Cerebral Venous Sinus Thrombosis - Diagnostic Strategies and Prognostic Models: A Review

In 1825, Ribes described a case of a 45-year old man who died after a 6-month history of epilepsy, seizures and delirium. The autopsy examination revealed thrombosis of the superior sagittal sinus, the left lateral sinus and a cortical vein in the parietal region. This was probably the first detailed description of extensive cerebral venous sinus thrombosis (CVST). Since then, the literature describing this disease has comprised of case reports, series and some newer prospective studies, including recent reviews and guidelines (statement) on the diagnosis and management of CVST (Siddiqui \u26 Kamal, 2006; Stam, 2005; Saposnik et al, 2011; Brown \u26 Thore, 2011). The cerebral venous sinus thrombosis is a challenging condition and it is most common than previously thought. CVST accounts for 0.5% to 1.0% of all strokes and usually affects young individuals. Important advances have been made in the understanding of the pathophysiology of this vascular disorder. The diagnosis of CVST is still frequently overlooked or delayed as a result of the wide spectrum of clinical symptoms and the often sub-acute or lingering onset. Patients with CVST commonly present with headache, although some develop a focal neurological deficit, decreased level of consciousness, seizures, or intracranial hypertension without focal neurological signs. Uncommonly, an insidious onset may create a diagnostic challenge. The main problem of this disorder is that it is very often unrecognised at initial presentation. In particular, a prothrombotic factor or a direct cause is identified in approximately 66% of the CVST patients (a list of most important causal and risk factors are listed in Table 1). Cerebral venous thrombosis is more common in women than men, with a female to male ratio of 3:1 (cited in Ferro \u26 Canhao, 2011). The imbalance may be due to the increased risk of CVST associated with pregnancy and puerperium and with oral contraceptives. The female predominance in CVST is found in young adults, but not in children or older adults

