Pre-surgical mapping of eloquent cortex for paediatric epilepsy surgery candidates: Evidence from a review of advanced functional neuroimaging.

PURPOSE: A review of all published evidence for mapping eloquent (motor, language and memory) cortex using advanced functional neuroimaging (functional magnetic resonance imaging [fMRI] and magnetoencephalography [MEG]) for paediatric epilepsy surgery candidates has not been conducted previously. Research in this area has predominantly been in adult populations and applicability of these techniques to paediatric populations is less established. METHODS: A review was performed using an advanced systematic search and retrieval of all published papers examining the use of functional neuroimaging for paediatric epilepsy surgery candidates. RESULTS: Of the 2724 papers retrieved, 34 met the inclusion criteria. Total paediatric participants identified were 353 with an age range of 5 months-19 years. Sample sizes and comparisons with alternative investigations to validate techniques are small and variable paradigms are used. Sensitivity 0.72 (95% CI 0.52-0.86) and specificity 0.60 (95% CI 0.35-0.92) values with a Positive Predictive Value of 74% (95% CI 61-87) and a Negative Predictive Value of 65% (95% CI 52-78) for fMRI language lateralisation with validation, were obtained. Retrieved studies indicate evidence that both fMRI and MEG are able to provide information lateralising and localising motor and language functions. CONCLUSIONS: A striking finding of the review is the paucity of studies (n=34) focusing on the paediatric epilepsy surgery population. For children, it remains unclear which language and memory paradigms produce optimal activation and how these should be quantified in a statistically robust manner. Consensus needs to be achieved for statistical analyses and the uniformity and yield of language, motor and memory paradigms. Larger scale studies are required to produce patient series data which clinicians may refer to interpret results objectively. If functional imaging techniques are to be the viable alternative for pre-surgical mapping of eloquent cortex for children, paradigms and analyses demonstrating concordance with independent measures must be developed.

Corticosteroids including ACTH for childhood epilepsy other than epileptic spasms.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2007.Epilepsy is a disorder with recurrent epileptic seizures. Corticosteroids have been used in the treatment of children with epilepsy and have significant adverse effects. Their efficacy and tolerability have not been clearly established. OBJECTIVES: To determine the efficacy, in terms of seizure control, improvements in cognition and in quality of life and tolerability of steroids compared to placebo or other antiepileptic drugs in children with epilepsy, excluding epileptic spasms. SEARCH METHODS: We searched the following databases: The Cochrane Epilepsy Group Specialized Register (1 August 2014); CENTRAL, (The Cochrane Library Issue 7, July 2014); MEDLINE (1946 to 1 August 2014); EMBASE (1966 to December 2004); Database of Abstracts of Reviews of Effectiveness (DARE; Issue 3 of the database published in The Cochrane Library Issue 7, July 2014); ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform ICTRP (1 August 2014).We checked the reference lists of retrieved studies for additional reports of relevant studies. SELECTION CRITERIA: All randomised controlled trials of administration of corticosteroids to children (less than 16 years) with epilepsy. DATA COLLECTION AND ANALYSIS: For this update two review authors independently selected trials for inclusion and extracted data. Outcomes included cessation of seizures, reduction in seizure frequency, improvement in cognition, quality of life and adverse effects of steroids. MAIN RESULTS: A single RCT was included that recruited five children in a double blind cross-over trial. One child was withdrawn prematurely from the study and another had infantile spasms and hence was excluded from further analysis. Adrenocorticotrophin hormone (ACTH 4-9) was administered. Of the three children analysed, one showed a reduction in seizures of 25% to 50% at both the low and higher doses of corticosteroids compared to placebo; one child showed a reduction in seizures at the higher dose only and one child showed no reduction in seizures at either dose. No adverse effects were reported. AUTHORS' CONCLUSIONS: Since the last version of this review no new evidence has been found for the efficacy of corticosteroids in treating childhood epilepsies. Clinicians using steroids in childhood epilepsies, other than for epileptic spasms, should take this into account before using these agents.

