. Here, we report an adolescent with autism who developed dietary vitamin A deficiency because of a restrictive diet. Despite supplementation with vitamin A, some of the visual loss was permanent with optic atrophy. Children with autism who have restrictive diets may need periodic serum vitamin levels assessed.

Neuroimaging Patterns of Central Nervous System Metastases in Neuroblastoma: Report of 2 Recent Cases and Literature Review

Balaji, R., Ramachandran, K., Kusumakumari, P. — Mon, 05 Oct 2009 16:39:19 PDT

The authors describe imaging patterns of intracranial metastases in 2 children with grade 4 neuroblastoma. Central nervous system metastases from neuroblastoma are extremely rare and may involve the cerebral parenchyma, leptomeninges, or dura. Cerebral parenchymal metastases can be cystic with mural nodules or solid with hemorrhagic elements. The first patient in our study had multiple cystic parenchymal metastases with calcific mural nodules, while the second patient developed solid hemorrhagic parenchymal metastatic lesions along with extensive leptomeningeal and dural deposits. Central nervous system involvement in both patients occurred within a time span ranging from 12 to 14 months from the time of initial diagnosis.

Is Hyperventilation an Effective ''Activating'' Procedure in Routine Clinical EEG Studies in Children?

Raybarman, C. — Mon, 05 Oct 2009 16:39:19 PDT

Electroencephalography (EEG) records of consecutive 275 children (ages 3-18 years; average 11 years; 34.5% females), with generalized epilepsy, consistent with epileptiform discharges in baseline EEG, who underwent 5 minutes of voluntary hyperventilation during standard EEG recordings were reviewed in this study to determine the actual value of the voluntary hyperventilation in routine clinical EEG in provoking epileptiform EEG abnormalities. Of the 275 EEG records, only in 11.6% hyperventilation revealed increased interictal epileptiform discharges as evidenced by increase in frequency during hyperventilation when compared with the baseline EEG and in 0.7% ictal epileptiform discharges without clinical seizure. None of the 275 children elicited clinical seizure during hyperventilation. The value of voluntary hyperventilation as an ‘‘activating’’ procedure in routine clinical EEG studies even in children with generalized epilepsy was questioned in this study.

SURF-1 Gene Mutation Associated With Leukoencephalopathy in a 2-Year-Old

Timothy, J., Geller, T. — Mon, 05 Oct 2009 16:39:19 PDT

Mutations in the nuclear SURF-1 gene lead directly to cytochrome-c oxidase deficiency, the most common respiratory chain defect in Leigh syndrome, a neurodegenerative mitochondrial disease involving the deep gray matter and brain stem. We describe the second documented case in the literature to have a SURF-1 mutation presenting with diffuse leukodystrophy, adding to the growing number of cases of mitochondrial syndromes presenting with white matter disease. We examine magnetic resonance imaging (MRI) findings, which suggest that high-grade cytotoxic edema on diffusion-weighted imaging may be a helpful diagnostic feature in differentiating mitochondrial leukodystrophy from other, more common leukodystrophies. We show how MRI white matter findings may progress to include the brain stem, suggesting that a leukodystrophy due to respiratory chain defects can precede more classic Leigh syndrome deep gray matter radiographic findings.

Inflammatory Myofibroblastic Tumor Involving Lung and Brain in a 10-Year-Old Boy: A Case Report

Mon, 05 Oct 2009 16:39:19 PDT

Inflammatory myofibroblastic tumors are rare tumors of unknown etiology, composed of proliferating myofibroblasts and accompanying lymphoplasmacytic infiltration. A 10-year-old boy who developed inflammatory myofibroblastic tumors in the lung as well as the brain is described. Surgery and radiation therapy were not feasible. The authors review the current literature and treatment options.

Depressive Episode With Catatonic Features in a Case of Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)

Ju Seok Ryu, , Sook Joung Lee, , In Young Sung, , Tae Sung Ko, , Han Ik Yoo, — Mon, 05 Oct 2009 16:39:19 PDT

Three months previously, a 17-year-old girl had complained of right-hand side hemiparesis, and her brain magnetic resonance imaging (MRI) showed a signal change in the left temporoparietooccipital area. The 3243A>G mutation was found in mitochondrial DNA. She was diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and was prescribed dichloroacetic acid to treat lactic acidosis. Her health improved. Two months later, she developed drowsiness and generalized weakness. A New lesion was not found on brain MRI, and electrodiagnostic findings were compatible with acute motor sensory axonal neuropathy. Her negative symptoms, such as depressed mood, loss of interest in activities, psychomotor retardation, and hypersomnia, were aggravated. She was prescribed antidepressants and psychostimulants by a psychiatrist after diagnosis of severe depression episode with catatonic features. One month later, her catatonic condition had improved with medication. Our experience shows that psychiatric diagnostic evaluation of abruptly regressed neurologic and clinical features is important, even in a patient with devastating underlying disease.

Mutations in VLDLR as a Cause for Autosomal Recessive Cerebellar Ataxia With Mental Retardation (Dysequilibrium Syndrome)

Mon, 05 Oct 2009 16:39:19 PDT

Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. Here, we report the first patient heterozygous for 2 novel mutations in VLDLR. An 18-month-old girl presented with significant hypotonia, global developmental delay, and truncal and peripheral ataxia. Magnetic resonance imaging of the brain demonstrated hypoplasia of the inferior cerebellar vermis and hemispheres, small pons, and a simplified cortical sulcation pattern. Sequence analysis of the VLDLR gene identified a nonsense and missense mutation. Six mutations in VLDLR have now been identified in 5 families with a phenotype characterized by moderate-to-profound mental retardation, delayed ambulation, truncal and peripheral ataxia, and occasional seizures. Neuroanatomically, the loss-of-function effect of the different mutations is indistinguishable. VLDLR-associated cerebellar hypoplasia is emerging as a panethnic, clinically, and molecularly well-defined genetic syndrome.

