Landau-Kleffner Research Articles

Epilepsy genetics: The ongoing revolution

Epilepsies have long remained refractory to gene identification due to several obstacles, including a highly variable inter- and intrafamilial expressivity of the phenotypes, a high frequency of phenocopies, and a huge genetic heterogeneity. Recent technological breakthroughs, such as array comparative genomic hybridization and next generation sequencing, have been leading, in the past few years, to the identification of an increasing number of genomic regions and genes in which mutations or copy-number variations cause various epileptic disorders, revealing an enormous diversity of pathophysiological mechanisms. The field that has undergone the most striking revolution is that of epileptic encephalopathies, for which most of causing genes have been discovered since the year 2012. Some examples are the continuous spike-and-waves during slow-wave sleep and Landau-Kleffner syndromes for which the recent discovery of the role of GRIN2A mutations has finally confirmed the genetic bases. These new technologies begin to be used for diagnostic applications, and the main challenge now resides in the interpretation of the huge mass of variants detected by these methods. The identification of causative mutations in epilepsies provides definitive confirmation of the clinical diagnosis, allows accurate genetic counselling, and sometimes permits the development of new appropriate and specific antiepileptic therapies. Future challenges include the identification of the genetic or environmental factors that modify the epileptic phenotypes caused by mutations in a given gene and the understanding of the role of somatic mutations in sporadic epilepsies.

Sleep and epilepsy syndromes.

Sleep and epilepsy have a close relationship. About 20% of patients suffer seizures only during the night, approximately 40% only during the day and approximately 35% during the day and night. In certain epilepsy syndromes, the occurrence of seizures is strongly related to sleep or awakening. Infantile spasms appear predominately on awakening, and hypsarrhythmia is sometimes visible only in sleep. Children with Panayiotopoulos syndrome or benign epilepsy with centrotemporal spikes (BECTS) have seizures mostly when asleep, and in both syndromes interictal spike waves are markedly accentuated in slow wave sleep. Electrical status epilepticus during slow sleep/continuous spike wave discharges during sleep (ESES/CSWS), atypical benign partial epilepsy, and Landau-Kleffner syndrome are epileptic encephalopathies with substantial behavioral and cognitive deficits, various seizures, and continuous spike-wave activity during non-rapid eye movement (NREM) sleep. The hallmark of juvenile myoclonic epilepsy and grand mal seizures on awakening are seizure symptoms within 2 hours after awakening, often provoked by sleep deprivation. Nocturnal frontal lobe epilepsy is sometimes mistaken for parasomnia. Differentiation is possible when the clinical symptoms and the frequency of the paroxysmal events per night and month are carefully observed and nocturnal video electroencephalography (EEG) performed. Sleep EEG recordings may be helpful in patients with suspected epilepsy and nonconclusive awake EEG. Depending on the clinical question, sleep recordings should be performed during nap (natural sleep or drug induced), during the night, or after sleep deprivation.

OP13 – 2799: Landau-Kleffner syndrome (LKS), continuous spike and waves during slow-wave sleep syndrome (CSWSS), and Rolandic epilepsy (RE) – A genetic and immunological study

