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Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s) of action is unknown. This review describes the emerging candidate mechanisms that can underlie the therapeutic effects of ACTH in infantile spasms. These mechanisms can ultimately help to improve understanding and treatment of the disease. An overview of current treatments of infantile spasms, novel conceptual and experimental approaches to infantile spasms treatment, and a perspective on remaining clinical challenges and current research questions are presented here. This summary derives from a meeting of specialists in infantile spasms clinical care and research held in New York City on June 14, 2010.

Neocortical Slow Oscillations Implicated in the Generation of Epileptic Spasms Lee CH, Le JT, Ballester-Rosado CJ, et al. Ann Neurol. 2020;89(2):226-241. doi:10.1002/ana.25935 Objective: Epileptic spasms are a hallmark of severe seizure disorders. The neurophysiological mechanisms and the neuronal circuit(s) that generate these seizures are unresolved and are the focus of studies reported here. Methods: In the tetrodotoxin model, we used 16-channel microarrays and microwires to record electrophysiological activity in neocortex and thalamus during spasms. Chemogenetic activation was used to examine the role of neocortical pyramidal cells in generating spasms. Comparisons were made to recordings from infantile spasm patients. Results: Current source density and simultaneous multiunit activity analyses indicate that the ictal events of spasms are initiated in infragranular cortical layers. A dramatic pause of neuronal activity was recorded immediately prior to the onset of spasms. This preictal pause is shown to share many features with the down states of slow-wave sleep. In addition, the ensuing interictal up states of slow-wave rhythms are more intense in epileptic than control animals and occasionally appear sufficient to initiate spasms. Chemogenetic activation of neocortical pyramidal cells supported these observations, as it increased slow oscillations and spasm numbers and clustering. Recordings also revealed a ramp-up in the number of neocortical slow oscillations preceding spasms, which was also observed in infantile spasm patients. Interpretation: Our findings provide evidence that epileptic spasms can arise from the neocortex and reveal a previously unappreciated interplay between brain state physiology and spasm generation. The identification of neocortical up states as a mechanism capable of initiating epileptic spasms will likely provide new targets for interventional therapies. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the clinical characteristics of patients presenting with hair-grooming syncope. It also discusses the importance of documenting the precipitating event for any syncopal episode and recommends when a pediatric neurological consultation is indicated. Neuroimaging was preformed on four patients prior to their neurologic consultation and syncopal events were similar between patients, consistent with a vasovagal etiology.

Abstract: Children with epilepsy are at risk for numerous psychological and social challenges. We hypothesized that art therapy focus groups would enhance the self-image of children and adolescents with epilepsy. Sixteen children with epilepsy, ages 7–18years, were recruited from pediatric neurology clinics at the University of Wisconsin to participate in four art therapy sessions. Pre-group assessments included psychological screens (Piers–Harris Children''s Self-Concept Scale; Childhood Attitude Toward Illness Scale; Impact of Childhood Neurologic Disability Scale) and art therapy instruments (Formal Elements Art Therapy Scale; Seizure Drawing Task; Levick Emotional and Cognitive Art Therapy Assessment). Developmental levels of drawings were significantly below age-expected standards. Following completion of focus groups, a repeat Childhood Attitude Toward Illness Scale showed no differences between pre- and post-test scores on any measure of this scale. However, subjects and parents were uniformly positive about their group experiences, suggesting a qualitative benefit from participation in art therapy focus groups. [Copyright &y& Elsevier]

Fragile X syndrome is the leading heritable form of cognitive impairment and the leading known monogenic disorder associated with autism. Roughly one-quarter of children with this disorder have seizures, most of which are relatively benign and are resolved beyond childhood. Because of the prevalence of fragile X syndrome, numerous animal models have been developed and electrophysiological studies have taken place to investigate its pathogenesis. The investigations have yielded a wealth of information regarding the synaptic dysfunction that underlies the hyperexcitability and epileptiform features associated with this disorder. [ABSTRACT FROM AUTHOR]

