Understanding Childhood Neuroimmune Diseases of the Central Nervous System

Immune-mediated diseases of the central nervous system (CNS) in childhood are a heterogeneous group of rare conditions sharing the inflammatory involvement of the CNS. This review highlights the growing knowledge of childhood neuroimmune diseases that primarily affect the CNS, outlining the clinical and diagnostic features, the pathobiological mechanisms and genetics, current treatment options, and emerging challenges. The clinical spectrum of these conditions is increasingly expanded, and the underlying mechanisms of dysregulation of the immune system could vary widely. Cell-mediated and antibody-mediated disorders, infection-triggered and paraneoplastic conditions, and genetically defined mechanisms can occur in previously healthy children and can contribute to different stages of the disease. The careful evaluation of the clinical presentation and temporal course of symptoms, the specific neuroimaging and immunological findings, and the exclusion of alternative causes are mandatory in clinical practice for the syndromic diagnosis. A common feature of these conditions is that immunotherapeutic agents could modulate the clinical course and outcomes of the disease. Furthermore, specific symptomatic treatments and comprehensive multidisciplinary care are needed in the overall management. We focus on recent advances on immune-mediated demyelinating CNS disorders, autoimmune encephalitis, interferonopathies, and possible neuroimmune disorders as Rasmussen encephalitis. Better knowledge of these conditions could allow prompt diagnosis and targeted immunotherapy, to decrease morbidity and mortality as well as to improve clinical outcomes, reducing the burden of the disease due to possible long-term neuropsychiatric sequelae. Persisting controversies remain in the rigorous characterization of each specific clinical entity because of the relative rarity in children; moreover, in a large proportion of suspected neuroimmune diseases, the immune "signature" remains unidentified; treatment guidelines are mostly based on retrospective cohort studies and expert opinions; then advances in specific molecular therapies are required. In the future, a better characterization of specific immunological biomarkers may provide a useful understanding of the underlying pathobiological mechanisms of these conditions in order to individualize more tailored therapeutic options and paradigms. Multicenter collaborative research on homogeneous groups of patients who may undergo immunological studies and therapeutic trials could improve the characterization of the underlying mechanisms, the specific phenotypes, and tailored management

Simultaneous onset of infantile spasms in monozygotic twins.

The clinical, electroencephalographic, and genetic findings are reported for three pairs of monozygotic twins who developed infantile spasms in their first year. In all three pairs, the spasms started on the same day in each member of the pair. Neither sequencing of the ARX and CDKL5 (alias STK9) genes nor array comparative genomic hybridization assessment revealed any abnormalities. The long-term outcome was poor in all twins, although with different severity in individual pairs. These findings suggest that genes other than those currently known likely play a role in predisposition to infantile spasms, and that genetic susceptibility is linked to a variable phenotypic expression, ranging from quite benign to very severe, in monozygotic twins with no other apparent risk factors

Gastaut type-idiopathic childhood occipital epilepsy and childhood absence epilepsy: a clinically significant association?

We report an unusual association between idiopathic occipital epilepsy and childhood absence epilepsy in 2 pediatric patients. At first clinical and electroencephalographic evaluation, the patients presented the peculiar signs of idiopathic occipital epilepsy Gastaut type: focal sensory visual seizures, migrainelike symptoms (only in one patient) and unilateral spike–wave discharges over occipital regions. Both children were treated with valproic acid and their seizures were rapidly controlled. After a seizure-free period, the patients presented typical absence with ictal electroencephalographies showing 3 cycles/s generalized and symmetrical spike–wave complexes. We discuss the possible association between these two epileptic syndromes and its common pathophysiological mechanisms

Topiramate in children and adolescents with epilepsy and mental retardation: a prospective study on behavior and cognitive effects.

The aim of the present study was to assess the behavioral and cognitive effects following treatment with topiramate in children and adolescents with epilepsy with mild to profound mental retardation. The study group comprised 29 children, 16 males and 13 females, aged 3 to 19 years, affected by partial (4) and generalized (25) crypto/symptomatic epilepsy and mental retardation (7 mild, 5 moderate, 15 severe, 2 profound), who were administered topiramate (TPM) as add-on therapy to their baseline antiepileptic treatment. At baseline, 3 months, 6 months, and 12 months, parents or caregivers of each patient were administered a questionnaire based on the Holmfrid Quality of Life Inventory. After a 3-month follow-up, the add-on topiramate caused overall mild to moderate cognitive/behavioral worsening in about 70% of children and adolescents with mental retardation and epilepsy. After 6 and 12 months of follow-up, global worsening persisted in 31 and 20.1% of cases, respectively. In conclusion, this trial confirms that TPM can have significant adverse cognitive and behavioral side effects, even in mentally disabled children and adolescents. 2007 Elsevier Inc. All rights reserved

Cognitive and linguistic abnormalities in benign childhood epilepsy with centrotemporal spikes

