Fatigue in Multiple Sclerosis: Background, Clinic, Diagnostic, Therapy

Preface
Contents
Part I: Background
	On the History of Fatigue
		References
			Further Reading
	Definitions, Epidemiology, and Etiological Factors
		1	 Definitions and Terminology
		2	 Prevalence and Significance of Fatigue
		3	 Demographic and Clinical Factors
		4	 Etiological Factors
			4.1	 Personality Traits
			4.2	 Autonomous Regulation
			4.3	 Endocrine Factors
			4.4	 Proinflammatory Cytokines
			4.5	 Attention Deficit Disorder
			4.6	 Structural and Functional Brain Changes
			4.7	 Summary of the Considerations on the Etiological Factors
		References
	Pathophysiology and Differentiation from Other Symptoms and Diseasess
		1	 Introduction
		2	 Primary Fatigue
			2.1	 Structural and Functional Imaging
			2.2	 Neurophysiological Findings
				2.2.1	 Electroencephalography
				2.2.2	 Transcranial Magnetic Stimulation
		3	 Secondary Fatigue
			3.1	 Sleep Disorders
			3.2	 Other Causes
		4	 Summary and Outlook
		References
	Immunopathology and Pathogenesis
		1	 Introduction
		2	 Immunopathology and Pathomorphological Changes in MS
			2.1	 Demyelination
			2.2	 Gray Matter Lesions
			2.3	 Axonal Lesions and Neurodegeneration
		3	 Inflammatory Mediators and Fatigue in MS
		4	 Pathological Patterns of Damage and Fatigue in MS
		5	 Neuroendocrine Regulatory Disorders in MS
		6	 Multidimensionality of Fatigue and Damage Processes in MS
		7	 Summary
		References
Part II: Clinic
	Motor Performance Fatigability in MS
		1	 Introduction
		2	 Clinician and Patient Perspective
		3	 Gait-Related Motor Performance Fatigability
			3.1	 Linear Approaches for Gait Analysis
				3.1.1	 Distance Walked Index
				3.1.2	 Deceleration Index
			3.2	 Nonlinear Approaches for Gait Analysis
				3.2.1	 Local Dynamic Stability
				3.2.2	 Fatigue Index Kliniken Schmieder
		4	 Motor Performance Fatigability and Perceived Fatigability
		5	 Interactions between Sustained Cognitive or Motor Activity and Performance Fatigability
		6	 Motor Performance Fatigability and Trait Fatigue
		7	 Motor Performance Fatigability and Trait Self-Control
		8	 Pharmacological and Non-pharmacological Treatment of Motor Performance Fatigability
		9	 Summary
		References
	Cognitive Fatigue
		1	 Introduction
		2	 Definition of Cognitive Fatigue
		3	 Neuroanatomical Correlates of Cognitive Fatigue
		4	 Cognitive Fatigue and Cognition
		5	 The Role of Attention in the Diagnosis of Fatigue
		6	 Summary
		References
	Personality Factors and Motivation
		1	 Introduction
		2	 Personality and MS
		3	 Personality Trait Assessment Instruments
		4	 Motivation
		5	 Behavioral Aspects: Coping and Disease Management
		6	 Conclusion
		References
	Fatigue and Depression
		1	 Introduction
		2	 Symptom Overlap Between Fatigue and Depression
		3	 Depression and Fatigue in MS from a Diagnostic Perspective
		4	 Depression and Fatigue in MS from a Research Perspective: Pathophysiology
		5	 Depression and Fatigue in MS from a Therapeutic Perspective
		6	 Summary
		References
	Sleep and Wake Disturbances
		1	 Epidemiology
			1.1	 Sleep Diagnostics
		2	 Sleep-Wake Disorders
			2.1	 Insomnia
			2.2	 Restless Legs Syndrome
			2.3	 Sleep-Disordered Breathing
			2.4	 Excessive Daytime Sleepiness and Fatigue
		3	 Nocturia
			3.1	 Other Sleep and Wake Disturbances
		References
Part III: Diagnostics
	Clinical Assessment Tools for Fatigue
		1	 Introduction
		2	 Neurological Interview
		3	 Fatigue Diaries
		4	 Fatigue Questionnaires
		5	 Neurophysiological Possibilities of Detection
		6	 Summary
		References
	Neuroimaging and Fatigue
		1	 Macrostructural Imaging Correlates of Primary Fatigue
			1.1	 Relevance of Inflammatory White Matter Lesions
			1.2	 Changes in Global and Regional Brain Volume
		2	 Microstructural Imaging Correlates of Primary Fatigue
		3	 Functional Imaging Correlates of Primary Fatigue
