An Approach to a Patient with Suspected Autonomic and Sleep Dysfunction

Abstract

This chapter briefly outlines the steps for an approach to a patient presenting with symptoms suggestive of autonomic dysfunction with or without sleep complaints.

The approach to a diagnosis must be followed in a logical manner for optimal care of the patients. The first step is a detailed history from the patient and the caregiver followed by physical examination of the patient as a whole including all body systems and must also include specific autonomic examination at the bedside or the clinics. Next step is to order appropriate autonomic function and other laboratory tests for confirming the clinical diagnosis. One must also formulate a differential diagnosis to differentiate from the mimics. Final step is addressing the principles of therapy (both drug and nondrug treatment). In nine subsections, I have outlined all the steps in a systematic manner to address how to approach a patient with a possible diagnosis of dysautonomia.

Introduction

An approach to an analysis of a patient’s complaints must begin with a clear understanding of the evaluation process (see further on) when confronted with a patient suspected to have autonomic dysfunction (AD) or dysautonomia that could be defined as derangement of sympathetic, parasympathetic, or enteric nervous system function [1]. This may manifest more commonly as hypoactivity (autonomic failure, AF) more often rather than hyperactivity (autonomic dysreflexia or autonomic storms) of the autonomic nervous system (ANS). A correct diagnosis of AD is essential to design appropriate treatment, and to assess natural history and prognosis of the condition. Therefore, an approach must be formulated in a way to making an accurate diagnosis. For this purpose, it is essential to have a basic knowledge of the classification of AD and this is the first step. In this chapter, I shall outline the approach and evaluation in the subsections in the following order:

• Classification of Dysautonomia

• General and Specific Clinical Manifestations of Autonomic Dysfunction and Physiology of Orthostatic Blood Pressure Control

• History and Physical Examination

• Clinical Scales and Questionnaires

• Autonomic Function and Other Laboratory Tests

• Brief Description of Some Important and Unusual Dysautonomic Entities

• Fits and Faints, Including Syncope and Other Mimics of Autonomic Dysfunction

• Clinical–Anatomical–Laboratory Correlations with Case Examples

• Principles of Therapy

Classification of Dysautonomia

The ANS by innervating all body systems and organs controls major bodily functions to maintain internal homeostasis. The major functions include control of cardiovascular (CV), respiratory, gastrointestinal (GI), genitourinary (GU), endocrine and thermoregulatory systems as well as pupillary function and regulation of states of our existence (active wakefulness, relaxed wakefulness, nonrapid eye movement [NREM], and rapid-eye movement [REM] sleep [2,3,4,5,6]). History, therefore, should address possible dysautonomic symptoms affecting each of these systems and organs (see further on), and must include 24-h history.

Autonomic manifestations may be primary (idiopathic without any known cause) or secondary to (comorbid with) other conditions, for example, neurological, other medical or primary sleep disorders and iatrogenic (medication-related or surgically induced) cases that could be generalized (Box 12.1) and localized (Box 12.2; e.g., Horner syndrome, Adie’s pupil, gustatory facial sweating, and Chagas disease [caused by Trypanosoma cruzi affecting predominantly Central and South American population, and affecting localized autonomic plexus in the heart and gut]). AD may also be transient or paroxysmal (Box 12.3), for example, vasovagal syncope in the young, and carotid sinus hypersensitivity in the elderly individuals. Sometimes patients present with features of autonomic overactivity or so called autonomic “storms” or dysreflexia (Box 12.4). An example of sympathetic overactivity in patients with spinal cord injury, particularly above T5 level may be cited causing paroxysmal hypertension resulting from spinal reflex activity (dysreflexia) in those with quadriplegia. Another example is excessive vagal activity causing bradycardia in vasovagal syncope (a neurally mediated syncope) in young person with prolonged standing in a crowded environment. AF could sometimes be related to medications taken (e.g., clonidine and L-dopa) for some medical or psychiatric (e.g., anxiolytics and antidepressants) conditions or may be caused by some street drugs (e.g., cocaine, amphetamine, “crack,” and phencyclidine) taken by many young individuals. Another iatrogenic cause of AF is surgical sympathectomy. Two important examples of primary diffuse chronic AF include multiple system atrophy (MSA, formerly known as the Shy-Drager syndrome) and pure autonomic failure (PAF) (see Box 12.1 and section “Brief Description of Some Important and Unusual Dysautonomic Entities”). Secondary diffuse AF may be caused by a variety of medical disorders. For example, diabetic autonomic neuropathy affecting cardiovagal function, postganglionic sympathetic sudomotor (with proximal–distal gradient), and adrenergic systems. Another example is familial amyloidotic polyneuropathy (somatic and autonomic) causing diffuse degeneration with selective loss of pain and temperature sensation (small fiber neuropathy), orthostatic hypotension, weight loss, and amyloid infiltration in the biopsied rectal and nerve tissues. Certain neurological diseases may cause secondary diffuse chronic AF (e.g., neurodegenerative disorders like Parkinson’s disease, diffuse Lewy body disease with dementia, hypothalamic and brain stem tumors, spinal cord injury, and many others (see Box 12.1)). An important category of neurological disorders causing AF is neurodevelopmental diseases, such as congenital central hypoventilation syndrome (CCHS), and congenital megacolon (Hirschsprung’s disease) (see Box 12.1). Fatal familial insomnia (FFI), a prion disease described relatively recently, presents with a variety of dysautonomic manifestations in addition to insomnia, ataxia, myoclonus, and oneiric behavior pursuing a relentlessly progressive course and ending in death in course of 1–2 years [7]. Most of the major entities listed in this section are described in separate chapters throughout this book.

Box 12.1 Classification of Generalized Autonomic Failure

• A. Primary Dysautonomia

  • 1. Pure autonomic failure (PAF) without associated somatic neurological deficits (Bradbury–Eggleston syndrome)

  • 2. Multiple system atrophy (MSA), a neurodegenerative disease with progressive autonomic failure associated with somatic neurological manifestations, characterized either by predominant cerebellar (MSA-C) or parkinsonian features (MSA-P) or both parkinsonian-cerebellar syndrome (MSA-PC). When dysautonomia is the initial dominant feature, the entity is also known as the Shy–Drager syndrome, which has recently been replaced by multiple system atrophy)

  • 3. Acute or subacute pandysautonomia (idiopathic variety)

  • 4. A subset of postural tachycardia syndrome (POTS; idiopathic type)

  • 5. Riley–Day syndrome (familial dysautonomia [FD])

• B. Secondary (Comorbid) Dysautonomia (Associated with Known Diseases or Iatrogenic)

• I. Neurological diseases

  • (a) Intracranial lesions

    • 1. Hypothalamic, pituitary and brain stem tumors

    • 2. Encephalitis and encephalopathies

    • 3. Wernicke encephalopathy

    • 4. Multiple encephalomalacia

    • 5. Demyelinating diseases (including multiple sclerosis)

    • 6. Neurodegenerative diseases (e.g., Parkinson’s disease, dementia with Lewy body disease)

    • 7. Oher brain stem lesions (e.g., trauma, stroke)

    • 8. Epilepsy including diencephalic autonomic seizure

  • (b) Spinal cord dysfunction

    • 1. Spinal cord injuries

    • 2. Spinal cord tumors

    • 3. Syringomyelia

    • 4. Hematomyelia

    • 5. Tabes dorsalis

  • (c) Neurodevelopmental or congenital disorders

    • 1. Hirschsprung’s disease (also known as aganglionic colon or megacolon), a developmental disorder due to absence or sparse enteric ganglia affecting most commonly the rectum or the distal sigmoid colon

    • 2. Rett syndrome

    • 3. Ehlers–Danlos syndrome

    • 4. Congenital insensitivity to pain with anhidrosis (CIPA)

    • 5. Congenital sensory neuropathy (HSAN Type II)

    • 6. Dopamine beta-hydroxylase deficiency

    • 7. Congenital central hypoventilation syndrome (CCHS)

  • (d) Peripheral neuropathies associated with Autonomic neuropathy

    • 1. Diabetic neuropathies

    • 2. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) [Landry–Guillain–Barré–Strohl syndrome]

    • 3. Alcoholic neuropathy

    • 4. Amyloidotic neuropathy

    • 5. Hereditary sensory neuropathies

    • 6. Acute pandysautonomia (secondary variety)

    • 7. Acute or subacute immune mediated neuropathy

    • 8. Toxic autonomic neuropathy (e.g., arsenic and thallium); Vacor, mercury, organic solvents (in some workers), n-hexane inhalation (industrial exposure), etc.

• (e) Neuromuscular Junctional Disorders Comorbid with Autonomic Dysfunction:

  • 1. Myasthenia gravis

  • 2. Myasthenic syndrome (Lambert–Eaton syndrome)

  • 3. Botulism

    • II. Nonneurological (general medical disorders):

      • 1. Diabetes mellitus

      • 2. Addison disease

      • 3. Panhypopituitarism

      • 4. Acute intermittent porphyria

      • 5. Chronic fatigue syndrome

      • 6. Collagen vascular disease (e.g., systemic lupus erythematosus [SLE] and Sjogren’s syndrome)

    • III. Iatrogenic (surgically or drug induced):

      • 1. Surgical sympathectomy (localized autonomic dysfunction)

      • 2. Cordotomy (spinal cord surgery for intractable pain)

      • 3. Drug induced

        • (i) Antidepressants

        • (ii) Tranquillizers

        • (iii) Hypotensive drugs

        • (iv) Other drugs (e.g., L-dopa, vincristine, amiodarone, cis-platinum)

        • (v) Anticholinergic (e.g., tricyclic antidepressants [amitriptyline] and antihistamines [Benadryl])

        • (vi) Diuretics

    • IV. Dysautonomia (hypo- or hyperactivity) in primary sleep disorders

      • 1. Obstructive sleep apnea syndrome

      • 2. Narcolepsy–cataplexy

      • 3. Restless legs syndrome—periodic limb movements in sleep

      • 4. Fatal familial insomnia (FFI)

      • 5. Parasomnias (NREM and REMs)

    • V. Miscellaneous

      • 1. Paraneoplastic autonomic neuropathy

      • 2. Hyperbradykininism

      • 3. Baroreflex Failure

      • 4. Postural tachycardia syndrome (POTS) secondary to hypovolemia, deconditioning, selective autonomic neuropathy

Box 12.3 Transient or intermittent (episodic or paroxysmal) dysautonomia

• Episodic autonomic dysfunction reflexly induced (includes neurally mediated syncope):

  • Vasovagal, cough and micturition syncope

  • Carotid sinus hypersensitivity

  • Glossopharyngeal neuralgia

• Cardiac syncope (related to structural cardiac disease)

• Epileptic autonomic discharges in generalized or focal seizures and diencephalic autonomic seizure

• Subarachnoid hemorrhage

• Cerebral or brain stem transient ischemic episodes

• Paroxysmal hyperhidrosis

• Raynaud’s phenomenon

• Erythromelalgia

• Shapiro syndrome (Agenesis of corpus callosum, hypothermia and hyperhidrosis)

Box 12.2 Localized Autonomic Dysfunction

• 1. Horner syndrome

• 2. Holmes–Adie syndrome

• 3. Argyll Robertson pupil

• 4. Ross syndrome

• 5. Harlequin syndrome

• 6. Gustatory sweating (auriculotemporal syndrome of Frey)

• 7. Crocodile tears (Bogorad syndrome)

• 8. Complex regional pain syndrome type I and type II

• 9. Chagas disease (caused by Trypanosoma cruzi, predominately in Central and South America)

• 10. Idiopathic palmar or axillary hyperhidrosis

Box 12.4 Autonomic Hyperactivity (Autonomic “Storms”) or Autonomic “Dysreflexia”

• A. Sympathetic hyperactivity (typically seen in complete spinal cord transection above the T5 segmental level interrupting the descending input to the spinal sympathetic preganglionic neurons. As a result of this interruption there is excessive sympathetic activity [autonomic dysreflexia]):

  • 1. Hyperhidrosis

  • 2. Altered thermal regulation

  • 3. High blood pressure

  • 4. Palpitation and tachycardia

  • 5. Pupillary dilation (mydriasis)

• B. Parasympathetic hyperactivity

  • 1. Excessive salivation and lacrimation

  • 2. Hypotension

  • 3. Bradycardia

  • 4. Pupillary constriction (miosis)

General and Specific Clinical Manifestations of Autonomic Dysfunction and Physiology of Orthostatic Blood Pressure Control

• I. The history and physical examination findings of a patient referred for possible dysautonomia must be critically analyzed by the autonomic physician and she/he should be aware of symptoms resulting from a dysfunction of the ANS. Patients may present with a set of positive or negative dysautonomic symptoms [2, 3]. Moreover, certain symptoms and signs may suggest a specific dysfunction of a particular division of the ANS or may direct one’s attention to a particular body system responsible for such manifestations.

