There are several authoritative books with contributions from experts recognized worldwide in all aspects of autonomic anatomy, physiology, and pharmacology, and in the clinical evaluation and management of autonomic disorders. These books are a valuable source of information for any physician involved in the care of patients with autonomic symptoms. The purpose of this book is not to provide a comprehensive coverage of all these areas but rather to present a focused approach to the pathophysiology, diagnosis, and management of the most common autonomic disorders that may present to the clinical neurologist.
For this purpose, Autonomic Neurology is divided into three sections. Part 1 includes five chapters that review the anatomical and biochemical mechanisms of central and peripheral nervous system control of autonomic function, principles of autonomic pharmacology, and, particularly, the clinical and laboratory approach to the diagnosis of autonomic disorders. Part 2 focuses on the pathophysiology and management of the main manifestations of autonomic dysfunction, with separate chapters devoted to orthostatic hypotension; postural tachycardia; baroreflex failure; syncope; disorders of sweating; neurogenic bladder and sexual dysfunction; gastrointestinal dysmotility; and autonomic hyperactivity. Part 3 is devoted to specific autonomic disorders by using an approach that emphasizes their clinical presentation. Chapters cover the central neurodegenerative disorders; common peripheral neuropathies with prominent autonomic failure; painful small fiber neuropathies; autoimmune autonomic ganglionopathies and neuropathies; focal brain disorders; focal spinal cord disorders; and chronic pain disorders with autonomic manifestations. Whereas most disorders associated with autonomic dysfunction will be mentioned in these chapters, a more detailed description will be restricted to disorders that are common, treatable, and disabling or life threatening.
This book is the product of the experience of its contributors in the evaluation and management of the many patients with autonomic symptoms who are referred for neurologic consultation at the Mayo Clinic in Rochester, Minnesota. The content reflects our many enriching discussions in the setting of caring for these patients. The development of clinical autonomic neurology as a subspe-cialty would have not been possible without the leadership of Phillip A. Low, MD, a pivotal figure in the field. All the contributors of this book have learned from Dr. Low and have been enriched by his creative ideas, mentorship, and friendship, I am also grateful for the help of Robert D. Fealey, MD, another recognized expert in autonomic neurology, for providing me with examples of the results of the thermoregulatory sweat test from his laboratory. I thank Kenna Atherton and other members of the Section of Scientific Publications at Mayo Clinic for copyediting the chapters, and Cindy Abair, from the editorial office of the journal Neurology, who helped me in the preparation of many figures that I have included in this book. Eduardo E. Benarrocb

Preface xv

PART 1 BASIC PRINCIPLES OF THE FUNCTIONAL ORGANIZATION, PHARMACOLOGY, AND EVALUATION OF THE AUTONOMIC NERVOUS SYSTEM

1. CENTRAL AUTONOMIC NETWORK 3

Eduardo E. Benarroch

      ANTERIOR LIMBIC CIRCUIT: EMOTIONAL AND BEHAVIORAL CONTROL OF AUTONOMIC FUNCTION 5

      Insular Cortex • Anterior Cingulate Cortex • Amygdala

      HYPOTHALAMUS: AUTONOMIC PATTERN GENERATOR FOR HOMEOSTASIS AND ADAPTATION 6

      Functional Anatomy • Autonomic Output • Integrative Function

      AUTONOMIC BRAINSTEM AREAS: REFLEX STATE-DEPENDENT CONTROL OF VISCERAL EFFECTORS 7

      Periaqueductal Gray • Parabrachial Complex • Barrington Nucleus • Nucleus of the Solitary Tract • Ventrolateral Medulla • Medullary Raphe • Brainstem Respiratory Network

      CONNECTIONS OF THE CENTRAL AUTONOMIC NETWORK 9

      Inputs • Outputs

2. ANATOMY AND FUNCTION OF THE PERIPHERAL AUTONOMIC SYSTEM 15

Eduardo E. Benarroch

      FUNCTIONAL ANATOMY OF THE SYMPATHETIC SYSTEM 17

      Preganglionic Sympathetic Units • Preganglionic Input to the Sympathetic Ganglia • Sympathetic Ganglia • Sympathetic Neurotransmission

      FUNCTIONAL ANATOMY OF THE PARASYMPATHETIC SYSTEM 21

      Output to Cranial Effectors • Vagal Output • Sacral Parasympathetie Output to Pelvic Organs • Parasympathetic Neurotransmission