15q11.2-13 Duplication, Mitochondrial Dysfunction, and Developmental Disorders

Frye, R. E. — Mon, 05 Oct 2009 16:39:19 PDT

Multiple developmental phenotypes have been associated with duplication in the 15q11-13 region. Recently, the 15q11-13 duplication has been associated with a distinct pattern of mitochondrial abnormalities that includes a deficiency in complex III. This report describes the third case with this duplication and a similar pattern of mitochondrial dysfunction. Genetic studies performed on this case rule out the previously suggested role of the UBE3A gene. It is proposed that interactions of the duplicated SNRPN gene with nuclear respiratory factor 1 could result in destabilization of mitochondrial complex formation and activation of apoptosis under metabolic stress, resulting in the pattern of abnormalities found in the current and previously reported cases. In light of the frequency of this duplication in children with developmental dishabilles, the wider implication of the association between this duplication and mitochondrial dysfunction needs to be considered.

Conflict of Interest in Peer-Reviewed Medical Journals: A Policy Statement of the World Association of Medical Editors (WAME)

Mon, 05 Oct 2009 16:39:19 PDT

Correspondence on ''Effect of Acupuncture on the Brain in Children With Spastic Cerebral Palsy Using Functional Neuroimaging (fMRI)''

Yiu Ming, M. W. — Mon, 05 Oct 2009 16:39:19 PDT

Response to Correspondence on ''Effect of Acupuncture on the Brain in Children With Spastic Cerebral Palsy Using Functional Neuroimaging (fMRI)''

Zou, L.-P., Wu, Y., Jin, Z. — Mon, 05 Oct 2009 16:39:19 PDT

JCN Calendar of Events

Mon, 05 Oct 2009 16:39:19 PDT

Injury to the Preterm Brain and Cerebral Palsy

Maria, B. L. — Thu, 10 Sep 2009 09:49:10 PDT

Injury to the Preterm Brain and Cerebral Palsy: Clinical Aspects, Molecular Mechanisms, Unanswered Questions, and Future Research Directions

Thu, 10 Sep 2009 09:49:10 PDT

Cerebral palsy will affect nearly 10% of the 60 000 very low-birth-weight infants born in the United States in the next year, and an even greater percentage will display some form of permanent neurological impairment resulting from injury to the preterm brain. The 2008 Neurobiology of Disease in Children Symposium, held in conjunction with the 37th annual meeting of the Child Neurology Society, aimed to define current knowledge and to develop specific aims for future clinical, translational, and fundamental science. A complex interplay of both destructive and developmental forces is responsible for injury to the preterm brain. Advances in imaging and histology have implicated a variety of cell types, though preoligodendrocyte injury remains the focus. Research into different mechanisms of injury is facilitating new neuroprotective and rehabilitative interventions. A cooperative effort is necessary to translate basic research findings into clinically effective therapies and better care for these children.

Cerebellum of the Premature Infant: Rapidly Developing, Vulnerable, Clinically Important

Volpe, J. J. — Thu, 10 Sep 2009 09:49:10 PDT

Brain abnormality in surviving premature infants is associated with an enormous amount of neurodevelopmental disability, manifested principally by cognitive, behavioral, attentional, and socialization deficits, most commonly with only relatively modest motor deficits. The most recognized contributing neuropathology is cerebral white matter injury. The thesis of this review is that acquired cerebellar abnormality is a relatively less recognized but likely important cause of neurodevelopmental disability in small premature infants. The cerebellar disease may be primarily destructive (eg, hemorrhage, infarction) or primarily underdevelopment. The latter appears to be especially common and relates to a particular vulnerability of the cerebellum of the small premature infant. Central to this vulnerability are the extraordinarily rapid and complex developmental events occurring in the cerebellum. The disturbance of development can be caused either by direct adverse effects on the cerebellum, especially the distinctive transient external granular layer, or by indirect remote trans-synaptic effects. This review describes the fascinating details of cerebellar development, with an emphasis on events in the premature period, the major types of cerebellar abnormality acquired during the premature period, their likely mechanisms of occurrence, and new insights into the relation of cerebellar disease in early life to subsequent cognitive/behavioral/attentional/socialization deficits.

Magnetic Resonance Imaging and Ultrasound Injury in Preterm Infants With Seizures

Thu, 10 Sep 2009 09:49:10 PDT

Although the utility of magnetic resonance imaging (MRI) as a universal screening tool in preterm infants has been contested, it is increasingly used to investigate neonatal seizures. The authors evaluated 236 infants <34 weeks’ gestation at birth. Seizures were documented according to the clinical standard of care. Infants underwent MRI and head ultrasound during the neonatal period, and a neuroradiologist and ultrasonologist performed detailed reviews of the images. During the hospital course, 9 infants (3.8%) had clinical suspicion of seizures. Magnetic resonance imaging was abnormal in each case. Periventricular hemorrhagic infarct was more common in infants with seizures. Infants with seizures were more likely to have white matter injury, though the difference was not significant. Head ultrasound failed to detect the extent of brain abnormality in 8 (89%) of the infants. In this large cohort, infants with clinical suspicion of seizures had a high rate of MRI abnormalities that were not as well characterized by head ultrasound. Magnetic resonance imaging may be the study of choice for evaluating preterm infants with seizures.

