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The infantile spasms (IS) syndrome is a catastrophic developmental epileptic encephalopathy syndrome characterized by an age-specific expression of epileptic spasms that are associated with extremely abnormal, oftentimes described as chaotic, interictal EEG pattern known as hypsarrhythmia. Patients with IS generally have poor neurodevelopmental outcomes, in large part because of the frequent epileptic spasms and interictal EEG abnormalities. Current first-line treatments such as adrenocorticotropic hormone or vigabatrin are often ineffective and are associated with major toxic side effects. There is therefore a need for better and safer treatments for patients with IS, especially for the intractable population. Hope is on the horizon as, over the past 10 years, there has been robust progress in the development of etiology-specific animal models of IS. These models have been used to identify potential new treatments for IS and are beginning to provide some important insights into the pathophysiological substrates for this disease. In this review, we will highlight strengths and weaknesses of the currently available animal models of IS in addition to new insights into the pathophysiology and treatment options derived from these models.

Author(s): Buchhalter, Jeffrey R; Scantlebury, Morris H; D'Alfonso, Sabrina; Pablo Appendino, Juan; Bello Espinosa, Luis; Brooks, Brian L; Claassen, Curtis; Corbeil, Jane; Czank, David; Dean, Stafford; Ho, Alice W; Jacobs, Julia; Mackay, Maarit; McMahon, Joka; Mineyko, Aleksandra; Rho, Jong M; Roberts, Trina; Rothenmund, Sonia; Ruta, Gary; Sawchuk, Tyson; Simms, Brett A; Smyth, Kim; Still, Tammy; Thornton, Nancy | Abstract: ObjectiveTo describe the development of the Pediatric Epilepsy Outcome-Informatics Project (PEOIP) at Alberta Children's Hospital (ACH), which was created to provide standardized, point-of-care data entry; near-time data analysis; and availability of outcome dashboards as a baseline on which to pursue quality improvement.MethodsStakeholders involved in the PEOIP met weekly to determine the most important outcomes for patients diagnosed with epilepsy, create a standardized electronic note with defined fields (patient demographics, seizure and syndrome type and frequency and specific outcomes- seizure type and frequency, adverse effects, emergency department visits, hospitalization, and care pathways for clinical decision support. These were embedded in the electronic health record from which the fields were extracted into a data display platform that provided patient- and population-level dashboards updated every 36nhours. Provider satisfaction and family experience surveys were performed to assess the impact of the standardized electronic note.ResultsIn the last 5nyears, 3,245 unique patients involving 13, 831 encounters had prospective, longitudinal, standardized epilepsy data accrued via point-of-care data entry into an electronic note as part of routine clinical care. A provider satisfaction survey of the small number of users involved indicated that the vast majority believed that the note makes documentation more efficient. A family experience survey indicated that being provided with the note was considered "valuable" or "really valuable" by 86% of respondents and facilitated communication with family members, school, and advocacy organizations.SignificanceThe PEOIP serves as a proof of principle that information obtained as part of routine clinical care can be collected in a prospective, standardized, efficient manner and be used to construct filterable process/outcome dashboards, updated in near time (36nhours). This information will provide the necessary baseline data on which multiple of QI projects to improve meaningful outcomes for children with epilepsy will be based.

The evidence is mounting for a role for abnormal signaling of the stress peptide pituitary adenylate cyclase activating polypeptide (PACAP) and its canonical receptor PAC1 in the pathogenesis of sudden infant death syndrome. In this study, we investigated whether the PACAP receptors PAC1 or VPAC2 are involved in the neonatal cardiorespiratory response to hypercapnic stress. We used head-out plethysmography and surface ECG electrodes to assess cardiorespiratory responses to an 8% hypercapnic challenge in unanesthetized and spontaneously breathing 4-day-old PAC1 or VPAC2 knockout (KO) and wild-type mouse pups. We demonstrate that compared with WTs, breathing frequency (RR) and minute ventilation ([Formula: see text]) in PAC1 KO pups were significantly blunted in response to hypercapnia. Although heart rate was unaltered in PAC1 KO pups during hypercapnia, heart rate recovery posthypercapnia was impaired. In contrast, cardiorespiratory impairments in VPAC2 KO pups were limited to only an overall higher tidal volume (VT), independent of treatment. These findings suggest that PACAP signaling through the PAC1 receptor plays a more important role than signaling through the VPAC2 receptor in neonatal respiratory responses to hypercapnia. Thus deficits in PACAP signaling primarily via PAC1 may contribute to the inability of infants to mount an appropriate protective response to homeostatic stressors in childhood disorders such as SIDS.

