Clinical features and genotype-phenotype correlations in epilepsy patients with de novo DYNC1H1 variants.

OBJECTIVE: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature. METHODS: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. RESULTS: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum. SIGNIFICANCE: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.

PedsQL™ Cognitive Functioning Scale in youth with epilepsy: Reliability and validity.

OBJECTIVE: The objective of the study was to report on the internal consistency reliability and discriminant, concurrent and construct validity of the Pediatric Quality of Life Inventory™ (PedsQL™) Cognitive Functioning Scale as a brief generic cognitive functioning measure in youth with epilepsy. METHODS: The 6-item PedsQL™ Cognitive Functioning Scale and 23-item PedsQL™ 4.0 Generic Core Scales were completed by 221 pediatric patients ages 5-18 years with epilepsy and 336 parents of patients ages 2-18 years in a national field test study for the PedsQL™ Epilepsy Module. Parents also completed the 86-item Behavior Rating Inventory of Executive Function (BRIEF), a widely validated measure of executive functioning. RESULTS: The PedsQL™ Cognitive Functioning Scale evidenced excellent reliability (patient self-report α = 0.88; parent proxy-report α = 0.96), distinguished between youth with epilepsy and an age, gender, and race/ethnicity-matched healthy sample supporting discriminant validity with large effect sizes (~20-30 point score differences, P < 0.001), and demonstrated concurrent and construct validity, respectively, through large effect size intercorrelations with the BRIEF (Behavioral Regulation Index, Metacognition Index, Global Executive Composite Summary Scores rs = 0.43-0.67, P < 0.001) and the PedsQL™ Generic Core Scales (Total Scale Scores rs = 0.67-0.74, P < 0.001). Minimal clinically important difference (MCID) scores ranged from 5.92 to 8.80. CONCLUSIONS: The PedsQL™ Cognitive Functioning Scale demonstrated excellent internal consistency reliability, discriminant, concurrent, and construct validity in youth with epilepsy and may be suitable as a brief generic patient-reported outcome (PRO) measure for clinical research, clinical trials, and routine clinical practice in pediatric epilepsy.

Indications and methodology for video-electroencephalographic studies in the epilepsy monitoring unit.

Although the epilepsy and neurology communities have position papers on a number of topics pertaining to epilepsy diagnosis and management, no current paper exists for the rationale and appropriate indications for epilepsy monitoring unit (EMU) evaluation. General neurologists, hospital administrators, and insurers also have yet to fully understand the role this type of testing has in the diagnosis and management of individuals with paroxysmal neurologic symptoms. This review outlines the indications for long-term video-electroencephalography (VEEG) for typical elective admissions to a specialized inpatient setting. The common techniques used in EMUs to obtain diagnostic information are reviewed. The added benefit of safety measures and clinical testing above that available for routine or long-term ambulatory electroencephalography is also discussed. The indications for admission to the EMU include differential diagnosis of paroxysmal spells, characterization of seizure types, presurgical epilepsy evaluations, seizure quantification, monitoring medication adjustment in a safe setting, and differentiation between seizures and side effects. We conclude that the appropriate use of this specialized testing can lead to an early and correct diagnosis in a variety of clinical circumstances. The EMU evaluation is considered the gold standard test for the definitive diagnosis of epilepsy and seizure-like spells.

Therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy is associated with short-term reduction of seizures after discharge from the neonatal intensive care unit.

INTRODUCTION: Therapeutic hypothermia for the treatment of moderate to severe neonatal hypoxic ischemic encephalopathy has been shown to reduce death and disability, but the effects on seizures after discharge from the Neonatal ICU are not known. METHODS: A retrospective cohort study was conducted involving 56 neonates admitted to the Neonatal ICU at Children's Hospital of Orange County, CA from January 1, 2007 to September 1, 2013 with hypoxic ischemic encephalopathy who met criteria for selective brain cooling. Fifteen patients received supportive care. Forty-one patients received cooling, of whom 25 were included for analysis. Sixteen patients from the hypothermia group and 12 from the no hypothermia group developed clinical seizures while inpatient. Up to 6 months, four patients (16%) had continued seizures in the therapeutic hypothermia group compared to eight (53%) patients who did not receive hypothermia. DISCUSSION: Our study shows an association between therapeutic hypothermia and reduced seizures after discharge from the neonatal intensive care unit. The short duration of follow-up, 6 months, is a limitation of this study. Another limitation is its observational nature, where reasons for treatment selection and exclusions are unmeasurable confounding factors. Further studies are needed to determine long-term effects.