  • A. General features: The four most common presenting features in a patient with dysautonomia (Box 12.5) include [8] (i) orthostatic intolerance (OI) symptoms such as presyncope (e.g., dizziness, blurring of vision, nausea, sensation of abdominal bloating, and fullness) or syncope (transient loss of consciousness), and orthostatic hypotension (OH) in the upright posture (as a result of cerebral hypoperfusion) relieved by changing from erect to supine position; (ii) symptoms of urinary dysfunction (e.g., enuresis and frequency of micturition), which are often attributed to diseases of the prostate gland in men delaying the diagnosis; (iii) anhidrosis or hypohydrosis; and (iv) erectile dysfunction in men (this symptom frequently precedes other major manifestations by many years).

    Additional manifestations that may be presenting features in some patients are also listed in Box 12.5 [2, 3, 9].

  • B. Positive dysautonomic phenomena that are infrequently the presenting features include the following:

    • 1. Autonomic dysreflexia or autonomic “storms” (e.g., after spinal cord transection usually above T5 level; see Box 12.4)

    • 2. Compensatory autonomic hyperactivity in normally innervated areas (e.g., facial hyperhidrosis in diabetic autonomic cranial neuropathy patients and segmental hyperhidrosis in partial peripheral nerve injuries)

    • 3. Hyperhidrosis seen in tetanus accompanied by hypertension and tachycardia

  • C. Negative autonomic phenomena: These are more common (compared with positive features) presentation of dysautonomic patients:

    • 1. Faint feeling and dizziness (cerebral hypoperfusion) due to orthostatic hypotension

    • 2. Heat intolerance or heat stroke

    • 3. Accidental hypothermia, particularly in the older individuals

    • 4. Anhidrosis or hypohidrosis in parts of the body

    • 5. Sphincter dysfunction (incontinence of urine and feces)

  • D. Specific features indicating parasympathetic failure:

    • 1. Dry mouth

    • 2. Dry eyes (keratoconjunctivitis sicca) as a result of absent or decreased tear production (alacrima): very common along with dry mouth in Sjogren syndrome

    • 3. Sexual dysfunction

    • 4. Urinary bladder problem (retention or enuresis)

    • 5. Impaired pupillary light reflex (dilated poorly responsive pupils)

    • 6. Persistent tachycardia or fixed heart rate (HR) in all body positions

    • 7. Reduced heart rate variability (HRV) or altered low frequency/high frequency (LF/HF) ratio in HR frequency domain analysis

    • 8. Widespread anhidrosis or hypohidrosis (anatomically sympathetic but functionally cholinergic failure)

  • E. Following symptoms or signs point to sympathetic failure:

    • 1. Orthostatic hypotension

    • 2. Diffuse anhidrosis or hypohidrosis

  • F. Features suggesting failure of the enteric nervous system (ENS):

    Gastrointestinal dysmotility (e.g., achalasia, gastroparesis, intestinal pseudo-obstruction, and colonic atonia) manifested by the following symptoms: (i) anorexia, (ii) swallowing difficulty, (iii) early satiety, (iv) postprandial abdominal pain, (v) vomiting, (vi) constipation, (vii) diarrhea, often nocturnal, (viii) abdominal distension, and (ix) symptoms of intestinal pseudo-obstruction (intestinal obstruction without any structural lesion in the lumen), such as abdominal pain and distension, nausea, vomiting, dysphagia, diarrhea, and constipation depending on the GI part affected by dysmotility [10].

  • G. Specific features pointing to an involvement of a particular body system and organ:

    These features provide clues as to the possible cause for secondary dysautonomia. During history taking and physical examination, particular attention should be paid to symptoms and signs for uncovering specific system related involvement as listed below [11]:

    • 1. Postural (orthostatic) hypotension in the head-up position (HUP; vertical) accompanied by OI symptoms normalized on lying supine (see above “A”). Of note, in the head-down position (HDP) BP and HR may increase above the baseline values in the supine position. The history must include inquiry into the following:

      • (a) Triggering (or aggravating) factors for OH, such as exercise, prolonged bed rest, ingestion of food, environment (hot stuffy surrounding), hot bath, and time of the day (e.g., worse in the morning).

      • (b) Sweat glands and sweating: see above “C”, “D,” and “E.”

      • (c) Cardiovascular system: see above “A” and “E.”

      • (d) Gastrointestinal system: see above “D’ and “F.”

      • (e) Genitourinary system: see above “A”, “C,” and “D”. Other symptoms may include recurrent urinary tract infection.

      • (f) Neurological system: in addition to symptoms related to possible involvement of extrapyramidal system (e.g., stooped posture, rest tremor, rigidity, gait problem, postural instability, slowness of body and mind), unsteadiness and ataxic gait (cerebellar dysfunction), symptoms related to memory and cognitive impairment; other features related to neurological involvement may include droopy eyelids (ptosis), dryness of eyes (alacrimia), blurriness of vision, abnormal movements, particularly at night (may suggest rapid eye movement sleep behavior disorder [RBD]).

      • (g) Respiratory system: this may have a variety of breathing problems, specifically during sleep (very common in multiple system atrophy), shortness of breath (dyspnea), and an unusual noise during sleep (e.g., stridor, which is very common in MSA).

• II. Physiology of orthostatic blood pressure control

  Orthostatic hypotension is a cardinal sign of AF and orthostatic intolerance. In order to understand its pathophysiology, it is essential to have at least a basic knowledge about the physiological changes in BP and other hemodynamic aspects when a normal individual changes from a supine to erect position [12,13,14,15]. When humans became Homo sapiens, they made an enemy of gravity [16]. Chapter 3 outlines pathophysiological mechanism of control of BP and other hemodynamic characteristics in the erect posture. Chapter 3 also critically discusses how a breakdown of such mechanisms may adversely affect an individual.

Box 12.5 Clinical Manifestations of Autonomic Failure

• A. The four most common presenting features

  • 1. Orthostatic intolerance symptoms related to orthostatic hypotension

  • 2. Urinary bladder dysfunction

  • 3. Anhidrosis or hypohidrosis

  • 4. Erectile dysfunction in men

• B. Additional manifestations related to dysfunction of the peripheral or central autonomic neurons:

  • 1. Horner syndrome

  • 2. Impairment of pupillary response to light and accommodation

  • 3. Diminished lacrimation and dryness of the mouth

  • 4. Persistent tachycardia (palpitations) or in some cases, cardiac arrhythmias

  • 5. Difficulty in swallowing or vomiting

  • 6. Chronic constipation (persistent or intermittent) and often nocturnal diarrhea

  • 7. Fecal incontinence

  • 8. Respiratory dysrhythmias, which are observed particularly in multiple system atrophy

History and Physical Examination

History is the most important initial step in the evaluation of a patient presenting with symptoms suggestive of dysautonomia [2, 3, 17]. It is important to have a high index of suspicion about AD based on the patient’s complaints. One must be vigilant about classification (see section “Classification of Dysautonomia”) and essential features (both general and specific, see section “General and Specific Clinical Manifestations of Autonomic Dysfunction and Physiology of Orthostatic Blood Pressure Control”) of dysautonomia. History should be followed by physical examination of each body system including neurological, cardiovascular, respiratory, and GI systems. History must include 24 h information including sleep history (e.g., bedtime, wake-up time, awakenings and abnormal movements during sleep at night, and any daytime sleepiness or impairment of daytime function). Many with dysautonomia have sleep disturbance and conversely, many primary sleep disorders (e.g., obstructive sleep apnea [OSA], REM behavior disorder [RBD], narcolepsy, and some NREM parasomnias) may have autonomia dysfunction (see Box 12.1). There is clear evidence that the brain stem respiratory and autonomic premotor neurons share common rhythms. Furthermore, the coupling of the central autonomic network and sleep–wake generating neurons plays an important role in controlling cardiovascular and respiratory regulation during sleep and wakefulness [18, 19]. Sleep-related physiological alterations in the ANS may cause profound changes in breathing in some cases of AF (e.g., MSA), and likewise breathing disturbance in sleep (e.g., OSA and central sleep apnea [CSA] may cause impaired ANS function) [20].

Step 1. History

An important initial step in the history is to seek answers to the following questions based on a critical analysis of symptoms and signs.

• Q1. Does the patient have dysautonomia?

• Q2. Is the patient’s AD significant? (Of note, many patients with mild AD remain asymptomatic requiring no treatment but may progress later to develop significant dysautonomia delaying the diagnosis.). Some autonomic scale scores (e.g., CASS, see further on) may determine severity and significance.

• Q3. If the patient has AD, is it primary or secondary, localized or generalized, transient, or persistent (see Box 12.1, 12.2, 12.3) or is it autonomic dysreflexia (see Box 12.4)?

• Q4. Does AD impair patient’s quality of life? This can certainly be improved by symptomatic treatment. Identifying the type of dysautonomia and differentiating it from mimics (e.g., neurally mediated versus cardiac or other types of syncope and other causes of “fits and faints” [see section “Fits and Faints, Including Syncope and Other Mimics of Autonomic Dysfunction”]) may help in making a final diagnosis, ascertaining prognosis, and preventing life-threatening complications (e.g., cardiac arrhythmias and sudden cardiac death) as well as in designing appropriate treatment.

It is notable that certain symptoms may strongly suggest presence of AD, for example, OI symptoms with or without orthostatic hypotension; sudomotor dysfunction (hypo- or anhidrosis or rarely localized or generalized hyperhidrosis); genitourinary dysfunction (erectile and ejaculatory difficulties in men, and nocturnal enuresis); and temperature dysregulation (hypothermia or hyperthermia of unknown cause), including coldness and discoloration of the hands and feet (intermittent or persistent) [11].

History must also include inquiry into the onset of symptoms (sudden or insidious), progression, and triggering (aggravating) factors. The onset of dysautonomia is in general insidious but sometimes could be sudden (e.g., acute pandysautonomia, acute inflammatory demyelinating polyneuropathy [Guillain–Barré syndrome], acute paraneoplastic or immune-mediated autonomic neuropathy). AD usually presents with diffuse or generalized manifestations (e.g., multiple system atrophy, pure autonomic failure, generalized hypo- [or rarely] hyperhidrosis, hypo-or hyperthermia, and OI symptoms). AD could sometimes be localized (see Box 12.2) or transient (see Box 12.3) and rarely may present with hyperactivity (see Box 12.4).

It is also important to inquire about family history (some dysautonomia can be familial, for example, CCHS, familial dysautonomia [FD], FFI [see Box 12.1]), past illnesses, psychiatric, and drug-alcohol histories as well as social history that are all important in understanding etiology and pathophysiological mechanisms of AD.

Step 2. Physical Examination

This must include specific autonomic examination [21] directed at uncovering signs pointing to a possible dysautonomia in addition to general physical examination and attention to neurological, cardiovascular, respiratory, GI, and genitourinary systems for possible cause (secondary) of AD.

Autonomic Examination

• (a) Record BP and HR in supine and standing positions. Significant fall of BP (>20 mm Hg fall of systolic and >10 mm Hg fall of diastolic BP) without any reflex tachycardia suggests neurally mediated OH. In contrast, reflex rise of HR (at least 30 beats more than the supine baseline reading in adults and 40 beats more in adolescents of 14–19 years in the erect position without significant fall of BP accompanied by OI symptoms [see section “General and Specific Clinical Manifestations of Autonomic Dysfunction and Physiology of Orthostatic Blood Pressure Control”]) suggests postural tachycardia syndrome (POTS) caused by hypovolemia, deconditioning, or restricted autonomic neuropathy.

• (b) Measure core body temperature to document hypo- or hyperthermia.

• (c) Inspect the skin for acrocyanosis (bluish discoloration of the hands or feet or tip of the nose) and pallor indicating vasospastic AD, and red-hot body parts, especially distally suggesting erythromelalgia.

• (d) Look for impaired sweating by inspection or palpation of the skin (dryness of the skin) or by the “spoon test” (gliding the convex side of the spoon should be smooth and uninterrupted over the anhidrotic skin but the flow is interrupted and sticky over the sweaty skin [22]. In AD, there may be localized or generalized hypo- or anhidrosis and rarely hyperhidrosis. A proximal–distal grading pattern of sweating impairment (e.g., the presence of sweating in the forehead and axilla but absent sweating distally) may be found in peripheral neuropathy with autonomic fibers involvement.

• (e) Examine the patient for allodynia ( pain triggered by non-noxious stimuli), hyperalgesia (excessive perception of pain to minimally painful stimuli) or hyperpathia (excessive feeling of pain following application of minimally noxious stimuli after a latency of a few seconds). These are all dysautonomic symptoms resulting from a dysfunction of central or peripheral ANS.