      PRIMARY AFFERENTS 22

      Functional Anatomy • Primary Afferents as Sensorimotor Nerves

      FUNCTIONAL INTEGRATION OF PERIPHERAL CONTROL OF THE VISCERAL ORGAN S 24

      Sympathetic Vasoconstrictor Output and Maintenance of Arterial Blood Pressure • Sympathetic Output to the Skin and Therrnoregulation • Control of Cardiac Function • Control of Cranial Effectors • Control of the Gastrointestinal Tract • Control of Pelvic Organs

3. AUTONOMIC NEUROTRANSMISSION 31

Eduardo E. Benarroch

      CHOLINERGIC TRANSMISSION 32

      Synthesis, Storage, Release, and Metabolism of Acetylcholine • Cholinergic Receptors

      ADRENERGIC TRANSMISSION 34

      Synthesis, Storage, and Release of Norepinepbrine • Uptake and Metabolism of Norepinephrine • Adrenergic Receptors

      NON-ADRENERGIC NON-CHOLINERGIC AUTONOMIC NEUROTRANSMITTERS 37

      Neuropeptides • ATP and Other Purines • Nitric Oxide • Serotonin

      FUNCTIONAL ASPECTS OF AUTONOMIC NEUROTRANSMISSION 38

      Cotransmission • Denervation Supersensitiviry

4. AUTONOMIC PHARMACOLOGY 42

Eduardo E. Benarroch

      CLINICAL PHARMACOLOGY OF THE CHOLINERGIC SYSTEM 42

      Drugs Affecting Synaptic Availability of Acetylcholine • Drugs Acting on Muscarinic Receptors

      CLINICAL PHARMACOLOGY OF THE ADRENERGIC SYSTEM 44

      Drugs Affecting Norepinephrine Synthesis, Release, and Uptake • Drugs Acting on Alpha-1 Adrenergic Receptors • Drugs Acting on Alpha-2 Adrenergic Receptors • Drugs Acting on Beta Adrenergic Receptors

      AUTONOMIC SIDE EFFECTS OF DRUGS USED FOR TREATMENT OF NEUROLOGIC AND PSYCHIATRIC DISORDERS 46

5. EVALUATION OF AUTONOMIC DISORDERS 49

Wolfgang Singer, Michelle L. Mauermann, and Eduardo E, Benarroch

      CLASSIFICATION OF AUTONOMIC DISORDERS 50

      Main Questions for Classification and Evaluation • Clinical Manifestations of Autonomic Failure • Clinical Manifestations of Autonomic Hyperactivity • Focal or Restricted Autonomic Manifestations

      CLINICAL EVALUATION 52

      History • Relevant Features in the Clinical History • Physical Examination

      LARORATORY TESTING 54

      Basic Studies • Antibody Testing • Special Laboratory Tests • Fractionated Plasma Catecholamines

      AUTONOMIC LABORATORY TESTING: GENERAL PRINCIPLES 56

      Indications • Potential Pitfalls

      EVALUATION OF SUDOMOTOR FUNCTION 57

      Thermoregulatory Sweat Test • Quantitative Sudomotor Axon Reflex Test • Silastic Imprint Method • Quantitative Direct and Indirect Test of Sudomotor Function • Sympathetic Skin Response

      CARDIOVASCULAR FUNCTION TESTS 60

      Physiological Principles • HR Response to Deep Breathing • Valsalva Maneuver • Head-Up Tilt • Other Cardiovascular Function Tests

      OTHER TESTS BASED ON THE CLINICAL SYNDROME 67

      Imaging Studies • Electrophysiological Studies • Polysomonography • Urodynamic and Gastrointestinal Motility Studies

      TISSUE BIOPSY IN THE DIAGNOSIS OF AUTONOMIC DISORDERS 67

      Diagnosis of Amyloidosis • Punch Skin Biopsy

      TESTS OF AUTONOMIC FUNCTION IN CLINICAL RESEARCH LABORATORIES 68

      Power Spectrum Analysis • Sympathetic Microneurography • Cardiac Sympathetic Imaging

PART 2 PATHOPHYSIOLOGY AND MANAGEMENT OF AUTONOMIC DISORDERS

6. NEUROGENIC ORTHOSTATIC HYPOTENSION 73

Eduardo E. Benarroch and Wolfgang Singer

      Neurogenic Orthostatic Hypotension • Variants

      REPRESENTATIVE CASE 74

      PATHOPHYSIOLOGY 75

      Responses to Orthostatic Stress • Arterial Baroreflex • Mechanism of Neurogenic OH

