Preface

**Section 2 Environmental Risk Factors and Clinical Issues in MS 167**

Chapter 7 **Association Between Multiple Sclerosis Risk and Human Immunodeficiency Virus Infection: Insights and**

Chapter 8 **The Role of Over-Nutrition and Obesity in Multiple**

Chapter 9 **Cognitive Deficits and Neuropsychological Assessment in**

Chapter 10 **Social Cognition Impairments in Patients with Multiple**

Chapter 12 **Neuroprotection and Recovery in Multiple Sclerosis 281**

Chapter 13 **Neuroprotection: A New Therapeutic Approach of Relapsing**

**Duration and Grade of Disability 227**

Chapter 11 **Sex Hormones and Multiple Sclerosis 257**

**Remitting Multiple Sclerosis 307**

Anastasiya G. Trenova

Dana Slavoaca

Rodríguez

Ehtishamul Haq, Insha Zahoor and Mushfiquddin Khan

Ema Kantorová, Egon Kurča, Daniel Čierny, Dušan Dobrota and

Alena Javůrková, Denisa Zimová, Katarína Tomašovičová and

**Sclerosis and Comparison with Imaging Studies, Disease**

Dafin F. Muresanu, Maria Balea, Olivia Rosu, Anca Buzoianu and

Juan Espinosa-Parrilla, Marco Pugliese, Nicole Mahy and Manuel J

Valentina Ignatova, Lyudmila Todorova and Jivko Surchev

Chapter 6 **Pediatric Multiple Sclerosis 169** Ozgul Ekmekci

**VI** Contents

**Challenges 187**

**Sclerosis 195**

**Multiple Sclerosis 211**

Jaroslava Raudenská

Štefan Sivák

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by progressive demyeli‐ nation and neurodegeneration in the central nervous system (CNS), constituting the most com‐ mon demyelinating disease of the CNS in humans. Oligodendrocytes and myelin appear to be the primary targets of the immune-mediated attack, but neurons are also damaged. Resident oligo‐ dendrocyte progenitor cells can remyelinate damaged axons during the first stages of the disease, where total or partial recovery is possible, but with time this mechanism fails. Axonal transection and degeneration occurring in the setting of acute inflammatory demyelination and as a conse‐ quence of chronic demyelination are considered to underlie permanent disability in MS patients.

Although intensive research over many decades has unveiled many pathophysiological mecha‐ nisms in the development of MS, the cause is still unknown. Nevertheless, it does seem clear that genetic susceptibility and environmental factors play crucial roles.

*Trending Topics in Multiple Sclerosis* is a book that provides an insight into some of the main prob‐ lems currently debated in this area of research, focusing on topics that deal with genetic and envi‐ ronmental risk factors, pathophysiological mechanisms, neurocognitive findings, and neuroprotective strategies. The book is divided in two sections: the first section is dedicated main‐ ly to **genetics and pathophysiology, while the second section deals largely with environmental risk factors and clinical and neurocognitive studies**.

Despite the fact that there is no evidence implicating classical Mendelian genetic inheritance with the risk for MS, numerous studies have offered results strongly supporting a genetic component of susceptibility to the disease. The first chapter deals with the possible role of genetic and bio‐ chemical markers in the modulation of the immune response in MS patients, which could thus be associated with MS risk and disability progression. The contribution of *HLA* and *non-HLA* genes and vitamin D in the pathogenesis of MS is reviewed, and the authors also present their personal experience in a Central European Slovak population.

The following chapters deal with gateway mechanisms for the entrance of immune cells to the CNS, oxidative stress, production of harmful catalytic antibodies, and intrathecal immunoglobu‐ lin synthesis.

In MS, demyelination often occurs at specific and discrete foci, suggesting that a certain signal might guide autoreactive T cells to particular site(s), regardless of the fact that brain autoantigens are widely distributed throughout the CNS. Chapter 2 engages in reviewing the gateway reflex, which can be triggered by various neural stimulations (gravity, electric stimulation, and pain), inducing gateways for immune cells to circumvent the blood-brain barrier (BBB), all of which in‐ volve sensory-sympathetic communication.

MS pathogenesis continues to be debated, but the most widely accepted theory recognizes that myelin destruction is mainly related to autoimmunity. While activated CD4+ myelin-reactive T cells are considered the major mediators in the pathogenesis of MS, the role of B cells and autoan‐ tibodies (auto-Abs) against myelin autoantigens has recently gained widespread recognition. In‐ trathecal synthesis (ITS) of immunoglobulins (Igs) is the strongest biological marker in MS. Nevertheless, since no specific target has been revealed, this synthesis has been persistently con‐ sidered to be disease irrelevant. In Chapter 3, a very interesting review is presented, providing pertinent information on the possible role of B cells and subsequently ITS of Igs in the patho‐ physiology of MS. On the other hand, Chapter 4 deals with a novel concept considering that IgG, IgA, and/or IgM autoantibodies with catalytic activities directed to DNA, RNA, polysaccharides, and myelin basic protein (abzymes) could cooperatively promote important neuropathological mechanisms in MS.

Chapter 5 reviews the relationship of oxidative stress, glutathione redox and ATPase systems, and membrane fluidity with the development of MS. Based on the results of clinical studies sug‐ gesting that omega-3 long-chain polyunsaturated fatty acids (PUFAs) have anti-inflammatory, an‐ tioxidant, and neuroprotective effects in MS and animal models of MS. The authors also describe the effects of PUFA supplementation on the parameters indicated above in patients with relaps‐ ing-remitting MS.