• (f) Inspect and feel for trophic sign (e.g., brittle nails, dry, scaly, or atrophic skin) or Charcot joints (disorganized joints with excessive range of motion), and alopecia.

• (g) Pupillary examination for size, shape or inequality of pupils, light reflex and convergence reaction for dysautonomia (e.g., Argyll Robertson pupil in tabes dorsalis, Adie’s pupil).

• (h) Look for dry eyes and dry mouth suggesting parasympathetic dysfunction.

Step 3. General Physical Examination

This should include vital signs, appearance of skin including its color (see above) or cyanosis, ankle edema, general appearance of the patient, and peripheral arterial pulsation for peripheral atherosclerosis. General physical examination should also include otolaryngological examination, and measurement of neck circumference (risk factor for sleep apnea).

Step 4. Special Examination of Each System

This must include complete neurological examination, as well as inspection, palpation and auscultation of the heart and lungs, abdominal examination for tenderness, peristalsis, presence or absence of bowel sounds for gut atonia, urinary bladder distension (suggesting urinary retention), physical evidence of endocrinopathies (e.g., slow pulse rate, nonpitting ankle edema, and hung-up muscle stretch reflexes seen in hypothyroidism) that might suggest a secondary cause for AD. Neurological examination may uncover signs of extrapyramidal dysfunction (e.g., masked facies, slow shuffling gait, rigidity, postural, and gait problems as well as resting tremor suggesting Parkinson’s disease) and cerebellar dysfunction (e.g., ataxic gait, intention tremor), which may indicate that the patient’s dysautonomia may be due to MSA. Other neurological conditions (see Box 12.1) may be causing dysautonomia and may have abnormal neurological findings indicating involvement of a particular system in the CNS. Neurological findings may also provide evidence of peripheral neuropathy (e.g., muscle weakness, decreased or absent muscle stretch reflexes, decreased sensation in the stocking, and glove distribution).

After history and physical examination, the purpose after Step 4 is to strengthen the clinical suspicion by using autonomic questionnaires and scales (see section “Clinical Scales and Questionnaires”) and assess severity.

The next step is to order a set of basic screening tests including scales, questionnaires (section “Clinical Scales and Questionnaires”), and autonomic functions (section “Autonomic Function and Other Laboratory Tests”) to confirm the clinical diagnosis (see section “Autonomic Function and Other Laboratory Tests”). Box 12.6 lists some logical steps in an orderly manner for diagnostic evaluation of dysautonomia.

Box 12.6 Logical and Relevant Steps for Diagnostic Evaluation of Dysautonomia

• Step 1: Detailed history from the patient and caregiver

  • (a) Think about relevant questions (see section “History and Physical Examination”)

  • (b) Be aware of general and specific dysautonomic symptoms (see section “General and Specific Clinical Manifestations of Autonomic Dysfunction and Physiology of Orthostatic Blood Pressure Control”)

  • (c) Be knowledgeable about classification of dysautonomia (see section “Classification of Dysautonomia”)

• Step 2:

  • (a) Physical examination with particular attention to general and autonomic examination findings and measurement of BP and HR in the supine and upright positions for 3–5 min (section “History and Physical Examination”)

  • (b) Specific physical examination findings in every body system to get some clues for the cause of orthostatic intolerance symptoms and orthostatic hypotension (section “History and Physical Examination”)

• Step 3: Use relevant questionnaires and scales (see section “Clinical Scales and Questionnaires”) to assess autonomic function and severity of its dysfunction

• Step 4: Formulate a provisional diagnosis and differentiate from mimics (section “Fits and Faints, Including Syncope and Other Mimics of Autonomic Dysfunction”)

• Step 5: Order a set of basic simple bedside screening tests to confirm the diagnosis of AD (section “Autonomic Function and Other Laboratory Tests”)

• Step 6: If needed, order more sophisticated and complex laboratory investigations for arriving at an etiological diagnosis (section “Autonomic Function and Other Laboratory Tests”)

• Step 7: Design appropriate treatment and arrange for follow-up evaluation and monitoring.

Clinical Scales and Questionnaires

Certain scales and questionnaires may help in supporting and strengthening the clinical impression of dysautonomia. There are, however, only a limited number of scales and questionnaires (e.g., ASP, COMPASS, SCOPA-AUT [see below]) available for evaluating dysautonomic symptoms [23,24,25].

The autonomic symptom profile (ASP) containing 169 questions (“domain of autonomic function was initially described by Suarez et al. [23]). There are too many questions and so the Composite Autonomic System Scale (COMPASS) was developed containing 84 questions derived from the ASP. Later COMPASS-31 containing 31 questions was developed that demonstrated high sensitivity but moderate specificity. The COMAPSS-31 [24] scores correlated reasonably well with the Composite Autonomic Scores Scale (CASS) derived from autonomic function test results. Many problems were noted with the COMPASS over the years including an overall weak correlation with symptoms of diabetic autonomic neuropathies [25, 26]. Another scale, the SCOPA-AUT [27], was originally developed to screen and assess autonomic function in PD as well as in MSA. This scale contains 25 items covering six domains (gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual functions) [27]. The latest validated questionnaire from the University of Maryland with high sensitivity and specificity is the Survey of the Autonomic Symptoms (SAS) consisting of 11 questions for women and 12 for men to diagnose early and mild diabetic autonomic neuropathy [26]. This one is easy to administer and is comparable to other validated questionnaires. There are two other questionnaires for a specific disorder of the ANS, for example, “the United Multiple System Atrophy Rating Scale (UMSARS)” to assess severity of motor and autonomic symptoms as well as to monitor progress of the disease in MSA [28]. Another example is an “Orthostatic Hypotension Questionnaire” (OHQ) used to assess the severity of symptoms and impact on day-to-day function in OH (a 10-item scale) [29].

Autonomic Function and Other Laboratory Tests

For more detail, see also Chap. 9.

• A. The purpose of autonomic function tests (AFTs) in patients suspected to have AD (hypo- or hyperactivity, positive, or negative symptoms) can be summarized as follows [2,3,4, 8, 9, 30, 31]:

  • 1. To confirm or exclude significant AD in a patient suspected to have dysautonomia from clinical evaluation (see above)

  • 2. To determine the severity and for confirmation of autonomic impairment as evident from clinical evaluation (see above) and the clinical scale scores (e.g., the COMPASS-31 and others; see section “Clinical Scales and Questionnaires”)

  • 3. To assess if the AD is affecting predominantly one or both the major subdivisions (sympathetic or parasympathetic) of the ANS

  • 4. To further localize the lesion responsible for AF to a particular part of the baroreflex pathway (e.g., afferent, efferent, central regions, or diffusely affecting)

  • 5. To confirm if AD is localized or generalized (i.e., distribution of dysautonomia)

  • 6. To evaluate if the AD is minimal requiring no intervention (many of the patients with minimal dysfunction remain functionally asymptomatic) or moderate to severe (determined by autonomic function severity scale (COMPASS-31 and CASS) [24, 25]) requiring treatment to improve symptoms and quality of life

  • 7. To find a cause for the autonomic symptoms (e.g., evaluation of the ANS involvement in sensorimotor peripheral neuropathies [autonomic involvement in distal small fiber neuropathy, DSFN [32] or autoimmune or paraneoplastic syndrome]; etiological evaluation in POTS or OI syndrome; to evaluate the role of the sympathetic nervous system in maintaining pain in some painful conditions, and in contributing to dysesthetic symptoms in RLS)

  • 8. To monitor patient’s response to drug therapy

  • 9. To ascertain progression and prognosis of the disease, and, finally

  • 10. To design appropriate treatment

• B. I shall briefly summarize the autonomic function tests, which can be performed to achieve the objectives as outlined above (for further details, the readers are referred to Chap. 9). The tests for ANS assessment can be grouped into noninvasive and invasive tests and those that can be used during sleep as well as in wakefulness.

  • I. Noninvasive ANS Function Tests

    (All these tests are age specific and must be compared with age-matched normal controls) [2, 3, 7, 8, 30, 31].

    • 1. Orthostatic stress testing (BP and HR responses to standing form a supine position and head-up tilt [HUT] to 70°. Normal changes in HR and BP on standing for 3–5 min may include a fall of systolic BP of ≤20 mm Hg and diastolic BP of ≤10 mm Hg or an increase of HR to 15 beats/min or no significant changes in BP.

    • 2. Valsalva ratio (VR): obtain a continuous electrocardiographic (ECG) monitoring during forced expiration for 10–15 s against a closed glottis maintaining a pressure of 35–40 mm Hg; the VR measures the ratio of longest R-R interval to the shortest R-R interval. Normal value for VR ≥ 1.21; (10–60 yrs. ≥1.45–1.50; >60 yrs. ≥1.35).

    • 3. Response to HR after deep breathing (HRDB): instruct the subject to breathe deeply at six breaths per minute (5 s for inspiration and 5 s for expiration in each breath) and determine mean HR (continuous one channel of EKG monitoring is needed) or pulse rate change (note that the HR increases on inspiration and decreases on expiration) during inspiration and expiration; also determine expiratory–inspiratory (E–I) ratio. Normative values: difference in HR increase: ≥15 beats/min; abnormal: ≤10.

    • 4. 30:15 Ratio: determine response to HR at 30 and 15 s after standing from a supine to upright position. Normative values: ≥1.04 (abnormal: 1.00 or less).

    • 5. Handgrip: BP and HR responses to handgrip: Normative value: Increase of diastolic BP ≥ 16 (abnormal: ≤10).

    • 6. Mental arithmetic (cognitive load) test (MAT): BP and HR response during simple mathematical calculation.

    • 7. Cold pressor test (CPT): BP and HR response on dipping the hand in ice-cold water (4 °C): both latencies to threshold (first perception of painful sensation) and tolerance (too painful to keep hand dipped in ice-cold water).

    • 8. Cold face test (CFT): (diving reflex): BP and HR response to submerging face in cold water.

    • 9. Noninvasive pharmacologic tests: determination of plasma levels of renin and norepinephrine in supine and upright positions.

    • 10. Sudomotor function tests: for cholinergic sympathetic integrity and for an early diagnosis of small fiber neuropathy [30, 31, 33].

      • (a) Thermoregulatory sweating of the entire body using quinizarin dye.

      • (b) Sympathetic skin response (SSR) [33]: This can be performed in the standard electromyographic (EMG) laboratory using an EMG machine and surface electrodes over the dorsum and palm of the hand or the dorsum and sole of the foot. This test is nonspecific and gives variable results.

  • II. Invasive Tests

    • 1. Invasive Valsalva maneuver (VM): intra-arterial recording of continuous BP and HR during four stages of VM; it is particularly important to see BP and HR responses during stage 4 of VM (note “overshoot” of BP and relative bradycardia in normal subjects) [14, 30, 31].

    • 2. Pharmacological tests after intravenous (IV) infusion:

      • (a) IV phenylephrine and norepinephrine infusion tests to determine denervation (postganglionic) supersensitivity to alpha receptors

      • (b) IV isoproterenol infusion (a test for beta-receptor supersensitivity)

      • (c) Baroreflex sensitivity (BRS) testing (expressed as a change in the slope of HR per mm Hg increase in BP after IV infusion or mechanical challenge (e.g., neck suction) [34].

    • 3. A cardiac MIBG scintigraphy (single photon emission tomographic [SPECT] scans) to determine uptake of metaiodobenzylguanidine (MIBG), a scintigraphic test for cardiac sympathetic innervation [35].

    • 4. Sudomotor test: the quantitative sudomotor axon reflex test (QSART) measures postganglionic sweat gland innervation for sweating after acetylcholine iontophoresis [36]. It is a very useful test to evaluate for dysautonomia in small fiber neuropathy.

      All the above autonomic function tests (AFTs) can be performed to assess ANS function during wakefulness.

  • III. The Following Tests Are Useful for Assessing ANS Function During Sleep

    (see also Chap. 9)

    • 1. Heart rate and heart period (HR [reciprocal of HR]): HR and HP can help in linear assessment of cardiac ANS tone (average ANS activity) throughout the night as well as transient variation (beat-to-beat) of HR. HP is related in a linear fashion to the frequency of cardiac sympathetic and parasympathetic activities.

    • 2. Heart rate variability (HRV) [37,38,39]: This is a quantitative measure of spectral power of HR broken down into low (0.04–0.15 Hz) and high (0.15–0.40 Hz) frequencies as well as measuring beat-to-beat variability of HR (i.e., time intervals between subsequent R-waves on the EKG). Low frequency (LF) reflects both sympathetic and vagal activities whereas high frequency (HF) reflects respiratory sinus arrhythmias and as such is an important measure of cardiac vagal modulation. LF/HF ratio is thought to reflect sympathovagal balance; although this has been challenged recently [40, 41]. HRV can be measured in “time domain” and “frequency domain” (see also Chap. 10).