In adult brain tissue, oxygen levels typically remain in the normoxic zone, but status epilepticus results in hyperoxia, whereas brief self-terminating seizures lead to postictal hypoxia. The dynamic changes in oxygen levels and the underlying mechanisms are unknown in juveniles with febrile seizures.Eight-day-old female and male rat pups were implanted with an electrode and oxygen-sensing optode in the hippocampus and then received once daily injections of lipopolysaccharide for 4 days to induce an immune response. Local partial pressure of oxygen (pOFebrile seizures resulted in predictable oxygen dynamics that were related to behavioral seizures and epileptiform activity. During a behavioral seizure, pOBrain oxygenation during and following a febrile seizure has a distinct pattern and multiple mechanisms. Brain oxygen dynamics may be an important consideration in the development of treatments for febrile seizures.

Over the past decade, a growing body of evidence has validated the essential role of the gut microbiome in regulating diverse physiologic processes, spanning gut-related disease to neural function. While many factors are involved, diet is the primary driver of global microbial composition and function. Studies from animal models and humans suggest that the ketogenic diet can reshape the gut microbiome. However, the relevance of the altered microbiota is still under investigation. Since the gut microbiome is implicated in modulating brain function via metabolic, immunologic, and endocrine pathways, a possible role of the microbiota–gut–brain axis in mediating the neural response to the ketogenic diet has been proposed. This chapter outlines how the ketogenic diet affects the gut microbiota and the implications of such ketogenic diet-induced phenotypes. Special attention is paid to interactions between the diet, gut microbiota, and neurodevelopmental disorders, including epilepsy and autism spectrum disorder.

Objective Brain tissue oxygen (partial oxygen pressure [pO2]) levels are tightly regulated to stay within the normoxic zone, with deviations on either side resulting in impaired brain function. Whereas pathological events such as ischemic attacks and brief seizures have previously been shown to result in pO2 levels well below the normoxic zone, oxygen levels during prolonged status epilepticus (SE) and the subsequent endogenous kindling period are unknown. Methods We utilized two models of acquired temporal lobe epilepsy in rats: intrahippocampal kainic acid infusion and prolonged perforant pathway stimulation. Local tissue oxygen was measured in the dorsal hippocampus using an optode during and for several weeks following SE. Results We observed hyperoxia in the hippocampus during induced SE in both models. Following termination of SE, 88% of rats initiated focal self‐generated spiking activity in the hippocampus within the first 7 days, which was associated with dynamic oxygen changes. Self‐generated and recurring epileptiform activity subsequently organized into higher‐frequency bursts that became progressively longer and were ultimately associated with behavioral seizures that became more severe with time and led to postictal hypoxia. Significance Induced SE and self‐generated recurrent epileptiform activity can have profound and opposing effects on brain tissue oxygenation that may serve as a biomarker for ongoing pathological activity in the brain.

A growing body of evidence supports a role of the gut microbiota in regulating diverse physiological processes, including neural function and metabolism via the gut-brain axis. Infantile spasms syndrome is an early-onset epileptic encephalopathy associated with perturbed brain mitochondrial bioenergetics. Employing a neonatal rat model of infantile spasms, mitochondria respirometry and biochemical analyses, the present study reveals that gut microbiota manipulation by diet, antibiotics and probiotics have the potential to enhance hippocampal mitochondrial bioenergetics. Although preliminary in nature, our data reveal that microbial manipulation that regulates brain mitochondrial function may be a novel strategy for the treatment of epileptic disorders.

