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Aristotle University of Thessaloniki ARISTOTLE UNIVERSITY OF THESSALONIKI FACULTY OF HEALTH SCIENCES SCHOOL OF MEDICINE Olfactory and gustatory function in patients with Multiple Sclerosis A thesis is submitted in fulfillment of the requirements for the degree of Master of Science in Medical Research Methodology By Marini Katerina Thessaloniki, October, 2019 Olfactory and gustatory function in patients with Multiple Sclerosis A MSc thesis submitted in fulfillment of the requirements for the degree of Master of Science in Medical Research Methodology At The Faculty of Health Sciences School of Medicine Aristotle University of Thessaloniki By Marini Katerina Thessaloniki, October, 2019 Supervisor Printza Athanasia (Assistant Professor of the First ENT Clinic of Thessaloniki Aristotle University Hospital AHEPA) Word count: ~ 9100 2 Members of advisory committee Printza Athanasia (Assistant Professor of the First ENT Clinic of Thessaloniki Aristotle University Hospital AHEPA) Constantinidis Ioannis (Professor of the First ENT Clinic of Thessaloniki Aristotle University Hospital AHEPA) Grigoriadis Nikolaos (Professor the Second Department of Neurology of Thessaloniki Aristotle University Hospital AHEPA-Multiple Sclerosis Center) 3 Table of contents Absract General part I. Anatomy of the nose • External and internal structures • Arteries • Veins • Lymphatic drainage • Nerves II. Histology of nose III. Physiology of nose and olfaction IV. Olfactory pathway V. Multiple Sclerosis • Introduction • Etiology • Immunology • Clinical presentation • Diagnosis • Treatment VI. Olfactory and gustatory dysfunction in Multiple Sclerosis Specific part I. Introduction II. Aim of the study III. Research Methodology IV. Inclusion and exclusion criteria V. Olfactory assessment 1. Odor identification test 2. Odor discrimination test 3. Odor threshold test VI. Gustatory assessment 4 VII. Questionnaires VIII. Statistical analysis IX. Results X. Discussion XI. Conclusion References Appendices 5 Abbreviations MS: Multiple Sclerosis CNS: Central Nervous System EDSS: Expanded Disability Status Scale RRMS: Relapsing Remitting Multiple Sclerosis SPMS: Secondary Progressive Multiple Sclerosis PPMS: Primary Progressive Multiple Sclerosis PRMS: Progressive Relapsing Multiple Sclerosis CIS: Clinically Isolated Syndrome MHC: Major Histocompatibility Complex HLA: Human Leukocyte Antigen IL2RA: Interleukin-2 receptor alpha IL7RA: Interleukin-7 receptor alpha EBV: Epstein-Barr virus IgG: Immunoglobulin G NK: Natural Killer Th1: T helper 1 CD4: cluster of differentiation 4 VLA-4: Very Late Antigen-4 VCAM-1: Vascular Cell Adhesion Molecule 1 APC: Antigen-presenting Cell CD8: cluster of differentiation 8 Th17: T helper 17 6 Treg: Regulatory T Cell MRI: Magnetic Resonance Imaging CSF: cerebrospinal fluid DIS: dissemination in space DIT: dissemination in time ACTH: Adrenocorticotropic Hormone BBB: Blood Brain Barrier GA: Glatiramer Acetate DMF: DimethylFumarate CD20: cluster of differentiation 20 ENT: Ear Nose Throat VAS: Visual Analogue Scale SNOT-22: Sino-nasal Outcome Test NOSE: Nasal Obstruction Symptom Evaluation EOG: electro-olfactogram OERPs: Odor Event-related Potentials UPSIT: University of Pennsylvania Smell Identification test CCCRC: Connecticut Chemosensory Clinical Research Center BUT/PEA: N-butanol or phenylethylalcohol 7 Abstract Background: Multiple Sclerosis (MS) is a chronic demyelinating neurodegenerative disease that affects central nervous system (CNS). Olfactory dysfunction as a clinical manifestation of MS was until recently underdiagnosed. It is now believed that olfaction is impaired particularly at early stages of MS. The aim of the study is to evaluate the extent of smelling detriment in patients with MS, while possible gustatory impairment was investigated. Methods: We assessed fifty-nine patients from sixteen to sixty-seven years old from the Multiple Sclerosis Center of the Second Department of Neurology of the Aristotle University Hospital AHEPA and all examined by the First ENT Clinic of the Thessaloniki Aristotle University Hospital AHEPA. The Sniffin’Sticks procedure was applied, while NOSE, SNOT-22 questionnaires, as well as Visual Analogue Scales for olfactory, gustatory disabilities and nose congestion problems were completed. Results: Without age discrimination, patients presented a mean TDI score of 33.92, meaning that they had normal olfaction (hyposmia < 30.75). Moreover, 27.11% (sixteen out of fifty-nine) of patients had TDI score equal or below 30.75. It considered more accurate to divide patients into six subgroups according to their age for further evaluation. Interestingly, by applying different cut-offs for hyposmia at each subgroup, subgroups 21-30, 31-40, 41-50 and 51-60 years old recorded hyposmia percentages fluctuating from 