Molecular Mechanisms Involved in Injury to the Preterm Brain

Kaindl, A. M., Favrais, G., Gressens, P. — Thu, 10 Sep 2009 09:49:10 PDT

Injury to the premature brain is a major contributor to infant mortality and morbidity, often leading to mental retardation and sensory-motor impairment. The disease process is believed to be caused, sustained, and aggravated by multiple perinatal factors that team up in a multi-hit fashion. Clinical, epidemiological, and experimental studies have revealed that key factors such as inflammation, excitotoxicity, and oxidative stress contribute considerably to white- and gray-matter injury in premature infants, whose brains are particularly susceptible to damage. Depending on the timing, lesions of the immature brain may influence developmental events in their natural sequence and redirect subsequent development. We review current concepts on molecular mechanisms underlying injury to the premature brain.

Fetal Inflammatory Response and Brain Injury in the Preterm Newborn

Malaeb, S., Dammann, O. — Thu, 10 Sep 2009 09:49:10 PDT

Preterm birth can be caused by intrauterine infection and maternal/fetal inflammatory responses. Maternal inflammation (chorioamnionitis) is often followed by a systemic fetal inflammatory response characterized by elevated levels of proinflammatory cytokines in the fetal circulation. The inflammation signal is likely transmitted across the blood-brain barrier and initiates a neuroinflammatory response. Microglial activation has a central role in this process and triggers excitotoxic, inflammatory, and oxidative damage in the developing brain. Neuroinflammation can persist over a period of time and sensitize the brain to subinjurious insults in early and chronic phases but may offer relative tolerance in the intermediate period through activation of endogenous anti-inflammatory, protective, and repair mechanisms. Neuroinflammatory injury not only destroys what exists but also changes what develops.

The Role of Systemic Hemodynamic Disturbances in Prematurity-Related Brain Injury

du Plessis, A. J. — Thu, 10 Sep 2009 09:49:10 PDT

Premature infants who experience cerebrovascular injury frequently have acute and long-term neurologic complications. In this article, we explore the relationship between systemic hemodynamic insults and brain injury in this patient population and the mechanisms that might be at play.

Apoptotic Mechanisms in the Immature Brain: Involvement of Mitochondria

Hagberg, H., Mallard, C., Rousset, C. I., Xiaoyang Wang, — Thu, 10 Sep 2009 09:49:10 PDT

Brain injury after hypoxic-ischemic encephalopathy often develops with delayed appearance, opening a therapeutic window. Clinical studies in newborns show that post-hypoxic-ischemic hypothermia improves outcome. This has generated renewed interest in the molecular mechanisms of hypoxic-ischemic brain injury. In this brief review, we propose that mitochondrial permeabilization is crucial for injury to advance beyond the point of no return. We suggest that excitatory amino acids, nitric oxide, inflammation, trophic factor withdrawal, and an increased pro- versus antiapoptotic Bcl-2 protein ratio will trigger Bax-dependent mitochondrial outer membrane permeabilization. Mitochondrial outer membrane permeabilization, in turn, elicits mitochondrial release of cytochrome C, apoptosis-inducing factor, second mitochondria-derived activator of caspase/Diablo, and HtrA2/Omi. Cytochrome C efflux activates caspase-9/-3, leading to DNA fragmentation. Apoptosis-inducing factor interacts with cyclophilin A and induces chromatinolysis. Blockage of mitochondrial outer membrane permeabilization holds promise as a strategy for perinatal brain protection.

Peroxisomal Dysfunction in Inflammatory Childhood White Matter Disorders: An Unexpected Contributor to Neuropathology

Singh, I., Singh, A. K., Contreras, M. A. — Thu, 10 Sep 2009 09:49:10 PDT

The peroxisome, an ubiquitous subcellular organelle, plays an important function in cellular metabolism, and its importance for human health is underscored by the identification of fatal disorders caused by genetic abnormalities. Recent findings indicate that peroxisomal dysfunction is not only restricted to inherited peroxisomal diseases but also to disease processes associated with generation of inflammatory mediators that downregulate cellular peroxisomal homeostasis. Evidence indicates that leukodystrophies (i.e. X-linked adrenoleukodystrophy, globoid cell leukodystrophy, and periventricular leukomalacia) may share common denominators in the development and progression of the inflammatory process and thus in the dysfunctions of peroxisomes. Dysfunctions of peroxisomes may therefore contribute in part to white matter disease and to the mental and physical disabilities that develop in patients affected by these diseases.

''Intraventricular'' Hemorrhage and Cystic Periventricular Leukomalacia in Preterm Infants: How Are They Related?

Kusters, C. D. J., Chen, M. L., Follett, P. L., Dammann, O. — Thu, 10 Sep 2009 09:49:10 PDT

Intraventricular hemorrhage and cystic periventricular leukomalacia are often co-occurring characteristics of brain damage in preterm infants. Using data from 1016 infants born before 30 completed weeks’ gestational age, we sought to clarify the relationship between severe intraventricular hemorrhage and cystic periventricular leukomalacia, with special emphasis on common antecedents and potential confounding. After comparing risk factors for intraventricular hemorrhage grades 1 through 4 and cystic periventricular leukomalacia, it appears the risk patterns for intraventricular hemorrhage grade 3, intraventricular hemorrhage grade 4, and cystic periventricular leukomalacia differ. The association between intraventricular hemorrhage grade 3 and cystic periventricular leukomalacia differs appreciably from the association between intraventricular hemorrhage grade 4 and cystic periventricular leukomalacia, supporting the notion that intraventricular hemorrhage grade 3 and intraventricular hemorrhage grade 4 are different entities. The presence of intraventricular hemorrhage grade 3 and intraventricular hemorrhage grade 4 increases the risk of cystic periventricular leukomalacia, even after adjusting for potential confounders. This raises the possibility that intraventricular hemorrhage grade 3 and intraventricular hemorrhage grade 4 cause cystic periventricular leukomalacia.

