Multiple Sclerosis

A Mechanistic View

Alireza Minagar

• Publisher: Academic Press
• Year: 2015
• Print ISBN: 9780128007631
• eBook ISBN: 9780128010051
• Topic: Biological Sciences
• Subtopic: Developmental Psychology
• Index: Biological Sciences

Multiple Sclerosis: A Mechanistic View provides a unique view of the pathophysiology of multiple sclerosis (MS) and related disorders. As the only book on the market to focus on the mechanisms of MS rather than focusing on the clinical features and treatment of the disease, it describes the role of genetic and environmental factors in the pathogenesis of MS, the role of specific cells in the pathophysiology of the disease, and the pathophysiology of inflammatory and neurodegenerative disorders related to MS.The book provides discussion of neurodegeneration and neuroregeneration, two critical emerging areas of research, as well as detailed discussion of the mechanisms of action of the approved and investigational drugs for treatment of MS and the emerging role of magnetic resonance spectroscopy (MRI) in investigations into MS.It is the only book on the market to offer comprehensive coverage of the known mechanisms of MS and related diseases, and contains contributions from physicians and researchers who are worldwide experts in the field of study.- Focuses on the pathophysiologic mechanisms of multiple sclerosis and the mechanisms of action in agents for the treatment of MS- Discusses the roles of neurodegeneration and neuroregeneration in MS and related diseases- Authored and edited by international leaders in the field of MS research

Chapter 1

Clinical Manifestations of Multiple Sclerosis

An Overview

Vijaykumar Javalkar, Jeanie McGee, and Alireza Minagar Department of Neurology, LSU Health Sciences Center, Shreveport, LA, USA

Abstract

Multiple sclerosis (MS) is a presumably immune-mediated, demyelinating, and neurodegenerative disease of the human central nervous system, which usually affects young adults and causes significant irreversible neurological disability. Up to 85% of newly diagnosed MS patients have relapsing–remitting (RR) disease which is characterized by periods of development of new or worsening of older neurological deficits followed by complete or partial improvement. In most cases, MS manifests between the ages of 20 and 40, with a peak age of 29 and females being predominantly affected, at least in the most common form of MS. MS lesions develop in various areas of the brain and spinal cord which in turn causes development of a wide array of clinical manifestations. In many cases the neurologic manifestations of MS present episodically and then advance to a progressive phase with steady accumulation of neurologic deficits. In many patients the severity and complexity of clinical manifestations of MS are severe and devastating and significantly compromise the patient's quality of life. The present chapter presents an overview of MS clinical features.

Keywords

Cognitive; Demyelinating; Disorder; Motor; Multiple sclerosis (MS)

Introduction

Multiple sclerosis (MS) is a presumably immune-mediated, demyelinating, and neurodegenerative disease of the human central nervous system, which usually affects young adults and causes significant irreversible neurological disability. Up to 85% of newly diagnosed MS patients have relapsing–remitting (RR) disease which is characterized by periods of development of new or worsening of older neurological deficits followed by complete or partial improvement. In most cases, MS manifests between the ages of 20 and 40, with a peak age of 29 and females being predominantly affected, at least in the most common form of MS. MS lesions develop in various areas of the brain and spinal cord which, in turn, lead to the development of a wide array of clinical manifestations. In many cases the neurologic manifestations of MS present episodically and then advance to a progressive phase with steady accumulation of neurologic deficits. In many patients the severity and complexity of clinical manifestations of MS are severe and devastating and significantly compromise the patient’s quality of life. The present chapter presents an overview of MS clinical features.

Motor and sensory manifestations

Weakness is a common finding in MS patients and significantly stems from the involvement of corticospinal tract. Patients describe their weakness as heaviness, stiffness, or giving way under their weight of their extremities. The lower extremities are more commonly and usually earlier affected than the upper extremities. Weakness begins in one lower extremity; however, both lower extremities eventually are affected. The weakness is usually associated with hyperactive reflexes and increased tone in the lower extremities, and many patients present with spastic paraparesis. Clonus is present at the ankle, and examination of these patients also reveals extensor plantar responses. Spasticity of the upper, lower, or four extremities is also a significant finding and may interfere with the patient’s gait and other physical activities.