    • 3. Beat-to-beat BP monitoring by ambulatory BP recording to assess normal “dippers” or “extreme” and “reverse” dippers as well as individuals who are “nondippers.” People in the latter three categories (extreme, reverse, and nondippers) are “at risk” for cardiovascular catastrophes [42].

    • 4. Microneurography: Uses tungsten microelectrodes to obtain multiunit recordings from cutaneous and muscle vessel nerve endings (i.e., intraneural recording) to assess peripheral sympathetic nerve activity [43].

    • 5. Photoplethysmography (PPG): Measures change in light absorption by skin vessels showing continuous changes in cutaneous blood perfusion. PPG can be obtained from pulse oximetry [44].

    • 6. Impedance cardiography (ICG) [45].

    • 7. Baroreflex sensitivity (see above).

  • IV. The Initial Simple Screening Tests

    The AFTs must be reliable, simple (easy to perform), reproducible and noninvasive for using in day-to-day autonomic medical practice. The following five tests known as the Ewing [46] battery of tests are easy to perform as the first screening step in evaluation of patients after initial history and physical examination: (i) BP and HR response to standing for 3–5 min from the supine position, (ii) HRDB, (iii) VR, (iv) BP and HR response to handgrip, and (v) 30:15 ratio. These tests can be performed at the bedside or outpatient clinic using the following: (a) a sphygmomanometer, (b) an electrocardiogram (1–2 channels), (c) an aneroid manometer, (d) a handgrip dynamometer, and (e) a mouthpiece for forced expiration against a closed glottis during VM. Most commonly tests for cardiovagal function (e.g., the Ewing battery of tests) and sudomotor tests (particularly QSART) are used as the initial AFTs to confirm clinical diagnosis of dysautonomia. Of note, hand grip tests are often omitted and more than one AFTs should be performed to confirm dysautonomia in a patient.

  • V. Other Laboratory Tests

    These may be needed in selected cases [2, 3, 5, 9, 11].

    • 1. Hematological studies, biochemical, and urinary analyses to exclude systemic diseases, for example, anemia, amyloidosis, and collagen vascular disorders (e.g., systemic lupus erythematosus [SLE] and Sjogren syndrome).

    • 2. Plasma volume measurement.

    • 3. Twenty-four-hour urinary sodium estimation.

    • 4. Autoantibody tests for suspected autoimmune disorders with AF and a paraneoplastic dysautonomia (see Chap. 25).

    • 5. Gastrointestinal motility study including esophageal and anorectal manometry as well as gastric emptying and colonic transit time (see Chap. 30).

    • 6. Tests to evaluate genitourinary systems in appropriate cases with dysautonomia.

    • 7. Laser Doppler and thermography for vascular assessment (important in suspected complex regional pain syndromes [CRPS I and II] and erythromelalgia.

    • 8. For suspected Sjogren syndrome, it will be useful to perform Schirmer’s test (for tear production) as well as Rose Bengal stain and lip biopsy (to assess status of salivary glands).

    • 9. Pharmacologic studies of the pupils in appropriate cases.

    • 10. PSG and other recordings for sleep disorders (see Chaps. 9 and 11).

    • 11. Specialized investigations like brain magnetic resonance imaging (MRI), single photon emission tomographic (SPECT), and positron emission tomographic (PET) scans of the brain as well as brain MRI spectroscopy may be needed in suspected neurological disorders causing dysautonomic symptoms (secondary dysautonomia). These tests may also be useful in differentiating MSA from PAF (see Chaps. 23 and 24).

    • 12. Skin biopsy: This may be considered (although evidence is weak for diagnostic sensitivity and specificity) in a symptomatic patient to uncover the presence of small fiber sensory neuropathy with associated autonomic neuropathy [32, 47].

    • 13. Urodynamic studies may be needed for evaluating possible neurogenic urinary bladder.

    • 14. In patients with urinary and fecal incontinence, needle electromyography (an invasive test) of the urethral and anal sphincters may be helpful [30, 31].

    • 15. Catecholamine fluorescence in muscle biopsy samples [8, 48].

• C. Limitations and Pitfalls of Autonomic Function Tests

  Certain limitations and pitfalls in the AFTs must be kept in mind otherwise the interpretation of the AFTs results may be invalid [49].

  • (i) No single test is diagnostic of a significant AD. One must perform at least two tests from each category (sympathetic or parasympathetic function) for a valid interpretation.

  • (ii) Several AFTs (e.g., HRDB, 30:15 ratio, VR) vary with age and therefore control values must be obtained from age-matched subjects. In addition, comorbidities must be taken into consideration for interpretation of the findings.

  • (iii) All tests must be performed according to a valid scientifically recommended standardized manner; otherwise, the significance of the test results must remain questionable.

  • (iv) All tests may not have sufficient sensitivity and specificity and may give false positive or negative results (e.g., MAT, CPT, CFT, intravenous infusion test, and SSR).

  • (v) Some tests may be too complex to perform (e.g., certain invasive tests, such as invasive Valsalva maneuver, intravenous infusion, microneurography).

  • (vi) Each autonomic function laboratory may not be equipped with facilities to perform the recommended and complex tests (e.g., QSART, cardiac MIBG scan, and intravenous infusion tests).

  • (vii) There is not a single specific laboratory test to assess a lesion of the afferent limb of the baroreceptor reflex arc. Similarly, there is no single specific test to assess central component of the baroreceptor reflex arc.

  • (viii) Many AFTs are invasive and the patients may be reluctant to undergo those tests. The autonomic physician thus must depend only on noninvasive tests, which may not give a satisfactory answer to the question.

  • (ix) Emotional state of the patient (e.g., anxiety and agitation) may affect the AFT making interpretation and validity of the test unreliable.

  • (x) Certain medications may affect AFT results (e.g., anticholinergics and antidepressants).

  • (xi) Skin temperature must be measured and controlled to avoid interference with certain tests (e.g., QSART may give wrong result if skin temperature is not standardized; another example is a patient with complex regional pain syndrome type 1 or type 2 who also requires attention to skin temperature).

  • (xii) Patient’s hydration states (by altering plasma volume) may affect BP and HR responses.

  • (xiii) For evaluating parasympathetic function patients must be in sinus rhythm; cardiac arrhythmia will invalidate the test results.

  • (xiv) Even after performing multiple AFTs, it may not be possible to locate the site of the lesion to the afferent, central, or efferent limbs of a reflex arc (e.g., baroreceptor reflex), and one may not be absolutely certain about affection of a particular division (sympathetic, parasympathetic, or localization to the preganglionic or postganglionic segments of the ANS). However, careful attention to the tests and their results may help the physician to localize the lesion (see further on).

  • (xv) Another limitation is an absence of standardized guidelines to perform minimum number of AFTs. Based on general consensus [49,50,51], there are certain suggestions for a minimum number of tests to evaluate autonomic function.

• D. Localization of the Lesion Based on Autonomic Function Tests

  In this segment, I shall list certain AFTs and their alteration that may suggest affection of either the sympathetic efferent (adrenergic dysfunction) or the parasympathetic (vagal) divisions of the ANS [8, 9, 17, 30, 31].

  • 1. Abnormalities of the following tests will suggest involvement of the efferent sympathetic division of the ANS.

    • (a) Head-Up Tilt (HUT) Table Test: OH without rise of HR or subnormal rise.

    • (b) Valsalva maneuver (VM): Failure of rise of BP and HR in Phase 2 (during sustained strain) and failure of “Overshoot” in Phase 4 (release of strain).

    • (c) Cold Pressor Test (CPT): Uses both sympathetic afferent and efferent pathways: Failure of rise of BP and HR.

    • (d) Mental Arithmetic Test (MAT): Uses sympathetic efferent limb: Failure of rise of BP and HR.

    • (e) Standing from supine position: Uses central and sympathetic efferent pathways: excessive fall of systolic BP by 20 mm Hg or more or diastolic BP by 10 mm Hg or more within 3–5 min of standing.

    • (f) Sustained hand grip (about 30% of maximum voluntary contraction for several minutes); abnormal response: rise of diastolic BP to ≤10 mm Hg.

    • (g) Noninvasive pharmacologic tests measuring plasma levels of norepinephrine and renin in supine and erect positions: low levels of norepinephrine in the supine and failure of rise of renin and norepinephrine significantly or subnormal rise in the upright position signify efferent sympathetic (postganglionic) involvement.

    • (h) Hypohidrosis or anhidrosis and impairment of sympathetic skin response.

  • 2. Impairment of cardiovagal function: Abnormalities of the following tests will indicate impairment of efferent vagal (parasympathetic) function [2, 8, 52].

    • (a) HRDB: Difference in HR between expiration and inspiration ≤10.

    • (b) VM: Absence of reflex bradycardia in the fourth phase (release of strain).

    • (c) VR: Abnormal value <1.21.

    • (d) CFT (Diving reflex): Failure to show bradycardia.

    • (e) 30:15 ratio: Abnormal value ≤1.00.

    • (f) Neostigmine test: Failure to cause bradycardia after neostigmine injection.

    • (g) Atropine test: Lack of tachycardia after intravenous atropine injection (provided sympathetic efferent is intact).

  • 3. Localization of lesion to different components of the baroreceptor reflex arc in OH [8]:

    • (a) Total baroreflex arc involvement

      • (i) Abnormal HUT Test

      • (ii) Abnormal VM

      • (iii) Abnormal VR

    • (b) Efferent arc: See above 1 and 2.

    • (c) Central lesion: No single reliable test is available but a combination of tests may help. There were two papers, one published in 1960 in the journal Lancet by Sharpey-Schaffer and Taylor [53] and the other published by Sharpey-Schaffer earlier [54] suggesting vasomotor center (VMC) responsiveness in the medulla: Post hyperventilation (15 s) fall of BP and bradycardia imply intact central mechanism.

    • (d) Afferent limb: Abnormal test of total reflex arc but normal efferent limb will suggest affection of either the afferent limb or the central component of the Baroreflex arc whereas presence of bradycardia after VM (phase 4) and intravenous norepinephrine infusion will imply intact (unaffected) afferent limb [8, 52].

  • 4. There are also tests to localize to a preganglionic or postganglionic segment of the ANS as well as intraocular and other tests, which are beyond the scope of this chapter [2, 3, 30, 31].

Brief Description of Some Important and Unusual Dysautonomic Entities

(Details of most of the entities are available throughout this book)

• I. Generalized Primary ANS Failure

  • 1. Acute Pandysautonomia

This is also known as autoimmune autonomic neuropathy (AAN) (see also Chap. 25). This condition must be differentiated from paraneoplastic autonomic neuropathy as well as drug-induced (e.g., heavy metals, such as inorganic mercury and arsenic poisoning, hexane inhalation [glue sniffing], acrylamide) autonomic neuropathies. The classic presentation of acute AAN is an acute onset of severe pandysautonomia (generalized sympathetic and parasympathetic failure) often preceded by a viral infection (e.g., flu-like or upper respiratory tract infection) and running a monophasic course with partial recovery in most cases (occasional complete recovery) [55, 56]. Evidence of an autoimmune mechanism is manifested by the presence of ganglionic nicotinic acetylcholine receptor (AChR) antibodies in high titers in serum in approximately 50% of cases. Most prominent clinical features include orthostatic hypotension with orthostatic intolerance symptoms, hypo- or anhidrosis, and in some cases also disturbances of gastrointestinal motility, urinary bladder and bowel dysfunction as well as dry mouth, dry eyes, and tonic pupils with impaired light reflex.

