Candice E. Crocker

The relevance of neuropsychiatric symptoms and cognitive problems in new-onset epilepsy — Current knowledge and understanding

Neurobehavioral and cognition problems are highly prevalent in epilepsy, but most research studies to date have not adequately addressed the precise nature of the relationship between these comorbidities and seizures. To address this complex issue and to facilitate collaborative, innovative research in the rising field of neurobehavioral comorbidities and cognition disturbances in new-onset epilepsy, international epilepsy experts met at the 3rd Halifax International Epilepsy Conference & Retreat at White Point, South Shore, Nova Scotia, Canada from September 18 to 20, 2014. This Conference Proceedings provides a summary of the conference proceedings. Specifically, the following topics are discussed: (i) role of comorbidities in epilepsy diagnosis and management, (ii) role of antiepileptic medications in understanding the relationship between epilepsy and neurobehavioral and cognition problems, and (iii) animal data and diagnostic approaches. Evidence to date, though limited, strongly suggests a bidirectional relationship between epilepsy and cognitive and psychiatric comorbidities. In fact, it is likely that seizures and neurobehavioral problems represent different symptoms of a common etiology or network-wide disturbance. As a reflection of this shared network, psychiatric comorbidities and/or cognition problems may actually precede the seizure occurrence and likely get often missed if not screened.

Increased X-linked inhibitor of apoptosis protein (XIAP) expression exacerbates experimental autoimmune encephalomyelitis (EAE).

Dysregulated apoptotic signaling has been implicated in most forms of cancer and many autoimmune diseases, such as multiple sclerosis (MS). We have previously shown that the anti-apoptotic protein X-linked inhibitor of apoptosis (XIAP) is elevated in T cells from mice with experimental autoimmune encephalomyelitis (EAE). In MS and EAE, the failure of autoimmune cells to undergo apoptosis is thought to exacerbate clinical symptoms and contribute to disease progression and CNS tissue damage. Antisense-mediated knockdown of XIAP, in vivo, increases the susceptibility of effector T cells to apoptosis, thus attenuating CNS inflammation and thereby alleviating the clinical signs of EAE. We report for the first time, generation of transgenic mice whereby the ubiquitin promoter drives expression of XIAP (ubXIAP), resulting in increased XIAP expression in a variety of tissues, including cells comprising the immune system. Transgenic ubXIAP mice and wild-type (WT) littermates were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freunds adjuvant and monitored daily for clinical symptoms of EAE over a 21-day period. The severity of EAE was increased in ubXIAP mice relative to WT-littermates, suggesting that XIAP overexpression enhanced the resistance of T cells to apoptosis. Consistent with this finding, T cells derived from MOG35-55-immunized ubXIAP mice and cultured in the presence of antigen were more resistant to etoposide-mediated apoptosis compared to WT-littermates. This work identifies XIAP is an important apoptotic regulator in EAE and a potential pharmacological target for treating autoimmune diseases such as MS.

Prefrontal glutamate levels differentiate early phase schizophrenia and methamphetamine addiction: A 1H MRS study at 3 Tesla

Acute symptoms of methamphetamine-induced psychosis are similar to those of primary schizophrenia. Understanding similarities or differences in the biological substrate of these psychoses could lead to early differentiation of these two clinical conditions resulting in more efficient treatment strategies. Proton magnetic resonance spectroscopy was acquired from the medial prefrontal cortex in 29 unmedicated patients with first episode of psychosis (FEP), 29 abstinent methamphetamine-addicted people (METH) and 45 healthy controls (HCs) (age range 17.3 to 29.9years old). The METH group displayed robust reductions in concentration levels of glutamate (Glu) relative to FEP (Cohens d=1.20) and HC (d=0.87). The METH group also displayed reduced levels of N-acetylaspartate (NAA) relative to FEP (d=0.53) and HC (d=0.76). The HC group displayed a positive association between levels of Glu and NAA, r(45)=0.52, p<0.001, while the two clinical groups failed to show this normal association. This suggests that the cellular metabolism is altered in both conditions. These data support the assumption that cellular abnormalities differ between primary schizophrenia and methamphetamine addiction despite the overlap in clinical presentation.

