Pediatric Neurology

Emerging Treatments in the Management of Tuberous Sclerosis Complex

Michael H. Kohrman — 2012-05-01

Abstract: Tuberous sclerosis complex is a genetic disorder characterized by the formation of nonmalignant hamartomas in the brain, heart, skin, kidney, lung, and other organs. It is associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. Wide phenotypic variation occurs in disease severity and natural course: some patients demonstrate minimal effects, e.g., skin changes; others manifest profound seizures and mental retardation. Tuberous sclerosis complex is caused by mutations in either the tuberous sclerosis complex 1 or 2 gene (coding for hamartin and tuberin, respectively). The tuberous sclerosis complex 1/tuberous sclerosis complex 2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin pathway, regulating cell growth and proliferation. Until recently, few options existed, other than surgery, for treating symptoms of tuberous sclerosis complex related to the growth of hamartomas. Increased understanding of the genetic cause of the disease and underlying dysregulation of the mammalian target of rapamycin pathway has led to clinical trials of mammalian target of rapamycin inhibitors, including sirolimus and everolimus. This review gives an overview of tuberous sclerosis complex and its molecular causes, and summarizes results from recent clinical trials of mammalian target of rapamycin inhibitors in patients with the disease.

Outcomes of Epileptic Spasms in Patients Aged Less Than 3 Years: Single-Center United States Experience

2012-05-01

Abstract: Retrospective review was performed of children aged <3 years with epileptic spasms at our center from 2004-2010. Short-term (<6 months) and long-term (≥6 months) outcomes were assessed. We included 173 children (104 boys; median age of onset, 6.8 months) with epileptic spasms of known (62%) and unknown (38%) etiology. Treatments included adrenocorticotropic hormone (n = 103), vigabatrin (n = 82), phenobarbital (n = 34), and other agents (n = 121). Short-term treatment with adrenocorticotropic hormone and vigabatrin provided better epileptic spasm control in groups with known and unknown etiology than other agents. At follow-up (6-27 months), 54% of children manifested seizures, and 83% manifested developmental delay. Known etiology was a predictor of poor developmental outcome (P = 0.006), whereas bilateral/diffuse brain lesions predicted both poor development and seizures (P = 0.001 and 0.005, respectively). Initial presentations of epileptic spasms with hypotonia or developmental delay most strongly predicted both seizures and neurodevelopmental outcomes (P < 0.001). In a child presenting with epileptic spasms with developmental delay or hypotonia, no specific treatment may offer superior benefit.

Utilization of Antiepileptic Drugs in Hong Kong Children

2012-05-01

Abstract: This study investigated the prescribing patterns of antiepileptic drugs, especially the uptake of newer drugs, among children and adolescents in Hong Kong. Data were retrieved from the Clinical Data Analysis and Reporting System. Children aged 0-19 years who received at least one prescription of anticonvulsants were selected. The study period extended from April 1, 2005 to March 31, 2009. The overall prevalence of anticonvulsants prescribing was 2.23/1000 children in 2005. A slight but steady decline in anticonvulsants prevalence was observed throughout the study period. Valproic acid was the most frequently prescribed drug, followed by carbamazepine and benzodiazepine derivatives. The use of newer anticonvulsants rose significantly, by 26.9%. The use of valproic acid remained unchanged, whereas the use of carbamazepine declined by 20%. Among newer drugs, the use of levetiracetam increased fourfold, and that of oxcarbazepine increased 15-fold. In the youngest age group, phenobarbital was the second most frequently used drug. A significant increase in lamotrigine prescriptions was not observed among adolescents. The persistent increase in using newer antiepileptic drugs implies not only an increase in drug expenditure. It also reflects the need to assess cost-effectiveness in terms of long-term outcomes, quality of life, and health economic outcomes.

Automatic Detection of Childhood Absence Epilepsy Seizures: Toward a Monitoring Device

2012-05-01

Abstract: Automatic detections of paroxysms in patients with childhood absence epilepsy have been neglected for several years. We acquire reliable detections using only a single-channel brainwave monitor, allowing for unobtrusive monitoring of antiepileptic drug effects. Ultimately we seek to obtain optimal long-term prognoses, balancing antiepileptic effects and side effects. The electroencephalographic appearance of paroxysms in childhood absence epilepsy is fairly homogeneous, making it feasible to develop patient-independent automatic detection. We implemented a state-of-the-art algorithm to investigate the performance of paroxysm detection. Using only a single scalp electroencephalogram channel from 20 patients with a total of 125 paroxysms >2 seconds, 97.2% of paroxysms could be detected with no false detections. This result leads us to recommend further investigations of tiny, one-channel electroencephalogram systems in an ambulatory setting.