• 2. Pure Autonomic Failure (Bradbury–Eggleston Syndrome)

In 1925 Bradbury and Eggleston [57] described three patients presenting with pure autonomic failure (PAF) without any somatic manifestations presenting with orthostatic hypotension associated with orthostatic intolerance symptoms (see below) in the erect posture relieved by assuming supine position (see also Chap. 24). It is noteworthy that almost 100 years before this description the French physician Piorry in 1826 first recognized the importance of the gravitational force on the circulation in the upright position. Under the title of “Research on the Influence of Gravity on the Circulation of Blood: Diagnosis of Syncope and Apoplexy; Cause and Treatment of Syncope,” Piorry gave a clinical description of four patients who became unconscious in the sitting and upright positions, but immediately regained consciousness when placed in the supine position [58]. Piorry concluded that the arterial, venous, and capillary circulation was under the influence of the law of gravity. However, in the absence of documentation of postural variation of BP (sphygmomanometer was not invented at that time), considerable doubt remains as to whether Piorry’s patients really had orthostatic hypotension. Nevertheless, Piorry was the first physician to realize the importance of the effect of gravity on circulation. Bradbury and Eggleston [57] from Cornell University Medical College, New York, however, were the first to define the syndrome of primary orthostatic hypotension (OH). Laubry and Doumer [59] first coined the term “orthostatic” in 1932 when they demonstrated the orthostatic nature of hypotension in a 41-year-old man. It is noteworthy that several publications with the description of Bradbury–Eggleston syndrome clearly showed phenoconversion of many PAF patients (≈10%) to a neurodegenerative disease (Shy–Drager syndrome, also known as multiple system atrophy [MSA] mostly and also as PD and DLBD) within an average interval of three to 5 years after onset [60] as exemplified by our case number one in section “Clinical–Anatomical–Laboratory Correlations with Case Examples”. Risk factors (predictors) for such conversion include [61] the following (see also Chap. 24): subtle motor CNS signs (gait imbalance and subtle tremor) at presentation; CASS (see section “Autonomic Function and Other Laboratory Tests”) score of <7; CASS vagal subscore of <2 (i.e., mild cardiovagal impairment); severe urinary bladder dysfunction; preganglionic pattern of sweat loss (e.g., impaired thermoregulatory sweating but preserved sweating in QSART [see section “Autonomic Function and Other Laboratory Tests”]); supine norepinephrine (NE) > 100 pg/ml; and orthostatic rise of NE > 65 pg/ml (in those converting to PD/DLBD).

• 3. Multiple System Atrophy (Shy–Drager Syndrome)

Since the description of PAF by Bradbury and Eggleston in 1925 [57], many reports of PAF appeared in the literature and some of these patients had diffuse CNS manifestations [62], but these were not emphasized and some even considered these as incidental features. However, in 1960, Shy and Drager gave a lucid clinical description of two patients with detailed postmortem findings on one of them, and for the first time suggested that a primary neurodegenerative disease may be one etiological factor in the so-called idiopathic orthostatic hypotension or PAF [63]. Subsequent reports [64] not only confirmed this suggestion but also changed the name of this neurodegenerative disease of the CNS to multiple system atrophy in 1969 by Graham and Oppenheimer and later researchers grouped this disease as one of the four synucleinopathies (e.g., Parkinson’s disease [PD], MSA, diffuse Lewy body disease [DLBD], and PAF) [65, 66]. For further details about MSA and PAF, the readers are referred to Chaps. 23 and 24, respectively. The median survival of MSA is 9.8 years. The best known condition with AF in which sleep and respiratory disturbances have been reported and well described includes MSA presenting initially with prominent dysautonomic features progressing relentlessly with subsequent development of somatic neurological manifestations [2, 3, 7,8,9, 67] (e.g., parkinsonian-cerebellar or cerebellar-parkinsonian syndrome, upper motor neuron dysfunction, in occasional patient also degeneration of anterior horn cells, and cognitive impairment in the more advanced stage [usually significant impairment 5–6 years after onset in up to 31% of cases], generally with normal sensory findings) [68]. Sleep disturbance is very common in MSA and includes insomnia with sleep fragmentation, REM behavior disorder (RBD), and sleep-related respiratory dysrhythmias. Box 12.7 lists these respiratory disturbances in MSA [69].

Box 12.7 Respiratory Disturbances in Multiple System Atrophy

• Central sleep apneas

• Obstructive apneas–hypopneas

• The above were noted in both NREM and REM sleep associated with oxygen desaturation

• Dysrhythmic breathing (irregular rate, rhythm and amplitude of respiration becoming worse in sleep)

• Cheyne–Stokes breathing

• Cheyne–Stokes variant breathing (hypopnea substituting apnea)

• Prolonged periods of central apnea in relaxed wakefulness as if the respiratory center forgot to breathe

• Periodic breathing in the erect posture accompanied by postural fall of blood pressure

• Inspiratory gasps

• Apneustic breathing

• Nocturnal stridor due to posterior cricopharyngeal muscle denervation atrophy or laryngeal dystonia (stridor is mostly inspiratory but can be expiratory depending on the site of obstruction

• 4. Neurogenic Orthostatic Hypotension

Orthostatic hypotension (OH) may result from impairment of sympathetically mediated baroreflex mechanism [60, 61, 70]. The etiology and pathogenesis are multifactorial and include central and peripheral efferent mechanisms (e.g., MSA, PAF, other central neurodegenerative synucleinopathies, brain stem and spinal cord structural lesion, peripheral autonomic neuropathies [see also Box 12.1], drug-induced and iatrogenic causes as well as some rare conditions like dopamine-beta hydroxylase [DBH] deficiency, and hyperbradykininism).

Clinical features include orthostatic intolerance (OI) symptoms that include the following: postural dizziness, faint feelings, obscuration or blurring of vision, nausea, and bloating feeling in the abdomen. These symptoms (presyncope) occur in the erect posture before syncope ( transient loss of consciousness) that may happen on prolonged standing when BP falls significantly with the relief of symptoms within 1 min after resuming the recumbent position. OI symptoms may worsen in the morning (time of day), after ingestion of food (postprandial), and after exercise. The presence of OI symptoms should direct attention to a possible generalized AF and the suspicion would be strengthened by documenting OH and abnormal autonomic function tests. Moreover, the fall of BP in the erect posture is accompanied by failure of rise or inadequate rise of HR. Elderly people are highly vulnerable that may be physiological and age-related impairment of baroreflex mechanism.

• 5. Postural Tachycardia Syndrome (POTS; See Also Chap. 20)

POTS is a heterogeneous syndrome (one subgroup is labeled “idiopathic”) of selective autonomic failure characterized by an increase of HR by 30 or more beats/min within 10 min of standing (or on head-up-tilt, HUT) in adults but 40 or more beats/minute in adolescents (12–19 years) or absolute HR ≥ 120 beats/min unaccompanied by OH (defined as sustained drop of 20/10 mm Hg or more BP within 3 min of upright posture [71,72,73]). Clinical manifestations include OI symptoms for ≥6 months (e.g., symptoms of presyncope or syncope [cerebral hypoperfusion] as described above as well as non-OI symptoms [the two most common are fatigue and sleep dysfunction [74, 75] besides others]). Standard battery of laboratory ANS function tests is generally normal. Therapy includes both nonpharamacologic (e.g., increased sodium and fluid intake, compression garments, and cognitive behavioral therapy) and pharmacologic measures (e.g., volume expanders, vasoconstrictive agents, sympatholytics, or drugs to reduce HR) [71, 72, 74, 75].

• 6. Hyperbradykininism

This is also known as Streeten syndrome who along with his collaborators first described this rare entity as a new orthostatic syndrome in 1971 [76]. This is most commonly seen in young people (20–35 years) but may also occur in children and older persons. The clinical manifestations are characterized by OI symptoms (see above) accompanied by orthostatic tachycardia and excessive fall of pulse pressure due to a fall in systolic but a rise in diastolic BP in the erect posture. The other characteristic features include flushing of the face and upper trunk (anterior chest) in the recumbent position as well as ecchymoses and purple discoloration of the legs standing for 3–4 min. Plasma bradykinin, a vasodilator, is increased above the normal limits (mean normal is <1 ng/ml in supine fasting state) due to bradykininase-I deficiency. Patients respond very well to propranolol (a beta blocker), at least temporarily. They also respond to fludrocortisone, and cyproheptadine (a serotonin antagonist) [76, 77].

• 7. Dopamine-Beta-Hydroxylase Deficiency

Dopamine-beta-hydroxylase (DBH) is an enzyme converting dopamine into noradrenaline. A few cases of DBH deficiency (some of which have been familial) causing postural hypotension and OI symptoms have been described due to sympathetic adrenergic failure [78, 79]. This is a rare entity and the key laboratory finding consists of virtual absence of plasma levels of noradrenaline and adrenaline with elevated levels of dopamine, and undetectable DBH activity. These patients respond very well to the racemic mixture of both the dextrorotatory and levorotatory forms as in dihydroxyphenylserine (DL—DOPS) as well as the levorotatory form as in L-DOPS [80].

• II. Generalized Secondary Autonomic Failure

• 1. Polyradiculoneuropathies, AF, Sleep, and Respiratory Disturbances

Diabetic , amyloidotic and paraneoplastic polyneuropathies with AF may cause a variety of sleep and respiratory disturbances. Mondini and Guilleminault [81], and Bottoni [82] and collaborators described central and upper airway obstructive sleep apneas-hypopneas in several diabetics with autonomic neuropathies. These sleep-respiratory disturbances have been observed in over 30% of nonobese patients independent of severity of their dysautonomia in Bottini’s series. The most common subtype of Guillain-Barré-Strohl (GBS) syndrome is an acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Mild autonomic dysfunction (AD) is common in most cases of GBS requiring no treatment. Some patients may have more severe AD that may be correlated with severe motor disability [83, 84] (although this has been contradicted by others). AD in GBS may involve both sympathetic and parasympathetic divisions. Cardiovascular autonomic neuropathy is common and potentially a serious complication of GBS [85].

• 2. Neurodegenerative Synucleinopathies (other than MSA and PAF)

Abnormal deposition of alpha-synuclein protein in the cytoplasm of neurons or glial cells constitutes a group of neurodegenerative diseases (e.g., PD and DLBD are two such additional synucleinopathies besides MSA and PAF) that may be associated with AF and sleep dysfunction.

• A. Parkinson’s Disease

Sleep dysfunction is a major nonmotor feature present in 70–90% of cases with progressive impairment concomitant with the progression of motor disability [86]. Sleep dysfunction includes sleep onset and maintenance insomnia, sleep fragmentation, and several nocturnal motor abnormalities, such as RBD (noted in 40–50% of cases) and PLMS. In addition, RLS, sleep-onset rapid blinking, REM-onset blepharospasm and intrusion of REMs into NREM sleep have been noted [86]. Respiratory dysrhythmias (e.g., obstructive and central apneas) are thought to be more common in PD than in age-matched controls, especially those with AF [87,88,89]. It is notable that Parkinson himself in his original description [90] alluded to sleep and respiratory problems in his patients and mentioned the following: “…but as the malady proceeds…in this state the sleep becomes much disturbed (pp. 6–7). …and at the last, [advanced stage] constant sleepiness…announce the wish for release (p. 9)…some fetched their breath rather hard (p. 40)”. The spectrum of respiratory dysrhythmias in PD includes sleep apnea–hypopnea, Cheyne–Stokes and Cheyne–Stokes variant pattern of breathing, nocturnal hypoventilation, dysrhythmic breathing, and nocturnal stridor [86]. Laryngeal spasm or stridor sometimes may be associated with off-states or dystonic episodes. Additionally, diaphragmatic dyskinesias as well as end-of-the-dose and peak-dose Levodopa-related respiratory dysrhythmias have been observed in some PD patients. Finally, many patients complain of daytime hypersomnolence and irresistible “sleep attacks” resembling narcolepsy phenotype that may be due to a combination of intrinsic disease process and dopaminergic medication [91].

AD in PD generally develops in more advanced stage of the illness affecting multiple systems, particularly cardiovascular, gastrointestinal and genitourinary systems as well as affecting sweating, thermoregulation, and saliva production. Some patients may have OH that may in part be related to Levodopa medication. Sometimes, AD may be present earlier in the course of the illness causing considerable difficulty in differentiating PD with AF from MSA. However, relentless progression of the disease, much shorter course of the natural history of the ailment compared with that in PD and absence of a dramatic response to Levodopa, at least initially may help in separating PD with AF from MSA (see also Chaps. 23 and 24).

• B. DLBD, Autonomic Failure, and Sleep

The core diagnostic features of DLBD as listed by McKeith et al. [92] include fluctuating cognition, recurrent visual hallucinations and parkinsonian features (e.g., cogwheel rigidity, postural instability, and akinesia or bradykinesia) combined with other features such as repeated falls, sensitivity to neuroleptics, and RBD. OH and syncope occur in up to 30% of DLBD patients. Urogenital disturbance may be cited as additional dysautonomic feature. Sleep dysfunction in DLBD includes RBD (noted in 70–80% of cases and frequently precedes the onset of the illness), sleep apnea, nocturnal visual hallucinations, insomnia, and excessive daytime sleepiness [93].