Objective LKS and CSWSS present with seizures, language and cognitive regression. Genetic studies have identified mutations in the GRIN2A gene, and copy-number-variants in genes encoding cell adhesion proteins (including CASPR2, contactin-2). Given that some affected patients respond to steroids we looked for autoantibodies to similar neuronal targets. Methods A previously genetically characterised cohort of patients with LKS (4 patients), CSWSS (23), RE (14), epilepsy with autism or neurodevelopmental disorder (2) and unaffected controls (10) was tested for neuronal surface antibodies (Abs) to GRIN1, GRIN2A and 2B, CASPR2 and contactin-2 proteins using cell-based-assays, and VGKC-complex-Abs by radioimmunoprecipitation. Results 8 samples were positive (8/53; 15%), 4 for CASPR2-Abs (low positive) and 4 for VGKC-complex-Abs (113–1102 pM). All samples were negative for contactin-2, GRIN1, 2A and 2B-Abs. Positive results were found in CSWSS patients (n=3; 2 VGKC-complex, 1 CASPR2), Rolandic epilepsy (n=3; 1 VGKC-complex, 2 CASPR2-Ab positive), and a neurodevelopmental disorder (dyspraxia, CASPR2-Ab); one control was VGKC-complex-Ab positive (unaffected father of an antibody positive patient). 3 positives were found in a single three-generation French family affected by LKS, CSWSS and RE, 2 also had GRIN2A mutations. Conclusion Overall, none of the 4 LKS patients in the cohort were antibody positive, 13% CSWSS (3/23) and 21% Rolandic epilepsies (3/14) had low positive CASPR2 or VGKC-complex-Abs. The three positive results in 3 different generations of the same GRIN2A family, which included an unaffected sibling with the disease associated GRIN2A mutation and an unaffected father with a positive antibody, suggests a possible dual aetiology in a small subset of epilepsy patients where autoantibodies might influence the presentation and severity of genetic cases. However, low level neuronal antibodies, and even genetic mutations, may not always be causal, but their coexistence in some patients suggests that these complex genetic diseases may also have a neuroinflammatory component.

P26 – 2615: Landau Kleffner syndrome following a minor head trauma – Case report

Background Landau Kleffner syndrome (LKS) is well defined epileptic encephalopathy best described by the synonym – acquired epileptic aphasia. Etiopathogenesis remains unknown. Structural lesions are rare. A few published cases postulated triggering role of head trauma in functional disconnection of cortical speech areas. Objective To evaluate the clinical presentation and management of a boy with LKS following a minor head trauma. Case report and results A ten years old boy of far consanguineous parents, at his age of six developed a generalized tonic clonic seizure following a head trauma two weeks before upon fall. The immediate period was uneventful, the child had only nose bleeding, brain CT was normal. However, consequent EEG showed ESES and he was started on valproates. Noncompliance led to another seizure six months later. Over that period, gradual regression in the ability to use or comprehend spoken language was noted. EEG showed more or less pronounced bilateral ESES affecting predominantly left temporo-parietal regions. Perinatal period and developmental before the onset of the illness were normal. Family history was unremarkable. Metabolic work up was normal. MRI brain done twice was unremarkable. Neurological status, apart from aphasia, was normal. Parents reported impulsivity and cognitive decline. He had one episode of focal seizure two years since the onset, but further has remained controlled. He went through several antiepileptic drugs combinations including valproates, clobazam, levetiracetam, clonazepam and lamotrigine. Ethosuximide was stopped due to intolerance. Two trials with oral prednisolone: the first lasting four months, complicated by hypertension, the second, of one month prednisolone with evening diazepam, resulted in transient clinical and EEG moderate improvement. Ketogenic diet was recommended. Conclusion Aphasia, inspite of various therapeutical attempts and favorable seizure control, remained the main concern. Corticosteoids transiently and partially improved the condition. Possible role of head trauma in LKS etiopatogenesis needs further consideration.

P10 – 2235: Effectiveness of a corticosteroid treatment regimen of a pulse methylprednisolone followed by alternate day oral prednisolone and a review of published treatment results of corticosteroids on refractory childhood seizures

Objective To report our experience with the treatment of refractory seizures in children with epilepsies other than West and Landau-Kleffner syndrome with a new treatment regimen and to put our results in perspective with a review of original papers of all corticosteroid and ACTH treatments for refractory epileptic seizures in children. Methods In this retrospective observational study 26 children diagnosed with epilepsy with refractory seizures other than West syndrome and Landau-Kleffner syndrome were eligible for a treatment regimen consisting of three days intravenous methylprednisolone (20 mg per kilogram per day) followed by twelve weeks oral prednisolone (0.5 mg per kilogram on alternate days), followed by a taper phase. Data on efficacy and side effects were obtained. End-points were the percentage of patients that became seizure free or showed a good response (50% or more seizure reduction). Results Twenty-one patients were treated according to the protocol. Forty-three percent of the children showed a good response and 29% became seizure free. All but one patient had a relapse of seizures. Four patients had reversible adverse effects. From the data extracted from the literature we found that 52% of 155 children, that were treated with different corticosteroids showed a good response and 69% of 103 patients treated with ACTH. Conclusion Corticosteroids are a promising treatment modality in refractory seizures, but relapses are common. Results on efficacy and safety shown in this paper justify a randomized controlled trial.