      CLINICAL FEATURES 76

      Manifestations of Hypoperfusion • Precipitating and Aggravating Factors

      ETIOLOGY 77

      Degenerative Synucleinopathies • Autoimmune Ganglionopathy • Small Fiber Neuropathy • Other Causes

      EVALUATION 78

      Clinical History • Physical Examination • Laboratory Tests • Autonomic Laboratory Testing • Other Studies

      MANAGEMENT 80

      Nonpharmacologic Approaches • Pharmaeologic Therapy • Prevention of Supine Hypertension

7. POSTURAL TACHYCARDIA SYNDROME 89

Wolfgang Singer and Eduardo E. Benarroch

      REPRESENTATIVE CASES 90

      Case 1 • Case 2

      PATHOPHYSIOLOGY 91

      Neuropathic POTS • Hyperadrenergic POTS • POTS and Volume Dysregulation • POTS and Physical Deconditioning

      COMORBIDITIES IN POTS 93

      Chronic Symptoms in Patients with POTS • Potential Mechanisms of Persistence of Symptoms

      EVALUATION 94

      Clinical History and Examination • Laboratory

      MANAGEMENT 94

      Nonphannacologic Approaches • Pharmaoologie Therapy

8. BAROREFLEX FAILURE 99

Eduardo E. Benarroch

      REPRESENTATIVE CASE 100

      PATHOPHYSIOLOGY AND ETIOLOGY 101

      Baroreceptor Reflex • Effects of Baroreceptor Afferent Denervation • Main Causes of Baroreflex Failure

      CLINICAL MANIFESTATIONS 103

      Hypertensive Crisis • Fluctuating Hypertension • Orthostatic Tachycardia • Malignant Vagotonia

      DIAGNOSIS 104

      History and Examination • Autonomic Testing • Measurements of Baroreflex Sensitivity

      MANAGEMENT 106

      General Principles • Management of Hypertension Episodes • Management of • Hypotension and Bradycardia

9. SYNCOPE AND OTHER CAUSES OF TRANSIENT LOSS OF CONSCIOUSNESS 110

Jeffrey W. Britton, Brian Moseley, and Eduardo E. Benarroch

      SYNCOPE 111

      Representative Case • Reflex (Neurally Mediated) Syncope • Syncope Due to Orthostatic Hypotension • Cardiac Syncope

      SEIZURES IN THE DIFFERENTIAL DIAGNOSIS OF SYNCOPE 116

      Representative Case • Differential Diagnosis between Seizures and Syncope • Ictal Bradycardia and Asystole • Coexistence of Arrhythmias and Seizures in Channelopathies

      FUNCTIONAL TLOC 119

      EVALUATION OF PATIENTS WITH TLOC 119

      Clinical History and Examination • Electrocardiogram • Further Cardiologic Evaluations • Neurologic Evaluation

      MANAGEMENT OF PATIENTS WITH REFLEX SYNCOPE 121

      Patient Education • Physical Counterpressure Maneuvers • Tilt or Exercise Training • Pharmacological Therapy • Cardiac Pacing • Syncope and Driving

10. DISORDERS OF SWEATING 126

Eduardo E. Benarroch

      PHYSIOLOGY 127

      Central Control of Sweating • Sympathetic Control of Swearing • Sweat Gland Physiology

      ASSESSMENT OF SUDOMOTOR FUNCTION 128

      Thermoregulatory Sweat Test • Sudomotor Axon Reflex Tests • Punch Skin Biopsy

      ANHIDROSIS 130

      General Concepts • Representative Case • Multiple System Atrophy • Autonomic Ganglionopathy • Small Fiber Neuropathies • Ross Syndrome • Isolated Acquired Idiopathic Anhidrosis • Focal Central Nervous System Disorders • Drug-Induced Anhidrosis • Management

      HYPERHIDROSIS 136

      Representative Case • Generalized Hyperbidrosis • Primary Focal Hyperhidrosis • Compensatory Hyperhidrosis • Secondary Facial Hyperhidrosis • Focal Hyperhidrosis Associated with • Intrathoracic Mass Lesions • Hyperhidrosis Associated with Focal Central Nervous System Lesions • Drug-Induced Hyperhidrosis • Management