Models of Transition.

Without a structure to address healthcare transition, adolescents and young adults with neurological disorders are likely to have disruptions in their care that result in a higher need for emergency care and hospitalization. There are numerous obstacles to implementing the existing transition guidelines: adequate numbers of skilled and willing adult providers, patient and family anxiety about transfer, changes in health insurance, inadequate reimbursement, and inefficient communication systems to pave the path for a smooth transition. The aim of this article is to provide practical information about developing a transition program, as well as a potential clinical model for transitioning care.

Child neurology in the 21st century: More than the sum of our RVUs.

In September 2017, the Child Neurology Society (CNS) convened a special task force to review the practice of child neurology in the United States. This was deemed a necessity by our membership, as our colleagues expressed discouragement and burnout by the increase in workload without additional resources; reliance on work relative value units (wRVUs) as the sole basis of compensation; a push by administrators for providers to see more patients with less allotted time; and lack of administrative, educational, and research support. The CNS Task Force designed and distributed a survey to multiple academic divisions of various sizes, as well as to private practices. Our findings were strikingly similar across different practices, demonstrating high workloads, lack of resources, poor electronic medical record support, and high provider symptoms of fatigue and burnout. From the results, the CNS Task Force has concluded that wRVUs cannot be the sole basis of compensation for child neurology. We have also made several specific recommendations for alleviating the current situation, including innovative ways to fund child neurology as well as ways to enhance job satisfaction.

Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy.

PURPOSE: Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS). METHODS: Medical records and 332 cranial MRIs from 205 infants (aged 16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T(2)-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated. RESULTS: Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p < 0.001). Of nine subjects in the prevalence population with at least one subsequent determinate MRI, resolution of MRI abnormalities occurred in six (66.7%)-vigabatrin was discontinued in four. Among adults and children treated with vigabatrin for CPS, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrin-naive subjects. DISCUSSION: Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for IS. The majority of these MRI abnormalities resolved, even in subjects who remained on vigabatrin therapy.

Long-term management of the ketogenic diet: seizure monitoring, nutrition, and supplementation.

The ketogenic diet (KD) is a medical nutrition therapy (MNT) for the treatment of epilepsy. As such, it can affect the outcome of an individual's health and chronic medical condition. The components of MNT which have been established by the American Dietetic Association as core guidelines for nutrition care include a diet history, assessment, diet therapy and a follow-up plan of care (American Dietetic Assoc 2002). We have utilized these guidelines in designing our approach to KD therapy in our pediatric population. Many of the practices described here have been adopted from our practical experience.

Neurocognitive Comorbidities in Pediatric Epilepsy: Lessons in the Laboratory and Clinical Profile.

Children with epilepsy are at risk for a variety of neurocognitive comorbidities. Animal models have increased our understanding about the neurobiological mechanisms underlying the association between seizures and these comorbidities. This article starts with an overview of the current data on animal model research, studying the influence of early-life seizures, followed by a summary of potential cellular and molecular mechanisms by which seizures can affect cognitive development. We then describe specific abnormal neuropsychological profiles that accompany specific pediatric epilepsy syndromes. Finally, we offer a potential guideline to the treatment and management of children with epilepsy and its neurocognitive comorbidities.

Felbamate: consensus of current clinical experience.

An expert panel convened to evaluate data and review current clinical practices regarding the novel antiepileptic drug (AED) felbamate. Felbamate has demonstrated efficacy against a variety of refractory seizures types, including seizures associated with Lennox-Gastaut syndrome, but postmarketing experience revealed serious idiosyncratic adverse effects that were not observed during clinical trials. Although felbamate is not indicated as first-line antiepileptic therapy, its utility in treating seizures that are refractory to other AEDs is undisputed, as shown by the number of patients who continue to use it. New exposures to felbamate number approximately 3200-4200 patients annually, and it is estimated that over the past 10 years, approximately 35,000 new starts have occurred. Recommendations by the American Academy of Neurology and a review of felbamate literature were evaluated in conjunction with the clinical experience of the expert panel to determine current medical opinion and practice regarding felbamate. The past 10 years of clinical experience have demonstrated that when used in accordance with existing recommendations and close clinical monitoring, felbamate is an effective treatment for some patients with seizures refractory to other AEDs. This review of clinical data and discussion of the current understanding of the risk:benefit of felbamate therapy supports its use as an important therapeutic option for some patients with refractory epilepsy.