Clinical Profile of Malay Children With Optic Neuritis

Ismail Shatriah, Abdul-Rahim Adlina, Salem Alshaarawi, Wan-Hazabbah Wan-Hitam — 2012-05-01

Abstract: Limited data are available on optic neuritis in Asian children. Clinical profiles tend to vary with different races. We aimed to determine the clinical manifestations, visual outcomes, and etiologies of optic neuritis in Malaysian children, and discuss the literature of optic neuritis in Asian children. A retrospective study involving 14 children with optic neuritis was performed at Hospital Universiti Sains Malaysia between July 2005 and January 2010 (follow-up, 18-60 months). Clinical features, laboratory results, possible etiologies, and visual acuity after 1 year were studied. Females were predominant (mean age at presentation, 11.1 years). All patients manifested bilateral involvement. Swollen optic discs were observed in 92.9% of eyes; 60.7% of patients demonstrated a visual acuity of 6/60 (or 20/200) or worse on presentation, whereas 14.3% remained at 6/60 (or 20/200) or worse, 1 year after their attack. Cecocentral scotoma comprised the most common visual field defect. Infection contributed to 50.0% of cases; 14.3% progressed to multiple sclerosis during follow-up, with no evidence of recurrent optic neuritis. The clinical profiles and etiologies of optic neuritis in Malay children differ slightly compared with other optic neuritis studies of Asian children. The frequency of progression to multiple sclerosis is relatively lower.

Later Onset Phenotypes of Krabbe Disease: Results of the World-Wide Registry

2012-05-01

Abstract: The majority of newborns screening positive for Krabbe disease have not exhibited the expected early infantile phenotype, with most clinically normal despite low galactocerebrosidase activity and two mutations. Most are expected to develop the later onset phenotypes. The World-Wide Krabbe Registry was developed in part to expand our understanding of the natural history of these rare variants. As of June 2011, 122 patients were enrolled in the registry: 62% manifested early infantile onset (previously reported), 10% manifested onset at 7-12 months (late infantile), 22% manifested onset at 13 months to 10 years (later onset), and 5% manifested adolescent/adult onset. Data on disease course, galactocerebrosidase activity, DNA mutations, and results of neurodiagnostic studies were obtained from questionnaires and medical records. Initial signs (late infantile) included loss of milestones and poor feeding, whereas later onset and adolescent/adult phenotypes presented with changes in gait. Elevated cerebrospinal fluid protein and abnormal magnetic resonance imaging results were present in most, but not all, patients at diagnosis. Phenotypic variability occurred in four sibships. Five-year and 10-year survivals for all later onset phenotypes were at least 50%. The later onset Krabbe phenotypes differ from those with early infantile disease, but no specific predictor of phenotype was identified.

Head Circumference Growth Reference Charts for Turkish Children Aged 0-84 Months

2012-05-01

Abstract: This study sought to produce updated head circumference references in a representative population of Turkish children aged 0 to <84 months. Head circumference measurements are very important in monitoring child growth, to evaluate macrocephaly and microcephaly. Primary sampling units involved family health centers in the city center and suburbs of Kayseri. In total, 2989 children (1479 boys and 1510 girls) were included. Head circumference was measured with a nonelastic tape on a line passing over the glabella and posterior occipital protrusion in children aged 0-2 years lying on a bed, and children aged more than 2 years standing up. We compared the 50th percentile of our cross-sectional data with longitudinal Belgian and American data. The comparison indicated that Turkish head circumference percentiles were similar to, or not much lower than, Belgian and American percentiles. Head circumference percentiles can be used to evaluate children with microcephaly and macrocephaly (±2 standard deviations), and to monitor growth.