Antiepileptic drug treatment of rolandic epilepsy and Panayiotopoulos syndrome: clinical practice survey and clinical trial feasibility.

BACKGROUND: The evidence base for management of childhood epilepsy is poor, especially for the most common specific syndromes such as rolandic epilepsy (RE) and Panayiotopoulos syndrome (PS). Considerable international variation in management and controversy about non-treatment indicate the need for high quality randomised controlled trials (RCT). The aim of this study is, therefore, to describe current UK practice and explore the feasibility of different RCT designs for RE and PS. METHODS: We conducted an online survey of 590 UK paediatricians who treat epilepsy. Thirty-two questions covered annual caseload, investigation and management practice, factors influencing treatment, antiepileptic drug preferences and hypothetical trial design preferences. RESULTS: 132 responded (22%): 81% were paediatricians and 95% at consultant seniority. We estimated, annually, 751 new RE cases and 233 PS cases. Electroencephalography (EEG) is requested at least half the time in approximately 70% of cases; MRI brain at least half the time in 40%-65% cases and neuropsychological evaluation in 7%-8%. Clinicians reported non-treatment in 40%: main reasons were low frequency of seizures and parent/child preferences. Carbamazepine is the preferred older, and levetiracetam the preferred newer, RCT arm. Approximately one-half considered active and placebo designs acceptable, choosing seizures as primary and cognitive/behavioural measures as secondary outcomes. CONCLUSIONS: Management among respondents is broadly in line with national guidance, although with possible overuse of brain imaging and underuse of EEG and neuropsychological assessments. A large proportion of patients in the UK remains untreated, and clinicians seem amenable to a range of RCT designs, with carbamazepine and levetiracetam the preferred active drugs.

Syncope-like epileptic seizures in Panayiotopoulos syndrome.

OBJECTIVE: To describe the clinical features of syncope-like epileptic seizures (SLES) and their frequency in Panayiotopoulos syndrome (PS). METHODS: This was a 6-year prospective study of all children aged 1-15 years referred for an EEG. PS was defined by the occurrence of at least one autonomic seizure (AS) in a neurodevelopmentally normal child and at least one EEG with focal spikes. SLES were defined as self-terminating events of sudden loss of postural tone and unresponsiveness, occurring either concurrently with other ictal autonomic symptoms and signs that characterize PS (AS + SLES) or on their own (pure SLES). RESULTS: PS was diagnosed in 33 of 394 consecutive children with at least one afebrile seizure (8.4%). SLES occurred at least once in 17 of 33 children (51.5%); 12 presented SLES in all their AS, and 5 had also AS without SLES. Overall, 53 of 74 AS manifested with SLES (71.6%); 25 were AS + SLES and 28 were pure SLES. The latter occurred in 7 children suddenly and without premonition or obvious triggers while standing, sitting, lying down, or asleep, did not resolve in the horizontal position, and were not associated with stiffening or any involuntary movements, even when longer than a few minutes. Concurrent autonomic symptoms during AS + SLES included emesis, incontinence, mydriasis, miosis, and cardiorespiratory abnormalities. CONCLUSIONS: SLES is a common ictal manifestation of PS and should be considered in the differential diagnosis of suspected syncope, particularly when clinical signs are atypical for neurocardiogenic syncope and the EEG shows focal spikes.

Recovery of consciousness following acute symptomatic seizures due to central nervous system infections in children.