PP13.7 – 2337: Systematic literature review of intravenous immunoglobulin use in paediatric neurological and neurodevelopmental conditions

Objective To perform a systematic literature review to summarise the evidence, provide recommendations for practice, and suggest future research regarding the use of intravenous immunoglobulins (IVIGs) in the treatment of paediatric neurological and neurodevelopmental disorders. Methods A MEDLINE search was performed for IVIG treatment in paediatric neuroinflammatory, neurodevelopmental and neurodegenerative conditions between September 2003–2013. Results From the 221 citations identified, 30 studies were included (3 randomised control trials, 3 cohort studies and 24 case series). Due to the heterogeneous outcome measures, meta-analysis was not possible within individual neurological disorders, and therefore findings were combined and evidence graded. Level 1: None Level 2: Guillain-Barre Syndrome: Reduces time to recovery (n=117), but not maximal disability (n=76), and is less effective than plasma exchange at reducing ventilation duration (n=41). Acute Encephalitis Syndrome with Myocarditis: Improves mortality and cardiac function (n=83). Rasmussen's: As effective as tacrolimus in preventing disease progression and treatment-resistant seizures (n=16). Level 3: None Level 4: NMDAR-Ab encephalitis: Good outcome at 2 years in conjunction with additional immunotherapy (n=298). Chronic Inflammatory Demyelinating Polyradiculoneuropathy: As effective as corticosteroids at improving neurological function (n=74). Acute Disseminated Encephalomyelitis: As effective as corticosteroids at inducing complete recovery (n=44). Narcolepsy: Reduces cataplexy symptoms (n=8). Tourette's Syndrome with caudate nucleus antibodies: Temporary reduction in tics (n=7). Limbic encephalitis, Landau-Kleffner Syndrome, Refractory Seizure Disorders: No improvement in outcome (n=4, n=10, n=12). Early IVIG therapy may improve efficacy in Rasmussen's, NMDAR-Ab encephalitis and Narcolepsy. No evidence available: Autism, Neurodegeneration. Conclusion In the last 10 years, there is growing evidence for the efficacy of IVIG in a handful of neurological conditions. Nevertheless, well designed, prospective, multi-centre studies with standardized outcome measures are now required to evaluate the efficacy and cost effectiveness of this expensive and resource limited therapeutic agent.

OP11 – 2424: Genotype–phenotype correlations in patients with GRIN2A variants

Objective The GRIN2A gene has been associated with both benign childhood epilepsies and severe epileptic encephalopathies. This study evaluates the genotype–phenotype correlations in patients with GRIN2A variants. Methods A systematic literature search was performed, identifying all patients reported before May 2014 with GRIN2A variants. Patients were classified in two groups based on their GRIN2A genotype. Group I genotypes had an expected detrimental effect on protein expression: nonsense, frameshift, splice site, or initiation codon sequence variants, translocations with breakpoints within GRIN2A, or deletions comprising GRIN2A. Group II genotypes were expected to result in an altered protein structure or function: missense or in-frame sequence variants. Results Of 136 patients, 74 were included in group I and 62 in group II. Epilepsy was diagnosed in 86% of patients in both groups, with focal seizures being most common (82%). Benign epilepsy with centrotemporal spikes (BECTS) was significantly more often diagnosed in group II than in group I (51% versus 27%, p=0.03). Continuous spikes and waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) occurred more often in group I than in group II (50% versus 37%), although not statistically significant (p=0.29). Mild to severe developmental problems related to speech and language (80%), cognition (66%), and motor skills (48%), and behavioural problems (61%) were present in both groups. Speech and language problems were significantly more often reported in group I than in group II (90% versus 69%, p=0.02), also in patients with no LKS/CSWS (94% versus 50%, p=0.01). Conclusion GRIN2A variants are associated with a spectrum of epilepsies, mainly accompanied by language developmental problems. This epilepsy-aphasia syndrome spectrum ranges from relatively mild BECTS to more severe LKS/CSWS. This study shows that GRIN2A genotypes with an expected milder effect on protein function are associated with a relatively more benign phenotype including BECTS without language problems.

