Epilepsy is defined as a condition with recurrent unprovoked seizures. When seizures are believed to be provoked they fall into another category of situation-related seizures, i.e. acute symptomatic seizures (ASS). The definition of ASS is a clinical seizure occurring in close temporal relationship with an acute insult in the central nervous system (CNS), which may be metabolic, toxic, structural, infectious or inflammatory. The prognosis after unprovoked seizures and ASS differs with regard to risk of seizure recurrence and mortality. This thesis focuses on seizures occurring in relation to common dysmetabolic conditions and subarachnoid haemorrhage (SAH). Specifically, the occurrence of ASS in patients with different levels of hyponatraemia and hypoglycaemia was studied. Furthermore an experimental study in rodents was conducted to explore the relationship between chemically induced status epilepticus (SE) and hyponatraemia. In addition, seizures in relation to acute SAH were recorded and related to appearance of development of delayed cerebral ischemia (DCI). Finally, measurement of neurofilament light (NFL) and tau in the cerebrospinal fluid (CSF) was performed. In a large number of patients with hyponatremia a gradual increase (2.5 % – 11 %) in risk of seizures with declining sodium levels was noted. Seizures were the only neurologic manifestation of hyponatraemia in patients with moderately decreased sodium levels (> 115 mM). In a study of patients with hypoglycaemia, a notably low risk for seizures was found. Absolute risk for neurological symptoms at glucose < 2.0 mM (95% CI) was 0.25 (0.13-0.41). This is a finding of potentially great clinical relevance, since seizures in the presence of hypoglycaemia are often presumed to be acutely symptomatic. In the animal study of acute hyponatraemia on kainic acid (KA) induced status epilepticus (SE) the hyponatraemic animals displayed an increased frequency of epileptiform activity and had longer duration of seizures. These results support the clinical observations that hyponatraemia aggravates SE. In the study of patients with SAH seizures were frequent (36% of all patients) but did not predict the development of DCI. Measurement of the CSF biomarker tau at different time points revealed increased tau concentration between days 4 and 10, and may be associated with DCI.

Post-stroke seizures are associated with worsened outcome following stroke, but the underlying pathophysiology is poorly understood. Here I combined behavioral, electrophysiological and histological assessments to examine acute seizures in adult mice following hypoxia-ischemia (HI). C57BL/6 mice aged 4-9 months received a permanent occlusion of the right common carotid artery and were then exposed to systemic hypoxia (8% O2, ~30 minutes). The HI episode resulted in decreases in cerebral blood flow, suppression of EEG activities and extensive brain injury in the hemisphere ipsilateral to the carotid artery occlusion. Generalized motor seizures were observed within 72 hours following HI. These seizures occurred nearly exclusively in animals with the extensive ipsilateral brain injury, but their generation was not associated with EEG discharges in bilateral hippocampal and cortical areas. Animals exhibiting these seizures had a high rate of mortality. Post-HI treatments with diazepam and phenytoin suppressed these motor seizures and improved post-HI animal survival. Based on these data, I conclude that these seizures are a consequence of HI brain injury, contribute to mortality following HI, and that they may originate from deep subcortical structures.

Post-stroke seizures are associated with worsened outcome following stroke, but the underlying pathophysiology is poorly understood. Here I combined behavioral, electrophysiological and histological assessments to examine acute seizures in adult mice following hypoxia-ischemia (HI). C57BL/6 mice aged 4-9 months received a permanent occlusion of the right common carotid artery and were then exposed to systemic hypoxia (8% O2, ~30 minutes). The HI episode resulted in decreases in cerebral blood flow, suppression of EEG activities and extensive brain injury in the hemisphere ipsilateral to the carotid artery occlusion. Generalized motor seizures were observed within 72 hours following HI. These seizures occurred nearly exclusively in animals with the extensive ipsilateral brain injury, but their generation was not associated with EEG discharges in bilateral hippocampal and cortical areas. Animals exhibiting these seizures had a high rate of mortality. Post-HI treatments with diazepam and phenytoin suppressed these motor seizures and improved post-HI animal survival. Based on these data, I conclude that these seizures are a consequence of HI brain injury, contribute to mortality following HI, and that they may originate from deep subcortical structures.