White Matter Damage After Chronic Subclinical Inflammation in Newborn Mice

Thu, 10 Sep 2009 09:49:10 PDT

Preterm infants exposed to inflammation are at increased risk of white matter injury and/or cerebral palsy. To investigate the effect of chronic inflammation on the developing white matter, we administered low-dose lipopolysaccharide once a day from postnatal days 3 to 11, examined white matter changes at postnatal day 12, and monitored serum levels of insulin-like growth factor 1 and insulin-like factor binding protein-3. A single injection of lipopolysaccharide decreased the serum insulin-like growth factor 1 level but not the insulin-like factor binding protein-3 level. At postnatal day 12, quantification of immunohistochemical staining for axonal, myelin, and oligodendrocyte markers revealed impaired myelination in subcortical white matter. In addition, brain gray matter volume decreased and spleen and liver weight increased at postnatal day 12. These data suggest chronic subclinical inflammation hampers development of white and gray matter in early life, which may be associated with insulin-like growth factor 1 deficiency.

Intrauterine Endotoxin Administration Leads to White Matter Diffusivity Changes in Newborn Rabbits

Thu, 10 Sep 2009 09:49:10 PDT

Maternal intrauterine inflammation has been implicated in the development of periventricular leukomalacia and white matter injury in the neonate. We hypothesized that intrauterine endotoxin administration would lead to microstructural changes in the neonatal rabbit white matter in vivo that could be detected at birth using diffusion tensor magnetic resonance imaging (MRI). Term newborn rabbit kits (gestational age 31 days) born to dams exposed to saline or endotoxin in utero on gestational day 28 underwent diffusion tensor imaging, and brain sections were stained for microglia. Comparison between normal and endotoxin groups showed significant decreases in both fractional anisotropy and eigenvalue (e₁) in all periventricular white matter regions that showed an increase in the number of activated microglial cells, indicating that after maternal inflammation, microglial infiltration may predominantly explain this change in diffusivity in the immediate neonatal period. Diffusion tensor imaging may be a clinically useful tool for detecting neuroinflammation induced by maternal infection in neonatal white matter.

Positron Emission Tomography Imaging of Neuroinflammation

Kannan, S., Balakrishnan, B., Muzik, O., Romero, R., Chugani, D. — Thu, 10 Sep 2009 09:49:10 PDT

Injury to the central nervous system is characterized by localization of activated microglia at the site of injury. The peripheral benzodiazepine receptor expressed on the outer mitochondrial membrane of the activated microglia is a sensitive biomarker for the detection of this neuroinflammatory response to an insult. PK11195, an isoquinoline ligand that specifically binds peripheral benzodiazepine receptor, can be tagged with a positron emitter and used as a tracer for molecular imaging of this receptor in vivo by positron emission tomography (PET). [¹¹C](R)PK11195 has been used in the imaging of various neuroinflammatory disorders, such as Alzheimer disease and multiple sclerosis. On the basis of our small-animal PET imaging studies using a neonatal rabbit model of maternal inflammation-induced cerebral palsy, we propose that PET imaging using [¹¹C](R)PK11195 may be a valuable tool for detecting neuroinflammation in the brain of newborns born to mothers with chorioamnionitis.

Rehabilitative Therapies in Cerebral Palsy: The Good, the Not As Good, and the Possible

Damiano, D. L. — Thu, 10 Sep 2009 09:49:10 PDT

In the past decade, growing recognition of the importance of motor activity for the development and maintenance of central nervous system pathways and for recovery of function post injury has provided new avenues for rehabilitation. Physical therapy is likely to have a prominent role in stimulating neuroplastic changes in damaged developing nervous systems that may finally alter the natural history of these disorders, which has not yet been possible. In this article, we discuss the scientific evidence for various physical therapy treatment options for children with cerebral palsy. Newer, more intense, and task-related exercise programs show the strongest level of evidence. Traditional approaches and newer ‘‘packaged’’ approaches have failed to provide evidence of superiority. Their continued prevalence among clinicians is puzzling and disconcerting, as evidence supporting other approaches continues to accumulate.

White Matter Damage Impairs Adaptive Recovery More Than Cortical Damage in an In Silico Model of Activity-Dependent Plasticity

Follett, P. L., Roth, C., Follett, D., Dammann, O. — Thu, 10 Sep 2009 09:49:10 PDT

Little is understood of how damaged white matter interacts with developmental plasticity. The authors propose that computational neuroscience methods are underused in this problem. In this article, they present a nondeterministic, in silico model of activity-dependent plasticity. Using this model, they compared the impact of neuronal cell loss or axonal dysfunction on the ability of the system to generate, maintain, and recover synapses. The results suggest the axonal dysfunction seen in white matter injury is a greater burden to adaptive plasticity and recovery than is the neuronal loss of cortical injury. Better understanding of the interaction between features of preterm brain injury and developmental plasticity is an essential component for improving recovery.

Neuroprotective Interventions: Is It Too Late?