The second section of this book starts by presenting in Chapter 6 Pediatric MS. Although MS is very infrequent in children and adolescents, pediatricians and neurologists should have this diag‐ nosis in mind and need to know the differences, concerning clinical presentation, magnetic reso‐ nance imaging (MRI) findings, and neuroimmunologic features, between pediatric and adult MS patients.

The next two chapters deal with the influence of environmental factors, such as HIV infection and nutrition, in the development of MS. Chapter 7 deals with the association between HIV (or its treatment) and a reduced risk of developing MS, a fact that could contribute to the development of more promising treatment strategies for MS. On the other hand, Chapter 8 engages in the im‐ portance of understanding how nutritional epigenetic factors could influence the risk for develop‐ ing MS and how this could help in establishing dietary interventions.

There is increasing recognition of cerebral cortical demyelination in MS and the role that this pathology may play in the neurological dysfunction—including cognitive deficits—experienced by most MS patients. Chapters 9 and 10 contend with the importance of neuropsychological as‐ sessment and social cognition in MS, respectively.

Chapter 11 is aimed to provide evidence on the immunomodulatory and neuroprotective effects of sex hormones on the pathological processes in MS and their importance for the development of new disease-modifying strategies.

Significant advances have been achieved in MS therapy with the use of disease-modifying drugs (DMDs), which are immunomodulatory or immunosuppressive, but these advances have been limited to the prevention of relapses, and long-term results are controversial. Neuroprotective strategies focusing simultaneously on several pathogenic mechanisms have been receiving in‐ creased attention. In this context, Chapter 12 approaches direct and indirect neuroprotective ef‐ fects of DMDs and current knowledge of potential neuroprotective therapies and remyelination strategies. Chapter 13 mainly focuses on new drugs with proposed neuroprotective or neurorege‐ nerative effects, highlighting the effect of diazoxide on neuroinflammation and the results of a clinical trial with this drug.

**Alina González-Quevedo, MD, PhD**

Department of Neurobiology Institute of Neurology and Neurosurgery University of Medical Sciences of Havana, Cuba **Genetics and Pathophysiology**

sidered to be disease irrelevant. In Chapter 3, a very interesting review is presented, providing pertinent information on the possible role of B cells and subsequently ITS of Igs in the patho‐ physiology of MS. On the other hand, Chapter 4 deals with a novel concept considering that IgG, IgA, and/or IgM autoantibodies with catalytic activities directed to DNA, RNA, polysaccharides, and myelin basic protein (abzymes) could cooperatively promote important neuropathological

Chapter 5 reviews the relationship of oxidative stress, glutathione redox and ATPase systems, and membrane fluidity with the development of MS. Based on the results of clinical studies sug‐ gesting that omega-3 long-chain polyunsaturated fatty acids (PUFAs) have anti-inflammatory, an‐ tioxidant, and neuroprotective effects in MS and animal models of MS. The authors also describe the effects of PUFA supplementation on the parameters indicated above in patients with relaps‐

The second section of this book starts by presenting in Chapter 6 Pediatric MS. Although MS is very infrequent in children and adolescents, pediatricians and neurologists should have this diag‐ nosis in mind and need to know the differences, concerning clinical presentation, magnetic reso‐ nance imaging (MRI) findings, and neuroimmunologic features, between pediatric and adult MS

The next two chapters deal with the influence of environmental factors, such as HIV infection and nutrition, in the development of MS. Chapter 7 deals with the association between HIV (or its treatment) and a reduced risk of developing MS, a fact that could contribute to the development of more promising treatment strategies for MS. On the other hand, Chapter 8 engages in the im‐ portance of understanding how nutritional epigenetic factors could influence the risk for develop‐

There is increasing recognition of cerebral cortical demyelination in MS and the role that this pathology may play in the neurological dysfunction—including cognitive deficits—experienced by most MS patients. Chapters 9 and 10 contend with the importance of neuropsychological as‐

Chapter 11 is aimed to provide evidence on the immunomodulatory and neuroprotective effects of sex hormones on the pathological processes in MS and their importance for the development of

Significant advances have been achieved in MS therapy with the use of disease-modifying drugs (DMDs), which are immunomodulatory or immunosuppressive, but these advances have been limited to the prevention of relapses, and long-term results are controversial. Neuroprotective strategies focusing simultaneously on several pathogenic mechanisms have been receiving in‐ creased attention. In this context, Chapter 12 approaches direct and indirect neuroprotective ef‐ fects of DMDs and current knowledge of potential neuroprotective therapies and remyelination strategies. Chapter 13 mainly focuses on new drugs with proposed neuroprotective or neurorege‐ nerative effects, highlighting the effect of diazoxide on neuroinflammation and the results of a

**Alina González-Quevedo, MD, PhD**

Institute of Neurology and Neurosurgery University of Medical Sciences of Havana, Cuba

Department of Neurobiology

ing MS and how this could help in establishing dietary interventions.

sessment and social cognition in MS, respectively.

new disease-modifying strategies.

clinical trial with this drug.

mechanisms in MS.

VIII Preface

ing-remitting MS.

patients.

**Chapter 1**