PP07.11 – 2695: Epilepsy in autism spectrum disorders

Objective Approximately one third of children with pervasive developmental disorders or autistic spectrum disorders reports an early regression of unknown cause in their children's language. Seizures are associated with language regression in acquired epileptic aphasia (Landau-Kleffner syndrome) and some other pediatric epileptic syndromes. Children with ASD and epilepsy had significantly more autism symptoms and maladaptive behaviors than children without epilepsy. Methods Children of our study were 72 boys and 20 girls on the autistic spectrum disorders seen consecutively in consultation by one child neurologist and psychiatrist in Universitary Hospital Center Tirana. Data on autistic regression, seizures, and cognitive function were entered prospectively into a data base. Results 28 (30%) had a history of regression, and 20 children (22%) had a history of epilepsy. Regression had occurred equally among children without seizures and in those with epilepsy. Regression was associated with an epileptiform EEG in 15% of 76 nonepileptic children who had undergone a regression. Mean age at regression was 23 months. Half of the epileptiform discharges were centro-temporal. Children with lower cognitive function were more likely to have undergone regression than those with better cognitive skills (30% vs 20%). Conclusion Epilepsy occur in a significant minority of autistic children with a history of regression and in a smaller minority without regression. There is no evidence-based treatment recommendation for individuals with autism, regression, and subclinical epilepsy.

P182 – 2399: Epileptic encephalopathy due to progressive severe hardly curable epilepsy forms in children with extremely low birth weight and very low birth weight

Objective Study of progressive epileptic encephalopathy at destructive epilepsy forms in small premature infants. Methods 5-years clinical-paraclinical (brain MRI, 24-hour Holter and video EEG monitoring) examination of 103 children with extremely low birth weight and 108 children with very low birth weight (ELBW and VLBW) with epileptic encephalopathy in the form of behavior and progressive dementia developed due to age-dependent epilepsy form who are primarily resistant to antiepileptic drugs. Results Rate of severe epileptic encephalopathy in children with ELBW and VLBW was 15% and 11% correspondingly at early infantile encephalopathy with suppressive-explosive pattern at EEG (Othahara syndrome); 9% and 6% at severe epilepsy with multiple independent spike focuses (Markand-Blume-Othahara syndrome); 6% and 4% at malignant migrating partial seizures at infancy (MMPSI). At epilepsy onset epileptic encephalopathy developed in 3% and 2% of children with ELBW and VLBW after 1 year of life at Doose syndrome; 5% and 3% at Lennox-Gastaut syndrome; 4% and 2% at hemiconvulsive seizures and hemiplegia syndrome provoked by hyperthermia; 5% and 4% at destructive epileptic encephalopathy in school-aged children caused by hyperthermia (FIRES-syndrome); 3% and 2% at Landau-Kleffner syndrome (acquired epileptic aphasia). Cognitive epileptiform disintegration with epileptic activity at EEG and without epileptic attacks occurred in 5% and 3% of children correspondingly. Often hyperthermia was the marker of life-threatening epileptic status occurrence in small premature infants – 10 to 100 per day. Primarily these epilepsy forms were resistant, rapidly transferred to epileptic encephalopathy. Conclusion Often cerebral pathology in small premature infants causes development of early destructive epileptic encephalopathy. Hyperthermia promotes to febrile-provoked epilepsy development at which infant psychic disorder progresses and dementia increases.

Effectiveness of a hybrid corticosteroid treatment regimen on refractory childhood seizures and a review of other corticosteroid treatments.