Infantile spasms (IS) syndrome is a catastrophic, epileptic encephalopathy of infancy that is often refractory to current antiepileptic therapies. The ketogenic diet (KD) has emerged as an alternative treatment for patients with medically intractable epilepsy, though the prospective validity and mechanism of action for IS remains largely unexplored. We investigated the KD’s efficacy as well as its mechanism of action in a rodent model of intractable IS. The spasms were induced using the triple-hit paradigm and the animals were then artificially reared and put on either the KD (4:1 fats: carbohydrate + protein) or a control milk diet (CM; 1.7:1). 31Phosphorus magnetic resonance spectroscopy (31P MRS) and head-out plethysmography were examined in conjunction with continuous video-EEG behavioural recordings in lesioned animals and sham-operated controls. The KD resulted in a peripheral ketosis observed both in the blood and urine. The KD led to a robust reduction in the frequency of spasms observed, with approximately a 1.5-fold increase in the rate of survival. Intriguingly, the KD resulted in an intracerebral acidosis as measured with 31P MRS. In addition, the respiratory profile of the lesioned rats on the KD was significantly altered with slower, deeper and longer breathing, resulting in decreased levels of expired CO2. Sodium bicarbonate supplementation, acting as a pH buffer, partially reversed the KD’s protective effects on spasm frequency. There were no differences in the mitochondrial respiratory profiles in the liver and brain frontal cortex measured between the groups, supporting the notion that the effects of the KD on breathing are not entirely due to changes in intermediary metabolism. Together, our results indicate that the KD produces its anticonvulsant effects through changes in respiration leading to intracerebral acidosis. These findings provide a novel understanding of the mechanisms underlying the anti-seizure effects of the KD in IS. Further research is required to determine whether the effects of the KD on breathing and intracerebral acid-base balance are seen in other paediatric models of epilepsy.

Infantile spasms syndrome (IS) is a type of epilepsy affecting 1.6 to 4.5 per 10,000 children in the first year of life, often with severe lifelong neurodevelopmental consequences. Only two first-line pharmacological treatments currently exist for IS and many children are refractory to these therapies. In such cases, children are treated with the ketogenic diet (KD). While effective in reducing seizures, the diet can result in dyslipidemia over time.Employing a neonatal Sprague-Dawley rat model of IS, we investigated how the KD affects hepatic steatosis and its modulation by a defined probiotic blend. A combination of multiple readouts, including malondialdehyde, fatty acid profiles, lipid metabolism-related enzyme mRNA expression, mitochondrial function, histone deacetylase activity, cytokines and chemokines were evaluated using liver homogenates.The KD reduced seizures, but resulted in severe hepatic steatosis, characterized by a white liver, triglyceride accumulation, elevated malondialdehyde, polyunsaturated fatty acids and lower acyl-carnitines compared to animals fed a control diet. The KD-induced metabolic phenotype was prevented by the co-administration of a blend of Streptococcus thermophilus HA-110 and Lactococcus lactis subsp. lactis HA-136. This probiotic blend protected the liver by elevating pAMPK-mediated signaling and promoting lipid oxidation. The strains further upregulated the expression of caspase 1 and interleukin 18, which may contribute to their hepatoprotective effect in this model.Our results suggest that early intervention with probiotics could be considered as an approach to reduce the risk of hepatic side effects of the KD in children who are on the diet for medically indicated reasons.This study was funded by the Alberta Children's Hospital Research Institute and Mitacs Accelerate Program (IT16942).

The stress peptide pituitary adenylate cyclase activating polypeptide (PACAP) and its specific receptor PACAP type 1 receptor (PAC1) have been implicated in sudden infant death syndrome (SIDS). PACAP is also critical to the neonatal cardiorespiratory response to homeostatic stressors identified in SIDS, including hypoxia. However, which of PACAP’s three receptors, PAC1, vasoactive intestinal peptide receptor type 1 (VPAC1), and/or vasoactive intestinal peptide receptor type 2 (VPAC2), are involved is unknown. In this study, we hypothesized that PAC1, but not VPAC2, is involved in mediating the cardiorespiratory response to hypoxia during neonatal development. To test this hypothesis, head-out plethysmography and surface ECG electrodes were used to assess the cardiorespiratory variables of unanesthetized postnatal day 4 PAC1 and VPAC2-knockout (KO) and wild-type (WT) mice in response to a 10% hypoxic challenge. Our results demonstrate that compared with WT pups, the early and late hypoxic rate of expired CO2(V̇co2), V̇co2and ventilatory responses were blunted in PAC1-KO neonates, and during the posthypoxic period, minute ventilation (V̇e), V̇co2and heart rate were increased, while the increase in apneas normally associated with the posthypoxic period was reduced. Consistent with impaired cardiorespiratory control in these animals, the V̇e/V̇co2slope was reduced in PAC1-KO pups, suggesting that breathing was inappropriately matched to metabolism. In contrast, VPAC2-KO pups exhibited elevated heart rate variability during hypoxia compared with WT littermates, but the effects of the VPAC2-KO genotype on breathing were minimal. These findings suggest that PAC1 plays the principal role in mediating the cardiorespiratory effects of PACAP in response to hypoxic stress during neonatal development and that defective PACAP signaling via PAC1 may contribute to the pathogenesis of SIDS.