Long-Term Everolimus Treatment in Individuals With Tuberous Sclerosis Complex: A Review of the Current Literature.

BACKGROUND: Tuberous sclerosis complex is a genetic disease usually caused by mutations to either TSC1 or TSC2, where its gene products are involved in the inhibition of the mammalian target of rapamycin pathway. Under normal cellular conditions, mammalian target of rapamycin (mTOR) regulates cell growth and proliferation in response to signals from nutrients or growth factors, but loss of TSC1 or TSC2 leads to overactivation of mTOR and uncontrolled cellular proliferation. Everolimus is an mTOR inhibitor approved for use in a number of indications where mTOR overactivation is implicated, including tuberous sclerosis complex. METHODS AND PATIENTS: We conducted a literature search of PubMed to identify published articles about the long-term efficacy and safety of everolimus in patients with tuberous sclerosis complex. RESULTS: The short-term efficacy and safety of everolimus in patients with tuberous sclerosis complex has been demonstrated in placebo-controlled trials, and open-label extension studies are ongoing to monitor long-term effects, including safety. Examples of regrowth following discontinuation of mTOR inhibitors suggest that everolimus needs to be given indefinitely to maintain suppression of subependymal giant cell astrocytoma and other tuberous sclerosis complex-associated disease manifestations. No additional safety concerns have been reported to date with long-term administration of everolimus, but published long-term data (>1 year treatment) are currently limited to a small open-label trial and case reports for this relatively rare condition. CONCLUSIONS: From the limited data available, long-term administration of everolimus appears feasible with few safety concerns beyond those associated with short-term use. Further investigation is needed to determine the long-term efficacy and safety of everolimus in patients with tuberous sclerosis complex.

Infantile spasms.

Infantile spasms is a catastrophic form of epilepsy found only in infants and young toddlers, with the peak incidence between 4 - 7 months of age. Estimated prevalence is 1 in 2000 - 6000 live births. There are many causes of infantile spasms, including tuberous sclerosis, hypoxic-ischaemic injury, congenital infectious diseases, inborn errors of metabolism, malformations of cortical development, genetic syndromes such as Aicardi's syndrome and chromosomal abnormalities. A small percentage of patients have idiopathic infantile spasms, with normal growth and development prior to the onset of infantile spasms and no known aetiology. Because of the poor prognosis of infantile spasms, treatment is usually aggressive and immediate, with the hopes of altering the natural history of the disease. The majority of patients with infantile spasms have a poor prognosis with intractable epilepsy, severe developmental delays and/or significant cognitive impairments. Of all patients with infantile spasms, 70 - 90% have mental retardation. Furthermore, 20 - 50% of patients with infantile spasms develop Lennox-Gastaut syndrome with multiple seizure types, cognitive impairments and a markedly abnormal electroencephalogram, arguably one of the most difficult epilepsy syndromes to treat. Infantile spasms are resistant to most of the standard antiepileptic drugs. Adrenocorticotropin hormone (ACTH) or oral steroids result in a significant reduction of seizures, as well as an improvement in the electroencephalogram. Some studies have indicated that infants treated with ACTH within the first month of onset have a more favourable prognosis. Vigabatrin has also been shown to be effective in the treatment, although it is not yet FDA-approved in the US. Valproate has also been used in the treatment of infantile spasms, with an efficacy of approximately 25 - 40%. However, in the very young infant, it does carry a high risk of fatal hepatotoxicity. Surgical resection may be the treatment of choice for those infants with focal cortical dysplasia and intractable infantile spasms. Emerging therapeutic possibilities include topiramate, felbamate, lamotrigine, zonisamide and perhaps levetiracetam. With the advancements in molecular biology, genetics and neuroimaging, there is the hope of novel therapies in the future.

Ketogenic diet: outpatient initiation, without fluid, or caloric restrictions.