Many different corticosteroid treatment schedules have been used in order to treat refractory epileptic seizures with encouraging effects on seizure reduction in many epileptic syndromes. The objective is to report our experience with a hybrid treatment regimen for refractory seizures in children with epilepsies other than West and Landau-Kleffner syndrome. We hypothesized that a pulse of corticosteroids effectively reduces seizures while low-dosage maintenance treatment reduces side effects. The results are compared with results from a review of reported corticosteroid and ACTH treatments. In this retrospective observational study, 26 children diagnosed with epilepsy with refractory seizures other than West syndrome and Landau-Kleffner syndrome were eligible for a treatment regimen consisting of three days intravenous methylprednisolone (20mg per kilogram per day) followed by twelve weeks oral prednisolone (0.5mg per kilogram on alternate days), concluded with a taper phase. Data on effectiveness and side effects were obtained. End-points were the percentages of patients who became seizure free or responded well. Twenty-one patients received the study treatment. Nine (43%) responded well and 6 (29%) became seizure free. All but one patient had a relapse of seizures. Four patients had reversible adverse effects. Data extracted from the literature were consistent with a good response in 48% of 192 children treated with different corticosteroids and in 69% of 103 patients treated with ACTH. This new hybrid therapy of a pulse of intravenous methylprednisolone and alternate day oral prednisolone is effective with a favourable side effect profile. Results on efficacy and safety justify a randomized controlled trial.

New genes for focal epilepsies with speech and language disorders.

The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20% of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.

Las evoluciones atípicas de la epilepsia rolándica son complicaciones predecibles

The development of atypical features in rolandic epilepsy is part of a clinical spectrum of phenotypes that are variable, idiopathic and age-dependent, as well as having a genetically determined predisposition. To study the electroclinical characteristics suggesting an atypical development in rolandic epilepsy. A retrospective search was performed in 133 children diagnosed with atypical benign focal epilepsy (ABFE), Landau-Kleffner syndrome and continuous spike-wave during sleep (CSWS). Nine patients were selected, all of whom presented atypical clinical features and an electroencephalogram (EEG) pattern of electrical status epilepticus during sleep (ESES) in the course of their rolandic epilepsy. The average age at onset of rolandic epilepsy was 5 years. Patients showed a deterioration of both their clinical features and their EEG recording one and a half years later, on average. ABFE was observed in three of them and CSWS in six. No cases of Landau-Kleffner syndrome were found. The EEG in wakefulness showed the focus to be in the left centrotemporal region in six patients and in three of them it was on the right-hand side. All the patients presented ESES in the EEG during sleep. An atypical pattern was observed in the regional ESES in three of the patients. Moreover, cognitive and behavioural disorders were detected due to deficits in specific learning areas, such as language, memory, attention and restlessness. The early onset of rolandic epilepsy, the appearance of new seizures with an increased frequency and the frontocentrotemporal focus in the EEG, which increases in frequency, both in wakefulness and in sleep, are all electroclinical characteristics of an atypical development.

Efficacy and tolerability of methylprednisolone pulse therapy in childhood epilepsies other than infantile spasms.

This retrospective study included 54 children with epilepsy. The treatment consisted of four pulses with single doses of 20 mg/kg/d methylprednisolone (MPR), administered every week on 3 consecutive days. After this initial phase, the intervals between the pulses were increased based on individual factors. MPR pulses were administered exclusively orally in 39 patients and 7.8% of all pulses were applied intravenously. After four pulses, 30 of 54 (56%) patients were responders, according to several clinical and electroencephalography criteria. A response was obtained in 12 of 20 (60%) cases with genetic, 7 of 17 (41%) with structural metabolic, and 11 of 17 (65%) with unknown etiology. Responder rates were 11 of 15 (73%) in patients with continuous spike-waves in slow sleep (CSWS) or Landau-Kleffner syndrome, 2 of 6 in patients with myoclonic astatic epilepsy or Lennox-Gastaut syndrome, and 17 of 31 (55%) in patients with unclassified epilepsies. A response was not correlated with any epilepsy-related clinical factor. The patients received a median of eight MPR pulses (range, 1-52), and the median duration of the therapy was 11 weeks. The response was maintained in 19 of 30 (63%) patients, and 3 of 24 (13%) without initial response became seizure-free (total responder rate at the end of the therapy 22/54 [41%]). The majority of patients experienced adverse effects that were typically mild and transient.

B-56 * Neurocognitive and Behavioral Profiles of Children with Landau-Kleffner Syndrome

This is a retrospective study of 14 cases of children with Landau-Kleffner syndrome (LKS), the most prominent feature of which is acquired aphasia. These children were followed at a tertiary care p...