The infantile spasms (IS) syndrome is a developmental epileptic encephalopathy disorder characterized by epileptic spasms occurring in infancy, hypsarrhythmia on the electroencephalography (EEG) and developmental arrest or regression. The etiologies include structural, metabolic, and genetic causes. We report an unusual case of IS due to a de novo variant in the MECP2 gene. The patient also had variants of uncertain significance in the SCN9A and SCN5A genes inherited from the father and mother, respectively. This report highlights the need for broad genetic testing in MECP2-related disorders with atypical presentations to better understand the disease etiology.

Objectives: The use of telemedicine has grown exponentially as an alternative to providing care to patients with epilepsy during the pandemic. We investigated the impact of the current pandemic among children with epilepsy from two distinct pediatric epilepsy centers. We also compared perceptions among those who received telemedicine against those who did not.Methods: We developed a questionnaire and invited families followed in Freiburg, Germany, and Calgary, Alberta, Canada, to participate during the initial 9 months of the pandemic. The survey contained 32 questions, 10 of which were stratified according to telemedicine exposure.Results: One hundred twenty-six families (80 in Freiburg, 46 in Calgary) participated, and 40.3% received telemedicine care. Most children (mean age 10.4 years, SD 5.1) had chronic epilepsy but poorly controlled seizures. Negative impacts were reported by 36 and 65% of families who had to reschedule appointments for visits and diagnostics, respectively. Nearly two-thirds of families reported no change in seizure frequency, while 18.2% reported either worsening or improvement of seizures. Although most families did not note behavioral changes, 28.2% reported behavior worsening. Families who received telemedicine care had a statistically significant reduction of parental self-reported anxiety level after virtual visits compared to those who did not experience telemedicine. Families with telemedicine consultations were more likely to consider future virtual care (84 vs. 65.2% of those without), even after the pandemic. Patient data safety, easy access to specialized services, and consistency with the same healthcare provider were graded as important in both centers, while a shorter waiting time was most relevant in Calgary.Conclusion: In our cohort, some children with epilepsy experienced increased seizures and worsening behavior during the first 9 months of the current pandemic. In addition, our data suggest that telemedicine might reduce parental anxiety symptoms, and families who experienced telehealth were more positive and open to similar appointments in the future.

The glycoprotein Reelin maintains neuronal positioning and regulates neuronal plasticity in the adult brain. Reelin deficiency has been associated with neurological diseases. We recently showed that Reelin is depleted in mice with a targeted disruption of the Ndel1 gene in forebrain postnatal excitatory neurons (Ndel1 conditional knockout (CKO)). Ndel1 CKO mice exhibit fragmented microtubules in CA1 pyramidal neurons, profound deterioration of the CA1 hippocampus and a shortened lifespan (~10 weeks). Here we report that Ndel1 CKO mice (of both sexes) experience spatial learning and memory deficits that are associated with deregulation of neuronal cell adhesion, plasticity and neurotransmission genes, as assessed by genome-wide transcriptome analysis of the hippocampus. Importantly, a single injection of Reelin protein in the hippocampus of Ndel1 CKO mice improves spatial learning and memory function and this is correlated with reduced intrinsic hyperexcitability of CA1 pyramidal neurons, and normalized gene deregulation in the hippocampus. Strikingly, when treated with Reelin, Ndel1 CKO animals that die from an epileptic phenotype, live twice as long as nontreated, or vehicle-treated CKO animals. Thus, Reelin confers striking beneficial effects in the CA1 hippocampus, and at both behavioral and organismal levels.

The infantile spasms syndrome is an early-onset epileptic encephalopathy presenting in the first 2 years of life, often with severe developmental consequences. The role of the gut microbiota and metabolism in infantile spasms remains unexplored.Employing a brain injury neonatal rat model of infantile spasms intractable to anticonvulsant medication treatments, we determined how the ketogenic diet and antibiotics affected specific microbial communities and the resultant circulating factors that confer spasms protection in the infantile spasms model. To confirm a role of kynurenine metabolism pathway in spasms protection, indoleamine 2,3-dioxygenase 1 was pharmacologically inhibited and comprehensive metabolomics was applied.We show that antibiotics reduced spasms and improved the effectiveness of the ketogenic diet when given in combination. Examination of the gut microbiota and metabolomics showed the downregulation of indoleamine 2,3-dioxygenase 1 and upregulation of hippocampal kynurenic acid, a metabolite with antiepileptic effects. To further test the involvement of indoleamine 2,3-dioxygenase 1, a specific antagonist 1-methyltryptophan and minocycline, an antibiotic and inhibitor of kynurenine formation from tryptophan, were administered, respectively. Both treatments were effective in reducing spasms and elevating hippocampal kynurenic acid. A fecal microbiota transplant experiment was then performed to examine the contribution of the gut microbiota on spasm mitigation. Transplant of feces of ketogenic diet animals into normal diet animals was effective in reducing spasms.These results highlight the importance of tryptophan-kynurenine metabolism in infantile spasms and provide evidence for new-targeted therapies such as indoleamine 2,3-dioxygenase 1 inhibition or microbiota manipulation to promote kynurenic acid production as a strategy to reduce spasms in infantile spasms.This study was funded by the Alberta Children's Hospital Research Institute and the Owerko Centre.