Although the ketogenic diet has been used for more than 80 years, the optimal methods of initiating the diet and its maintenance have not been clearly defined. This retrospective study was performed to review our experience with initiation of the ketogenic diet in the outpatient and inpatient settings and maintenance of the diet without fluid or caloric restriction. We analyzed 54 patients who had medically intractable epilepsy of whom 44% manifested some degree of mental retardation, 80% had multiple seizure types, and failed on average 4.8 antiepileptic drugs. Forty-four patients underwent induction of the ketogenic diet on an outpatient basis and 21 as inpatients. Three patients in each group were fasted at the initiation of the diet. No significant differences were observed with regard to seizure control in that 62% and 71% had greater than 50% improvement in the outpatient and inpatient groups, respectively. Both groups manifested improvement in alertness and social interaction. The efficacy of a ketogenic diet in the symptomatic epilepsies was confirmed, and benefit for medically refractory childhood absence epilepsy was documented. We conclude that a prospective, randomized trial is necessary to compare outpatient vs inpatient initiation of the ketogenic diet and the utility of fluid and caloric restriction.

Neonatal seizures.

Neonatal seizures typically indicate significant underlying disease.They are poorly classified, under-recognized, and often difficult to treat. Recognition of etiology is often helpful in prognosis and treatment; the most common is hypoxic-ischemic encephalopathy. Patients generally have a poor prognosis, with most developing a severe encephalopathy and epilepsy. Studies suggest that neonatal seizures and their etiology have a significant impact on the developing brain; it is critical to recognize seizures early and initiate immediate antiepileptic therapy. Continuous computerized simultaneous video electroencephalograph monitoring is imperative;at-risk infants will frequently have electrographic seizures without clinical manifestations. Although there are antiepileptic therapies for neonatal seizures, they are ineffective in over 35% of cases. The goal of research should be the development of more effective therapies for neonatal seizures, regardless of etiology.

Neurodevelopmental outcomes of children born to mothers with epilepsy.

Most children born to women with epilepsy are normal, but there is an increased risk of abnormal functional neurodevelopment in these children. Although there are many contributing factors, antiepileptic drugs (AEDs) may play a role. Most women with epilepsy must take AEDs during pregnancy because the potential for injury from seizures to both mother and fetus is a greater risk. AEDs are also used to treat other disorders, including depression and pain. Thus, an understanding of the effects of AEDs on the unborn child is relevant to physicians who treat nonepileptic mothers as well. This review discusses animal and human studies of the neurodevelopmental effects of AEDs and briefly reviews the possible mechanisms underlying these effects. Flaws in the methodology of some studies of these effects require that the results be interpreted cautiously and highlight the need for well-designed studies to explore this issue further.

The ketogenic diet for the treatment of pediatric status epilepticus.

BACKGROUND: Refractory status epilepticus carries a high risk of morbidity and mortality for children. Traditional treatment of status epilepticus consists of multiple anticonvulsant drugs and, if needed, induction of a medical coma. The ketogenic diet has been used for intractable epilepsy for many years. The purpose of this article is to report a case series of five patients with refractory status epilepticus successfully managed with the ketogenic diet. METHODS: A summary of pediatric patients with refractory status epilepticus treated with diet was performed. CONCLUSIONS: Ketogenic diet therapy should be considered as a treatment option in pediatric patients with refractory status epilepticus.

Corpus callosotomy in multistage epilepsy surgery in the pediatric population.

OBJECT: The object of this study was to evaluate surgical outcome in a select group of patients with medically refractory epilepsy who had undergone corpus callosotomy combined with bilateral subdural electroencephalography (EEG) electrode placement as the initial step in multistage epilepsy surgery. METHODS: A retrospective chart review of 18 children (ages 3.5-18 years) with medically refractory symptomatic generalized or localization-related epilepsy was undertaken. A corpus callosotomy with subdural bihemispheric EEG electrode placement was performed as the initial step in multistage epilepsy surgery. All of the patients had tonic and atonic seizures; 6 patients also experienced complex partial seizures. All of the patients had frequent generalized epileptiform discharges as well as multifocal independent epileptiform discharges on surface EEG monitoring. Most of the patients (94%) had either normal (44%) MR imaging studies of the brain or bihemispheric abnormalities (50%). One patient had a suspected unilateral lesion (prominent sylvian fissure). RESULTS: Of the 18 patients who underwent corpus callosotomy and placement of subdural strips and grids, 12 progressed to further resection based on localizing data obtained during invasive EEG monitoring. The mean patient age was 10.9 years. The duration of invasive monitoring ranged from 3 to 14 days, and the follow-up ranged from 6 to 70 months (mean 35 months). Six (50%) of the 12 patients who had undergone resection had an excellent outcome (Engel Class I or II). There were no permanent neurological deficits or deaths. CONCLUSIONS: The addition of invasive monitoring for patients undergoing corpus callosotomy for medically refractory epilepsy may lead to the localization of surgically amenable seizure foci, targeted resections, and improved seizure outcomes in a select group of patients typically believed to be candidates for palliative surgery alone.