Jenkins, D. D., Chang, E., Singh, I. — Thu, 10 Sep 2009 09:49:10 PDT

In most cases of neonatal hypoxic-ischemic encephalopathy, the exact timing of the hypoxic-ischemic event is unknown, and we have few reliable biomarkers to precisely identify the phase of injury or recovery in an individual patient. However, it is becoming increasingly clear that for neuroprotection in neonates to succeed, an understanding of the phase of injury is important to ascertain. In addition, in utero antecedents of chronic hypoxia, hypoxic preconditioning, intrauterine infection, and fetal gender may change the expected time course of injury. Neuroprotective interventions, such as hypothermia and N-acetylcysteine, currently have efficacy in human and animal studies only if instituted early in the inflammatory cascade. Although these cascades are currently being investigated, molecular mechanisms of recovery have received little attention and may ultimately reveal a window for therapeutic intervention that is much longer than current paradigms.

JCN Calendar of Events

Thu, 10 Sep 2009 09:49:10 PDT

Management of Prolonged Seizures and Status Epilepticus in Childhood: A Systematic Review

Fri, 07 Aug 2009 15:09:47 PDT

Pediatric prolonged seizures and status epilepticus are medical emergencies necessitating immediate life-support and seizure-control measures. A systematic review of published data on the management of prolonged seizures and status epilepticus showed that buccal midazolam was significantly more effective than rectal diazepam, reaching a seizure-control rate of 70% and recurrence rate of 8%. Intranasal lorazepam was as effective as intramuscular paraldehyde in a cost-restrained setting. In refractory status epilepticus, both intravenous midazolam and valproate were equally effective to intravenous diazepam, with valproate exhibiting significantly faster seizure cessation and safer profile than diazepam, even in infancy. In conclusion, buccal midazolam is efficacious and safe thanks to its convenient route of administration, which may serve as first-line in the treatment of prolonged seizures. Intranasal lorazepam is an effective, easy-to-use, and safe drug for prolonged seizures. Intravenous valproate exhibits favorable efficacy and safety profile as third-line in status epilepticus, refractory to diazepam and phenytoin.

Early Signs of Visual Perception and Evoked Potentials in Radiologically Asymptomatic Boys With X-linked Adrenoleukodystrophy

Furushima, W., Inagaki, M., Gunji, A., Inoue, Y., Kaga, M., Mizutani, S. — Fri, 07 Aug 2009 15:09:47 PDT

The aim was to identify the electrophysiological and psychological signs at a very early stage in asymptomatic boys with childhood cerebral X-linked adrenoleukodystrophy. Flash visual evoked potentials, pattern reversal, and visual event-related potentials were recorded in 6 radiologically asymptomatic boys with adrenoleukodystrophy and 22 control boys. The latency and amplitude of P100 of visual evoked potentials and P1 of event-related potentials were evaluated. Though all patients had normal intelligence quotient, performance intelligence quotient was significantly lower than verbal intelligence quotient in 2 patients. Both P100 and P1 amplitudes were significantly greater in adrenoleukodystrophy than in controls. The difference between performance intelligence quotient and verbal intelligence quotient exhibited significant correlation with P100 amplitude. Enlargement of visual evoked potentials might be a sign of cerebral involvement preceding the appearance of abnormalities on magnetic resonance imaging. Follow-up of asymptomatic boys with both electrophysiological and neuropsychological tests may serve as an aid for deciding the timing of therapeutic intervention.

Parent-Based Sleep Education Workshops in Autism

Fri, 07 Aug 2009 15:09:47 PDT

To determine if parents can successfully teach their children with autism spectrum disorders to become better sleepers, we piloted small group parent education workshops focused on behavioral sleep strategies. Workshops consisted of three 2-hour sessions conducted over consecutive weeks by 2 physicians. Curricula included establishing effective daytime and nighttime habits, initiating a bedtime routine, and optimizing parental interactions at bedtime and during night wakings. Baseline and treatment questionnaires and actigraphy were analyzed in 20 children, ages 3 to 10 years. Improvements after treatment were seen in the total scale and several insomnia-related subscales of the Children's Sleep Habits Questionnaire. Actigraphy documented reduced sleep latency in children presenting with sleep onset delay. Improvements were also noted in measures of sleep habits and daytime behavior. Brief parent-based behavioral sleep workshops in children with autism spectrum disorders appear effective in improving subjective and objective measures of sleep, sleep habits, and daytime behavior.

Rapid Infusion of a Loading Dose of Intravenous Levetiracetam With Minimal Dilution: A Safety Study

Fri, 07 Aug 2009 15:09:47 PDT

Intravenous antiepileptic drugs are required in patients needing urgent treatment or unable to take oral medication. The safety of intravenous levetiracetam has been established in prospective studies of adult epilepsy and healthy participants. The authors performed a prospective, single-center study to evaluate the safety of a rapid loading dose of intravenous levetiracetam. Patients were divided into 3 equal dosing groups (N = 15 each): 20, 40, and 60 mg/kg (corresponding to maximum doses of 1, 2, and 3 g). Electrocardiogram and safety assessment were performed during the infusion. Ages were 4 to 32 years. Postinfusion serum levetiracetam concentrations were 14 to 189 µg/mL. There were no significant changes in blood pressure, no local infusion site reactions, and no electrocardiogram abnormalities. The authors concluded that high serum levels of parenteral levetiracetam can be achieved rapidly and safely, in a small infusion volume. This finding has important implications for the treatment of status epilepticus.

