Preface

Multiple sclerosis (MS) has for years been a crucial unsolved problem in the field of neurosciences, and is a serious cause of suffering for millions of patients worldwide, affecting psychosomatic homeostasis in the majority of patients.

The etiopathological background of the disease, which is presumably a progressive inflammation of the central nervous system (CNS), inducing demyelination in the white matter and degenerative alterations in the gray matter, provoking a multitude of polymorphic clinical phenomena, is still an open field of intensive, constantly progressive investigation.

The incidence of MS varies across geographic regions, with high rates in high latitude, affecting three times more women than men at any age. Many genetic factors, major histocompatibility complex and non-major histocompatibility complex, may play an important role in the innate immune mechanisms and in the modulation of the immune system under the influence of the many exterior environmental risk factors and viral infections.

A large number of patients have from the onset experienced relapses and remissions of various neurological phenomena, lasting for many years, whereas a substantial number of untreated patients face the tragedy of continuous deterioration of their physical and mental condition, resulting in a serious irreversible disability.

Energy failure is the substantial cause of functional impairment in the majority of patients who suffer from MS. That cause is reasonably associated with neuronal degeneration, demyelination, and axonal loss based on a wide spectrum of innate autoimmune mechanisms, inflammatory reactions, mitochondrial dysfunction, cytokine interactions, intracellular and interstitial edema, and perivascular cell reactions.

The clinical manifestations of the disease vary from person to person, from time to time, and from age to age, and most of them are changeable in the majority of the cases even from the initial stages of the disease. Vertigo, nausea, vomiting, hiccups, motor deficits, tremors, dysarthria, cutaneous sensory deficits, sensory phenomena from mucosae, cerebellar dysfunction, gait instability, diplopia, vision impairment, visual field defects, dyschromatopsia, phosphenes, painful conditions, autonomic dysfunction, sphincter insufficiency, fatigue, and cognitive decline, such as episodic memory deficits and impaired visuospacial estimation, emerging early in the disease compose a part of the resizing pattern of the disease. Cognitive decline, which would be attributed to association of gray and white matter lesions, in addition to disconnection and dissociation syndrome, is frequently underestimated in the initial stages of the disease, necessitating neuropsychological evaluation by properly designed tools for MS patients. Cognitive rehabilitation, which is essential for the improvement of the quality of life of patients, may include various methods and techniques enabling patients to overcome common problems of everyday life, coping harmoniously with the disease burden. Language disorders are not rare phenomena in patients who suffer from MS, necessitating appropriate speech therapy.

**II**

**Section 5**

Non-Pharmacologic Therapies

Epstein-Barr Virus in Multiple Sclerosis *by Gulfaraz Khan and Asma Hassani*

*by Seyyedeh Zahra Safi*

Therapeutical Approach **85**

**Chapter 6 87**

**Chapter 7 101**

Diagnostic criteria for MS have been proposed and introduced for many years, and have been revised many times. Most of them may simply facilitate the approach of the diagnosis of the disease. Among them, diffusion imaging, resting state functional magnetic resonance imaging, magnetic resonance spectroscopy, evoked potentials, optical coherence tomography (OCT), OCT angiography, and immunological analysis of the cerebrospinal fluid may lead to a prompt diagnosis of the disease even in patients with atypical clinical manifestations and course heterogeneity.

However, in the differential diagnoses of MS a substantial number of other conditions mimicking the clinical manifestations of the disease should be under consideration. Among them neuromyelitis optica spectrum disorder (Devic's disease) would be differentially diagnosed on the basis of anti-aquaporin 4 antibody, acute disseminated encephalomyelitis on the basis of the clinical profile and neuroimaging data, myelin oligodendrocyte glycoprotein (MOG) antibody disease on the basis of the level of MOG antibodies, and antiphospholipid syndrome by the detection of lupus anticoagulant and anticardiolipin antibodies. In addition, systemic lupus erythematosus, small vessel disease, and Susac's syndrome have also a place in the expanded spectrum of the differential diagnosis of MS.

There is no definite targeted therapeutic approach for MS. An efficient therapeutic strategy should be based on clear knowledge of the pathogenetic mechanisms of the disease. Investigation of the role of myeloid cells and the infiltration of the CNS by peripheral lymphoid and myeloid cells may be crucial for a deeper understanding of the progression of the disease and the chronicity of the clinical phenomena. Novel therapeutic attempts aimed at modulating the activities and reactions of myeloid cells might be hopeful in treating MS patients at the initial stages of the disease. In addition, the application of autologous Epstein-Barr virus-specific T cell therapy may improve the clinical condition of patients. Non-pharmacological therapies, such as appropriate diet, proper environment, physical exercise, relaxation and progressive muscle relaxation therapy, psychotherapy, cognitive behavioral therapy, music therapy, and emotional, social, and spiritual support may also play a beneficial role in the amelioration of the quality of life in the large majority of patients.

In this volume, the authors discuss some of the crucial aspects of the MS drama, attempting to contribute to finding a way that may lead to catharsis.

> **Stavros J. Baloyannis MD, PhD** Professor Emeritus, Aristotelian University, Thessaloniki, Greece

> > **1**

Section 1

Introduction

Section 1 Introduction

**3**

**Chapter 1**

Sclerosis

*Stavros J. Baloyannis*

**1. In the labyrinth of multiple sclerosis**

social disability in the suffering people [3, 4].

edema, and perivascular cell reactions [15, 16].

**2. The multiform suffering**

matic homeostasis substantially in the majority of the patients.

days, and 700,000 among them are registered in Europe [5–7].

incidence of MS, particularly among pediatric patients [10–12].

Introductory Chapter: Multiple

Multiple sclerosis (MS) remains a crucial unsolved problem in the field of neurosciences, being also a serious cause of suffering for millions of patients worldwide affecting the quality of life, the personal and social economy, and the psychoso-

The etiopathological background of the disease, which is a progressive inflammation of the CNS [1, 2], inducing demyelination in the white matter and degenerative alterations in the gray matter in various areas of the brain hemispheres, the cerebellum, the brain stem, and the spinal cord, may provoke a multitude of polymorphic clinical phenomena inducing a variable type of physical, mental, and

The incidence of MS varies considerably across geographic regions, with high rates in high latitude and low in the tropical zone, affecting three times more women than men at any age, though the climax is between 20 and 40 years. Approximately 2.5 million people in the world suffer from multiple sclerosis nowa-

Many genetic factors, MHC and non-MHC, may play an important role in the innate immune mechanisms and in the modulation of the immune system under the influence of the many exterior environmental risk factors and viral infections [8, 9]. Among the viruses, the infection with Epstein–Barr virus (EBV), which is a common human herpes virus, seems to have a considerable association with the

A large number of patients have from onset the experience of relapses and remissions of the various neurological phenomena, lasting for many years, whereas a substantial number of untreated patients face the tragedy of the continuous deterioration of their physical and mental condition, resulting in a serious irreversible disability eventually, though primary progressive forms starting from the onset

Energy failure is obviously the substantial cause of the functional impairment in the majority of patients who suffer from multiple sclerosis. That cause is reasonably associated with demyelination, neuronal degeneration, and axonal loss, based on a wide spectrum of innate autoimmune mechanisms, inflammatory reactions, mitochondrial dysfunction, cytokine interactions, intracellular and interstitial

The multiform clinical manifestations of the disease vary from person to person, from time to time, from age to age, and most of them are unstable and

of the disease may also occur in approximately 10–15% of patients [13, 14].

## **Chapter 1**