Definition of new-onset epilepsy versus newly diagnosed epilepsy: Role of time domain

To the Editors: We were very pleased to see the recent article ‘‘Standards for Epidemiological Studies and Surveillance of Epilepsy’’ and with the fact that the commission in charge distinguished between newly diagnosed epilepsy (NDE) and new-onset epilepsy (NOE) (Thurman et al., 2011) which, in our opinion, reflects different concepts and dynamics of epilepsy. ‘‘The magnitude of the incidence of new onset epilepsy and the incidence of newly diagnosed epilepsy will differ, because the measures have different numerators. For new onset epilepsy, the numerator includes people identified at their second unprovoked seizure. In contrast, the numerator for newly diagnosed epilepsy (NDE) includes both new onset epilepsy and people with more than two unprovoked seizures who are first diagnosed with epilepsy during the study period...’’, p. 14. We have two comments from our side. First, we were wondering, on which data this definition is based and if a reference could be provided for this important definition. Secondly, we would like to suggest implementation of a time domain in the definitions of NOE and NDE, rather than the absolute number of seizures, which often is hard to assess and speculative. In our own First Seizure Clinic we decided to use the term new-onset epilepsy for any patient with evidence of two or more seizures within the last 12 months. Patients with their first generalized tonic– clonic seizure and preceding epigastric auras for a couple of months (up to a maximum 12 months prior) are accordingly diagnosed with NOE. We also see NOE as a subcategory of NDE. We diagnose newly diagnosed epilepsy if there is evidence of ongoing seizures for more than 1 year. Often these patients have undiagnosed seizures for a decade or more. We believe that ‘‘our definition’’ better addresses the different stages of epilepsy. We would be highly interested in the commission’s opinion on our approach and if we could arrive at a consensus on these crucial definitions.

The interaction of gender and cannabis in early phase psychosis

Cannabis is the third most common recreational drug used world-wide after tobacco and alcohol. Globally, cannabis legalization is becoming more common. In light of its known link to psychosis development, it is imperative that we are well-informed regarding the impact of cannabis on the course of psychosis, in both males and females. However, the majority of the work to date on the role of cannabis in psychosis outcomes has not had a gender focus, important when considering patient specific treatments. This review examines what is currently known, from gender focused studies, about the interaction of gender, cannabis use and psychotic disorders.

A conceptual framework for the use of neuroimaging to study and predict pharmacoresistance in epilepsy

Twenty percent to 49% of newly treated patients with epilepsy will develop pharmacoresistance (PR). The mechanisms leading to PR are unclear. There is currently no unifying theory to explain the variety of presentations of PR and the diversity of potential contributing factors. Etiology of seizures seems to play a critical role in at least a subset of PR. Many magnetic resonance imaging (MRI) studies in the advanced stages of epilepsy suggest a strong association between lesions such as hippocampal sclerosis and focal cortical dysplasia and PR. Unfortunately, almost all of these studies are cross‐sectional and retrospective. There is a need for a new perspective on the role of preexisting lesions in the evolution of epilepsy and PR. We propose in this article to study a unique population of drug‐naive patients with either first seizure or new‐onset epilepsy longitudinally with advanced MRI imaging techniques, including magnetic resonance spectroscopy and diffusion tensor imaging. We hope to be able to monitor imaging findings and the development of PR early in the course of the disease in a subset of these patients with temporal lobe epilepsy (TLE). Our goal is to understand the pathogenesis of PR, to dissect changes associated with the development of PR from changes associated with chronic seizures and medication, and ultimately to predict PR at the onset of disease.