The impact of early life seizures on cognitive development

Il est connu que les déficits cognitifs sont une des comorbidités fréquentes des syndromes épileptiques de l’enfance à l’âge adulte. Ces déficits portent une atteinte significative au fonctionnement et à la qualité de vie des patients affectés. Ils sont typiquement reliés à l’étiologie, à l’âge à la première crise, au traitement par anticonvulsants ainsi qu’à la sévérité, durée, et type de crise. Cependant, la littérature livre des résultats plutôt divergents quant aux séquelles d'une convulsion isolée. Suite à un épisode de status épilepticus (SE) chez l'enfant, reconnu comme étant le type de convulsion le plus sévère puisque les symptômes persistent pour une durée d'au moins 30 minutes, la littérature démontre des changements physiologiques significatifs qui sont reliés à des déficits cognitifs à long terme, notamment au niveau du développement, de l'intelligence globale, des capacités d'apprentissage et des fonctions exécutives. L'étude des troubles reliés au SE permet de soulever les séquelles qui pourraient être attribuées à des convulsions moins sévères, telles les convulsions fébriles (CF), le type de convulsions le plus fréquemment rencontré chez l'enfant pour lesquelles les séquelles cognitives demeurent peu connues. Il y a plusieurs types de CF (simple et complexe) et elles sont dans l'ensemble caractérisées par une crise survenant dans un contexte de fièvre en l'absence d'une infection du SNC. Bien que des changements physiologiques à la suite des CF plus sévères aient souvent été démontrés, les conséquences de ces convulsions sur la cognition sont peu étudiées et les résultats demeurent controversés. Quelques études ont porté sur l'impact des formes de CF les plus sévères sur les trajectoires développementales immédiatement suivant la convulsion et plusieurs études démontrent une intelligence globale normale plus tard dans la vie. Cependant, l'étude standardisée, spécifique et objective mesurant l'évolution du développement de la petite enfance à l'âge scolaire n'a pas encore été effectuée. Cette thèse comporte deux objectifs principaux. Le premier objectif était de comprendre les déficits cognitifs suite à un épisode de SE à travers une revue de la littérature (Article 1). Le deuxième objectif était d'étudier le développement cognitif suite à une CF complexe de l'apparition de la convulsion jusqu'à l'âge scolaire, dans le contexte de facteurs de risques connus pour un développement moins favorable (Article 2). Plus précisément, nous avons investigué le développement à l'intérieur de la première année suivant la convulsion (Article 2, Infant Cohort). De plus, nous avons étudié le développement cognitif des enfants de 5 à 6 ans ayant une histoire de CF, afin d'évaluer les fonctions cognitives plus complexes de manière spécifique et standardisée. Nous avons évalué l'apprentissage, la mémoire, et les fonctions exécutives (Article 2, School-Age Cohort). Les résultats de l'étude clinique (Article 2) ont démontré un développement cognitif demeurant dans la norme à l'intérieur de la première année suivant l'apparition de la convulsion, sans impact de la durée de la crise ou de l'âge à l'apparition de la crise. À l'âge scolaire, les résultats ont démontré que intelligence globale n'est pas affectée suite à une CF complexe. Par contre, des différences de groupes significatives ont indiqué des difficultés cognitives spécifiques, particulièrement au niveau des fonctions exécutives, de l'apprentissage et de la mémoire, qui s'aggravent en fonction de la durée de la convulsion. Des difficultés émotionnelles ont également été démontrées chez les enfants ayant subi une CF complexe, particulièrement au niveau du perfectionism. Ces difficultés étaient modulées par l'âge au moment de la crise. L’ensemble de ces résultats démontre que, bien que le développement ne soit pas altéré dans la première année suivant une CF complexe, des séquelles cognitives sont apparentes à l’âge scolaire, caractérisées par des faiblesses significatives au niveau des fonctions exécutives, de l'apprentissage et de la mémoire. De façon générale, les résultats obtenus démontrent que les CF complexes peuvent affecter le développement de fonctions cognitives spécifiques, bien qu’à un degré moindre que ceux observés à la suite d'un SE. Il faudra plus de recherche pour approfondir notre compréhension de la nature hétérogène des CF et de leur impact sur le fonctionnement et la qualité de vie des enfants affectés.Cognitive impairment has consistently been shown to be a common comorbidity of epileptic syndromes throughout the lifespan, typically in relation to etiology, age at onset, treatment and seizure type, severity and duration, and significantly impacting function and quality of life in affected patients. However, evidence related to the impact of seizure events occurring in isolation, without defining or being part of any broader syndrome has been equivocal. Evidence supports significant physiological alterations following early-life status epilepticus (SE), arguably the most severe form of seizure as symptoms persist for at least 30 minutes, which has further been linked to long-term cognitive residua related to altered development, global intelligence, learning capacities and executive function, particularly as they occur in the developing brain. Understanding cognitive outcome following SE events can orient our understanding of the impact of less severe forms of seizures on the developing brain, namely febrile seizures. Febrile seizures (FS), which represent a group of seizures (i.e., simple and complex types) that occur in association with a febrile illness in the absence of a CNS infection, are the most common form of childhood seizure, for which cognitive outcome remains unclear. Although physiological alterations have been shown, particularly but not exclusively in the most severe forms of FS, cognitive and behavioral outcome has been understudied to date and remains controversial. Few studies have investigated the impact of development immediately following the most severe form of FS, and evidence demonstrates unaltered global intelligence in later life. However, the evolution of the impact of FS on cognitive development from infancy into childhood using standardized, specific and objective measures has yet to be studied. The general objectives of the current thesis were two-fold. The first objective was to understand cognitive outcome following SE through a review of the literature (Article 1). The second objective was to investigate development and cognition following an initial complex FS from onset to school-age, in the context of known risk factors for poor outcome, including all types of complex features (Article 2). More specifically, we aimed to study development within the first year-post onset (Article 2, Infant Cohort). Furthermore, we aimed to examine cognitive development in a cohort of children old enough for cognitive functions to be sufficiently differentiated (i.e., school-age) to allow specific, objective and standardized assessment of the impact of different complex features on specific functions, particularly related to learning/memory and executive function (Article 2, School-age cohort). Results of the clinical investigation revealed normal cognitive and behavioral development within the first year-post complex FS onset as compared to controls, without impact of seizure duration or age at seizure onset. At school-age, results revealed unaltered global intelligence following early-life complex FS. Significant group differences however indicated difficulties in specific cognitive domains, including executive functioning, and to a lesser extent, learning and memory in these children, as a function of seizure duration. Emotional challenges, particularly perfectionism, were further noted in children having suffered complex FS, as a function of precocity of seizure onset. Taken together, our findings demonstrate that although development was unaltered following early-life FS, cognitive sequelae are apparent at school-age, characterized by challenges in executive functioning and learning/memory. Overall, the current results support the hypothesis that complex FS, even without meeting criteria for FSE, may affect the development of specific cognitive functions, although to a lesser extent than those observed following SE. Future research is nevertheless required to better understand the heterogeneous nature of FS, as well as their outcome and impact on quality of life

