EARLY DIAGNOSIS OF STROKE IN PATIENTS WITH DIABETES MELLITUS

ORADEA UNIVERSITY FACULTY OF MEDICINE AND PHARMACY DOCTORAL THESIS EARLY DIAGNOSIS OF STROKE IN PATIENTS WITH DIABETES MELLITUS AUTHOR BRISC MIHAELA CRISTINA COORDINATOR Prof.Dr.MARIUS MOTOCU CONTENTS OF THE DOCTORAL THESIS INTRODUCTION List of Abbreviations STAGE OF KNOWLEDGE Chapter I The Particularities of Vascular Bed in Patients with Diabetes Mellitus 1.1 Atherosclerosis in diabetic patients 1.2 High blood pressure in diabetic patients Chapter II The Particularities of Neurons in Diabetic Patients 2.1 Neuronal hyperglycemic- induced modifications 2.2 Neuronal hypoglycemic-induced modifications 2.3 Peripheral neuron modifications Chapter III The Anatomy of Cerebral Vascular System 3.1 Common carotid artery 3.2 External carotid artery 3.3 Internal carotid artery 3.4 Collaterally circulation circuits in cerebral area 3.5 Cerebral hemodynamic 1

Chapter IV The Stroke 4.1 Classification of stroke 4.2 Epydemiologic data concerning stroke Mortality in stroke Epydemiological aspects in stroke in Bihor county 4.3 Cerebral ischemia physiopathology 4.4 Symptoms and sings in early and constituted ischemic stroke Chapter V Imagistic Assessment of Cerebral Vascular Area 5.1 Introduction 5.2 Imagistic methods of investigating cerebral vessels 5.2.1 Computed tomography 5.2.2 Magnetic resonance imaging 5.2.3 Ultrasound examination of the cerebral vascular system Ultrasound examination in Doppler technique- generalities Intracranial Doppler ultrasound examination Extracranial Doppler ultrasound examination Intraluminal ultrasonography 5.2.4 Arteriography 5.2.5 Cerebral scintigraphy PERSONAL CONTRIBUTIONS Chapter VI Work Hypothesis Chapter VII Objectives Chapter VIII Material and Method 8.1 Material 8.2 Method Chapter IX Results and Discussions 9.1 Particularities of stroke in patients with diabetes mellitus Distributions of cases induced by sex Distributions of cases induced by age Distributions of cases induced by environment 2

Distributions of cases induced by profession Distributions of cases induced by the type of diabetes mellitus Distributions of cases induced by evolution of diabetes Distributions of cases induced by type of stroke Distributions of cases induced by family history Distributions of cases induced by personal history Distributions of cases induced by toxics intake Distributions of cases induced by weight Distributions of cases induced by symptoms Assessment of biological parameters Carotidal Doppler evaluation Assessment of spinal fluid Assessment of electroencephalogram CT scan evaluation Antihypertensive treatment Treatment with anti clotting agents Treatment of diabetes Evolution 9.2 Brain Natriuretic Peptide Marker for Stroke in Diabetic Patients Type of diabetes Distributions of cases induced by sex Distributions of cases induced by age Distributions of cases induced by environment Distributions of cases induced by family history Distributions of cases induced by personal history Distributions of cases induced by toxics intake Distributions of cases induced by weight Distributions of cases induced by symptoms Complications of diabetes mellitus Type of stroke Affection of cranial nerves 3