11. NEUROGENIC BLADDER AND SEXUAL DYSFUNCTION 144

Eduardo E. Benarroch and Michelle L. Mauermann

      NEUROGENIC BLADDER 145

      Representative Case • Physiology • Pathophysiology • Evaluation • Neurologic Disorders Commonly Associated with Neurogenic • Bladder • Management

      NEUROGENIC SEXUAL DYSFUNCTION 153

      Physiology • Pathophysiology and Common Autonomic Causes • Evaluation • Management

12. GASTROINTESTINAL DYSMOTILITY 158

Eduardo E. Benarroch

      REPRESENTATIVE CASE 159

      PHYSIOLOGY 159

      Enteric Nervous System • Dorsal Motor Nucleus of the Vagus • Sacral Parasympathetic Nucleus • Prevertebral Sympathetic Ganglia and Reflexes

      PATHOPHYSIOLOGY 161

      Dyspbagia • Upper Gastrointestinal Dysmotility • Constipation • Defecatory Impairment • Diarrhea

      EVALUATION 162

      Dysphagia • Gastroparesis • Constipation • Defecatory Dysfunction

      DISORDERS COMMONLY ASSOCIATED WITH GASTROINTESTINAL DYSMOTILITY 163

      Spinal Cord Injury • Diabetic Neuropathy • Amyloid Neuropathy • Immune Enteric Neuropathies • Familial Enteric Neuronopathies • Parkinson Disease

      MANAGEMENT 165

      Gastroparesis • Constipation

13. AUTONOMIC HYPERACTIVITY 170

Eduardo E. Benarroch

      GENERAL FEATURES OF AUTONOMIC HYPERACTIVITY 171

      Pathophysiology • Complications • Principles of Management

      PAROXYSMAL SYMPATHETIC HYPERACTIVITY IN SEVERE HEAD INJURY 175

      Typical Features • Representative Case • Differential Diagnosis • Management

      SUBARACHNOID HEMORRHAGE 176

      FOCAL DISORDERS 177

      Insular Stroke • Seizures • Paroxysmal Hypothermia with Hyperhidrosis • Brainstem Lesions

      AUTONOMIC HYPERACTIVITY ASSOCIATED WITH SUBACUTE ENCEPHALOPATHY 178

      Delirium Tremens • Fatal Insomnia • Autoimmune Encephalitis

      AUTONOMIC HYPERACTIVITY IN SPINAL CORD DISORDERS 179

      Autonomie Dysreflexia in Spinal Cord Injury

      AUTONOMIC HYPERACTIVITY IN PERIPHERAL NERVE DISORDERS 180

      Guillain-Barre Syndrome

      IATROGENIC CAUSES OF AUTONOMIC HYPERACTIVITY 180

PART 3 COMMON NEUROLOGIC AUTONOMIC DISORDERS

14. NEURODEGENERATIVE AUTONOMIC DISORDERS 187

Eduardo E. Benarroch and Wolfgang Singer

      MULTIPLE SYSTEM ATROPHY 188

      Definition and Overview • Representative Case • Autonomie Manifestations of MSA • Motor Features • Sleep Related Motor and Respiratory Manifestations Natural History • Neuropathology

      LEWY BODY DISORDERS 194

      Definition and Overview • Parkinson Disease • Dementia with Lewy Bodies • Pure Autonomie Failure

      EVALUATION AND DIFFERENTIAL DIAGNOSIS 197

      Autonomie Testing • Neuroimaging • Cardiac Uptake of Norepinephrine Analogs or Precursors • Urodynamic Studies and Anal Sphincter EMG • Folysomnography • Other Studies

      MANAGEMENT 200

15. AUTONOMIC NEUROPATHIES 205

Michelle L. Mauermann, Jennifer A. Tracy, and Wolfgang Singer

      AMYLOID NEUROPATHY 206

      Definition and Overview • AL Amyloidosis • Familial Amyloid Polyneuropathy • Representative Case • Neuropathy Patterns • Autonomie Manifestations • Other Organ Involvement • Neuropathology • Evaluation

      DIABETIC NEUROPATHY 210

      Definition and Overview • Representative Case • Neuropathy Patterns or Types • Autonomie Manifestations • Neuropathology • Evaluation and Differential Diagnosis

      AUTONOMIC TESTING AND MANAGEMENT 214

16. NEUROPATHIC PAIN DISORDERS WITH AUTONOMIC COMPONENT 217

Michelle L. Mauermann and Wolfgang Singer

      PAINFUL SMALL FIBER NEUROPATHIES: DIFFERENTIAL DIAGNOSIS AND EVALUATION 218

      Differential Diagnosis • Evaluation

      HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY 219

      HSAN I • Background • Neuropathy • Autonomic Manifestations • Genetics • Representative Case • HSAN II-V