11% to 33%. Concerning the gustatory dysfunction, 31.25% of hyposmic patients had affected taste according to the VAS results. Finally, comparisons between normosmic and hyposmic patients and their results of NOSE and SNOT-22 questionnaires were performed and SNOT-22 registered statistically significant difference (p value=0.001). Conclusion: This study supports the presence of olfaction impairment in patients with MS, while gustatory dysfunction was recorded too. Patients with hyposmia had more severe nose obstruction (according to SNOT-22). Olfactory and gustatory assessment should be performed for a more complete and effective diagnosis, treatment and follow-up. 8 General part I. Anatomy of the nose • External and internal structures Nose represents the part of the body responsible for the perception of sense of smell. It contains the external part (external nose) and the internal part (nasal cavity). The former is a face protrusion, which is formed to the upper one third from bony pyramid and the lower two thirds are the cartilaginous part. Pyramid contains the rhinal process of frontal bone at the top, the right and left nasal bone at the middle and laterally the frontal process of maxilla. The nasofrontal angle is developed by the frontal bone and the nasal bones and varies among individuals [1]. Concerning the cartilaginous part, at the middle third of nose are located the upper lateral cartilages, which come in contact with the nasal bones externally and the septal cartilage internally providing support to the nose. The lowest one third is formed by the major alar cartilages (each one is consisted of the lateral, middle and medial crus), shaping the tip of nose, which is the most protruded part. Columella is located from the tip of nose to the upper lip of mouth and is formed by the medial crus of the lateral cartilages. Columella separates the right from left nostril and through them airflow enters the nasal cavity. Finally, minor alar and sesamoid cartilages are also included in the cartilaginous part [2]. Internally, nose is divided by the nasal septum into the right and left nasal cavity, which extends from nostrils to the pharynx. Septum is composed of three parts, the ethmoid bone at the top, the vomer below, while the septal cartilage is located at the front. Each nasal cavity is consisted of the vestibule and the main part. Nasal vestibule is covered by skin containing hair follicle, as well as sweat and sebaceous glands. Subsequently, the main part is expanded from the vestibule to the nasal choana, which is the connection to nasopharynx. 9 It is worth mentioning that nasal cavity is consisted of the inner, upper, lower and lateral wall. The inner wall is set by the nasal septum with its bony and cartilaginous part. The upper wall contains the nasal, frontal, ethmoid (cribriform plate) and sphenoid bones. The palatine process of maxilla delimits the lower wall at the anterior three quarters and at the posterior quarter the horizontal plate of palatine bone. To the formation of the lateral wall participate the maxilla, ethmoid, palatine and sphenoid bone, as well as inferior concha and lacrimal bone. That part of nasal cavity includes the three conchae or turbinate bones-the superior, middle and inferior. About 50% of people have the supreme turbinate too, which lies above the superior. Their role is increasing, warming and humidifying the inhaled air by increasing the surface of the nasal cavity and decelerating the airflow. The inferior concha is a separate bone, while the superior and middle are extensions of the ethmoid bone. Underneath each turbinate the corresponding meatus is formed and create four ways allowing air to flow: The inferior meatus is located above the floor of the nasal cavity and under the inferior concha and its main function is emptying the nasolacrimal duct to the nasal cavity. It is a part of the formation of the nasal valve, which will be described below. The middle meatus is between the inferior and middle conchae at the lateral wall of the nasal cavity, while it offers the destination where maxillary, frontal and anterior ethmoid sinuses are emptying their content. The largest of the anterior ethmoid sinuses is the so-called ethmoidal bulla. At the external wall of the middle meatus a thin bonny structure is formed-the uncinate process. The smallest and shallowest meatus is the superior one where the posterior ethmoid sinuses emit. Between the posterior edge of the superior concha and the sphenoid bone, a space that remains is the sphenoethmoidal recess [2]. 10 Moreover, a structure of paramount importance is the nasal valve area. It represents the area with the highest nasal flow resistance and even small changes of the structure modify the physiology of respiration. It is divided into
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