Benefit of Corticosteroid Therapy in Angelman Syndrome

Forrest, K. M. L., Young, H., Dale, R. C., Gill, D. S. — Fri, 07 Aug 2009 15:09:47 PDT

Angelman syndrome is often associated with an intractable seizure disorder. We describe 4 children who demonstrated an excellent response to corticosteroid therapy. The benefits included not only reduction in clinical seizures but also modification of the ``typical'' Angelman electroencephalogram. In addition, there was improvement in the myoclonic jerks, sleep pattern, and developmental progress. Corticosteroids appeared to have a broad benefit on the epileptic encephalopathy. We believe that these cases pose a challenge to the conventional management of intractable epilepsy in Angelman syndrome.

Evidence-Based Review of Bone Strength in Children and Youth with Cerebral Palsy

Cohen, M., Lahat, E., Bistritzer, T., Livne, A., Heyman, E., Rachmiel, M. — Fri, 07 Aug 2009 15:09:47 PDT

Children with cerebral palsy have various risk factors for compromised bone health. Evidence concerning their bone fragility is gathering; however, there is no consensus regarding risk factors, indications for evaluation, follow-up, or treatment. We performed an evidence-based review targeted to address the following questions concerning children with cerebral palsy: Is bone strength impaired and what are the risk factors? Are these children at increased risk for bone fractures? What are the relations between bone mineral density and fracture risk? What methods can be used for bone health assessment? How can bone strength be improved? Currently, the most acceptable method for evaluating bone status in children is dual-energy x-ray absorptiometry. Evidence demonstrates reduced bone mass in children with cerebral palsy; yet, no clear association with fractures. Preventive methods are suggested.

Clinical Outcome Measures in Spinal Muscular Atrophy

Montes, J., Gordon, A. M., Pandya, S., De Vivo, D. C., Kaufmann, P. — Fri, 07 Aug 2009 15:09:47 PDT

Spinal muscular atrophy is one of the most devastating neurological diseases of childhood. Affected infants and children suffer from often severe muscle weakness caused by degeneration of lower motor neurons in the spinal cord and brainstem. Identification of the causative genetic mutation in most cases has resulted in development of potential treatment strategies. To test these new drugs, clinically feasible outcomes are needed. Several different assessments, validated in spinal muscular atrophy or similar disorders, are being used by national and international research groups; however, their sensitivity to detect change is unknown. Acceptance of a few standardized, easily administered, and functionally meaningful outcomes, applicable to the phenotypic spectrum of spinal muscular atrophy, is needed. Consensus is imperative to facilitate collaboration and explore the ability of these measures to identify the therapeutic effect of disease-modifying agents. Following is an evidence-based review of available clinical outcome measures in spinal muscular atrophy.

Ketogenic Diets: An Update for Child Neurologists

Kossoff, E. H., Zupec-Kania, B. A., Rho, J. M. — Fri, 07 Aug 2009 15:09:47 PDT

The ketogenic diet, modified Atkins diet, and low-glycemic-index treatment have all emerged over the past decade as important therapeutic options for children with intractable epilepsy. Whereas only a decade ago the ketogenic diet was seen as an ``alternative'' treatment of last resort, it has become more frequently used throughout the world. The past year alone 2 randomized and controlled trials of the ketogenic diet were published, as well as the use of the ketogenic diet for new-onset epilepsy (infantile spasms), and a 26-member international consensus statement guiding optimal clinical management. There has been an equally dramatic increase of interest into mechanisms of action using various experimental models. Researchers are also highly interested in using diets for neurologic disorders other than epilepsy, including autism and brain tumors. This review will update child neurologists on the recent advances in the use of ketogenic diets.

Trigeminal Neuralgia Due to Anterior Inferior Cerebellar Artery Loop: A Case Report

Koul, R., Alfutaisi, A., Jain, R., Alzri, F. — Fri, 07 Aug 2009 15:09:47 PDT

Trigeminal neuralgia is uncommon in children. Idiopathic type is less often seen than the secondary or symptomatic type. We report a 6-year-old girl with trigeminal neuralgia. Magnetic resonance imaging revealed an arterial loop at the exit of the trigeminal nerve.

Clinical Heterogeneity in Ethylmalonic Encephalopathy

Pigeon, N., Campeau, P. M., Cyr, D., Lemieux, B., Clarke, J. T. R. — Fri, 07 Aug 2009 15:09:47 PDT

Ethylmalonic encephalopathy is a recently described inborn error of metabolism characterized clinically by developmental delay and regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. We describe monochorionic twins presenting with hypotonia in infancy and diagnosed with ethylmalonic encephalopathy on the basis of biochemical findings. They are compound heterozygote for missense mutations in ETHE1. Magnetic resonance imaging changes affecting the white matter, corpus callosum, and basal ganglia were seen in both patients. At 10 years of age, they have severe axial hypotonia but never displayed petechiae, orthostatic acrocyanosis, or chronic diarrhea. Their clinical courses differ markedly; one had an episode of coma when she was 3 years old and now has spastic quadraparesis and cannot speak. The other can freely use her upper extremities, her pyramidal syndrome being mostly limited to the lower extremities, and can speak 2 languages. These patients illustrate the clinical heterogeneity of ethylmalonic encephalopathy, even in monochorionic twins.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy, in an 8-Year-Old Girl, Complicated by Deafness and Kidney Fibrosis

Fri, 07 Aug 2009 15:09:47 PDT

Based on case history and clinical and electrophysiological examinations, the authors report on a case of an 8-year-old girl who was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy. The disease was complicated by deafness and kidney fibrosis. During treatment with methylprednisolone and intravenous immunoglobulin, followed by mycophenolate mofetil, prompt improvement of neurological findings occurred. The improvement of hearing was poor. Because the pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy has still not been clear, and on the grounds of several cases of chronic inflammatory demyelinating polyradiculoneuropathy conjoined with the kidney disease described in literature (glomerulopathy, interstitial nephritis), every patient with chronic inflammatory demyelinating polyradiculoneuropathy needs to undergo the urinalyses.