      FABRY DISEASE 222

      Clinical Features • Treatment • Representative Case

      CHANNELOPATHIES 224

      Sodium (Na_v 1.7) • Potassium

17. AUTOIMMUNE AUTONOMIC DISORDERS 227

Andrew McKeon and Eduardo E. Benarroch

      AUTOIMMUNE AUTONOMIC GANGLIONOPATHY 228

      Clinical Manifestations • Ganglionie AChR Antibodies • Seronegative AAG • Evaluation

      PARANEOPLASTIC AUTONOMIC DISORDERS 230

      Subacute Autonomic Neuropathy • Other Paraneoplastic Disorders with Autonomic Features

      OTHER AUTONOMIC DISORDERS WITH OR WITHOUT IDENTIFIED ANTIBODIES 233

      Acute Autonomic and Sensory Neuropathy • Guillain-Barre Syndrome • Sjogren Syndrome

      TREATMENT 234

      Acute Therapy • Chronic; Therapy

      REPRESENTATIVE CASES 236

      Case 17.1 • Case 17.2

18. FOCAL DISORDERS OF THE CEREBRAL HEMISPHERES AND BRAINSTEM 240

Jeffrey W. Britton, Brian Moseley, and Eduardo E. Benarroch

      DISORDERS OF THE CEREBRAL HEMISPHERES 241

      Stroke • Seizures

      DISORDERS OF THE DIENCEPHALON AND BRAINSTEM 244

      Hypothalamic Disorders • Brainstem Disorders

      LEUKOENCEPHALOPATHIES AND OTHER INHERITED DISORDERS 247

      Adult-Onset Autosomal Dominant Leukodystrophy • Alexander Disease • Leukoencephalopathy with Neuroaxonal Spheroids • Fragile X-Tremor/Ataxia Syndrome • Vitamin B12 Deficiency

19. FOCAL DISORDERS OF THE SPINAL CORD 252

Eduardo E. Benarroch

      PATHOPHYSIOLOGY AND LOCALIZING FEATURES 253

      Cardiovascular Function • Micturition • Gastrointestinal Motility • Thermoregulation • Representative Case

      TRAUMATIC SPINAL CORD INJURY 254

      Neurogenic Shock • Orthostatic Hypotension • Neurogenic Bladder • Gastrointestinal Dysmotility • Sexual Dysfunction • Temperature Dysregulation

      MULTIPLE SCLEROSIS 257

      Bladder Dysfunction • Bowel Dysfunction • Sexual Dysfunction • Thermoregulatory Dysfunction • Cardiovascular Abnormalities

      OTHER SPINAL CORD DISORDERS 259

      Neuromyelitis Optica • Syringomyelia • Stiff Man Syndrome

      AUTONOMIC DYSREFLEXIA 259

      Hypertensive Episodes • Triggering Factors

      BACLOFEN WITHDRAWAL SYNDROME 260

      MANAGEMENT ISSUES 261

      Orthostatic Hypotension • Neurogenic Bladder • Bowel Dysfunction • Autonomic Dysreflexia

20. CHRONIC PAIN DISORDERS WITH AUTONOMIC FEATURES 265

Eduardo E. Benarroch

      PHYSIOLOGY AND PATHOPHYSIOLOGY OF PAIN-AUTONOMIC INTERACTIONS 266

      Peripheral Nociceptors • Peripheral Sensitization by Inflammation • Central Sensitization • Relay of Nociceptive Information to the Central Autonomic Network • Patterned Autonomic Responses to Pain • Cortical Reorganization in Chronic Pain States

      COMPLEX REGIONAL PAIN SYNDROME 270

      Definition • Clinical Manifestations • Pathophysiology • Evaluation • Treatment

      SYMPATHETIC IMPAIRMENT IN PAINFUL PERIPHERAL NEUROPATHIES 273

      Effects of SCNA9 Mutations • Erythromelalgia (Erythermalgia)

      PRIMARY HEADACHE DISORDERS 274

      Clinical Manifestations • Pathophysiology • Autonomic Manifestations of Migraine • Differential Features of Trigemino-Autonomic Cephalalgias

      CHRONIC VISCERAL PAIN 277

      Unique Features of Visceral Sensation • Manifestations of Chronical Visceral Pain

Index 281

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