Thermal hyperpnea, a pattern of breathing during hyperthermia that is characterized by an increase in tidal volume as well as breathing frequency, is known to lead to respiratory alkalosis. Thermal hyperpnea-induced respiratory alkalosis is linked to febrile seizures (FS). The heat-sensitive transient receptor potential vanilloid-1 (TRPV1) receptors are localized in, and implicated in the heat sensitivity of peripheral and central structures involved in the respiratory response to hyperthermia. We, therefore, hypothesize that TRPV1 activation increases susceptibility to experimental FS (EFS) in immature rats due to an exacerbated thermal hyperpnea. We found that peripheral, but not central TRPV1 activation had pro-convulsant effects. These pro-convulsant effects were associated with an increased rate of expired CO2 due to an exaggerated ventilatory response to hyperthermia. The TRPV1 antagonist, AMG-9810, and TRPV1 deletion abolished the pro-convulsant effects, while exposure to 5% CO2, bilateral vagotomy and DREADD (designer receptor exclusively activated by designer drugs)-mediated inhibition of TRPV1-containing cells in the vagal nodose ganglia significantly attenuated these effects. These findings suggest that vagal TRPV1-driven thermal hyperpnea likely increases susceptibility to FS in immature rodents. This identifies a novel peripheral anatomical and molecular target that should be considered when developing therapeutics for FS.

The importance of so called variants of undetermined significance in the development of Infantile Epileptic Encephalopathy is discussed and an illustrative case is presented.

Though the term "inflammation" is traditionally defined as proliferation or infiltration of lymphatic cells of the lymphatic immune system and macrophages or as immunoreactive proteins including cytokines, interleukins and major histocompatibility complexes, recently recognized reactions to tissue injury also are inflammation, often occurring in the central nervous system in conditions where they previously were not anticipated and where they may play a role in both pathogenesis and repair. We highlight 4 such novel inflammatory conditions revealed by neuropathologic studies: (1) inflammatory markers and cells in the brain of human fetuses with tuberous sclerosis complex and perhaps other disorders of the mechanistic target of rapamycin genetic or metabolic pathway, (2) inflammatory markers in the brain related to febrile seizures of infancy and early childhood, (3) heat-shock protein upregulation in glial cells and neurons at sites of chronic epileptic foci, and (4) the emerging role of astrocytes in the presence of and participation in inflammation. Novel evidence shows that cerebral inflammation plays a role in some genetic diseases as early as midgestation and thus is not always acquired postnatally or in adult life.

Type 3 Gaucher disease (GD3) is characterized by progressive neurological features in addition to the typical systemic manifestations. Enzyme replacement therapy (ERT), the main stay treatment for Gaucher disease (GD), is not efficacious for the neurological manifestations. Ambroxol, in combination with ERT has been suggested to have potential as a promising therapy for patients with GD3. The purpose of this study is to assess the effect of Ambroxol on glucosylsphingosine (Lyso-Gb1) levels, and on the neurological morbidity, in two Canadian patients with GD3. Keywords: Ambroxol, Glucosylsphingosine, Gaucher, Ataxia, Epilepsy, Lyso-Gb1, Lyso-GL1

Aminoacyl transfer RNA (tRNA) synthetase complex-interacting multifunctional protein I is a noncatalytic component of tRNA multi-synthetase complexes. Although important in joining tRNAs to their cognate amino acids, AIMP1 has several other functions including axonal growth, cytokine activity, and interactions with N -acetylaspartic acid in ribosomal tRNA synthetase complexes. Further, N -acetylaspartic acid donates an aspartate during myelination and is therefore important to axonal integrity. Mutations in AIMP1 can disrupt these functions, as demonstrated in this clinical case study of 2 monozygotic twins, who display congenital opisthotonus, microcephaly, severe developmental delay, and seizures. Whole exome sequencing was used to identify a premature stop codon in the AIMP1 gene (g. 107248613_c.115C>T; p.(Gln39). In the absence of whole exome sequencing, we propose that decreased N -acetylaspartic acid peaks on magnetic resonance spectroscopy could act as a biomarker for AIMP1 mutations.