Anxiety and Depression in Adult First Seizure Presentations

OBJECTIVE To define the prevalence of psychiatric symptoms of anxiety and depression in patients at the time of their first seizure presentation to a neurologist. METHODS Our pilot study uses a cohort approach with multimodal data (clinical, social, structural [3T magnetic resonance imaging], and functional [electroencephalogram]). We screened 105 patients referred to the Halifax First Seizure Clinic between 2014 and 2016 and 51 controls. All participants completed two screening questionnaires: Neurological Disorders Depression Inventory for Epilepsy and Generalized Anxiety Disorder 7-Item. After applying the exclusion criteria, the study population consisted of 57 patients with unprovoked first seizure and 31 controls. The prevalence of anxiety and depression was based on cutoff scores of >15 and >14 respectively. RESULTS Unprovoked first seizure patients showed higher prevalence of depression (33%) compared with control (6%) with an odds ratio (OR) of 2.75 (95% confidence interval [CI], 0.72-10.5). There was no significant difference in the prevalence of anxiety between control subjects (9.7%) and unprovoked first seizure patients (23%). Subcategory analysis conducted after diagnosis confirmation revealed significantly increased OR of depression in patients diagnosed with new-onset epilepsy (OR, 11.6; 95% CI, 2.1-64.0) and newly diagnosed epilepsy (OR, 20.0; 95% CI,2.2-181), but not first seizure only patients (OR, 2.2; 95% CI,0.28-17.6) compared with control. CONCLUSIONS Our study supports a bidirectional relationship between the first seizure and depression. Prevalence rate of depression increased with duration of undiagnosed epilepsy at the time of first clinical assessment.

Role of neuroimaging in first seizure diagnosis

The primary goal of neuroimaging in a first, unprovoked seizure is to identify a lesion that can explain the seizure. Secondarily, neuroimaging may be used to predict seizure recurrence and assist with the diagnosis of epilepsy. However, the events leading from a first seizure to epilepsy, with or without an identifiable epileptogenic lesion, are not well understood, and it is not always clear which lesions are epileptogenic as opposed to incidental. Much neuroimaging research to date has focused on findings in chronic epilepsy, rather than first seizure. Dedicated epilepsy imaging with high quality MRI protocols maximizes the likelihood of a diagnosis. However, a significant proportion of patients are MRI-negative, prompting researchers in the field to continue the search for better imaging strategies. Here we describe the role of neuroimaging in the assessment of a first seizure, the current state of the art and possible future directions.

Enduring changes in brain metabolites and executive functioning in abstinent cocaine users

BACKGROUND There is a paucity of data connecting the metabolic and cognitive functioning of abstinent cocaine users. This is a pressing public health concern as approximately 1% of the Canadian population and 0.4% of the global population is estimated to have used cocaine in the past year. METHODS Our clinical study compared the in vivo neurochemical profiles in the prefrontal cortex to cognitive tests associated with the same region in 21 moderate term abstinent cocaine users (average 187days abstinent, range 15-1432days), and 30 healthy controls using 3T 1H MRS. RESULTS The abstinent cocaine users exhibited a 10% decrease in N-acetylaspartate (NAA) relative to healthy control subjects (p<0.01, Cohens d=1.15). When subdivided by method of administration, a significant decrease in glutamate levels in former crack smokers compared to healthy controls (p<0.05) was observed, this decrease was not present in powder users. Abstinent users were significantly worse than healthy controls on the Trail Making Test B (p<0.05), and performance on this task was inversely related to NAA levels (p<0.05). Abstinent cocaine users showed deficits in the Wisconsin card sorting test with failures to maintain set (p<0.01). CONCLUSIONS Our work suggests that there are subtle but important changes in the brain that remain even with the moderate term cessation of cocaine use.

Neuroimaging Findings in Adolescent Cannabis Use and Early Phase Psychosis

Abstract There is ongoing debate around the effects of cannabis on the developing adolescent brain and, in particular, on its role in the development of psychosis in those at risk. Epidemiological evidence reports that consumption of cannabis in adolescence increases the risk of developing psychosis. However, there is very little scientific evidence to show the mechanism by which cannabis and the developing adolescent brain interact. Much of the evidence that does exist is from in vitro experiments or preclinical work in mice. This work suggests a possible role of oligodendrocytes in the mechanism of psychosis development. Neuroimaging provides an effective tool for examining changes in oligodendrocytes noninvasively in the living human brain. This chapter is focused on examining what we know from neuroimaging by two techniques, diffusion tensor imaging and proton magnetic resonance spectroscopy, in cannabis use in adolescence and early phase psychosis.