Short-Term Response of Sleep-Potentiated Spiking to High-Dose Diazepam in Electric Status Epilepticus During Sleep

2012-05-01

Abstract: We describe the short-term effects of high-dose oral diazepam on sleep-potentiated epileptiform activity in patients with electric status epilepticus during sleep. We enrolled patients treated with high-dose oral bedtime diazepam from 2001-2009. We defined spike percentage as the percentage of 1-second bins containing at least one spike, and calculated it during three randomly selected 5-minute samples of wakefulness throughout the day and during the first 5 minutes of every hour of non-rapid eye movement sleep at night. In this study, patients were considered to demonstrate sleep-potentiated epileptiform activity when their spike percentage during sleep was increased by ≥50% compared with wakefulness. Twenty-nine children (18 boys) were included (median age, 7.4 years). Twenty-four hours after receiving high-dose diazepam, epileptiform activity was significantly reduced (76.7% at baseline vs 40.8% 24 hours after high-dose diazepam; Wilcoxon signed ranks test, Z = −4.287, P < 0.0001). Seven patients (24.1%) manifested mild, reversible side effects during the first 48 hours after diazepam administration. High-dose oral diazepam effectively and safely reduced epileptiform activity in patients with electric status epilepticus during sleep.

Kikuchi-Fujimoto Disease Complicated by Peripheral Neuropathy

2012-05-01

Abstract: Kikuchi-Fujimoto disease is a necrotizing lymphadenitis, mainly characterized by lymphadenopathy, fever, hepatosplenomegaly, nocturnal sweats, myalgia, weight loss, and arthralgia. Its diagnosis is most often based on lymph node biopsy. Differential diagnoses with several other diseases, e.g., malignant lymphoma, necrotizing lymphadenitis, and infective lymphadenopathies, may be challenging. Neurologic involvement is rarely reported in patients diagnosed with Kikuchi-Fujimoto disease. In this subset of patients, the great majority manifest signs involving the central nervous system. We present a 14-year-old boy with a severe form of Kikuchi-Fujimoto disease, complicated by peripheral neuropathy. This patient is interesting for both his age and his peculiar complication.

Ataxia-Telangiectasia Presenting With a Novel Immunodeficiency

2012-05-01

Abstract: Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene. The patient presented at age 3 years with a perineal cellulitis associated with profound neutropenia and T-cell lymphopenia. Serum immunoglobulin levels and antibody titers were normal. Neurologic evaluation revealed minimal hypotonia and wide-based gait, without other signs of cerebellar dysfunction. The alpha-fetoprotein level was elevated, and molecular genetic testing confirmed the diagnosis of ataxia-telangiectasia, uncovering a novel ATM gene mutation c.3931C>T (p.Gln1311X) in exon 28. This patient presents a unique immunologic pattern with normal immunoglobulin levels, significant lymphopenia, and profound neutropenia. The diagnosis of ataxia-telangiectasia should be considered in children presenting with gait disorder and immunologic defects, regardless of subtype and severity.

Novel Neuroimaging Finding in Palmitoyl Protein Thioesterase-1-Related Neuronal Ceroid Lipofuscinosis

Mahesh Kamate, Virupaxi Hattiholi — 2012-05-01

Abstract: Palmitoyl protein thioesterase-1 (PPT1)-related neuronal ceroid lipofuscinosis is a type of neuronal ceroid lipofuscinosis caused by a deficiency of the enzyme palmitoyl protein thioesterase-1. Cranial magnetic resonance imaging reveals more severe atrophy in the cerebral hemispheres than in the cerebellum. The basal ganglia and particularly the thalamus demonstrate low signal intensity on T2-weighted images from an early age. We present three patients with PPT1-related neuronal ceroid lipofuscinosis who exhibited isolated, symmetric signal changes in the bilateral dentate nucleus as sole early neuroimaging abnormality. Neither cerebral or cerebellar atrophy nor signal changes in the thalamus/basal ganglia were evident. This neuroimaging finding in PPT1-related neuronal ceroid lipofuscinosis was not previously reported.