• 3. Narcolepsy–Cataplexy (Narcolepsy Type 1)

Narcolepsy is classified in the international classification of sleep disorders (ICSD-3) [93] as a prominent and a chronic debilitating neurological disorder in the category of central hypersomnolence. This is divided into two subtypes: narcolepsy 1 (with cataplexy) and narcolepsy 2 (without cataplexy). Narcolepsy type 1 is characterized by excessive daytime sleepiness with irresistible and uncontrollable “sleep attacks” under inappropriate circumstances and in inappropriate places, cataplexy (sudden loss of muscle tone triggered mostly by emotional excitement) and characterized by head nodding, dropping of things from hands, knee buckling and falling to the ground, sleep paralysis (hypnagogic or hypnopompic), visual hallucinations (vivid, often fearful dreams), and sleep maintenance difficulties with repeated awakenings. Another important manifestation is automatic behavior (e.g., repeatedly doing the same thing, missing an exit on the highway as a result of microsleep). This disorder (narcolepsy) is associated with many comorbid conditions including RBD. Narcolepsy 1 is associated with 85–90% loss of hypocretin (orexin) neurons in the perifornical and lateral hypothalamic regions. Cerebrospinal fluid (CSF) hypocretin 1 deficiency (< 110 pg/ml) is noted in over 90% of cases of narcolepsy type 1. An important laboratory test is multiple sleep latency test (MSLT) preceded by an overnight PSG. A mean sleep latency of ≤8 min accompanied by two sleep-onset REM periods (SOREMs) out of 4–5 naps obtained after 20-min of recording every 2 h (one sleep onset REM obtained in the preceding overnight PSG may substitute one of two SOREMS in the MSLT) is strongly suggestive of a diagnosis of narcolepsy in context of appropriate clinical features (ICSD-3).

Hypocretins 1 and 2 (orexins A and B) are neuropeptides responsible for regulating circadian timing and sleep–wakefulness that also have multiple other physiologic functions such as feeding, energy homeostasis, arousal, as well as controlling thermoregulation, neuroendocrine, and cardiovascular functions via changes in the ANS [94,95,96,97]. Diffuse projections of hypocretins to rostral ventrolateral medulla (RVLM) [premotor sympathetic excitatory neurons in the so-called vasomotor center], caudal ventromedial medulla (RVMM), noradrenergic neurons in the locus coeruleus (LC), nucleus ambiguus, and dorsal motor nucleus of the vagus (parasympathetic premotor neurons) as well as nucleus tractus solitarius (NTS) [an important relay station for cardiovascular, pulmonary, and gastrointestinal afferents] may be responsible for ANS control by hypocretin neurons [98]. Orexin control of thermoregulation and metabolism remains controversial. However, experimental studies in animal models of narcolepsy–cataplexy point to an involvement of the orexin system in the sleep-state stabilization and arousal as well as in control of cardiovascular (CV) and respiratory functions (CO₂-induced breathing increase in orexin gene knockout mice while causing spontaneous apneas in both REM and NREM sleep) through the influence of orexin neurons on the ANS [95,96,97]. Controlled clinical studies in narcolepsy–cataplexy patients may provide further insight into the role of the hypocretin neurons in the ANS control, which will be clinically relevant because of increasing endeavor in finding orexin antagonist for treatment of obesity and insomnia, and for future drug development in CV disorders and narcolepsy.

Summary of ANS Dysfunction in Narcolepsy–Cataplexy

Several autonomic abnormalities have been observed in narcolepsy–cataplexy patients, which may be summarized as follows [99,100,101] (see also Chap. 17):

• (a) Abnormal pupillary reaction in darkness (pupillometry study).

• (b) Impaired REM-related penile tumescence in men.

• (c) Impaired autonomic control of the CV system: the studies for assessing effect on CV functions have been inconsistent. But, overall, various studies suggest that orexin deficiency in narcolepsy may be associated with sympathetic cardiovascular withdrawal (deficiency) and may increase CV risks in these patients. A recent survey in general population confirmed these suggestions by showing an increased prevalence of cardiometabolic diseases (e.g., hypertension, diabetes and heart disease) in narcolepsy–cataplexy patients contrasted with matched controls. In a previous study [97], an enhanced sympathetic activity (using heart rate variability [HRV] study at rest and during orthostatic stress compared with controls) was noted but found no abnormalities in CV reflex tests in the narcoleptic patients. Grimaldi et al. [101] published their observations in 2012 on the 24-h-circadian rhythms including state-dependent changes in BP and HR in narcoleptic patients (on no medications) compared to controls. The pertinent findings in a recent study by Grimaldi et al. [97] include the following: (a) nondipping of nocturnal BP, (b) higher systolic BP during REM sleep, and (c) increased sleep fragmentation and arousal index including PLMS-related arousals.

• 4. Idiopathic Hypersomnia and AF

The entity of idiopathic hypersomnia (IH), included in the ICSD-3 [93] in the central hypersomnolence category, remains controversial and is often mistaken with and difficult to differentiate from narcolepsy type 2. In the past, there was cursory mention of autonomic dysfunction in IH (e.g., OH, Raynaud’s phenomenon, tension headache, and migraine) but the symptoms were thought to be nonspecific but no formal autonomic function studies were available. Sforza and colleagues [102] found a significant rise of HF power during sleep and wakefulness and concluded that in IH there is an enhancement of vagal tone during wake and sleep that may explain some of the vegetative symptoms experienced by the IH patients (see also Chap. 17). These findings are in contrast to those noted in narcoleptic patients (see above).

• III. Generalized ANS Hyperactivity

• 1. Sleep, Autonomic Hyperactivity, Cardiac Arrhythmia, and Sudden Cardiac Death

In normal young individuals, the most frequent cardiac dysrhythmia is sinus arrhythmia, many of whom (about 30%) had sinus pauses of 1.8–2 s and in about 6% episodes of atrioventricular block were noted [103]; in addition, sinus arrest lasting up to 9 s during REM sleep without associated apnea–hypopnea or oxygen desaturation was noted in some young healthy adults. There was a case report of several episodes of atrioventricular complete heart block lasting up to 7.8 s during phasic REM sleep associated with mild sleep apnea with minimal oxygen desaturation during both NREM and REM sleep but the episodes of block persisted despite normalization of apnea–hypopnea index and oxygen saturation following upper airway pressurization [104]. There are several reports of ventricular arrhythmia during arousal from sleep [105]. Nocturnal EKG changes (T wave inversion and ST segment elevation or depression) have been reported in patients with ischemic heart disease.

Muller et al. in 1987 [106] published an important paper reporting a high incidence of sudden cardiac death among hospitalized inpatients between 7 am and 11 am similar to the high incidence of nonfatal myocardial infarction and ischemia at that time (most likely due to sympathetic hyperactivity in the morning). There are three other entities which may cause sudden unexpected cardiac death: (i) congenital long QT syndrome (CLQTS), (ii) Brugada syndrome, and (iii) sudden unexpected nocturnal death syndrome (SUNDS) in South-East Asian young individuals. Both autonomic dysfunction and genetic mutation have been suggested as possible causes [107, 108].

Samuels [109] provided evidence suggesting that a generalized “autonomic storm” (ANS dysreflexia or hyperactivity) related to life-threatening stressor may explain so-called “voodoo” death (a term originally coined by Walter B. Cannon in 1942 [110]) meaning sudden unexpected death (SUD) in adults that remains unexplained. SUD is also noted in neurological disorders, sudden infant death syndrome (SIDS), sudden death during asthmatic attacks, alcohol withdrawal, and cocaine–amphetamine-related SUD [109]. It is speculated that this may also be the explanation in some cases of sudden unexpected death in epilepsy (SUDEP). All of these conditions associated with SUD may be linked by stress and catecholamine surge.

• 2. Baroreflex Failure

Baroreflex failure, an important but an uncommon condition manifesting autonomic dysfunction, may result from injury to the carotid and aortic baroreceptors or their afferents in the sinus nerve of Hering (a branch of glossopharyngeal nerve) and the aortic nerve of Ludwig and Cyon (a branch of vagus nerve) as well as the central medullary relay station in the nucleus tractus solitarius (NTS) [111]. The causes for this injury may consist of neck surgery including carotid surgery, carotid dissection and tumors, radiation to the neck, brain stem stroke or trauma, and syringobulbia. The clinical manifestations often resemble pheochromocytoma (which needs to be excluded by appropriate tests) and consist of hypertensive crises (fluctuating hypertension, tachycardia, profuse sweating, palpitation and headache resembling autonomic hyperreflexia, and marked elevation of plasma norepinephrine levels during hypertensive crises, less commonly presenting with OH, orthostatic tachycardia, severe bradycardia, and syncope) [111, 112]. Clonidine (a central alpha-2 agonist blocking RVLM sympathoexcitatory neurons) is the treatment of choice.

• 3. Neuroblastoma

Neuroblastoma is an example of secondary autonomic hyperactivity. This tumor, most frequently found within or adjacent to the sympathetic ganglia and adrenal tissue [113], causes catecholaminergic hyperactivity (e.g., hypertension, tachycardia, and hyperhidrosis) associated with excessive synthesis of norepinephrine and dopamine [113]. An unusual feature is an acute cerebellar encephalopathy, which is most likely a paraneoplastic expression. Clinical manifestations include truncal and limb ataxias as well as opsoclonus–myoclonus syndrome (rapid, ataxic, and chaotic conjugate eye movements accompanied by diffuse myoclonus). The onset is commonly before the age of 3 years. Most often the tumor is highly anaplastic and aggressive. Prognosis depends on the age of onset as survival varies inversely with age.

• 4. Diencephalic Autonomic Seizure (DAS)

This is an example of paroxysmal autonomic hyperactivity, first described by Penfield in 1929 [114]. The lesion is thought to be in the hypothalamus or related to lesions causing pressure on this structure. Clinical manifestations include paroxysmal episodes (occurring several times a day and each time lasting 30–60 s) of bifrontal headache, hypertension, restlessness, flushing, lacrimation, salivation, excessive sweating, tachycardia, pupillary dilation or constriction, periodic hypothermia, and periodic breathing of Cheyne–Stokes type. The episodes are often preceded by stereotypic symptoms of olfactory hallucination characterized by strange smell and abdominal sensation with nausea and retention of awareness but associated with increased surge of plasma catecholamines (about double the basal value) during these episodes with subsequent falls to normal levels after the spells are over [115]. EEG in most reports showed no epileptiform discharges. DAS should be differentiated from paroxysmal autonomic dysfunction, sometimes noted in epilepsy, especially temporal lobe epilepsy (TLE) as a result of excessive sympathetic discharge. Electroencephalogram (EEG) in TLE is generally positive showing epileptiform spikes or sharp waves in the temporal region. Some cases of SUDEP may be related to this autonomic hyperactivity.

• 5. Fatal Familial Insomnia (FFI ) (See Chap. 18)

• IV. Localized ANS Dysfunction

• 1. Holmes–Adie Syndrome

The other name is Adie’s pupil or “Tonic pupil” with light-near dissociation [9, 116]. In 80% of cases, patients present with unilateral dilated pupil (larger than the unaffected eye). It is more commonly present in women than in men. The characteristic finding is impaired light reflex and slow but exaggerated response to convergence, and the pupil in the affected eye becomes smaller than that in the unaffected eye; then it dilates slowly. Another characteristic finding in most cases (90%) is absent (or markedly attenuated) muscle stretch reflexes [117], the cause of which remains disputed (one plausible suggestion is degeneration of spinal dorsal root ganglia). The site of lesion for the tonic dilated pupil is thought to be located in the postganglionic parasympathetic fibers in the ciliary ganglion; the cause is most likely degeneration of the fibers as was also documented by denervation supersensitivity (exaggerated response with marked constriction of the affected pupil to instillation of 2.5% mecholyl or dilute solution of pilocarpine [1%] which has no appreciable effect in normal pupils). There have been occasional reports of associated OH or impaired sweating response casting doubt on the concept of localized ANS dysfunction.

• 2. Argyll Robertson Pupil [9, 118, 119]

Both the pupils (in bilateral cases) are irregular, small with absent light reflexes but preserved convergence reaction (accommodation). The site of lesion is thought to be in the dorsal midbrain region interrupting the light reflex pathway. This was originally described in Tabes Dorsalis but Argyll Robertson-like pupil may be seen in diabetes mellitus.

• 3. Ross Syndrome

This is another rare entity with localized ANS dysfunction of unknown cause and a variant of Holmes–Adie syndrome. In addition to tonic pupil and areflexia, there is progressive segmental hypohydrosis [120].

• 4. Harlequin Syndrome

A rare condition with localized ANS dysfunction of the pre- and postganglionic cervical sympathetic fibers with normal ocular sympathetic innervation manifested by the loss of thermoregulatory sweating on one side of the face [121].

• 5. Horner Syndrome

The triad of Horner syndrome consists of miosis, mild ptosis, and ipsilateral (if unilateral) facial anhidrosis or hypohydrosis as a result of pre- or postganglionic cervical sympathetic dysfunction [9, 118]. Pharmacologic study with local instillation of eye drops shows evidence of sympathetic denervation supersensitivity in case of postganglionic dysfunction [9, 119].