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Voltage-gated sodium ion channels play a vital role in neuron function, which becomes evident when variants in these genes disrupt their function. Mutations in SCN8A have only recently been linked to an epilepsy phenotype characterized by early-onset of seizures, delayed development, and intellectual disability. Using patient data from published papers (n = 75) as well as an online support group (n = 61), we were able to identify several patterns in the pathogenic mutations and compare them to a group of healthy individuals from the Exome Aggregation Consortium (ExAC) (n = 960). Most of the variants are missense, with one reported nonsense mutation in an individual with ataxia instead of epilepsy. The average age of onset from 85 individuals combined from the published papers and the online support group was 4.45 months. Notably, the ages of onset have a bimodal distribution instead of normal, with one peak within the first month of life and a second peak at 4 months of age. Pathogenic mutations are more likely to appear in the transmembrane regions of the protein encoded by SCN8A (Nav1.6) (Proportion Test: p-value = 9.1 x 10⁻⁵) while non-pathogenic variants were more likely to appear in the connecting loops of the protein (Proportion Test: p-value<2.2 x 10⁻¹⁶). This is most likely due to the transmembrane regions having a greater functional role than the loops. When we further separate the mutations into functional parts of the protein, we generally see that areas with more pathogenic mutations have fewer non-pathogenic variants, and vice versa. For example, the inactivation gate of the protein has more pathogenic variants (Exact Binomial Test: p-value = 3.52 x 10⁻⁶) while the N-terminus has more non-pathogenic variants (Exact Binomial Test: p-value = 0.0128). This suggests that areas with more pathogenic variants are less tolerable to variation while those with more non-pathogenic variants are more tolerable. Interestingly, there are some areas of the protein with very few pathogenic and non-pathogenic variants, such as the pore regions of the protein. This is likely due to the vital functional nature of the pore, and any variants in that region lead to lethality. Further analyses are needed to determine if there are correlations between categories of pathogenic mutations and the phenotypes of the patients.

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CASE: A 6-year-old boy with a diagnosis of autism spectrum disorder (ASD) presented to primary care for a newpatient, transfer-of-care evaluation. At the initial encounter, the patient used a maximum of 60 words and was receiving speech and language therapy (SLT) through school. Family history was positive for seizures in the father and paternal grandfather as well as ASD in an older brother. Referrals to genetics, private SLT, and an autism specialist were offered, although the latter was declined by family. The subsequent genetics evaluation resulted in discovery of a small gain on chromosome 1q42.2 and associated partial duplication of the DISC1 gene. The assay could not determine the exact clinical significance of the abnormality, but similarly sized and located abnormalities involving the DISC1 gene are reported in some patients with ASD and developmental delay. During a follow-up pediatrics appointment, the father expressed his wish for further evaluation of causes of autism spectrum disorder (ASD) and requested an electroencephalography (EEG) evaluation. The family concomitantly reported slow improvement in speech with therapy, the use of up to 200 words, and the ability to count to 10. The primary care physician reiterated that EEG and imaging studies are not indicated for an isolated ASD diagnosis with no supporting history or physical examination indications. The clinician discussed ASD-recommended therapies with the family. Neurology referral was made per parental request. The patient subsequently presented to neurology at the age of 7 years. The parents reiterated during the initial neurologic developmental history that the patient had shown some improvement with speech and language therapy in the past 18 months, knew as many as 200 to 300 words, and could put some words together into simple sentences. Gross and fine motor development were felt to be within the normal range for age. The parents also reported some scripting, and mild echolalia was noted on examination. Notably, there was no history of language regression. Apart from language delay, the neurologic examination was otherwise normal at initial evaluation. Given this clinical picture, ASD treatment options were again discussed. Despite education, parents continued to request for EEG evaluation as a workup for the etiology of the patient's ASD. Electroencephalography was ultimately ordered owing to the strong and repeated paternal request despite denial of any seizure-like episodes in the patient. EEG unexpectedly showed extremely frequent, almost constant focal electrographic seizures arising from the T3/T5 electrodes in the speech area of the left temporal lobe, prompting the initiation of oxcarbazepine maintenance therapy. Because of the noted abnormalities on EEG, magnetic resonance imaging (MRI) was obtained. Mild abnormalities were noted on MRI study including possible minimal inferior cerebellar vermian hypoplasia, mildly prominent bodies of the lateral ventricles, and nonspecific, nonenhancing punctate T2 hyperintensities in the subcortical white matter. These findings were not felt to be clinically relevant to the patient's presentation or seizure evaluation. No repeat imaging was ordered. Hindsight is always 20/20. As a clinician evaluating the patient initially, would you have pursued further workup sooner?

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