Aminoacyl transfer RNA (tRNA) synthetase complex-interacting multifunctional protein I is a noncatalytic component of tRNA multi-synthetase complexes. Although important in joining tRNAs to their cognate amino acids, AIMP1 has several other functions including axonal growth, cytokine activity, and interactions with N-acetylaspartic acid in ribosomal tRNA synthetase complexes. Further, N-acetylaspartic acid donates an aspartate during myelination and is therefore important to axonal integrity. Mutations in AIMP1 can disrupt these functions, as demonstrated in this clinical case study of 2 monozygotic twins, who display congenital opisthotonus, microcephaly, severe developmental delay, and seizures. Whole exome sequencing was used to identify a premature stop codon in the AIMP1 gene (g. 107248613_c.115C>T; p.(Gln39). In the absence of whole exome sequencing, we propose that decreased N-acetylaspartic acid peaks on magnetic resonance spectroscopy could act as a biomarker for AIMP1 mutations.

Access to quality healthcare remains a challenge that is complicated by mounting pressures to control costs, and now, as we witness, the unprecedented strain placed on our healthcare delivery systems due to the COVID-19 pandemic. Challenges in healthcare access have driven a need for innovative approaches ensuring connectivity to health providers. Telehealth services and virtual clinics offer accessible disease management pathways for patients living in health resource limited areas or, as in the case of the COVID-19 pandemic, where there may be potential barriers to existing healthcare resources. Those suffering with serious chronic disorders often cannot be seen by a healthcare specialist due to their limited availability, or the lack of a specialist within a reasonable proximity. Epilepsy represents such a disorder where most of the world's population lacks the availability of necessary specialists. Virtual clinics allow for specialist care and an ability to perform necessary ambulatory electroencephalogram (EEG) monitoring by placing the technologies directly in patients' homes or at local clinics near the patients' homes. By moving the diagnostic process out of the hospital or epilepsy center, it becomes possible to overcome growing gaps in neurology services. Virtual clinics have the potential to expand access to high-quality, cost-effective care for the patient. The virtual clinic remotely connects those in need of medical support with specialists anywhere in the world, at any time of the day., Highlights • Healthcare access is a challenge for people in resource limited regions of the world. • Telehealth services better connect people with epilepsy to EEG diagnostic solutions. • Virtual clinics for epilepsy allow optimized remote specialist health management. • The COVID-19 pandemic requires the ability to provide continuity of care safely.

Purpose Infantile spasms (IS) are a devastating epileptic encephalopathy syndrome of infancy. Analysis of infraslow EEG activity (ISA) has shown potential in the presurgical evaluation of patients with epilepsy and in differentiating between focal and generalized epilepsy syndromes. Infraslow EEG activity analysis may provide insights into the pathophysiology of some difficult-to-treat epilepsy syndromes, such as IS. To our knowledge, there are no published reports describing ISA in patients with IS. The purpose of this study was to describe ictal patterns of ISA in patients with IS and to correlate with clinical data. Methods EEG recordings of all cases of IS in the past 10 years at the Alberta Children's Hospital were reviewed. Inclusion criteria were a technically adequate video EEG recording that captured at least one spasm. For each patient, the first 10 confirmed spasms were examined. Spasms were evaluated for changes in ISA, which were either generalized, lateralized, or absent ISA (g-ISA, l-ISA, or n-ISA, respectively). Results were correlated with treatments, clinical course, and information pertinent to likely etiology of the IS. Results A total of 77% of spasms were associated with ISA; 57% with g-ISA, 20% l-ISA, and 21% n-ISA. All patients with exclusively g-ISA showed at least a partial response to initial therapy, while this was the case in 66.7% of those with at least some l-ISA and 50% of those with exclusively n-ISA. Other seizure types occurred in 60% of patients with exclusively g-ISA versus 83% with some l-ISA and all patients with exclusively n-ISA. Conclusions Ictal ISA was observed in the majority of IS. Trends were observed suggesting that the presence of exclusive g-ISA changes may be a positive prognostic factor in IS.

