Epilepsy in women of reproductive age. Clinical, imagistic, electroencephalographic study: Abstract of the doctoral thesis in medical sciences: 321.05 – Clinical neurology

Abstract

INTRODUCTION. Actuality and importance of the issue addressed. Three important aspects can be highlighted, which outline the research directions of the work: (a) the issue of prevalence, clinical, electroencephalographic and imagistic semiology of epilepsy in women of reproductive age, taking into account the age of onset of the disease and its evolution over time (after a follow-up of patients for 5 years); (b) to identify and describe (parameterise) correlations between the semiological picture, EEG or MRI descriptions, with the possibility of using them to guide the exact diagnosis and adaptation of antiepileptic treatment; (c) attempt to find an answer regarding possible scenarios of disease evolution (e.g. worsening, remission, resistance to antiepileptic drugs, occurrence of status epilepticus), preferably - objective, based on simple, reproducible observable indicators that can be included in a mathematical probability estimation model. It is believed that these three aspects, if known, would significantly improve the quality of life of patients with epilepsy of reproductive age and increase the effectiveness of prescribed treatments. Description of the situation in the field and identification of the research problem Despite remarkable advances in neuroscience, pharmacology and imaging technologies, epilepsy continues to have a high prevalence and remains an important public health problem. In Republic of Moldova, according to data from the National Bureau of Statistics, about 60,000 people suffer from epilepsy, of which 13,500-15,000 are women. The prevalence of epilepsy in Republic of Moldova is 19 cases per 1000 inhabitants (2015 data) [1]. The prevalence of epilepsy in women is variably reported in the literature, being considered rarer in women than in men (41 vs. 49 cases per 100,000 population or 6.0 vs. 6.5 cases per 1000 population). However, the given disease is considered to be underestimated in women due to the stigma of the disease, its non-reporting or the natural variability of the actual prevalence of the disease throughout life [2- 5]. In addition to the lack of knowledge of the true prevalence of epilepsy in women of reproductive age, an important problem is the lack of a complete description of the seizure itself (aura, semiology, circumstances, triggers, duration, postictal signs, EEG tracings or MRI images, involving specific structural changes). This prevents the correct classification of seizure type (subtype). It was not until 2017-2021 that the consensus definition of epilepsy syndrome was given by the International League Against Epilepsy, ILAE [6, 7]. Contemporary electroencephalographic examination allows the differentiation of cortical areas involved in abnormal electrical activity in the brain (seizure initiation area, epileptogenic area, as well as symptomogenic, irritative and epileptogenic lesion areas), as well as distinguishing the phases of the given activity (ictal wave front, followed by excitation and inhibition wave propagation front) [8, 9]. Equipping hospitals in the Republic of Moldova with high-performance nuclear magnetic resonance machines opens up new possibilities for identifying and differentiating brain lesions with epileptogenic potential. Contemporary MRI imaging algorithms can identify and classify these lesions automatically, thus becoming important tools in diagnosis, choice of treatment tactics or prognosis of disease evolution [10, 11]. This trend in the use of MRI imaging in epileptology is nowadays current internationally, and the corroboration with clinical and neurophysiological results opens new paradigms of approach. All these descriptions allowed the formulation of the research hypothesis, the purpose of the work and the research objectives. Purpose. To describe the interrelationships over time between clinical, neurophysiological and imagistic features of epilepsy in women of reproductive age, with the development of predictive mathematical models for the most important clinical events. Research objectives 1) Characterization of the evolution over time of the clinical, neurophysiological and imaging features of epilepsy in women of reproductive age, according to the age of onset of the disease; 2) Identification and parameterization of clinically important clinico-neurophysiological and clinico-imaging correlations in women with epilepsy of reproductive age, according to the age of onset of the disease.; 3) Argumentation, development and characterization of predictive mathematical models for the most important clinical events (worsening of the condition over time, risk of progression to status epilepticus, development of resistance to antiepileptic drugs and stable remission of the disease) in patients of reproductive age with epilepsy. Research hypothesis Epilepsy in women of reproductive age has distinct and possibly different clinical, imaging and neurophysiological features that may correlate with each other, depending on the age of onset or progression of the disease, and the likelihood of clinically important events can be estimated by mathematical models based on the features identified. General research methodology The study in the thesis was a prospective-retrospective, cohort, descriptive-analytical study, with approval of the research protocol by the Research Ethics Committee (minutes no. 55 of 03.06.2016). Data were collected for 5 years (primary visit and the 3 annual conclusive follow-up visits of patients, neurophysiological and neuroimaging examinations) in the Institute of Neurology and Neurosurgery "Diomid Gherman", State Hospital of the Republic of Moldova and Private Medical Institution "Excellence". After the numeration of the primary data, the database was imported into the statistical analysis software GraphPad Prism, v. 9 trial (Graph Pad Software, Boston, USA). The data were analyzed both in terms of age categories of onset of illness (3 groups, group 1 - 0-11 years; group 2 - 12-18 years; group 3 - 19-49 