• 6. Unilateral Gustatory Sweating (Auriculotemporal Syndrome of Frey)

Abnormal unilateral gustatory facial sweating during eating may occur most commonly after lesions including surgery of the parotid gland as a result of damage and subsequent regeneration of the parasympathetic fibers innervating salivary glands that are then misdirected to the postganglionic cervical sympathetic sudomotor pathways [2, 3, 5, 9]. The name auriculotemporal syndrome is derived from the fact that there is affection of the cervical sympathetic sudomotor fibers distributed along the auriculotemporal branch of the trigeminal nerve. This has also been described in diabetes mellitus and after upper thoracic sympathectomy [2, 3, 5, 9].

• 7. Crocodile Tears (Bogorad Syndrome)

Most commonly this has been described after a lower motor neuron facial nerve palsy (e.g., Bell’s palsy) as a result of regenerating parasympathetic fibers (destined originally for submandibular glands) aberrantly coursing along the parasympathetic fibers to the lacrimal glands [2, 3, 9, 122]. Whenever there is salivation (e.g., eating or even thinking of food), there is tearing of the eye on the affected side. In most of the cases, it is not sufficiently distressing requiring treatment.

• 8. Hirschsprung’s Disease

This is a congenital developmental condition, also known as megacolon , presenting in children and adolescents with the complaint of severe constipation since birth [10].The symptom results from obstruction of distal bowel showing radiographically as a spastic segment of the distal bowel with proximal dilation: the condition is due to congenital absence of intestinal ganglion cells (aganglionic segment) in the myenteric (Auerbach) and submucosal (Meissner) plexus due to arrest of embryonic development. Anorectal manometry reveals absence of internal anal sphincter relaxation. Resection biopsy has shown characteristic histopathological findings.

• 9. Achalasia

This is a rare disorder of the esophagus [2, 3, 10] due to incomplete relaxation of the lower esophageal sphincter (also known as cardiospasm) due to postganglionic denervation of the smooth muscles in the lower esophageal sphincter (degeneration of the myenteric [Auerbach] plexus of the enteric nervous system [ENS] division of the ANS). The cause is mostly undetermined (may be an autoimmune disease) but sometimes it is due to Chagas disease caused by Trypanosoma cruzi , mostly noted in Central and South America. Clinical manifestations of this GI dysautonomic disease include dysphagia, regurgitation, chest pain, aspiration pneumonia, and weight loss.

• 10. Gastroparesis

This is another manifestation of autonomic neuropathy due to dysfunction of the ENS division of the ANS [10]. A common cause is uncontrollable diabetes mellitus. Clinical features include epigastric discomfort, nausea, abdominal bloating, vomiting (may be projectile), weight loss, and anorexia. The condition may be a localized AD but often is part of a generalized autonomic failure. The gold standard test for gastroparesis is radiolabeled scintigraphy to quantify the emptying of a physiologic meal and evaluate stomach’s motor function ( gastric atonia) [123].

Fits and Faints, Including Syncope and Other Mimics of Autonomic Dysfunction

Orthostatic hypotension and syncope are two cardinal manifestations of autonomic dysfunction. This section briefly addresses syncope and various other conditions that may mimic and be mistaken for conditions causing AD. Box 12.8 lists these conditions (mimics), and Box 12.9 includes different types of syncope. All these entities must be kept in mind when approaching a patient with symptoms suggestive of dysautonomia [15, 124, 125].

Box 12.8 Fits, faints, and mimics mistaken for autonomic dysfunction (differential diagnosis)

• Syncope

  • Reflex (as listed in Box 12.9)

  • Cardiac

  • Autonomic Failure with orthostatic hypotension related syncope

  • Pseudosyncope

• Seizure

  • Generalized (especially atonic and akinetic seizures)

  • Focal impaired awareness seizure (formerly partial complex seizure)

• Psychogenic or nonepileptic seizure (NES)

• Postural tachycardia syndrome

• “Drop attacks”

• Vertebrobasilar ischemia (transient ischemic-attack [TIA])

• Narcoleptic sleep attacks

• Cataplexy (as in narcolepsy type 1)

• Psychiatric disorders (e.g., generalized anxiety disorder [GAD], major depression)

• Hypovolemia (e.g., related to internal bleeding, dehydration and ingestion of diuretics)

• Deconditioning

  • Prolonged immobilization

  • Space flight

• Posttraumatic concussion

Syncope, the most frequent cause of transient loss of consciousness (TLOC) as a result of transient cerebral hypoperfusion, may result from diverse lesions [15, 124, 125] (see Box 12.9). The list in Box 12.8 includes “common faint” (reflex syncope or vasodepressor syncope), cardiac arrhythmia and structural lesions (“cardiac syncope”), autonomic failure (specifically, OH [see section “Brief Description of Some Important and Unusual Dysautonomic Entities”]), epileptic seizure and nonepileptic or psychogenic seizure (NES), pseudo-syncope (PS), “drop attack” (e.g., frequently due to vertebrobasilar insufficiency or transient ischemic attacks [TIA], and other mimics (e.g., narcoleptic “sleep attacks”, cataplectic episodes and posttraumatic concussion). All these should be differentiated from syncope and orthostatic intolerance (OI) symptoms associated with OH, particularly when a patient with OH has anoxic seizure. Reflex syncope could be vasovagal syncope including cough, swallow, and micturition syncope as well as carotid sinus hypersensitivity [15, 124, 125]. History will provide clues most of the time based on the presenting complaints and direct attention to a particular condition and etiology.

Box 12.9 Types of Syncope [124, 127]

• 1. Cardiac syncope.

• 2. Reflex syncope

  • (i) Vasovagal or vasodepressor syncope (neurally mediated or neurocardiogenic syncope)

  • (ii) Situational syncope

    • (a) Cough syncope (pulmonary syncope)

    • (b) Swallow syncope (esophageal syncope)

    • (c) Micturition and defecation syncope (pelvic syncope)

    • (d) Exercise-induced syncope

    • (e) Valsalva-like maneuver syncope

    • (f) Trumpet player’s syncope

    • (g) Postprandial syncope

  • (iii) Carotid sinus supersensitive syncope

• 3. Convulsive syncope

• 4. Autonomic failure (primary or secondary): syncope associated with orthostatic hypotension

• 5. “Drop attacks” (cerebral syncope)

• 6. Hyperventilation syncope

• 7. Drug-induced syncope

• 8. Postural tachycardia syndrome (POTS) associated with orthostatic intolerance symptoms (presyncope-posture-related)

• 9. Breath-holding syncope

• 10. Overdrive pacemaker related syncope

• 11. Syncope with deafness and sudden death (Romano–Ward syndrome)

One must remember that consciousness has two components: Awareness (e.g., aware of the surrounding environment) and arousal (e.g., an ability to respond to a stimulus). In epileptic seizures, TIAs and TLOC associated with syncope (except “focal aware seizures”) there is no awareness whereas in cataplexy, NES or PS there should be awareness but these subjects may not be arousable unless vigorous stimuli are applied.

In true epileptic seizures (generalized and focal impaired awareness seizure [“partial complex seizure” of old terminology]), there is evidence of postictal confusion but not in other conditions listed above [124,125,126].

Tongue biting (particularly lateral side of the tongue) is commonly seen in generalized (primary or secondary generalization) and focal impaired awareness seizures; however, some patients with syncope rarely may have tongue biting (usually seen in the tip of the tongue).

In “drop attacks” due to vertebrobasilar TIAs besides TLOC, there may be other neighboring signs of brain stem dysfunction.

In generalized true seizure, any motor phenomena are usually synchronous (in phase) and symmetrical whereas in NES any movements (e.g., clonic versus myoclonic) are in general asynchronous or out of phase.

Vasovagal syncope (VVS) often occurs under circumstances of prolonged standing or straining in an overcrowded stuffy environment [15, 124, 125, 127]. OH is often associated with OI symptoms including presyncope or prodromal features (e.g., faint feeling, lightheadedness, dizziness, blurry vision, nausea, abdominal bloating feelings). Figure 12.1 schematically outlines suggested mechanism for VVS [127]. History should include the events in the preictal, ictal, postictal, and interictal periods for differentiating various conditions causing TLOC including syncope and seizures. Recording of BP and HR in supine and standing positions is important for diagnosis of OH and others causing syncope.

Fig. 12.1

Schematically shown the mechanism of vasovagal syncope [127]

Most important items for diagnosis consist of the following: (i) history including that from the witness and family members; (ii) physical examination, particularly of the heart and nervous system; (iii) electrocardiography (ECG), and (iv) electroencephalography (EEG).

Types of Syncope (see Box 12.9) [15, 124, 125, 127]

• A. Cardiac syncope (see further on and Box 12.10)

• B. Reflex syncope

  • (i) Vasovagal (common faint): Neurally mediated or neurocardiogenic syncope in the elderly (vasodepressor syncope)

  • (ii) Situational syncope

  • (iii) Carotid sinus hypersensitivity syndrome with syncope

• C. Others (see Box 12.9) [124]

• D. Cardiac syncope (Box 12.10) [127]

Box 12.10 Points in favor of a diagnosis of cardiac syncope [127]

• Age of onset of syncope: 35 years or more

• Gender: Male

• A previous history of atrial fibrillation/flutter or other cardiac arrhythmias (e.g., sinus arrest, sinoatrial block, atrioventricular heart block, paroxysmal supraventricular arrhythmia or brady–tachy arrhythmia syndrome [sick sinus syndrome], pacemaker malfunction, and congenital deficit in cardiac conduction including congenital prolonged Q-T syndrome)

• Known history of hypertension and structural heart disease including cardiomyopathy, congestive heart failure, ischemic and congenital heart disease, and cardiac valvular disease

• Cyanosis witnessed during the episode of syncope

• Chest discomfort or dyspnea before transient loss of consciousness (TLOC)

• Abnormal cardiac examination

• Palpitation before TLOC

• Abnormal EKG

• Evaluation of Guidelines in Syncope Study (EGSYS) score of 3 points or more; (palpitation [4 points]; abnormal ECG/heart disease [3 points]; effort syncope [3 points]; syncope in supine position [2 points]; neurovegetative prodromes [−1 point]; predisposing and precipitory factors [−1 point])

• Vasovagal score (VVS): Less than −2

• Family history of sudden cardiac death, syncope or drowning

• History of two or fewer syncope episodes

A small percentage of patients presenting with syncope result from structural lesions of the heart or cardiac arrhythmias that should be differentiated form the common faint (vasovagal syncope) and other conditions listed in Box 12.9 as cardiac syncope carries high morbidity and mortality [127]. A careful clinical history and physical examination can identify patients with cardiac syncope most of the time but may require ECG, Holter monitoring, and other laboratory tests for confirmation in challenging situation [127]. Box 12.10 lists the pertinent features favoring a diagnosis of cardiac syncope [127].

Drop Attacks

The term was introduced by Kremer in 1958 [128, 129]. The condition is common in women and in up to 65% of cases no cause is found. Most likely cause (if found) is cardiovascular (evidence of heart disease; needs EKG and Holter monitoring) or cerebrovascular disease (history and neurological examination to detect other signs of brainstem ischemia; may require magnetic resonance imaging of the brain and magnetic resonance angiography (MRI-MRA) for investigation). Other causes may include narcoleptic “drop attack” (related to emotionally triggered cataplectic episodes or irresistible narcoleptic “sleep attacks” [93] and rarely “drop attacks” may be caused by psychogenic or true seizure (e.g., atonic or akinetic seizure). Most of the neurologists consider brain stem ischemia due to vertebrobasilar insufficiency (transient ischemic attacks-TIA) as a frequent cause of so-called “drop attacks.”

Carotid Sinus Supersensivity Syncope

This is a type of reflex syncope similar to VVS but is due to hypersensitivity of carotid sinus in certain individuals as manifested by syncope triggered by carotid sinus massage (extreme caution is needed as this may trigger cardiac asystole) [15, 124, 127].

Miscellaneous: Four entities (e.g., glossopharyngeal neuralgia, postprandial syncope and hypotension, esophageal or swallow syncope, and pelvic syncope [see Box 12.9]) may all be due to similar reflex mechanism as in VVS and carotid sinus supersensitivity syndrome causing syncope.

Mastocytosis-Related Syncope

This is a rare condition [124]. There is overproduction of mast cells (normally found in connective tissue) in multiple organs releasing histamine as well as an overproduction of prostaglandin D2 (PGD2) causing diffuse allergic reactions. Women outnumber men (4:1) and the onset is most commonly around 45 years. Clinical features include flushing, palpitation, syncope, fatigue, and shortness of breath without any wheeze. A prominent cutaneous finding is urticaria pigmentosa, present in 99% of cases and is a useful diagnostic sign of mastocytosis. Narcotic analgesics, nonsteroidal anti-inflammatory agents as well as beta-receptor antagonists, alpha receptor and cholinergic agonists, and aspirin should be avoided as these may activate mast cells. The most effective medications are epinephrine, chlorpheniramine, and cimetidine.