Cognition and resective surgery for diffuse infiltrative glioma: an overview

Compared to classical oncological outcome measures such as time to progression and survival, the importance of cognitive functioning in patients with diffuse infiltrative brain tumors has only recently been recognized. Apart from the relatively low incidence and the invariably fatal outcome of gliomas, the general assumption that cognitive assessment is time-consuming and burdensome contributes to this notion. Our understanding of the effects of brain surgery on cognition, for instance, is largely based on studies in surgical patients with refractory epilepsy, with only a limited number of studies in surgical patients with gliomas. The impact of other factors affecting cognition in glioma patients such as direct tumor effects, radiotherapy and chemotherapy, and medical treatment, including anti-epileptic drugs and steroids, have been studied more extensively. The purpose of this paper is to provide an overview of cognition in patients with diffuse infiltrative gliomas and the impact of resective surgery as well as other tumor and treatment-related factors

Surgical treatment of drug-resistant focal epilepsy: selection, economic considerations and long-term outcomes

Epilepsy surgery can be an effective treatment for drug-resistant focal epilepsy, but requires careful selection of appropriate candidates to achieve optimal results and minimise the chance of adverse outcomes, including seizure recurrence. Long-term data on multimodal outcomes and a better appreciation of various factors influencing surgical suitability will help facilitate informed discussions between clinicians and prospective surgical candidates. This thesis includes a comprehensive analysis of a cohort of individuals who had epilepsy surgery at a tertiary neurosciences centre over the last 30 years, supplemented by data on individuals who completed presurgical evaluation at the same centre but did not proceed to surgical resection. An inability to localise the epileptogenic zone (EZ), multifocal epilepsy, or an individual choice not to have either intracranial electroencephalography or surgery were the most common reasons why people referred for presurgical evaluation did not proceed to a definitive resection. A predictive model based on demographic, imaging and electroclinical data was constructed to assist early discussions about surgical suitability. Those with normal MRI, extratemporal epilepsy and evidence of bilateral seizure onsets on video telemetry had an estimated 2.9% chance of proceeding to surgery, and people with a normal MRI brain invariably required intracranial EEG. Frontal lobe epilepsy surgery was safe and effective, with a long-term (median seven years) seizure freedom rate of 27%, and another 11% having auras only. Psychiatric comorbidity frequently improved postoperatively and paralleled seizure freedom. Focal MRI abnormality and fewer anti-seizure medications at the time of surgery could help predict a good outcome. In contrast, the site of resection and intracranial monitoring were not independently significant. Localisation of the EZ should rely on clinical features and multimodal investigation, as in our cohort frontal lobe semiology alone could correctly lateralise the EZ in only 77% and localise to a sublobar level in 52%. For those who completed presurgical evaluation but did not have surgery, under 5% had >12 months of seizure-freedom following the decision not to proceed, although a quarter had substantial improvement with further anti-seizure medication (ASM) or neurostimulation. Evaluation for epilepsy surgery was lengthy for individuals and costly for the public health system. Both duration and cost depended on what investigations were required and varied according to different routes through the presurgical pathway, especially the need for intracranial EEG. The median duration of evaluation was 29.7 months (IQR 18.6-44.1 months), with a median cost per person of £9,138 (IQR £6,984-£14,868). Approximately £123,500 was spent per additional person seizure-free

Assessment and outcomes in mild traumatic brain injury in the Emergency Department