Social Skills Training for a Young Adult With Landau–Kleffner Syndrome

We present the differential diagnosis and treatment of Frank, a 26-year-old man with Landau–Kleffner syndrome (LKS). At the time of assessment, Frank was no longer suffering from primary symptoms of LKS; however, he presented with significant social and behavioral difficulties including social anxiety and social skills deficits. Frank participated in Social Effectiveness Therapy (SET), an empirically supported, multi-component behavioral treatment program aimed at reducing social anxiety and improving social functioning. Although Frank exhibited significant reductions in social anxiety at post-treatment, functional behavioral assessment of social behavior suggested that Frank continued to experience social difficulties (e.g., speech length, latency to respond, rigidity in interactions). It appears that the application of an empirically supported treatment such as SET may result in attenuated treatment effects when social anxiety is secondary to a neurological condition such as LKS. Treatment needs for secondary symptoms of LKS are discussed.

Corticosteroid therapy in regressive autism: Preliminary findings from a retrospective study.

Some children with autism spectrum disorders (ASD; 15% to 30% of patients) show a significant and persistent regression in speech and social function during early childhood. There are no established treatments for the regressive symptoms. However, there are some known causes of this type of regression, such as Rett syndrome and Landau-Kleffner syndrome (LKS). In LKS, steroids have been used as a treatment. Some evidence suggests an autoimmune contribution to the pathophysiology of autism (Chez MG, Guido-Estrada N: Immune therapy in autism: historical experience and future directions with immunomodulatory therapy. Neurotherapeutics 2010, 7:293–301, Wasilewska J, Kaczmarski M, Stasiak-Barmuta A, Tobolczyk J, Kowalewska E: Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Arch Med Sci 2012, 8:324–331, Stefanatos G: Changing perspectives on Landau-Kleffner syndrome. Clin Neuropsychol 2011, 25:963–988), raising the possibility that steroids might be a useful therapy for regression in ASD. A retrospective study published in BMC Neurology by Duffy et al. (Duffy, et al: Corticosteroid therapy in regressive autism: A retrospective study of effects on the Frequency Modulated Auditory Evoked Response (FMAER), language, and behavior. BMC Neurol 2014, 14:70) reviewed 20 steroid treated R-ASD (STAR) patients and 24 ASD control patients not treated with steroids (NSA). Improvements in clinical function and in a neurophysiological biomarker were seen in the steroid-treated children pre- to post-prednisolone treatment. This research provides a rationale for a randomized trial with steroid therapy to determine the longer term benefits and complications of steroids in this population.Please see related article http://www.biomedcentral.com/1471-2377/14/70/abstract.

Corticosteroid therapy in regressive autism: a retrospective study of effects on the Frequency Modulated Auditory Evoked Response (FMAER), language, and behavior.

BackgroundUp to a third of children with Autism Spectrum Disorder (ASD) manifest regressive autism (R-ASD).They show normal early development followed by loss of language and social skills. Absent evidence-based therapies, anecdotal evidence suggests improvement following use of corticosteroids. This study examined the effects of corticosteroids for R-ASD children upon the 4 Hz frequency modulated evoked response (FMAER) arising from language cortex of the superior temporal gyrus (STG) and upon EEG background activity, language, and behavior. An untreated clinical convenience sample of ASD children served as control sample.MethodsTwenty steroid-treated R-ASD (STAR) and 24 not-treated ASD patients (NSA), aged 3 - 5 years, were retrospectively identified from a large database. All study participants had two sequential FMAER and EEG studies;Landau-Kleffner syndrome diagnosis was excluded. All subjects’ records contained clinical receptive and expressive language ratings based upon a priori developed metrics. The STAR group additionally was scored behaviorally regarding symptom severity as based on the Diagnostic and Statistical Manual IV (DSM-IV) ASD criteria list. EEGs were visually scored for abnormalities. FMAER responses were assessed quantitatively by spectral analysis. Treated and untreated group means and standard deviations for the FMAER, EEG, language, and behavior, were compared by paired t-test and Fisher’s exact tests.ResultsThe STAR group showed a significant increase in the 4 Hz FMAER spectral response and a significant reduction in response distortion compared to the NSA group. Star group subjects’ language ratings were significantly improved and more STAR than NSA group subjects showed significant language improvement. Most STAR group children showed significant behavioral improvement after treatment. STAR group language and behavior improvement was retained one year after treatment. Groups did not differ in terms of minor EEG abnormalities. Steroid treatment produced no lasting morbidity.ConclusionsSteroid treatment was associated with a significantly increased FMAER response magnitude, reduction of FMAER response distortion, and improvement in language and behavior scores. This was not observed in the non-treated group. These pilot findings warrant a prospective randomized validation trial of steroid treatment for R-ASD utilizing FMAER, EEG, and standardized ASD, language and behavior measures, and a longer follow-up period.Please see related article http://www.biomedcentral.com/1741-7015/12/79