Metabolic regulation of neuronal excitability is increasingly recognized as a factor in seizure pathogenesis and control. Inhibiting or bypassing glycolysis may be one way through which the ketogenic diet provides an anticonvulsant effect. 2-deoxy-D-glucose (2DG), a nonmetabolizable glucose analog that partially inhibits glycolysis, was tested in several acute and chronic seizure models. Acutely, 2DG decreases the frequency of high-K+-, bicuculline- and 4-aminopyridine-induced interictal bursts in the CA3 region of hippocampal slices; 2DG also exerts anticonvulsant effects in vivo against perforant path kindling in rats. Chronically, 2DG has novel antiepileptic effects by retarding the progression of kindled seizures. Finally, 2DG has a favorable preliminary toxicity profile. These factors support the possibility that 2DG or other modifiers of glycolysis can be used as novel treatments for epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: Seizures in the developing brain cause less macroscopic structural damage than do seizures in adulthood, but accumulating evidence shows that seizures early in life can be associated with persistent behavioral and cognitive impairments. We previously showed that long-term spatial memory in the eight-arm radial-arm maze was impaired in rats that experienced a single episode of kainic acid (KA)-induced status epilepticus during early development (postnatal days (P) 1-14). Here we extend those findings by using a set of behavioral paradigms that are sensitive to additional aspects of learning and behavior. Methods: On P1, P7. P14, or P24, rats underwent status epilepticus induced by intraperitoneal injections of age-specific doses of KA. In adulthood (P90-P100), the behavioural performance of these rats was compared with that of control rats that did not receive KA. A modified version of the radial-arm maze was used to assess short-term spatial memory; the Morris water maze was used to evaluate long-term spatial memory and retrieval; and the elevated plus maze was used to determine anxiety. Results: Compared with controls, rats with KA seizures at each tested age had impaired short-term spatial memory in the radial-arm maze (longer latency to criterion and more reference errors), deficient long-term spatial learning and retrieval in the water maze (longer escape latencies and memory for platform location), and a greater degree of anxiety in the elevated plus maze (greater time spent in open arms). Conclusions: These findings provide additional support for the concept that seizures early in life may be followed by life-long impairment of certain cognitive and behavioral functions. These results may have clinical implications, favoring early and aggressive control of seizures during development. [ABSTRACT FROM AUTHOR]

Reply to Sharawat et al. "Efficacy of High-Dose Oral Steroids in Children With Epileptic Spasms" Steroid-related side effects absolutely may (and do) occur; all these infants should be closely monitored, and the dose should be lowered if necessary. 3 E.H. Kossoff, E.F. Hedderick, Z. Turner, J.M. Freeman, A case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms. [Extracted from the article]

Abdelmalik PA, Liang P, Weisspapir M, Samoilova M, Burnham WM, Carlen PL. Neurobiol Dis 2008;29(2):201–209. Epub 2007 Aug 29. The brain is heavily dependant on glucose for its function and survival. Hypoglycemia can have severe, irreversible consequences, including seizures, coma and death. However, the in vivo content of brain glycogen, the storage form of glucose, is meager and is a function of both neuronal activity and glucose concentration. In the intact in vitro hippocampus isolated from mice aged postnatal days 8–13, we have recently characterized a novel model of hypoglycemic seizures, wherein seizures were abolished by various neuroprotective strategies. We had hypothesized that these strategies might act, in part, by increasing cerebral glycogen content. In the present experiments, it was found that neither decreasing temperature nor increasing glucose concentrations (above 2 mM) significantly increased hippocampal glycogen content. Preparations of isolated frontal neocortex in vitro do not produce hypoglycemic seizures yet it was found they contained significantly lower glycogen content as compared to the isolated intact hippocampus. Further, the application of either TTX, or a cocktail containing APV, CNQX and gabazine, to block synaptic activity, did not increase, but paradoxically decreased, hippocampal glycogen content in the isolated intact hippocampus. Significant decreases in glycogen were noted when neuronal activity was increased via incubation with l-aspartate (500 μM) or low Mg2+. Lastly, we examined the incidence of hypoglycemic seizures in hippocampi isolated from mice aged 15–19 and 22–24 days, and compared it to the incidence of hypoglycemic seizures of hippocampi isolated from mice aged 8–13 days described previously (Abdelmalik et al., 2007 Neurobiol Dis 26(3):646–660). It was noted that hypoglycemic seizures were generated less frequently, and had less impact on synaptic transmission in hippocmpi from PD 22–24 as compared to hippocampi from mice PD 15–19 or PD 8–13. However, hippocampi from 8- to 13-day-old mice had significantly more glycogen than the other two age groups. The present data suggest that none of the interventions which abolish hypoglycemic seizures increases glycogen content, and that low glycogen content, per se, may not predispose to the generation of hypoglycemic seizures. [ABSTRACT FROM AUTHOR]