Acute Disseminated Encephalomyelitis with Bilateral Thalamic Necrosis

Dardiotis, E., Kountra, P., Kapsalaki, E., Protogerou, G., Markopoulou, K. — Fri, 07 Aug 2009 15:09:47 PDT

Acute disseminated encephalomyelitis is a monophasic inflammatory demyelinating disease of the central nervous system involving the white matter, and to a lesser extent, the gray matter. Bilateral thalamic lesions have been reported in 12% of pediatric patients with acute disseminated encephalomyelitis. In most cases, there is a benign clinical course and complete resolution of the lesions. Here, we describe a case in which acute disseminated encephalomyelitis is associated with severe neurological deficits and bilateral thalamic necrosis. Necrosis should be considered in cases of acute disseminated encephalomyelitis with persistent severe neurological deficits. Its presence is a poor prognostic indicator.

Methylphenidate Induction of Complex Visual Hallucinations

Halevy, A., Shuper, A. — Fri, 07 Aug 2009 15:09:47 PDT

A 15-year-old boy with attention-deficit hyperactivity disorder (ADHD) presented with complex visual hallucinations of rats running around and touching and smelling him soon after receiving a first low dose of methylphenidate. The hallucinations resolved upon discontinuation of the drug. Reintroduction of the drug 7 years later at an even lower dose had the same effect. Other cases of vivid complex hallucinations of living creatures associated with methylphenidate have been reported in the literature. The pathogenetic mechanism is still unknown. In our case, the occurrence of hallucinations after a very low dose of the drug on 2 occasions may suggest an idiosyncratic reaction. The phenomenon might also be explained by a drug-induced dysfunction of the monoamine transmitters. Given the wide use of methylphenidate, clinicians should be aware of this possible side effect.

Childhood Mefloquine-Induced Mania and Psychosis: A Case Report

Thapa, R., Biswas, B. — Fri, 07 Aug 2009 15:09:47 PDT

Mefloquine, a commonly used oral antimalarial is occasionally associated with severe, neuropsychiatric adverse effects, especially in adults. Such events are extremely rare in children. The authors report on an 11-year-old, otherwise healthy girl from Eastern India, a malaria-endemic region, who developed mania and psychosis following intake of a therapeutic dose of mefloquine for Plasmodium falciparum malaria. She recovered satisfactorily with risperidone therapy. To our knowledge, there is only one documented instance of mefloquine-induced psychosis in the pediatric literature to date. Those caring for children need to realize that severe neuropsychiatric manifestations may be seen in the pediatric age group. A positive history of intake of the offending drug with careful exclusion of other etiologies usually clinches the diagnosis.

Oral Administration of the Thyrotropin-Releasing Hormone (TRH) Analogue, Taltireline Hydrate, in Spinal Muscular Atrophy

Fri, 07 Aug 2009 15:09:47 PDT

Spinal muscular atrophy is an entity of neurodegenerative disorders at the anterior horn neuron of the spinal cord caused by telomeric survival motor neuron gene abnormality. There is no definitive treatment for spinal muscular atrophy, but recent reports have indicated the efficacy of intravenous injection, but not oral administration, of thyrotropin-releasing hormone (TRH). We treated an 18-year-old male patient with spinal muscular atrophy type III by oral administration of the thyrotropin-releasing hormone analogue, taltireline hydrate. His muscle strength increased significantly after the therapy, and he showed no clinical or laboratory identifiable adverse effects, including thyroid-stimulating hormone suppression that had been observed with intravenous thyrotropin-releasing hormone therapy. Oral administration of this thyrotropin-releasing hormone analogue should be noted as a promising therapy for spinal muscular atrophy.

Posterior Reversible Encephalopathy Syndrome Associated With Methotrexate Neurotoxicity: Conventional Magnetic Resonance and Diffusion-Weighted Imaging Findings

Fri, 07 Aug 2009 15:09:47 PDT

The addition of intrathecal methotrexate to treatment protocols has increased survival rates in children with acute lymphoblastic leukemia but is also associated with varying degrees of neurotoxicity. We describe a 15-year-old female patient diagnosed with acute lymphoblastic leukemia presenting with status epilepticus after receiving intrathecal methotrexate. Magnetic resonance imaging showed reversible cortical and subcortical changes consisting of high-intensity lesions on T2-weighted and fluid-attenuated inversion recovery sequences with postgadolinium enhancement, low signal intensity on diffusion-weighted imaging and increased apparent diffusion coefficient. These findings were consistent with the posterior reversible encephalopathy syndrome. We report our conventional magnetic resonance and diffusion-weighted imaging findings and briefly discuss the pathophysiology of the syndrome.

Recurrent Posterior Circulation Stroke in an Infant With Basilar Artery Aneurysm

Frosk, P., Salman, M. S., Wrogemann, J., Shah, N., Rafay, M. F. — Fri, 07 Aug 2009 15:09:47 PDT

Arterial ischemic stroke involving the posterior circulation is uncommon in children. The underlying etiologies and risk factors predisposing to posterior circulation stroke include vasculopathies, intracranial trauma, cardiac disease, infection, and hematologic disorders. However, in many children with posterior circulation stroke, the underlying mechanisms are poorly understood. We describe a 14-month-old infant with recurrent arterial ischemic stroke involving the posterior circulation secondary to an aneurysm of the basilar artery.