		4	 Functional Imaging Correlates of Fatigability
		5	 Secondary Fatigue and Imaging Findings
		6	 Summary and Outlook
		References
	Electrophysiology and Fatigue
		1	 Introduction
			1.1	 Fatigue and Exhaustibility
			1.2	 Heterogeneity of Studies on Exhaustibility
			1.3	 Peripheral and Central Fatigue
			1.4	 Electrophysiological Methods for the Investigation of Fatigue
		2	 Electrophysiological Findings in Healthy Subjects
			2.1	 Corticospinal Excitability
			2.2	 Intracortical Excitability
			2.3	 Cortical Silent Period
			2.4	 Potential Influencing Factors
		3	 Electrophysiological Findings in MS Patients
			3.1	 Corticospinal Excitability
			3.2	 Intracortical Excitability
			3.3	 Cortical Silent Period (CSP)
			3.4	 Event-Related Potentials
			3.5	 “Event-Related Desynchronization”
			3.6	 High Frequency Oscillations
			3.7	 Fronto-Thalamic Networks
		4	 Effects of Therapeutic Approaches on Electrophysiological and Clinical Parameters in MS Patients
			4.1	 Pharmacological Therapeutic Approaches
			4.2	 External Brain Stimulation
				4.2.1	 Transcranial Direct Current Stimulation (tDCS)
				4.2.2	 Repetitive Transcranial Magnetic Stimulation (rTMS) and Intermittent Theta Burst Stimulation (iTBS)
		5	 Summary
		References
	Expert Opinion and Medicolegal Assessment
		1	 Basics of Expert Opinions
		2	 Objectification of Fatigability
			2.1	 Fundamental Aspects
			2.2	 Value of Questionnaires
			2.3	 Objectification of Cognitive Fatigability
			2.4	 Objectification of Motor Fatigability
				2.4.1	 Upper Extremities
				2.4.2	 Lower Extremities
		3	 Symptom Validity Assessment
			3.1	 Basics
			3.2	 Fatigue-Related Symptom Validity Assessment
				3.2.1	 Medical History
				3.2.2	 Cognitive Fatigability
				3.2.3	 Motor Fatigability
				3.2.4	 Clinical Symptom Validation
		4	 Assessing Occupational Capacity
			4.1	 Quantification of Fatigability According to ICF
		5	 Assessing Driving Ability
			5.1	 Basics
			5.2	 Driving with Fatigue Symptoms
				5.2.1	 Orientation towards Self-Perception
				5.2.2	 Orientation towards Occupational Capacity
				5.2.3	 Orientation to Daytime Sleepiness
		References
Part IV: Therapy
	Disease Modifying Immunotherapies and Fatigue
		1	 Immunotherapies for Mild/Moderate Forms of MS
			1.1	 Interferons
			1.2	 Glatiramer Acetate
			1.3	 Dimethyl Fumarate
			1.4	 Teriflunomide
		2	 Immunotherapies for (Highly) Active Forms of MS
			2.1	 Fingolimod
			2.2	 Cladribine
			2.3	 Natalizumab
			2.4	 Alemtuzumab
			2.5	 Ocrelizumab
			2.6	 Rituximab
		3	 Classic Immunosuppressants
		4	 New Immunotherapeutics in MS
			4.1	 Siponimod
			4.2	 Ozanimod
			4.3	 Ponesimod
		5	 Summary
		References
	Symptomatic Drug Treatment of Fatigue
		1	 Introduction
		2	 Symptomatic Therapeutic Approaches
		3	 Drug Treatment Approaches
		4	 Immunological Treatment Approaches
			4.1	 Cytokines
		5	 Immunosuppressive Therapies
			5.1	 Cortisone
		6	 Endocrine Treatment Approaches
			6.1	 Hydrocortisone/Fludrocortisone
			6.2	 ACTH
			6.3	 Alfacalcidol
		7	 Neurotransmitter-Oriented Treatment Approaches
			7.1	 Amantadine
			7.2	 Ketamine
			7.3	 Modafinil
			7.4	 Ondansetron
		8	 Treatment Approaches with Channel Blockers
			8.1	 Fampridine (Syn. 4-Aminopyridine)
		9	 Treatment Approaches with Stimulants
			9.1	 L-Amphetamine
			9.2	 Methylphenidate
		10	 Antidepressant Therapy Methods
			10.1	 Selective Serotonin Reuptake Inhibitors (SSRI)
		11	 Other Drug Therapy Approaches
			11.1	 Ginseng
			11.2	 N-Acetylcysteine
			11.3	 Pemoline
			11.4	 Carnitine
		References
	Non-drug Treatment Approaches and Neurorehabilitation
		1	 Introduction
		2	 Exercise Therapy
		3	 Cryotherapy
		4	 Training and Empowerment
		5	 Cognitive Behavioral Therapy
		6	 Nutrition
		7	 Non-invasive Brain Stimulation
		8	 Neurorehabilitation
		9	 Summary
		References