Treatment Biological parameters Pro BNP assessment 9.3 Algorithm for diagnosis early stroke in patients with diabetes mellitus Chapter X FINAL CONCLUSIONS BIBLIOGRAPHY SUMMARY OF THE DOCTORAL THESIS ANNEXES : Published Papers ABSTRACT Key words: diabetes mellitus, vascular complications, early ischemic stroke, pro-brain natriuretic peptide, diagnosis algorithm The doctoral thesis entitled The early diagnosis of stroke in patients with diabetes mellitus extends for 226 pages and is structured according to the criteria in force. After the first part which is Contents, there is presented a 3 pages Introduction which presents the importance of the diabetic pathology and its complications, a few words about involved pathogenesis and mechanisms, and the importance of the early treatment in developing vascular complications. There were shortly presented some epidemiologic data about international and local prevalence of stroke and some literature studies which provide the important role played by the brain natriuretic peptide in developing cardiovascular diseases. Also, I presented here the main parts of the thesis. Further on I have presented a list of abbreviations with 85 points, abbreviations used throughout the thesis. Starting with page 12, over 58 pages, I have presented The Stage of Knowledge, regarding diabetes mellitus, vascular and neuronal particularities of these patients, anatomy of cerebral vascular system, classification of stroke and imagistic ways of investigation in stroke. 4

A large part of this chapter is related to the early onset of atherosclerosis in patients with diabetes mellitus, some particularities of arterial hypertension in diabeticsand risk factors for this kind of patients being noted. Anatomic relations of cerebral vascular arteries with cerebral hemodynamic data were largely described. Also, some aspects of physiopathology in stroke and correlations with signs and symptoms were presented. Further more, there were largely presented the imagistic investigations used in detection of early signs of stroke: computer tomography, magnetic resonance imaging, bidimensional and Doppler ultrasound of the largest artery of neck, arteriography and scintigraphy. The Personal Contributions chapter which extends for pages comprises four great themes. The Work Hypothesis starts from the fact that cardiovascular diseases consist in an important part of morbidity and mortality in a national and international scale, and the stroke represent an important percentage of them. The social impact of diabetes mellitus and its complications, associated to partially or totally work incapacity, induced by palsy in stroke, will transform diabetic patients in a target for more and more studies which refers to the management of diabetes mellitus and associated diseases, inclusively in a prophylactic way. Also, the treatment costs are very high which requires a diagnosis as correct and as early as possible. There were two Objectives of the study. The first is the complex assessment of the particularities of diabetic patients with stroke regarding clinical picture, evolution, imagistic investigations and treatment compare to the nondiabetic patients with acute stroke, as well as a complex investigation of diabetic patients without stroke from the perspective of evolution and risk of developing such an incident. The second objective included developing a diagnosis algorithm, recording to the first purpose conclusions which can provide in a useful way an early diagnosis for diminishing the death and/or motor deficiency. The studied Matherial was resented by a group of 180 patients whom I have separated into three groups. First group A- contented 80 diabetic patients with ischemic stroke, second group B- contented 80 nondiabetic patients with 5

ischemic stroke and the last group was constituted by 80 diabetics without stroke. All the patients were admitted in the Clinical County Hospital Oradea and in Clinical Neurology and Psychiatry Hospital Oradea, over a period of five years. From this patients, I have randomized selected 30 diabetic patients- 15 with stroke and 15 without stroke- in whom nobody diagnosed a cardiovascular disorder yet. The Method used comprises neurological examination, body mass index determination, lumbar punction, biochemical investigation of the spinal fluid, electrocardiogram,electroencephalogram, computed-tomography, ultrasound examination of the main arteries of the neck, ophthalmoscopy, oscylometry and biochemical examination of serum. The Results and Discussions chapter is divided into three sub-chapters. The first of them refers to the particularities of the diabetic patients with stroke concerning clinical picture, history, toxic use, type of diabetes, complications of the disease, (especially vascular ones), spinal fluid biochemical investigations and evolution. Regarding clinical picture I studied the main symptoms, after American Stroke Association, convention which tried to classify them after physiopathology and topography. A large part of this study was concerning the therapy and evolution in case of associated high blood pressure and insulin and diabetic drugs treatment of this patients, correlated with complications and evolution. The second sub-chapter provides information about the brain natriuretic peptide, a substance relatively newly described as a marker of cardiac damage, but not yet studied in stroke. This was the main reason of choosing its serum assessment in diabetic patients with or without stroke. Our results completed the actually literature which provides lower information about correlation of the serum values of the brain natriuretic peptide in cerebrovascular diseases. Although, the high costs of this determination makes this parameter not yet a national or international convention for early detection of stroke, its important role in the onset of cardiovascular events can not be denied. 6