Sensory symptoms, including numbness, pins and needles sensation, dysesthetic pain, tingling, and burning, are among the most common complaints of MS patients and often present early in its clinical course. These sensory presentations may be more indicative of the demyelination of the posterior columns than spinothalamic tracts. Neurologic examination of these patients may reveal impairment and decrease in feeling of the vibration and abnormalities in fine touch and joint position senses. Pinprick and temperature sensations are less commonly affected over the course of MS. An interesting sensory symptom of MS is Lhermitte’s sign wherein the patient experiences an acute feeling of electric shock sensation which travels down the spine and the extremities. This event occurs when the individual bends the neck forward. A number of painful sensory experiences in MS patients include persistent and painful dysesthesia, burning pain, and painful cramps and spasms of the muscles, particularly in the lower extremities.

Fatigue

Mental and physical fatigue constitutes the most common problem voiced by MS patients. Many report an increase of their fatigue prior to and during the clinical exacerbation. During pathophysiology of MS, the demyelination of the axons leads to tardy and desynchronized transmission of nervous impulses to the point that the impulse conduction may completely cease. Interestingly, exposure to heat intensifies the fatigue in MS patients. They describe fatigue as an unusual and overwhelming feeling of mental and physical exhaustion, which is worse with heat exposure and may slightly improve with rest and sleep. Fatigue significantly restricts patients’ mental and physical activity and adversely affects their performance on neuropsychological evaluations. Fatigue is worse during relapses of MS and does not show any meaningful correlations with brain magnetic resonance imaging (MRI) parameters such as gadolinium-enhancing lesions, lesion load, or any known inflammatory biomarkers. Primary mechanisms for fatigue in MS include pro-inflammatory cytokines, endocrine influences, axonal loss, and altered patterns of cerebral activation (Braley & Chervin, 2010). Secondary mechanisms for fatigue include sleep disorders, depression, disability status, MS subtype, and iatrogenicity (Braley & Chervin, 2010). Alterations in basal ganglia connectivity may contribute to pathophysiology of fatigue in MS (Finke, Schlichting, Papazoglou, et al., 2015). Thalamic involvement in MS may manifest with fatigue, movement disorders, painful syndromes, and cognitive decline (Minagar, Barnett, Benedict, et al., 2013).

Cognitive decline

Cognitive dysfunction in MS occurs in 30–70% of patients (Rao, Leo, Bernardin, & Unverzagt, 1991; Kujala, Portin, & Ruutiainen, 1996). Patients develop reduced information processing speed causing intellectual slowing, attention problems, impairment in abstract reasoning, problem solving, and memory dysfunction (Piras, Magnano, Canu, et al., 2003). Patients with progressive MS may commonly exhibit language and visuospatial deficits (Connick, Chandran, & Bak, 2013). Cognition is more impaired in patients who smoke cannabis than in those who do not (Pavisian et al., 2014). A study using 7 Tesla (T) MRI revealed that leukocortical (type I) and subpial (III–IV) cortical lesions identified on 7T FLASH-T2 sequences are potential cortical biomarkers of the cognitive status in MS (Nielsen et al., 2013). Atrophy of the corpus callosum is strongly associated with cognitive impairment in MS (Granberg, Martola, Bergendal, et al., 2014; Yaldizli, Penner, Frontzek, et al., 2014). Meticulous neuropsychological assessment of MS patients reveals that up to 65% of these patients suffer from cognitive decline.