Discusses research being done on the ionic conductances mediating the hyperpolarizing and depolarizing components of electrographic seizures from neocortex of cats anesthetized with ketamine/xylazine. Reference to a study by I. Timofeev and colleagues published in the 2004 issue of the "Journal of Neurophysiology"; Findings of the study; Role of intrinsic cellular factors in the generation of depolarizing and hyperpolarizing components of seizures.

Swann JW, Le JT, Lee CL. Dev Neurosci 2007;29(1–2):168–178. Recurrent seizures in animal models of early-onset epilepsy have been shown to produce deficits in spatial learning and memory. While neuronal loss does not appear to underlie these effects, dendritic spine loss has been shown to occur. In experiments reported here, seizures induced either by tetanus toxin or flurothyl during the second postnatal week were found to reduce the expression of NMDA receptor subunits in both the hippocampus and neocortex. Most experiments focused on alterations in the expression of the NR2A subunit and its associated scaffolding protein, PSD95, since their expression is developmentally regulated. Results suggest that the depression in expression can be delayed by at least 5 days but persists for at least 3-4 weeks. These effects were dependent on the number of seizures experienced, and were not observed when seizures were induced in adult mice. Taken together, the results suggest that recurrent seizures in infancy may interrupt synapse maturation and produce persistent decreases in molecular markers for glutamatergic synapses – particularly components of the NMDA receptor complex implicated in learning and memory. [ABSTRACT FROM AUTHOR]

Presents a study which examined the involvement of gap junctions in the manifestation and control of the duration of seizures. Information on the function of gap junctions in the brain; Description of the molecular biology of gap junctions; Assessment of gap junctional transmission.

Hippocampal Programmed Cell Death after Status Epilepticus: Evidence for NMDA-receptor and Ceramide-mediated Mechanisms PURPOSE: Status epilepticus (SE) can result in acute neuronal injury with subsequent long-term age-dependent behavioral and histologic sequelae. To investigate potential mechanisms that may underlie SE-related neuronal injury, we studied the occurrence of programmed cell death (PCD) in the hippocampus in the kainic acid (KA) model. METHODS: In adult rats, KA-induced SE resulted in DNA fragmentation documented at 30 hours after KA injection. Ceramide, a known mediator of PCD in multiple neural and nonneural tissues, increased at 2 to 3 hours after KA intraperitoneal injection, and then decreased to control levels before increasing again from 12 to 30 hours after injection. MK-801 pretreatment prevented KA-induced increases in ceramide levels and DNA fragmentation, whether a reduction in seizure severity occurred or not (achieved with 5 mg/kg and 1 mg/kg of MK-801, respectively). RESULTS: Both ceramide increases and DNA fragmentation were observed after KA-induced SE in adult and in P35 rats. Ceramide did not increase after KA-induced SE in P7 pups, which also did not manifest any DNA fragmentation. Intrahippocampal injection of the active ceramide analogue C2-ceramide produced widespread DNA fragmentation, whereas the inactive ceramide analogue C2-dihydroceramide did not. CONCLUSIONS: Our data support the hypotheses that (a) N -methyl-d-aspartate–receptor activation results in ceramide increases and in DNA fragmentation; (b) ceramide is a mediator of PCD after SE; and (c) age-related differences occur in PCD and in the ceramide response after SE. Differences in the ceramide response could, potentially, be responsible for observed age-related differences in the response to SE. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the incidence of seizures and epilepsy in the first decade of life among children born extremely premature (less than 28 weeks' gestation).Method: In a prospective, multicenter, observational study, 889 of 966 eligible children born in 2002 to 2004 were evaluated at two and ten years for neurological morbidity. Complementing questionnaire data to determine a history of seizures, all caregivers were interviewed retrospectively for postneonatal seizures using a validated seizure screen followed by a structured clinical interview by a pediatric epileptologist. A second pediatric epileptologist established an independent diagnosis based on recorded responses of the interview. A third epileptologist determined the final diagnosis when evaluators disagreed (3%). Life table survival methods were used to estimate seizure incidence through ten years.Results: By age ten years, 12.2% (95% confidence interval: 9.8, 14.5) of children had experienced one or more seizures, 7.6% (95% confidence interval: 5.7, 9.5) had epilepsy, 3.2% had seizure with fever, and 1.3% had a single, unprovoked seizure. The seizure incidence increased with decreasing gestational age. In more than 75% of children with seizures, onset was after one year of age. Seizure incidence was comparable in both sexes. Two-thirds of those with epilepsy had other neurological disorders. One third of children with epilepsy were not recorded on the medical history questionnaire.Significance: The incidence of epilepsy through age ten years among children born extremely premature is approximately 7- to 14-fold higher than the 0.5% to 1% lifetime incidence reported in the general pediatric population. Seizures in this population are under-recognized, and possibly underdiagnosed, by parents and providers. [ABSTRACT FROM AUTHOR]