The last sub-chapter contents the diagnosis algorithm for ischemic stroke adapted to diabetic persons, which includes all the statistic significant parameters assessed before. Through mathematical study I used positive predictive value and relative risk to define and note the main parameters, which I have included into algorithm. I used clinical criteria after American Stroke Association, the main parameters being pondered using mathematic formulas for risk factors ( age, time of evolution for diabetic disease, history, biological findings, at least two vascular complications, and treatment. The most important pondered parameter was the brain natriuretic peptide and the imagistic investigations were ultrasound examinations concerning arterial stenosys and CT scan. At last but not least, evaluation of spinal fluid, as an invasive way of investigation, separates the main diagnosis: possible or constituted stroke. Associated to all three sub-chapters, there were taken into account several discussions involving different parameters and correlations, which I have found in the specialty literature. The results of the present work were comparable, or were completing the results of other studies and papers. The chapter of Final Conclusions comprises 22 ideas and results that have appeared throughout the thesis, out of which I will enumerate: 1. The proposed algorithm different clinical, biological and imagistic parameters, which can sustain an early stroke diagnosis, avoiding expensive imagistic methods as well as invasive ways of diagnosis, such as lumbar puncture, this being the last intention procedure. 2. It is imperious necessary an extreme carefully evaluation of all diabetic patients, with their education concerning changing lifestyle, weight status and insulin treatment as soon as possible. It is also very useful, a large screening for detecting the prediabetic status and the risk of developing cardiovascular events, the most important role being played by the brain natriuretic peptide. The Bibliography chapter totalizes a number of 281 studied works, most of them being studies published after 2000. 7

Also, at the end of the thesis, I have annexed photocopy of the papers published in Romanian and international magazines as Romanian Diabetes Journal and The Archives of Balkan Medical Union. CURRICULUM VITAE 1. General information Name: BRISC MIHAELA CRISTINA Date of birth: 14.09.1970. Place of birth: SIGHETU-MARMATIEI, MARAMURES, ROMANIA Marital status: MARRIED, 2 CHILDREN Address: Str. MIHAI EMINESCU, Nr. 35, Apt. 2, ORADEA, BIHOR, ROMANIA Tel. home: 00-40-59-440734 Hospital : 00-40-59-211345 Int. 154. E-mail: briscristina@ yahoo.com. 2. Educational background : 2002- Internal Medicine Specialist Physician based on Residency Exam promoted with 626 points 1997- Undergoing my PhD Program- University of Oradea, PhD Univ. Marius Motocu 1990-1996 UMF Timisoara- Faculty of General Medicine 1985-1989 History Phlology High school Oradea 1977-1984- Primary and Secondary School, Alesd and Oradea 3. Professional background : 2001-2005- Lecturer, Faculty of Medicine and Pharmacy Oradea Medical Departament V 1996-2001- Assistant Lecturer, Faculty of Medicine and Pharmacy Oradea Medical Departament V 4. Competences, member in societies, courses, congresses, papers: Competences in: General Ecography Member in Societies: 8

Romanian Society of Ultrasonography in Medicine and Biology Balkan Medical Union Romanian Society for Study of the Liver Postgraduated Courses: 3 middle and long-term courses (1-6 weeks) in UMF Cluj Napoca and University of Oradea 3 European postgraduated Courses 10 short-term courses ( pre-congress) ; 8 national and 2 international European and World Congresses : 4 participations Congresses and Conferences organized by National Societites: 15 participations Member of The Organizing Committee of the Balkan Medical Union Congress, September, 2004 ( Vice- President) Other Medical Symposiums: 18 participations Books: Author : 1 Joint author: 1 Extensive papers: Single author: 1 First author: 2 Joint author:3 Summary papers: Single author : 1 First author : 7 Joint author :22 Posters: 30 9