ACTH, a member of the melanocortin family of peptides, is often used in the treatment of the developmental epileptic encephalopathy spectrum disorders including, Ohtahara, West, Lennox Gastaut and Landau-Kleffner Syndromes and electrical status epilepticus of sleep. In these disorders, although ACTH is often successful in controlling the seizures and/or inter-ictal EEG abnormalities, it is unknown whether ACTH possesses other beneficial effects independent of seizure control. We tested whether ACTH can ameliorate the intrinsic impairment of hippocampal-based learning and memory in epileptic Kcna1-null (KO) mice. We found that ACTH - administered in the form of Acthar Gel given i.p. four times daily at a dose of 4 IU/kg (16 IU/kg/day) for 7days - prevented impairment of long-term potentiation (LTP) evoked with high-frequency stimulation in CA1 hippocampus and also restored spatial learning and memory on the Barnes maze test. However, with this treatment regimen, ACTH did not exert a significant effect on the frequency of spontaneous recurrent seizures. Together, our findings indicate that ACTH can ameliorate memory impairment in epileptic Kcna1-null mice separate from seizure control, and suggest that this widely used peptide may exert direct nootropic effects in the epileptic brain.

Febrile seizures (FS) are the most common seizure disorder to affect children. Although there is mounting evidence to support that FS occur when children have fever-induced hyperventilation leading to respiratory alkalosis, the underlying mechanisms of hyperthermia-induced hyperventilation and links to FS remain poorly understood. As transient receptor potential vanilloid-1 (TRPV1) receptors are heat-sensitive, play an important role in adult thermoregulation and modulate respiratory chemoreceptors, we hypothesize that TRPV1 activation is important for hyperthermia-induced hyperventilation leading to respiratory alkalosis and decreased FS thresholds, and consequently, TRPV1 KO mice will be relatively protected from hyperthermic seizures. To test our hypothesis we subjected postnatal (P) day 8-20 TRPV1 KO and C57BL/6 control mice to heated dry air. Seizure threshold temperature, latency and the rate of rise of body temperature during hyperthermia were assessed. At ages where differences in seizure thresholds were identified, head-out plethysmography was used to assess breathing and the rate of expired CO2 in response to hyperthermia, to determine if the changes in seizure thresholds were related to respiratory alkalosis. Paradoxically, we observed a pro-convulsant effect of TRPV1 deletion (∼4min decrease in seizure latency), and increased ventilation in response to hyperthermia in TRPV1 KO compared to control mice at P20. This pro-convulsant effect of TRPV1 absence was not associated with an increased rate of expired CO2, however, these mice had a more rapid rise in body temperature following exposure to hyperthermia than controls, and the expected linear relationship between body weight and seizure latency was absent. Based on these findings, we conclude that deletion of the TRPV1 receptor prevents reduction in hyperthermic seizure susceptibility in older mouse pups, via a mechanism that is independent of hyperthermia-induced respiratory alkalosis, but possibly involves impaired development of thermoregulatory mechanisms, although at present the mechanism remain unknown.

Introduction: Symptomatic infantile spasms (SIS) constitute a debilitating epileptic encephalopathy due to an identifiable lesion in the developing brain. Perinatal and infantile arterial ischemic stroke (AIS) result in a large spectrum of developmental outcomes. Risk factors for worse outcome are not well understood, with epilepsy diagnosis being a poor prognostic factor. As a focal injury in an otherwise healthy brain, early stroke provides unique insight into the developmental effects of epileptic encephalopathy. Hypothesis: SIS are a rare complication of AIS in infancy/early childhood. Additional neurological comorbidities are seen in stroke patients with SIS. Methods: A population-based cohort of pediatric stroke (Calgary Pediatric Stroke Program) was screened. Inclusion criteria were: (1) MRI-confirmed AIS (2) age at stroke 2 and non-motor outcomes >1. Results: One hundred and sixty-three children with AIS at Conclusions: Early AIS can be complicated by infantile spasms but usually only in the context of additional neurological comrobidity. Neurological outcomes are poor but discerning the contribution of the epileptic encephlapathy is challenging as in other IS populations.

A developmentally normal adolescent boy with a history of childhood absence epilepsy presented with recurrence of pyknolepsy after a seven-year period of remission. The characteristics of his EEG showed the same 3-Hz generalised spike-wave discharge as in his previous EEG in childhood. To our knowledge, this is the first case report describing recurrence of childhood absence epilepsy as pyknolepsy in an adolescent. [Published with video sequences].