Breath-holding Spells

In the very young (infants and children), special types of syncopal episodes have been described [124]. Breath-holding spells (two forms: cyanotic type [the most common type] related to a combination of apneic hypoxemia and forceful Valsalva-like maneuver and pallid type like a vasovagal spell related to sudden unexpected pain).

Other rare types in infants and children

Other rare types in infants and young children include syncope associated with prolonged Q-T interval, familial deafness, and sudden death (Jervell–Lange–Nielsen syndrome), Romano–Ward syndrome (a similar syndrome as above but without deafness and associated with syncope and sudden death in an infant), overdrive pacing causing syncope and faster HR with prolonged Q-T interval as well as syncope in children with multiple extrasystoles, and ventricular fibrillation.

Clinical–Anatomical–Laboratory Correlations with Case Examples

From an account of the functional neuroanatomy of the ANS as described in Chap. 3 as well as AFTs (section “Autonomic Function and Other Laboratory Tests”) and brief clinical entities (section “Brief Description of Some Important and Unusual Dysautonomic Entities”) described above, it will now be easy to understand the various clinical manifestations resulting from autonomic deficits.

The following three cases serve to illustrate clinical–anatomical correlations in three different types of autonomic disorders [52].

Case 1

A 57-year-old patient was admitted with a history of urinary frequency and incontinence, and impotence for 5 years. He also had been having syncopal episodes in assuming the upright posture. These fainting spells in the upright posture became very disabling. Neurological examination revealed that syncopal attacks were associated with severe postural hypotension. There was no evidence of somatic neurologic dysfunction. The patient denied any history of diabetes mellitus.

His BP in the supine position was 120/70 and the pulse rate was 80 per minute. Tilt-table examination showed that on tilting the table to 60° the BP fell rapidly to 40/0 but the pulse rate remained fixed at 80 per minute. The patient felt faint. Simultaneous EEG recording during the tilt-table test showed diffuse slowing of the background rhythm. Valsalva test showed reduced Valsalva ratio. Cystometrogram revealed an atonic urinary bladder. Intravenous norepinephrine infusion test revealed a supersensitive BP response but no reflex bradycardia. Intramuscular atropine did not produce any change in the pulse rate or the BP. Supine fasting plasma norepinephrine level was reduced and showed no further rise in the upright position. Plasma renin activity did not change significantly from the supine to the erect position. Cold pressor and mental arithmetic tests did not raise the BP or the HR. Thermal sweating was impaired over the abdomen and the legs. Conjunctival instillation of dilute (0.062%) pilocarpine solution produced pupillary constriction and 1:1000 adrenaline produced pupillary dilatation.

Comments

This patient’s symptoms of fainting spells accompanied by orthostatic hypotension, urinary incontinence, and impotence suggest autonomic deficits that are not associated with any somatic neurological dysfunction. The postural hypotension was confirmed by tilt-table test accompanied by slowing of the EEG background suggesting critical cerebral hypoperfusion. These findings in association with a fixed HR suggest an impairment of the ANS function affecting the heart as well as the resistance and the capacitance vessels. A supersensitive BP response after norepinephrine infusion and a supersensitive pupillary response to dilute (1:1000) adrenaline suggest peripheral sympathetic fiber denervation. Impairment of thermal sweating, abnormal cold pressor, and mental arithmetic tests in conjunction with other findings suggest widespread impairment of sympathetic efferent fibers. Absence of bradycardia despite supersensitive BP response to norepinephrine infusion, impotence, atonic urinary bladder and failure of pulse rate, and BP change after atropine injection as well as pupillary constriction after dilute pilocarpine solution (denervation super sensitivity) indicate that the parasympathetic system is also involved. Reduced fasting plasma norepinephrine and its failure to rise in the erect posture suggest postganglionic sympathetic dysfunction. Failure of plasma renin to rise in the upright position also suggests depletion of the sympathetic neurotransmitter at the renal sympathetic nerve endings. In summary, the clinical features and the AFTs suggest that this patient has been suffering from pure AF and fulfill the criteria of Bradbury–Eggleston syndrome [57].

Approximately 3 years after initial presentation neurological examination showed that he was developing parkinsonian-cerebellar syndrome consistent with conversion to MSA phenotype [14].

Case 2

A 52-year-old man was admitted for investigation of episodes of syncope in the upright position, urinary incontinence and frequency of 5 years duration, and impotence for 8 years. Recently, he noticed progressive difficulty in walking due to incoordination. His BP in the supine position was 140/90 mm Hg and the HR was 80 per minute. In the upright position, the BP fell rapidly to unrecordable level accompanied by faint feelings but the pulse rate remained fixed. Neurological examination showed evidence of cerebellar dysfunction in the upper and lower extremities including ataxia of gait. These findings continued to progress and later he developed mild cogwheel rigidity in both hands, stooped posture, and bradykinesia. The plantar responses were bilaterally extensor. Sensory examination and mental functions (no formal testing was performed) were normal. In the terminal stage, he developed dysrhythmic breathing and sleep apnea on PSG recording.

Cystometrogram showed an atonic bladder. A barium swallow and cineradiography of the esophagus showed evidence of mild impairment of the peristaltic waves. Thermal sweating was severely impaired over the trunk and the lower extremities. Valsalva test showed no “overshoot” of the BP. Cold pressor and mental arithmetic tests did not show any changes in the BP or the HR. Plasma renin activity remained unchanged in the erect position. Norepinephrine infusion test revealed small rise of BP and HR. Conjunctival instillation of dilute pilocarpine solution (0.062%) and 1:1000 adrenaline solution did not produce any alterations in pupillary size.

Three years after onset of the somatic neurological dysfunction, the patient died of pneumonia and respiratory failure. Postmortem examination disclosed significant structural alterations in the brain stem, cerebellum, basal ganglia, and spinal cord.

Comments

The clinical manifestations of fainting spells in the upright position accompanied by orthostatic fall of BP and fixed HR, urinary incontinence and impotence suggest autonomic deficits. The initial presentation of these autonomic manifestations followed later by cerebellar-parkinsonian syndrome fulfills the criteria for the diagnosis of MSA with progressive AF (the Shy–Drager syndrome). The AFTs showing marked reduction of BP in the erect posture, relatively fixed HR in all body positions, absence of “overshoot” after Valsalva maneuver, no rise of BP and HR after cold pressor and mental arithmetic tests, failure of rise of plasma renin and norepinephrine in the erect posture all suggest evidence of sympathetic denervation. Absence of a supersensitive BP response after intravenous norepinephrine infusion and a lack of supersensitivity of the pupillary response to intraocular dilute adrenaline solutions suggest a central lesion and not a lesion of the postganglionic sympathetic fibers.

Absence of a rise of HR after atropine injection, absence of bradycardia after Valsalva maneuver, reduced Valsalva ratio, cystometric finding of an atonic bladder, impairment of respiratory beat-to-beat variation of HR, impairment of the peristaltic waves on cineradiography, and barium swallow examination of the esophagus as well as a lack of super sensitivity of the pupillary response to intraocular dilute pilocarpine solution all suggest evidence of parasympathetic denervation in this patient. Therefore, the clinical and AFTs provide evidence of central autonomic deficits accompanied by somatic neurological dysfunction, particularly involving extrapyramidal and cerebellar pathways. These findings are characteristic of those noted in the Shy–Drager syndrome (MSA).

The pathological findings [2, 3, 8, 14, 63, 67, 130] of olivopontocerebellar atrophy as well as degeneration and gliosis in the corpus striatum, substantia nigra, and locus ceruleus correlate anatomically with the cerebellar-parkinsonian syndrome in this patient. Intermediolateral neuronal cell loss in the spinal cord (also noted in every case of the Shy–Drager syndrome) and lesions around the NTS and ventral medulla explain severe sympathetic denervation including profound OH in this patient. Lesions of the nucleus tractus solitarius and nucleus ambiguus likely are responsible for respiratory dysrhythmia while involvement of the dorsal motor nucleus of the vagus and nucleus ambiguus explain GI motility disturbances and cardiac parasympathetic denervation. Lesions of the sacral spinal cord including Onuf’s nuclei are responsible for the urinary and sexual dysfunction. Pyramidal tract degeneration correlates with extensor plantar responses. Loss of neurons in the sympathetic ganglia, anterior horn cells of the spinal cord, and the oculomotor nucleus are consistent with those noted in MSA.

Case 3

A 45-year-old patient has suffered from insulin-dependent diabetes mellitus for 15 years. He now complains of tingling and numbness in both feet and the hands, and mild weakness of the legs for the last 1 year. Recently, he has been having episodes of fainting spells in the upright position, urinary incontinence, and impotence. He has also noted lack of sweating in his feet. In addition, he has intermittent diarrhea, particularly nocturnal diarrhea. Occasionally, he has some difficulty in swallowing both solids and liquids.

On neurological examination, he has evidence of mild sensory-motor polyneuropathy in the legs. The feet and legs are dry and are relatively hairless. Supine BP is 150/95 and the pulse rate is 78 per minute. On standing for a minute the BP fell to 50/0 and the pulse rate increased to 80 per minute. Cold pressor and mental arithmetic tests show no change in BP or the HR. Valsalva test shows reduced VR and absence of “overshoot” of BP and a lack of reflex bradycardia. There is impairment of respiratory HR variation. Nerve conduction study shows evidence of sensory-motor axonal polyneuropathy. Sympathetic skin responses are absent in the palms and soles. Barium swallow with cineradiography shows impairment of the peristaltic waves. Thermal sweating is severely impaired in the trunk and legs. Supine fasting plasma norepinephrine level is markedly reduced and there is no rise on standing up. Intramuscular injection of atropine does not change the HR or the BP. Intravenous norepinephrine infusion test shows supersensitive BP response. Pupillary constriction after pilocarpine (0.062%) and pupillary dilation after 1:1000 adrenaline eye drops suggest postganglionic autonomic denervation.

Comments

This patient with longstanding insulin dependent diabetes mellitus developed an axonal type of somatic polyneuropathy, which later was accompanied by evidence of autonomic neuropathy as is obvious from the clinical, nerve conduction, and the autonomic function tests. The abnormalities in the AFTs suggest evidence of affection of both sympathetic and parasympathetic fibers in the postganglionic regions.

The characteristic pathological changes (not obtained from this patient) as reported in the literature in diabetic autonomic neuropathy [131, 132] consist of involvement of the sympathetic and parasympathetic postganglionic neurons associated with lymphocytic infiltration, vacuolation, and poor Nissl staining. Additional findings include depletion of myelinated fibers in the vagus and greater splanchnic nerves, and the white rami communicantes [124, 125]. Thus, there is good clinical–physiological–anatomical correlation in diabetic autonomic neuropathy.

Principles of Therapy

In this last section, I shall briefly allude to principles of therapy in autonomic dysfunction but the details are beyond the scope of this chapter and are addressed in various chapters throughout this book.

Treatment should ideally include nonpharmacologic and drug treatment [2, 3, 5, 9]. Those with mild or minimal AD who are asymptomatic require no treatment. Those with mild AD and are symptomatic should benefit from nonpharmacologic therapy that includes avoidance of triggering factors and adherence to nonpharmacologic measures that may consist of use of compression stockings and other physical countermeasures for OH as well as drinking of plenty of fluids, especially in the morning and adequate intake of sodium chloride (salt) for POTS. Other nondrug therapy includes exercise, specifically designed for a particular type of AD. For specific sleep dysfunction appropriate measures include common sense sleep hygiene practice for all, cognitive behavioral therapy for chronic insomnia (CBT-I), as well as upper airway pressurization for OSA and other ventilatory measures for sleep-hypoventilation or central sleep apnea.

Secondary AD requires treatment of primary disorder supplemented by drug to control dysautonomic symptom for debilitating and symptomatic patients along with appropriate measures for sleep disorders. The pharmacologic treatment for OH (which is a cardinal and severely debilitating feature in many patients with dysautonomia) and orthostatic intolerance symptoms may include the following in a particular patient (treatment needs to be individualized): (i) volume expanders, (ii) medications to reduce heart rate (particularly in POTS), (iii) vasoconstrictive agents, and (iv) sympatholytics, especially in POTS.

Non-orthostatic and other systemic symptoms may benefit from melatonin (especially, circadian rhythm disorder), wake-promoting agents for fatigue, immunosuppressants for autoimmune AD, SSRIs for comorbid anxiety and depression, appropriate measures for GI motility and genitourinary disorders, and analgesics for comorbid painful conditions and headache.

In conclusion, an approach whether at the bedside or in the clinics should consist of pursuing the diagnostic steps in a logical and systematic manner as outlined above (see also Box 12.6) for optimal care of patients. Most important first step is clinical history and physical examination including specific autonomic examination before ordering laboratory tests in a haphazard manner otherwise the physician may run into a state of confusion in terms of correct diagnosis and appropriate treatment.