AIM: The aim of this study was to assess whether acute symptomatic epileptic seizures associated with central nervous system infections (AS(inf) ) have a different ictal and postictal course to seizures of other aetiologies. METHOD: A case note analysis of 81 children (47 males; 34 females; age range 1mo-15y 6mo; median age 12mo) with central nervous system infections was undertaken. Seizure type, duration, aetiology, and timing were recorded. Recovery time to full consciousness in those not intubated was determined. Intubation rates and recovery times were compared with those from previous studies. RESULTS: Of the 81 children, 40 (49.4%) had one or more AS(inf) . The different aetiologies were bacterial meningitis, aseptic meningitis, abscess/empyema, encephalitis, and postoperative infection. Twenty-two had status epilepticus. The intubation rate in children with AS(inf) was higher than that in children with seizures of other aetiologies (21/40 [52.5%] vs 4/124 [3.23%]; p < 0.0001). Median postictal recovery time was 4.33 hours (0-207h). Children with AS(inf) took 4.3 (p<0.01), 3.0 (p=0.004), and 8.8 (p<0.001) times longer to recover than children who had seizures from all causes, remote symptomatic seizures, and febrile seizures respectively. INTERPRETATION: AS(inf) in children are often longer, more likely to be associated with status epilepticus, more likely to necessitate intubation, and take longer to recover from than seizures of other aetiologies. This may help in the early diagnosis of central nervous system infection in children presenting with seizures.

Rufinamide: a new antiepileptic drug treatment for Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is a relatively rare epilepsy syndrome that usually begins in early-mid childhood and is characterized by multiple seizure types, particularly generalized seizures, which are often resistant to antiepileptic drug medication. Rufinamide is a new antiepileptic drug approved as adjunctive therapy to treat seizures in Lennox-Gastaut syndrome in those 4 years of age and older. In this article, the putative mechanism of action is described, along with data relating to its pharmacokinetics and metabolism. Key findings from clinical trials are presented and discussed. Adverse effects are summarized and compared with those encountered with competitor antiepileptic drugs. Finally, the role of rufinamide in the holistic management of subjects with Lennox-Gastaut syndrome is considered.

Panayiotopoulos syndrome: an important childhood autonomic epilepsy to be differentiated from occipital epilepsy and acute non-epileptic disorders.

Panayiotopoulos syndrome is a common multifocal autonomic childhood epileptic disorder with significant clinical, pathophysiological and management implications. It affects otherwise normal children with onset at around 3-6 years. It is characterized by seizures, often prolonged, with predominantly autonomic symptoms and mainly ictal vomiting. EEG shows shifting and/or multiple foci, often with occipital dominance. Despite characteristic clinical and EEG manifestations Panayiotopoulos syndrome is often confused with occipital epilepsy and acute non-epileptic disorders such as encephalitis, syncope, cyclic vomiting or atypical migraine. This review aims to describe Panayiotopoulos syndrome on the basis of independent major studies and provide clinical clues for diagnosis and management.

Cogan's syndrome: a rare cause of meningoencephalitis.

We report a 14-year-old boy who presented with meningoencephalitis. Other features particularly auditory, vestibular, and ocular lead to the diagnosis of Cogan's syndrome. Treatment with prednisolone resulted in a rapid improvement and recovery of his hearing. Cogan's syndrome is a rare primary vasculitis, characterized by ocular, auditory, and vestibular symptoms, which can have significant morbidity and mortality. Presentation with a meningoencephalitic picture is unusual. Increased awareness of its clinical features among pediatricians and pediatric neurologists should lead to earlier diagnosis and increased recognition of the serious systemic manifestations. Early use of prednisolone can prevent hearing loss and can also be useful in treating the other vasculitic manifestations.

Treatment of Lennox-Gastaut Syndrome (LGS).