Traumatic brain injury (TBI) is common, affecting up to 600/100,000 people. Mild TBI accounts for up to 90% of all TBI. The Emergency Department attendance rate for head injuries is as high as 1800/100,000 population, and 15-20% of those attendances result in hospital admission. Mild TBI causes symptoms such as headaches, dizziness, disordered balance, cognitive dysfunction and depression which in turn impact on quality of life. Accurate risk assessment and prognostication of patients with acute neurological conditions in the Emergency Department is essential. This PhD consists of a systematic review that examines the hard outcome of ‘return to work’ following a mild TBI; a prospective observational cohort study that reports the difference in neurocognitive function and symptoms that patients experience at baseline and three days after mild TBI; and a prospective observational cohort study that reports the number of patients that attend the Emergency Department with seizure secondary to TBI, and the value of two biomarkers in predicting the recurrence of seizures in patients that attend the Emergency Department having had a seizure. This thesis comprises three studies in which I investigated the short and long-term effects of mild traumatic brain injury (TBI) and prognostication in seizure. In study one, I undertook a systematic review and meta-analysis to determine return to work times for adults with mild TBI. The primary objective was to determine the time taken to return to work following a mild TBI. Articles were included if they reported on adults with mild TBI and recorded the outcome return to work. Six electronic databases and eight clinical trial registries were searched. A narrative synthesis and a random-effects meta-analysis was performed. Bias was assessed using a modified version of the Newcastle Ottawa quality assessment tool. The second study was a prospective observational cohort study of adults with mild TBI and a comparison group of Emergency Department patients without brain injury. The primary outcomes were neurocognitive function and concussion symptom severity at baseline and 72 hours. Adult patients with mild TBI within the last 24 hours were included in the mild TBI group, and adults that attended the Emergency Department with trauma beneath the clavicle, or with a non-neurological medical condition, were included in the comparison group. Outcomes were measured on the Standardized Assessment of Concussion (SCA) and the Concussion Symptom Inventory (CSI) at baseline in the Emergency Department and at follow up at 72 hours. Comparisons were made between baseline and follow up, and between groups at single time points. The third study was a prospective observational cohort study designed to assess the prognostic value of the biomarkers S100B and copeptin in patients with seizure. Adult patients attending the Emergency Department with seizure of any cause were included. The primary outcome was a composite of seizure recurrence, death, hospitalisation, rehospitalisation or re-attendance at the Emergency Department at seven days. S100B and copeptin were measured in the Emergency Department. Statistical comparison of the two groups was performed, optimum thresholds of the biomarkers for diagnosing the endpoint were derived, diagnostic test characteristics were calculated, and logistic regression modelling was performed to identify variables most closely associated with the outcome. The aetiology of the seizure was identified and the proportion that had a seizure secondary to TBI was recorded. In the systematic review and meta-analysis, 14 studies were included. Three reported the average time taken to return to work, and 12 reported the proportion of patients that have returned to work by a pre-specified time point. The pooled proportion of people returned to work at one, three, six and 12 months was 56%, 75%, 83%, and 89% respectively. In the study of short-term effects of mild TBI, 240 patients were included, of which 189 had mild TBI and 51 comprised the non-brain injured comparison group. Patients with mild TBI had marked neurocognitive impairment (SAC at baseline 25 [23-27], difference in SAC score between brain injured and non-brain injured 1, p=0.02, [95% confidence interval [CI] -1.4 to -2.4]), worse symptom severity (CSI at baseline 9 [4-21], difference in CSI between brain injured and non-brain injured 9, p<0.001 [95% CI 8.4 to 13.7]), and high numbers of symptoms (number of symptoms at baseline 4 [2-8], difference between brain injured and non-brain injured 4, p<0.001 [95% CI 2.6 to 4.4]), all of which persisted at 72 hours. In the study of patients with seizures, 97 patients were recruited, of which 52% met the composite primary endpoint. No patients attended with a seizure as a consequence of TBI. S100B and copeptin were significantly higher in patients with compared to without the composite primary endpoint: 0.22 μg/L (95% CI 0.14 to 0.31) vs 0.11 μg/L (95% CI 0.08 to 0.14) (difference 0.02 μg/L, p = 0.01, 95% CI 0.02 to 0.2) for S100B; and 77.0 pmol/L (95% CI 44.3 to 109.7) vs 27.0 (95% CI 18.2 to 35.9) (difference 50 pmol/L, p = 0.004, 95% CI 16.2 to 83.8) for copeptin. Thresholds of 0.088 μg/L and 6.26 pmol/L were identified for S100B and copeptin respectively. At those thresholds, S100B sensitivity and specificity was 58% (95% CI 43-72) and 60% (95% CI 44-74); and copeptin sensitivity and specificity was 80% (95% CI 66-90) and 21% (95% CI 11-36). Epilepsy, complex partial seizure, provoked/acute symptomatic seizure, and pyrexia were identified as factors independently associated with the primary outcome but there was no additional value when the biomarkers were included in the model. In this body of work, I have shown that patients with mild traumatic brain injury have impaired neurocognitive function and a significant symptom burden that persists for several days, and in some patients is likely to persist for many months. Although most patients return to normal activities, including working, by three months after a mild traumatic brain injury, up to a tenth of patients are still unable to return to work at one year after the injury. Around half of patients that attend an Emergency Department with a seizure go on to be admitted or have another seizure by one week, but the biomarkers S100B and copeptin add no extra value to current prediction tools in identifying who will have a recurrent seizure, and few patients have a seizure secondary to TBI

Impact of waiting time for first clinic assessment and seizure outcomes of pediatric epilepsy