Childhood-Onset Myasthenia Gravis With Thymoma

2012-05-01

Abstract: Juvenile myasthenia gravis is an acquired, autoimmune disease occurring before age 16 years. Thymoma is exceedingly rare in children, especially in association with juvenile myasthenia gravis. We describe a 14-year-old boy with juvenile myasthenia gravis and thymoma. He presented with difficulties chewing and swallowing, nasal speech, and fluctuating weakness of the leg muscles. Neurologic examination revealed masticatory and bulbar muscle weakness with nasal speech, proximal muscle weakness, fatigability of the arms and legs, and distal muscle weakness of the legs. A diagnosis of juvenile myasthenia gravis was confirmed by a positive neostigmine test, a decremental response on repetitive nerve stimulation, and increased titers of serum anti-acetylcholine receptor antibodies. The patient received anticholinesterases, corticosteroids, azathioprine, and thymectomy. A pathohistologic analysis of the thymus gland indicated thymoma, Masaoka grade II. After 2 years of an unstable disease course, remission was achieved. Because only 10 cases of thymoma-associated myasthenia gravis are described in the pediatric population, this report offers an important contribution to a better understanding of this rare association.

Predisposition to Subdural Hemorrhage in X-Linked Myotubular Myopathy

Hiroshi Koga, Kenichi Miyako, Naohiro Suga, Tomoko Hidaka, Noboru Takahashi — 2012-05-01

Abstract: X-linked myotubular myopathy is a severe congenital myopathy that can involve multiple organs. We report on a 10-month-old boy who manifested X-linked myotubular myopathy with subdural hemorrhage. The diagnosis of X-linked myotubular myopathy was based on typical muscle pathology and MTM1 missense mutation. The patient had undergone no traumatic episodes or bleeding diathesis. Axial growth acceleration is known to occur in X-linked myotubular myopathy, potentially leading to dolichocephaly. In our patient, an enlarged subdural space apparently stretched the bridging veins, increasing susceptibility to subdural hemorrhage. Patients who manifest X-linked myotubular myopathy with typical dolichocephaly are at increased risk for subdural hemorrhage.

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

Abe Chutorian — 2012-05-01

The report by Ravid et al. is flawed by its misrepresentation of the term “pseudotumor cerebri.” Pseudotumor cerebri is defined by well recognized clinical features, normal cerebrospinal fluid except for elevated pressure, and normal results of brain imaging.

Response

Sarit Ravid — 2012-05-01

We appreciate the comments regarding our report. Although only one of our patients had undergone computed tomography of the brain (patient 1), the other two had undergone cranial magnetic resonance imaging.

Erratum

2012-05-01

In the article “Dual Diagnosis of Dihydropyrimidine Dehydrogenase Deficiency and GM1 Gangliosidosis” by Ong et al. in the March 2012 issue (2012;46:178-181; doi: 10.1016/j.pediatrneurol.2011.12.005), “15 base pair homozygous deletion” should read “16 base pair homozygous deletion” in both the abstract and the penultimate sentence of the fourth paragraph in the Case Report section.

Erratum

2012-05-01

In the article “A Treatable Cause of Ataxia in Children” by Facchini et al. in the February 2001 issue (2001;24:135-138; doi: 10.1016/S0887-8994(00)00241-1), the author line was incorrect. The corrected author line and affiliations appear below. The authors regret the error.

Calendar

2012-05-01

Instructions to Contributors

2012-05-01

Pediatric Neurology

Emerging Treatments in the Management of Tuberous Sclerosis Complex

Outcomes of Epileptic Spasms in Patients Aged Less Than 3 Years: Single-Center United States Experience

Utilization of Antiepileptic Drugs in Hong Kong Children

Automatic Detection of Childhood Absence Epilepsy Seizures: Toward a Monitoring Device

Clinical Profile of Malay Children With Optic Neuritis

Later Onset Phenotypes of Krabbe Disease: Results of the World-Wide Registry

Head Circumference Growth Reference Charts for Turkish Children Aged 0-84 Months

Short-Term Response of Sleep-Potentiated Spiking to High-Dose Diazepam in Electric Status Epilepticus During Sleep

Kikuchi-Fujimoto Disease Complicated by Peripheral Neuropathy

Ataxia-Telangiectasia Presenting With a Novel Immunodeficiency

Novel Neuroimaging Finding in Palmitoyl Protein Thioesterase-1-Related Neuronal Ceroid Lipofuscinosis

Childhood-Onset Myasthenia Gravis With Thymoma

Predisposition to Subdural Hemorrhage in X-Linked Myotubular Myopathy

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

Response

Erratum

Erratum

Calendar

Table of Contents

Instructions to Contributors