Lennox-Gastaut Syndrome (LGS) is a severe form of epilepsy that usually starts in early to mid childhood and is characterized by multiple seizure types, abnormal electroencephalogram with slow spike-and-wave discharges and cognitive problems. Numerous approaches are currently used to treat LGS, including use of conventional antiepileptic drugs (most commonly sodium valproate, lamotrigine and topiramate), other drug interventions (corticosteroids and intravenous immunoglobulin) and nonpharmacologic treatments (ketogenic diet, corpus callosotomy and vagus nerve stimulation). Rufinamide is the most recent antiepileptic drug to have shown efficacy in the treatment of LGS. Despite the variety of therapeutic options, there have been only five double-blind, placebo-controlled clinical trials of antiepileptic drugs in LGS and none of these were head-to-head comparison trials. The evidence supporting the use of available treatments for LGS is, therefore, not robust. Here, we review the evidence supporting the use of specific therapies in LGS and provide recommendations on how to set appropriate treatment goals, select treatments and minimize polypharmacy. A suggested treatment algorithm is presented and discussed. Sodium valproate is recommended for first-line therapy; if seizures persist, alternative interventions should be trialed on an individually tailored basis.

tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia.

Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.

Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Ethnic differences in the incidence of seizure disorders in children from Bradford, United kingdom.

We sought to determine if there are differences in the incidence of seizure disorders between the children of the indigenous and immigrant (predominantly Pakistani) populations of Bradford, United Kingdom. Annual incidence rates per 100,000 for new onset seizures were calculated along with Townsend deprivation scores. The incidence of seizures (including febrile and single) was 153 (95%CI 104-139). The rate was significantly higher in south Asians (SA) (220; 184-255) compared to non-south Asians (non-SA) (121; 104-139), mainly because of febrile seizures whose incidence was 87 (136-169) overall and 142 (114-170) and 61 (49-74) in SA and non-SA, respectively. There were no significant differences in the rates of nonfebrile seizures (non-FebSz) overall and of idiopathic non-FebSz between racial groups but the rate for symptomatic/cryptogenic non-FebSz was significantly higher in SA (22; 10-34) compared to non-SA (6; 2-10). The occurrence of seizure disorders correlated with social deprivation.

Autonomic status epilepticus in Panayiotopoulos syndrome and other childhood and adult epilepsies: a consensus view.

PURPOSE: To discuss and propose a definition of autonomic status epilepticus (SE), describe its clinical and EEG features, and review what is known about its epidemiology, pathophysiology, differential diagnosis, and management. METHODS: An international consortium of established researchers in the field was identified from their published work, agreed the purpose of the project, searched the literature, and, by use of e-mail communication, agreed the consensus document. RESULTS: Autonomic SE is a condition lasting at least 30 min and characterized by epileptic activity causing altered autonomic function of any type at seizure onset or in which manifestations consistent with altered autonomic function are prominent (quantitatively dominant or clinically important) even if not present at seizure onset. It is best described, and probably most commonly encountered in children, with Panayiotopoulos syndrome. However, it also occurs in children with symptomatic epilepsies and, exceptionally, in adults. Its pathogenesis and most appropriate management are poorly understood. CONCLUSIONS: It is hoped that this document will help clinical recognition of Autonomic SE, reduce misdiagnosis, and promote further interest and studies into what has been a relatively neglected area.

Idiopathic generalized epilepsies imitating focal epilepsies.

Classification of epileptic seizures and epilepsy syndromes as either focal or generalized is a fundamental and early part in the diagnostic process and is generally fairly easily accomplished. However, in patients with idiopathic generalized epilepsies, seizure and EEG features may suggest, particularly to the unwary, the occurrence of focal rather than generalized seizures. Misinterpretation of typical absence seizures as focal seizures, especially as temporal lobe seizures and of myoclonic seizures as focal clonic seizures, is a relatively common error and focal features during generalized tonic-clonic seizures may also be quite common. Sequences of seizures in idiopathic generalized epilepsies (such as absences or jerks followed by generalized tonic-clonic seizures) may also cause confusion. Versive and circling seizures are seizure types whose ictal semiology is clearly focal; nevertheless such seizures are described in idiopathic generalized epilepsies accompanied by generalized EEG discharges. The occurrence of focal EEG abnormalities in certain idiopathic generalized epilepsy syndromes is common. This is best known in juvenile myoclonic epilepsy.