Psychiatric manifestations

About 20–40% of patients with MS present with personality changes characterized by irritability and apathy (Stathopoulou, Christopoulos, Soubasi, & Gourzis, 2010). The frequency of depression in MS patients and their family members is up to three times higher than the general population. The depression of MS patients is a potential psychiatric presentation of MS. In addition, depression may be a reactive response to the devastating impact of MS on one’s life or it may be a side-effect of treatment with β-interferons. Clinicians should bear in mind that treatment of MS patients with β-interferons, in a minority of patients, is associated with depression, and attention to this side-effect is important. Patients with MS have a higher tendency to attempt suicide and such a devastating event is more frequent in these patients. In addition to personality changes and depression, other psychiatric disorders and symptoms such as bipolar disorder, pseudobulbar affect, euphoria, and anxiety are also over presented in patients with MS (Iacovides & Andreoulakis, 2011).

Optic neuritis and other neuroophthalmologic manifestations

The optic nerve is an extension of the brain within the orbit and is commonly affected in the course of MS. A significant portion of MS patients present with optic neuritis (ON) as the initial manifestation or at one point in the course of their disease develop ON. The other neuroophthalmological manifestations include internuclear opthalmoplegia, nystagmus, saccadic dysmetria, ocular convergence spasm, Pulfrich phenomenon, Uhthoff phenomenon, and retrogeniculate visual field defects (Torres–Torres & Sanchez-Dalmau, 2015). Patients with ON usually develop monoocular subacute visual loss. The scotoma significantly affects central visual field, and patients report a dark patch in the center of their visual field. Other visual capabilities such as color perception and contrast sensitivity are compromised and patients report significant decrease in light intensity perception. Up to 90% of patients with ON present with retroorbital pain upon eye movement (Optical Neuritis Study Group, 1991). Neurologic examination of patients with ON reveals the presence of relative pupillary afferent defect (RAPD or Marcus Gunn pupil). Funduscopic examination demonstrates blurring of the optic disc margin or swelling of the disc (papillitis). In one study the optic disc appeared swollen in 35% of the patients and normal in 65% (Opti...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Chapter 1. Clinical Manifestations of Multiple Sclerosis: An Overview
• Chapter 2. Novel Therapies for Multiple Sclerosis: A Mechanistic View
• Chapter 3. Role of B Cells in the Pathogenesis of Multiple Sclerosis: Mechanisms of Action
• Chapter 4. Role of CD4+ T Cells in the Pathophysiology of Multiple Sclerosis
• Chapter 5. Granulocyte-Macrophage Colony-Stimulating Factor in Central Nervous System Autoimmunity
• Chapter 6. Role of Cytokine-Mediated Crosstalk between T Cells and Nonimmune Cells in the Pathophysiology of Multiple Sclerosis
• Chapter 7. Vitamin D: Role in Pathogenesis of Multiple Sclerosis
• Chapter 8. Role of Genetic Factors in Pathophysiology of Multiple Sclerosis
• Chapter 9. Neuropathology of Multiple Sclerosis
• Chapter 10. Pathophysiology of Acute Disseminated Encephalomyelitis
• Chapter 11. Pathophysiology of Experimental Autoimmune Encephalomyelitis
• Chapter 12. Pathophysiology of Optic Neuritis
• Chapter 13. Neurodegeneration and Remyelination in Multiple Sclerosis
• Chapter 14. Mechanisms of Action of Glatiramer Acetate in the Treatment of Multiple Sclerosis
• Chapter 15. Mechanism of Action of Interferon Beta in Treatment of Multiple Sclerosis
• Chapter 16. Mechanisms of Blood–Brain Barrier Disintegration in the Pathophysiology of Multiple Sclerosis
• Chapter 17. Mechanisms and Potentials of Stem Cells in the Treatment of Multiple Sclerosis: The Unpaved Path
• Chapter 18. Role of Neuroimaging in Multiple Sclerosis
• Chapter 19. Pathophysiology of Lymphatic Drainage of the Central Nervous System: Implications for the Pathophysiology of Multiple Sclerosis
• Index