Aim: To assess the cognitive function and language ability in children with benign partial epilepsy with centrotemporal spikes. Methods: Twenty-five patients with benign partial epilepsy with centrotemporal spikes were included. They were divided into two subgroups. Group I: 10 patients with rolandic focus who were not treated. Group II: 15 patients with rolandic focus receiving treatment. A third Group of 12 healthy subjects have been studied. All children underwent standardized neuropsychological testing: electroencephalogram recording, Wechsler Intelligence Scale for Children-revised, Peabody Picture Vocabulary Test-III (PPVT-III) and Boston Naming Test (BNT), both during active disease (T1) and 2 years after recovery from epilepsy (T2). Results: At T1 evaluation, no significant differences in group I and II patients about general intelligence, when compared with controls, were found. Group I and II patients were impaired with respect to controls in the receptive and expressive vocabulary evaluated with PCVT-III and BNT, respectively. At T2 evaluation, group I and II patients showed a normalization of the language abnormalities. Conclusion: Deficits of speech-related abilities can be detected in children with this type of epilepsy: these dysfunctions seem to be independent of the effects of antiepileptic treatment and are reversible after remission of epilepsy

Low glycemic index diet in children and young adults with refractory epilepsy: first Italian experience.

This is the report on the first Italian experience with the low glycemic index diet (LGIT) in a group of children, adolescents and young adults with refractory epileptic encephalopathies. A retrospective chart review was performed on patients initiating the LGIT in an outpatient setting from 2005 to 2010. Demographic and clinical information including seizure type, baseline seizure frequency, medications, blood chemistry, side effects, and anthropometrics were collected. Patients were educated and followed by a dietician to restrict foods with high glycemic index and to limit total daily carbohydrates to 40-60g. Change in seizure frequency was assessed at each 3-month follow-up intervals in the first year and then at each 6-month intervals. Fifteen consecutive patients (13 males and 2 females, aged between 11.3 years and 22 years), almost all affected by generalized cryptogenic or symptomatic refractory epilepsy, were enrolled in the study. After a mean follow-up period of 14.5±6.5 months (median 12.0; range 1-60 months), 6 patients (40%) had a 75-90% seizure reduction, while seizures decreased by 50% in other 2 (13.3%) and were unchanged in 7 (46.7%). The diet was discontinued in 4 patients within the first 5 months. No adverse events occurred during the diet. In conclusion, this initial experience confirms that some refractory patients may improve on the LGIT, even as first dietary option

Valproic acid and phenobarbital blood levels during the first month of treatment with the ketogenic diet.

Objective – The aim of this study was to assess how the ketogenic diet influences the blood levels of antiepileptic drugs in the first month of treatment in a pediatric population with drug-resistant epilepsy. Methods – The plasma concentrations of antiepileptic drugs were investigated in an open study on 36 consecutive children and adolescents (20 males), aged between 6 months and 16 years (mean age 4.7 years), who were put on the ketogenic diet because of medically refractory epilepsy. The plasma levels of antiepileptic drugs were determined 30 days and immediately before the diet and on days 8, 15, 22 and 29 after the start of the diet. The daily dose of each drug was not changed during the first month of treatment, while the daily dose of benzodiazepines was reduced by up to 30% if excessive sedation or drowsiness occurred. Results – While plasma concentrations of phenobarbital did not change in the first month on the ketogenic diet (mean increase of 2.3 mg ⁄ l 1.0), valproic acid showed a slight but not significant decrease (mean decresase of 6.7 mg ⁄ l 3.2), 2 weeks after the start of the diet. Conclusions – Adjustments in the daily dose of either drug before the start of the diet do not however appear to be justified

Efficacy and safety of felbamate in children under 4 years of age: a retrospective chart review.

Background and purpose: To review our experience of the efficacy and tolerability of felbamate in children younger than 4 years. Methods: We used a retrospective chart review to identify 53 children with seizures who were younger than 4 years. Efficacy was evaluated based on the occurrence of responsiveness, defined as seizure frequency reduction of more than 50% for a minimum period of 4 months. Tolerability was based on parent-reported side effects. Results: Twenty-two (41%) patients resulted to be responders and 31 (59%) did not. By univariate analysis, those achieving seizure remission were probably much older, to have a shorter history of epilepsy and a lower frequency of seizures before felbamate therapy. The number of antiepileptic drugs (AEDs) used before felbamate therapy was the only significant predictor of the duration of response to felbamate, with a longer responsiveness to the drug seen in those who were placed under fewer than three AEDs before felbamate compared with those who had taken more than three (median, 16 months vs. 7 months; P < 0.0084). Side effects occurred in 30% of the subjects, but these did not require discontinuation of the drug. Discussion: Felbamate is an effective medication for a wide range of epilepsy syndromes in children younger than 4 years. Although caution is necessary when the drug is used in children, felbamate might represent a possible option for the treatment of epilepsy in this age group. Introduction The incidence of epilepsy is high during the first year of life and it declines steadily during childhood and adolescence. Few of the new antiepileptic drugs (AEDs) are indicated officially for children younger than 4 years [1–3]. None of them is approved for children younger than 2 years [1,3,4]. There is a striking discrepancy between the high incidence of epilepsy in infancy and the relatively few approved AEDs available for this age group [5]. Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a derivative of the anti-anxiety drug meprobamate, exerting additional anticonvulsant and neuroprotective properties [6–8]. The drug has been approved since 1993 for the treatment of several types of epilepsy. Experimental studies suggested that felbamate might inhibit voltage-dependen