Towards the identification of a genetic basis for Landau‐Kleffner syndrome

To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases. We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment. A variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2. A single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Temporoparietal Resection in a Patient With Landau-Kleffner Syndrome

Landau-Kleffner syndrome (LKS) was originally described by Landau, a neurologist, and Kleffner, a speech pathologist, in 1957 as an epileptic disorder with an acquired aphasia. LKS is a childhood epileptic encephalopathy on the electroclinical spectrum of electrical status epilepticus in sleep (ESES). ESES is an electrographic pattern in which there is significant activation of spike wave discharges throughout slow wave sleep. LKS is an electroclinical syndrome presenting with language regression, seizures, and behavior abnormalities with the electroencephalography (EEG) findings of ESES. Other related syndromes include continuous spike and wave in slow wave sleep (CSWS) and benign childhood epilepsy with centrotemporal spikes (BECTS). In contrast to these other disorders, the primary clinical manifestation of LKS is language regression. Additional clinical findings seen in LKS include attention-deficit disorder, irritability, and autistic-like behaviors. Seizures are present in 70%-80% of children with LKS and typically occur infrequently. The findings on neuroimaging are typically normal in LKS. Although this epileptic encephalopathy resolves spontaneously in adolescence, there is often permanent neurologic sequela, especially if the epilepsy is pharmacoresistant. Numerous therapies have been used in LKS, including antiepileptics such as ethosuximide, valproic acid, and benzodiazepines; corticosteroids; adrenocorticotropic hormone; and immunotherapy. In cases of pharmacoresistance, surgical therapy such as multiple subpial transections has been performed. In children with pharmacoresistant ESES with lateralization, cortical resection has been previously reported but is not commonly used, even in those with lateralized seizure onset.

Attention deficit associated with early life interictal spikes in a rat model is improved with ACTH.

Children with epilepsy often present with pervasive cognitive and behavioral comorbidities including working memory impairments, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder. These non-seizure characteristics are severely detrimental to overall quality of life. Some of these children, particularly those with epilepsies classified as Landau-Kleffner Syndrome or continuous spike and wave during sleep, have infrequent seizure activity but frequent focal epileptiform activity. This frequent epileptiform activity is thought to be detrimental to cognitive development; however, it is also possible that these IIS events initiate pathophysiological pathways in the developing brain that may be independently associated with cognitive deficits. These hypotheses are difficult to address due to the previous lack of an appropriate animal model. To this end, we have recently developed a rat model to test the role of frequent focal epileptiform activity in the prefrontal cortex. Using microinjections of a GABAA antagonist (bicuculline methiodine) delivered multiple times per day from postnatal day (p) 21 to p25, we showed that rat pups experiencing frequent, focal, recurrent epileptiform activity in the form of interictal spikes during neurodevelopment have significant long-term deficits in attention and sociability that persist into adulthood. To determine if treatment with ACTH, a drug widely used to treat early-life seizures, altered outcome we administered ACTH once per day subcutaneously during the time of the induced interictal spike activity. We show a modest amelioration of the attention deficit seen in animals with a history of early life interictal spikes with ACTH, in the absence of alteration of interictal spike activity. These results suggest that pharmacological intervention that is not targeted to the interictal spike activity is worthy of future study as it may be beneficial for preventing or ameliorating adverse cognitive outcomes.