Background: SCN8A mutations are rare and cause a phenotypically heterogeneous early onset epilepsy known as early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558). There are currently no clear genotype-phenotype correlations to help guide patient counseling and management.Patient Description: We describe a patient with EIEE13 (de novo heterozygous pathogenic mutation in SCN8A - p.Ile240Val (ATT>GTT)) who presented prenatally with maternally reported intermittent, rhythmic movements that, when observed on ultrasound, were concerning for fetal seizures. Ultrasound also revealed abnormal developmental states. With maternal administration of levetiracetam, the rhythmic fetal movements stopped. After birth, the patient developed treatment-refractory multi-focal epilepsy confirmed by electroencephalogram. Neuroimaging revealed restricted diffusion in the superior cerebellar peduncles, a finding not reported previously in EIEE13.Conclusion: This is the first report of EIEE13 associated with clinical prenatal-onset seizures. Ultrasonography can be useful for identifying fetal seizures, which may be treatable in utero. Ideally, the clinical approach to fetal seizures should involve a multidisciplinary team spanning the pre- and postnatal course to expedite early diagnosis and optimize management, as illustrated by this patient. [ABSTRACT FROM AUTHOR]

Background: We developed a seizure questionnaire that could be administered by a trained research assistant in a two-step process, approximating the clinical diagnostic process of a pediatric epileptologist. This questionnaire was designed to study seizure prevalence in a research population of 10-year-old children at risk for epilepsy.Methods: English-speaking parents of children 6 months to 12 years old were recruited from the pediatric neurology clinics at Boston Medical Center and interviewed using a computerized questionnaire. An algorithm of parent responses rendered a 4-level ranking scale of seizure probability for events: (1) not likely, (2) indeterminate, (3) probable, (4) almost certain. Blinded to questionnaire results, pediatric neurologists served as the diagnostic gold standard, ranking each patient event using the same four-level scale based on clinical history and examination.Results: The questionnaire was completed by 150 of 177 (84.7%) enrolled parents. Seizure prevalence among participants was 38.6%. The seizure questionnaire yielded a fitted receiver operating characteristic area of 0.93 (95% confidence interval [CI], 0.89-0.97). Based on optimal sensitivity and false-positive fraction, we dichotomized the questionnaire results as consistent with seizure (levels 3 and 4) or without seizure (levels 1 and 2). Overall, findings included a 91.4% sensitivity (95% CI, 84.2%-98.6%) and an 82.6% specificity (95% CI, 74.9%-90.4%). The positive predictive value was 76.8% (95% CI, 66.9%-86.8%) and the negative predictive value was 93.8% (95% CI, 88.6%-99.1%).Conclusions: This pediatric seizure questionnaire was both sensitive and specific for detecting clinically confirmed seizures. This tool may be useful to researchers and clinicians in screening large populations of children, decreasing the time and cost of added neurological assessments. [ABSTRACT FROM AUTHOR]