Infantile spasms are the classical seizure type of West syndrome. Infantile spasms often herald a dismal prognosis, due to the high probability to evolve into intractable forms of epilepsies with significant cognitive deficits, especially if not adequately treated. The current therapies-high doses of adrenocorticotropic hormone, steroids, or the gamma-aminobutyric acid (GABA) transaminase inhibitor vigabatrin--are often toxic and may not always be effective. The need to identify new therapies for spasms has led to the generation of a number of rodent models of infantile spasms. These include acute and chronic models of infantile spasms, with cryptogenic or symptomatic origin, many of which are based on specific etiologies. In this review, we summarize the clinical experience with treating infantile spasms and the main features of the new animal models of infantile spasms and discuss their utility in the preclinical development of new therapies for infantile spasms.

Infantile spasms are characterized by age-specific expression of epileptic spasms and hypsarrhythmia and often result in significant cognitive impairment. Other epilepsies or autism often ensue especially in symptomatic IS (SIS). Cortical or subcortical damage, including white matter, have been implicated in the pathogenesis of SIS. To generate a model of SIS, we recreated this pathology by injecting rats with lipopolysaccharide and doxorubicin intracerebrally at postnatal day (P) 3 and with p-chlorophenylalanine intraperitoneally at P5. Spasms occurred between P4 and 13 and were associated with ictal EEG correlates, interictal EEG abnormalities and neurodevelopmental decline. After P9 other seizures, deficits in learning and memory, and autistic-like behaviors (indifference to other rats, increased grooming) were observed. Adrenocorticotropic hormone (ACTH) did not affect spasms. Vigabatrin transiently suppressed spasms at P5. This new model of SIS will be useful to study the neurobiology and treatment of SIS, including those that are refractory to ACTH.

Summary: Purpose: To determine the effects of focal corti- cal dysplasia on the behavioral and electrographic features of hyperthermia-induced seizures (HSs) in rats. Methods: A right sensorimotor cortex freeze lesion was in- duced in postnatal day 1 (P1) rat pups, and HSs were provoked at P10 under continuous monitoring of core temperature; EEGs were recorded from the right amygdala during and after hyper- thermia. Controls included both sham-operated at P1 and na¨ ive rats. Results: HSs began with jaw myoclonus, followed by hindlimb clonus and generalized convulsions (GCs), and termi- nated by a period of posthyperthermia depression. The threshold temperature and latency of jaw myoclonus were similar across the groups. However, both the threshold temperature and latency of GCs were significantly lower in lesioned pups than in controls (40.5 ± 0.5 ◦ C, n = 24, vs. 42.0 ± 0.2 ◦ C, n = 21; p < 0.001; 6.7 ± 0.6 min, n = 20, vs. 8.4 ± 0.6 min, n = 22; p < 0.05). In lesioned pups, the threshold and latencies for jaw myoclonus and hindlimb clonus were similar, whereas in controls, the pro- gression from one to the other was marked by significant dif- ferences in both parameters. Posthyperthermia depression was longer in lesioned (13.3 ± 1.2 min, n = 21) than in control (8.0 ± 0.8 min, n = 20; p < 0.0001) pups. Ictal EEG activity was recorded during both behavioral seizures and posthyperthermia depression. Conclusions: An HS in rats with a localized freeze lesion results in lower threshold GC and prolonged ictal manifestations, thus supporting a pathophysiologic link between focal cortical dysplasia and atypical febrile seizures, conditions that have a high prevalence in children with mesial temporal lobe epilepsy.

Infantile spasms are the classical seizure type of West syndrome. Infantile spasms often herald a dismal prognosis, due to the high probability to evolve into intractable forms of epilepsies with significant cognitive deficits, especially if not adequately treated. The current therapies-high doses of adrenocorticotropic hormone, steroids, or the gamma-aminobutyric acid (GABA) transaminase inhibitor vigabatrin--are often toxic and may not always be effective. The need to identify new therapies for spasms has led to the generation of a number of rodent models of infantile spasms. These include acute and chronic models of infantile spasms, with cryptogenic or symptomatic origin, many of which are based on specific etiologies. In this review, we summarize the clinical experience with treating infantile spasms and the main features of the new animal models of infantile spasms and discuss their utility in the preclinical development of new therapies for infantile spasms.

Facial nerve palsies are uncommon in infants. We report on 10-week-old monozygotic twins, diagnosed with cystic fibrosis by newborn screening, who developed facial palsy and increased intracranial pressure. Cranial imaging and cerebrospinal fluid analysis produced normal results. Levels of serum vitamin A were below normal range. Low levels of vitamin A are associated with facial nerve paralysis, and are at least partly implicated in the development of increased intracranial pressure in infants with cystic fibrosis.