Introduction: Pediatric epilepsy has increased in global incidence. Children with epilepsy require immediate healthcare evaluation and monitoring. Waiting times between first seizure onset and pediatric neurology assessment may impact seizure outcome at follow-up. Quality of medical care for children with first seizure onset will be assessed and the impact of pediatric neurology clinic waiting times on seizure outcomes will be determined. Methods: This retrospective study, based on chart review, includes patients with first seizure evaluation at the Royal University Hospital in Saskatoon between January 2012 and December 2015. The interim period before first assessment and other factors were studied in relation to seizure outcome on follow-up. Results: 1158 patients were assessed. 197 patients had epileptic events. The mean age of patient at diagnosis was 6.2 years (±5.2). The mean waiting time for assessment by a pediatric neurologist was 4.3 (±3.6) months. The mean duration of follow-up was 20.9 (±11.0) months. At the last seizure assessment, 132 patients were seizure-free and 65 patients had seizure recurrence. Factors independently associated with poor seizure outcome included waiting time, language not age-appropriate, and gait not age-appropriate. Factors collectively associated with poor seizure outcome included waiting time and gait not age-appropriate. Total number of anti-epileptic drugs was significant at 18 months in both univariate and multivariate models. Conclusion: First seizure assessment is crucial for management of children with epilepsy. Waiting time and other factors may influence seizure outcome, representing opportunities to improve standard medical care

Prevention of Recurrent Affective Episodes Using Extinction Training in the Reconsolidation Window: A Testable psychotherapeutic strategy.

Stressors may initially precipitate affective episodes, but with sufficient numbers of recurrences, episodes can occur more autonomously. It is postulated the memory engram for these recurrent depressions moves from the conscious representational memory system to the unconscious habit memory system encoded in the striatum. If this were the case, cognitive behavior therapy targeted toward extinction of habit memories could be an effective maneuver for helping reverse the automaticity of affective episode recurrence. Extinction training in the reconsolidation window (which opens about 5 min to 1 h after active memory recall) can revise, reverse, or eliminate the long term memories associated with PTSD and other anxiety disorders and with drug abuse craving. We hypothesize that similar cognitive behavioral work in the reconsolidation window could inhibit stress-induced and spontaneous affective episodes. Some initial formulations of possible therapeutic strategies are presented and discussed, as well as caveats. It is hoped that preliminary exposition of this theoretical approach to recurrences in the affective disorders based on principles dependent on work in the reconsolidation window will lead to more detailed elaboration of the therapeutic maneuvers most likely to be successful and ones that can be specifically tested for their clinical efficacy

Informatics for EEG biomarker discovery in clinical neuroscience

Neurological and developmental disorders (NDDs) impose an enormous burden of disease on children throughout the world. Two of the most common are autism spectrum disorder (ASD) and epilepsy. ASD has recently been estimated to affect 1 in 68 children, making it the most common neurodevelopmental disorder in children. Epilepsy is also a spectrum disorder that follows a developmental trajectory, with an estimated prevalence of 1%, nearly as common as autism. ASD and epilepsy co-occur in approximately 30% of individuals with a primary diagnosis of either disorder. Although considered to be different disorders, the relatively high comorbidity suggests the possibility of common neuropathological mechanisms. Early interventions for NDDs lead to better long-term outcomes. But early intervention is predicated on early detection. Behavioral measures have thus far proven ineffective in detecting autism before about 18 months of age, in part because the behavioral repertoire of infants is so limited. Similarly, no methods for detecting emerging epilepsy before seizures begin are currently known. Because atypical brain development is likely to precede overt behavioral manifestations by months or even years, a critical developmental window for early intervention may be opened by the discovery of brain based biomarkers. Analysis of brain activity with EEG may be under-utilized for clinical applications, especially for neurodevelopment. The hypothesis investigated in this dissertation is that new methods of nonlinear signal analysis, together with methods from biomedical informatics, can extract information from EEG data that enables detection of atypical neurodevelopment. This is tested using data collected at Boston Children’s Hospital. Several results are presented. First, infants with a family history of ASD were found to have EEG features that may enable autism to be detected as early as 9 months. Second, significant EEG-based differences were found between children with absence epilepsy, ASD and control groups using short 30-second EEG segments. Comparison of control groups using different EEG equipment supported the claim that EEG features could be computed that were independent of equipment and lab conditions. Finally, the potential for this technology to help meet the clinical need for neurodevelopmental screening and monitoring in low-income regions of the world is discussed