Coma Blisters in 2 Children on Anticonvulsant Medication

Basu, A., Brown, S., Kirkham, N., Ramesh, V., Leech, S., Devlin, A. — Fri, 07 Aug 2009 15:09:47 PDT

Blister formation and eccrine sweat gland necrosis have been recognized to occur in states of impaired consciousness and were first reported following barbiturate intoxication. Their etiology is complex and cannot simply be explained by pressure effects. Now that barbiturates are less frequently used, clinicians are likely to be less aware of the phenomenon of coma blister formation; however, newer drugs have also been associated with the occurrence of coma blisters. We describe 2 new associations of coma blisters and anticonvulsants in children. In the first child, blisters recurred on multiple occasions along with obtundation and edema. Our aims are to alert clinicians to the occurrence of coma blisters in children sedated on anticonvulsant medications and to report the new finding of recurrent coma blisters.

Neck Myoclonia With Absence Seizures: Report of 3 Cases

Zhixian Yang, , Xiaoyan Liu, , Jiong Qin, , Yuwu Jiang, — Fri, 07 Aug 2009 15:09:47 PDT

Absence seizures associated with myoclonic phenomena can be seen in typical absences, myoclonic absences, eyelid myoclonia, and perioral myoclonia, all of which have diagnostic electroclinical features. The authors report 3 patients who encountered prominently rhythmic neck myoclonias with and without absences (loss of awareness). The descriptive symptoms of attacks by witnesses were head shaking or turning repeatedly instead of absences. The seizures were induced by hyperventilation in all 3 cases. Two cases had a history of previous febrile seizures. In all patients, video-electroencephalography showed a one-to-one correspondence relationship between the 2.5- to 3.5-Hz generalized spike and wave discharges and the rhythmic myoclonic jerks of the neck, which was further confirmed by sternocleidomastoideus electromyography recording in 1 patient. Seizures had been controlled by 1 or 2 antiepileptic drugs. Neck myoclonia with absences might be classified either as 1 special subtype of typical absence or as an independent seizure type. Paying close attention to the special phenomenon will help to clarify the clinical spectrum of this seizure.

The Principle of Double Effect, Genetic Testing, and Global Developmental Delay

Tervo, R. C., Wojda, P. — Fri, 07 Aug 2009 15:09:47 PDT

Well-intended efforts to diagnose a child's developmental delay may have unintended negative consequences for a child and his family. Consequently, clinicians may feel caught in a moral dilemma: between doing the good they seek and avoiding the harm they foresee. The dilemma is that when investigating global developmental delay it is not possible to avoid all the anticipated negative outcomes of genetic testing and concurrently fulfill our obligations to do the good from which these harmful effects result. It is imperative to recognize dilemmas especially where the moral questions or relevant facts are not as clear cut as in ethics textbooks and to bring their moral questions into a structured dialogue with the patient and his or her family. A modified principle of double effect is a useful method for deliberating about these moral cases. Three case examples illustrate the utility of the principle of double effect when investigating global developmental delay.

Neurological Problems of Jazz Legends

Pearl, P. L. — Fri, 07 Aug 2009 15:09:47 PDT

A variety of neurological problems have affected the lives of giants in the jazz genre. Cole Porter courageously remained prolific after severe leg injuries secondary to an equestrian accident, until he succumbed to osteomyelitis, amputations, depression, and phantom limb pain. George Gershwin resisted explanations for uncinate seizures and personality change and herniated from a right temporal lobe brain tumor, which was a benign cystic glioma. Thelonious Monk had erratic moods, reflected in his pianism, and was ultimately mute and withdrawn, succumbing to cerebrovascular events. Charlie Parker dealt with mood lability and drug dependence, the latter emanating from analgesics following an accident, and ultimately lived as hard as he played his famous bebop saxophone lines and arpeggios. Charles Mingus hummed his last compositions into a tape recorder as he died with motor neuron disease. Bud Powell had severe posttraumatic headaches after being struck by a police stick defending Thelonious Monk during a Harlem club raid.

Neurological Problems of Famous Musicians: The Classical Genre

Newmark, J. — Fri, 07 Aug 2009 15:09:47 PDT

Neurological histories of great musicians allow for a unique perspective on music physiology. Bedrich Smetana's autobiographical string quartet ends with the musical equivalent of tinnitus in the fourth movement, rendering the youthful and passionate themes of earlier movements moot as the piece ends depicting his ultimately fatal disease, neurosyphilis. Dmitri Shostakovich survived the censorship of Joseph Stalin's apparatchiks but suffered a prolonged form of paralysis attributable to slowly progressive motor neuron disease, although the viola sonata he wrote on his deathbed has become standard repertoire. Glenn Gould was a hypochondriacal pianist with obsessive-compulsive disorder and suspected Asperger syndrome. Vissarion Shebalin and (Ira) Randall Thompson had strokes followed by aphasia without amusia. Domenico Scarlatti provides an example of how even great composers must alter their technical expectations depending upon the skills and body habitus of their chief patrons. The focal dystonia afflicting Leon Fleisher and Gary Graffman catalyzed the discipline of performing arts medicine.

The White Coat Ceremony: A Tribute to the Humanism of Arnold P. Gold

Kavan, M. G., Brumback, R. A. — Fri, 07 Aug 2009 15:09:47 PDT

JCN Calendar of Events

Fri, 07 Aug 2009 15:09:47 PDT