years) and in terms of time course of illness (visits 1-4). From these perspectives, the clinical, electrophysiological and imaging features of epilepsy were characterized using the Fisher or extended Mantel-Haenszel test. After generalizing the results and obtaining the general characteristics, a correlational analysis (Pearson's r-test) was performed; the given analysis allowed the identification of those data, which correspond to a statistically significant degree of clinical-neurophysiological and clinical-imaging correlation, from which clinically significant correlations were selected. The results obtained allowed to argue, develop and characterize probabilistic models for 4 clinically important outcomes (worsening of the condition over time, risk of progression to status epilepticus, development of resistance to antiepileptic drugs, stable remission of the disease). The selection of clinical, electroencephalographic and imaging parameters that entered the probability formula was based on multivariate analysis, testing for multicollinearity (variance inflation factor calculation) and the contribution of each parameter in the formula using the Akaike informativeness criterion. The performance of the predictive models developed was expressed by the area under the ROC curve, positive and negative prognostic power. Based on the results obtained, practical recommendations were developed. Scientific innovation of the obtained results 1. For the first time, some patterns of evolution over time and the interrelationships between clinical, neurophysiological and imaging parameters in women of reproductive age with epilepsy were characterized according to the age of onset of the disease. 2. Several statistically significant correlations between clinical, neurophysiological and imaging parameters were found to exist, but only some of them have real clinical significance. 3. Also, as a result of our own research, it has been possible to develop, for the first time, mathematical models that can accurately predict the worsening of the condition over time, the risk of developing status epilepticus, the development of resistance to antiepileptic drugs and stable remission of the disease in patients of reproductive age with epilepsy. 4. The particularities of the evolution over time of clinical, neurophysiological and imaging features and their interrelationships in patients of reproductive age with epilepsy were identified, which made it possible to develop predictive mathematical models for the 4 important events listed. 5. The paper provides an elaborated, adapted methodology for the clinical and instrumental investigation, documentation and monitoring over time of patients of reproductive age with epilepsy, allowing the identification of clinical, neurophysiological and imaging features over time, according to the age of onset of the disease. The paper also provides the theoretical and methodological support for the development and application of predictive mathematical models for 4 important events (worsening of the condition over time, risk of developing status epilepticus, development of resistance to antiepileptic drugs and stable remission of the disease). The applied value of the work. The research results provide simple practical solutions for neurologists in assessing, risk stratifying, monitoring patients of reproductive age with epilepsy. Clinically significant correlations between clinical, neurophysiological and imaging features (brain lesions with epileptogenic potential, identifiable on MRI) were identified. The mathematical models developed make it possible to predict with a significantly higher accuracy the 4 important events identified in the study (worsening of the condition over time, risk of progression to status epilepticus, development of resistance to antiepileptic drugs, stable remission of the disease) specific to women of reproductive age with epilepsy. Implementation of scientific results. The research results were implemented in the current clinical practice (part of the institutional clinical protocol, standard operating procedure of the workplace) in the Neurology Department of the State Hospital, Chisinau, Republic of Moldova. Approval of the results. The results of the study were presented and discussed in the following national and international scientific fora: 3rd Congress of the European Academy of Neurology (24-27 June 2017), Netherlands, Amsterdam; Congress dedicated to the 75th Anniversary of the founding of USMF "Nicolae Testemitanu", Chisinau, Republic of Moldova; World Congress of Neurology, XXIV edition of 2019 (27-31 October, 2019), Dubai, United Arab Emirates; Congress of Young Researchers "MedEspera" (3-5 May, 2018), Chisinau, Republic of Moldova; Conference "Days of the University USMF Nicolae Testemitanu", section no. 8 "Current problems of neurology and neurosurgery" (October 19, 2017), Chisinau, Republic of Moldova; Conference "Days of the University USMF Nicolae Testemitanu", section no. 8 "Current Problems of Neurology and Neurosurgery" (20 October 2016), Chisinau, Republic of Moldova; 4th Congress of the European Academy of Neurology (16-19 June 2018), Lisbon, Portugal; European Stroke Association Conference, 4th edition (16-18 May, 2018), Gothenburg, Sweden; European Congress of Epileptology, 13th edition (26-30 August 2018), Vienna, Austria; European Academy of Neurology Congress, 5th edition, (June 2019), Oslo, Norway. Publications on the thesis topic. The basic materials of the thesis have been published in 11 scientific papers, including, 5 articles in nationally indexed journals, 6 abstracts published in collections of papers at scientific events (including, 4 abroad); 5 intellectual property objects, 10 presentations and oral communications at various international scientific events (4 in the country and 6 abroad). Volume and structure of the thesis. The text of the thesis is set out on 164 computerprocessed basic text pages, consisting of: list of abbreviations, introduction, 4 chapters, general conclusions, practical recommendations, bibliography of 245 sources and 4 appendices. Illustrative material includes 32 tables, 22 figures.