Efficacy of felbamate in the treatment of intractable pediatric epilepsy.

The antiepileptic drug felbamate has demonstrated efficacy against a variety of seizure types in the pediatric population, particularly seizures associated with Lennox-Gastaut syndrome. Postmarketing experience, however, revealed serious idiosyncratic adverse effects not observed during clinical trials, including aplastic anemia and liver failure. As a result, many physicians have been hesitant to prescribe felbamate. This retrospective study evaluated the efficacy of felbamate in a pediatric population with intractable epilepsy. Of 38 patients, 22 had Lennox-Gastaut syndrome (58%); 6 had myoclonic-astatic epilepsy of Doose (16%); 5 had symptomatic generalized epilepsy, not otherwise specified (13%); and 5 had symptomatic localization-related epilepsy (13%). Most patients had multiple seizure types and had been tried on a variety of antiepileptic medications. With felbamate treatment, 6 patients (16%) became seizure free, including 4 of the 6 patients with myoclonic-astatic epilepsy of Doose; 24 patients (63%) had a greater than 50% reduction in seizure frequency. In this population felbamate appeared to be safe, with minimal adverse effects. The study is limited by the small number of patients and by its retrospective nature, but nonetheless adds to the evidence that felbamate is an important antiepileptic drug for medically refractory epilepsy in children and is well tolerated with few adverse effects.

Epilepsy surgery outcomes: quality of life and seizure control.

A consecutive, retrospective analysis of seizure control and quality of life was performed among 83 pediatric patients undergoing epilepsy surgery at Children's Hospital of Wisconsin. Seizure outcomes were generally favorable, with 68.7% class I outcomes; class II, 12%; and class III, 19.3%. Seizure freedom was highest among temporal lobectomies (84.2%) and hemispherectomies (76.2%). Outcomes among hemispherectomies were substantially superior to those of multilobar resections. Cortical dysplasia was associated with lower seizure freedom, at 57.5%. Among age groups, seizure-free outcomes in infants were lowest, at 50%. The lower infant seizure-free rate was likely attributable to frequency of multilobar resections and type of pathology (cortical dysplasia). Quality-of-life measures generally paralleled seizure outcomes. These results indicate that epilepsy surgery in children with intractable epilepsy can result in significant improvements in seizure control, quality of life, and development. Anticipated type of surgery, presumed location of epileptogenic site, absence of a defined lesion on magnetic resonance imaging scan of the brain, and patient's age should not prevent surgical evaluations of children with intractable epilepsy.

Clinical evaluation and diagnosis of severe epilepsy syndromes of early childhood.

The developing brain is particularly susceptible to seizures. Diffuse central nervous system pathology or injury in early infancy, when the brain is most vulnerable, may lead to catastrophic epilepsies such as Ohtahara's epileptic encephalopathy and early myoclonic epileptic encephalopathy. These epileptic encephalopathies are difficult to treat and have poor prognoses. As the brain undergoes programmed synaptogenesis, apoptosis, and myelination, the epilepsy phenotypes and electroencephalography (EEG) findings change, producing age-dependent epileptic encephalopathies. Specifically, as they grow older, 40% to 60% of infants with infantile spasms and a concomitant hypsarrhythmia on EEG will develop Lennox-Gastaut syndrome with tonic and atonic seizures, associated with a synchronous, generalized 1.5- to 2-Hz spike and slow wave discharges on EEG. In the context of age-dependent epileptic encephalopathies, as an epilepsy syndrome is evolving, it is often difficult to accurately diagnose the specific epilepsy syndrome in a young child who presents with seizures. It is the clinical evolution of the seizure types and the EEG that helps the clinician make an accurate diagnosis. As more is known about the underlying pathophysiology for the various epilepsy syndromes, not only the clinical picture and EEG but also a genetic blood test will be used to accurately diagnose a specific epilepsy syndrome. A case in point would be severe myoclonic epilepsy of infancy (classically known as Dravet syndrome) and severe myoclonic epilepsy of infancy-borderland/ borderline, which are associated with specific mutations in the sodium ion channel gene SCN1A.