Disorders of the Autonomic Nervous System¶

Chapter 451 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 451

Key Clinical Points¶

Orthostatic hypotension (OH) is defined by a drop in SBP ≥20 mmHg or DBP ≥10 mmHg within 3 min of standing.
Neurogenic OH (NOH) is characterized by an inadequate heart rate (HR) increase (<15 beats/min) or a ΔHR/ΔSBP ratio <0.5 beats/min/mmHg.
POTS is defined by an HR increase >30 beats/min (or >40 in adolescents) within 10 min of standing without significant SBP drop.
Supine hypertension, often seen in NOH, is a major risk factor for end-organ damage (kidney, cardiac, cerebrovascular).
NOH carries high mortality: ~44% over 30 months and >60% over 10 years.
Pharmacotherapy includes Fludrocortisone (0.1–0.2 mg/d) and Midodrine (2.5 mg 3x daily, last dose before 6 p.m.).
The 'shotgun' pattern of sweating (Figure 1) is a hallmark of autonomic dysfunction affecting specific nerve fibers.
The 'hot cross bun' sign (Figure 6) on MRI is characteristic of Multiple System Atrophy, cerebellar type (MSA-C).
Valsalva ratio is a measure of the parasympathetic arm of the baroreflex; it is diminished in autonomic failure.
Small-fiber neuropathy can be identified via skin biopsy for epidermal nerve fiber density (ENFD).

DEFINITION & CLASSIFICATION¶

• Autonomic Nervous System (ANS): Large CNS organization and extensive PNS network influencing all organ systems. • Components: ◦ Parasympathetic: Craniosacral localization (brainstem, sacral cord). ◦ Sympathetic: Thoracolumbar localization (T1–L2). ◦ Enteric Nervous System (ENS): Own neurons/neurotransmitters; heavily regulated by CNS and PNS. • Neurotransmitters: ◦ Acetylcholine (ACh): Preganglionic neurotransmitter for both systems; postganglionic for parasympathetic. ◦ Norepinephrine (NE): Postganglionic neurotransmitter for sympathetic, except sweat glands (which use ACh). • Table 1 Summary: Illustrates opposing effects of Sympathetic and Parasympathetic systems on organs like Pupil (dilation vs. constriction), Heart (positive vs. negative chron/inotropic effects), and Gastrointestinal tract (decreased motility vs. increased motility).

Classification of Clinical Autonomic Disorders¶

• Categorization by Anatomy: Brain, Spinal Cord, or Neuropathies. • Table 2 Summary: ◦ I. Brain Involvement: Includes multisystem degeneration (MSA, Parkinson's) and focal CNS disorders (cerebral cortex, limbic circuits, hypothalamus, brainstem/cerebellum). ◦ II. Spinal Cord Involvement: Includes traumatic quadriplegia, syringomyelia, MS, ALS, and tumors. ◦ III. Autonomic Neuropathies: ◦ Acute/Subacute: AAG, paraneoplastic, GBS, Botulism, drug-induced, etc. ◦ Chronic Peripheral: Small fiber neuropathy (CSPN), combined sympathetic/parasympathetic failure (Amyloid, Diabetic, Fabry's, etc.). ◦ Disorders of Orthostatic Intolerance: OH, POTS, reflex syncope.

EPIDEMIOLOGY¶

• Prevalence: ◦ <5% in population under age 50. ◦ Up to 20% in population over age 70. • Clinical Impact: Often overlooked as patients may be asymptomatic or have minor symptoms. • Risk Factors: ◦ Physical deconditioning (exacerbates OH and POTS). ◦ Radiation to the neck (suggests arterial baroreflex failure via carotid sinus injury). ◦ Aging, prolonged exercise, and intensified antihypertensive treatment.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Orthostatic Intolerance (OI) Mechanism: ◦ Standing/Tilt → 500–700 mL blood shifts to peripheral vessels → reduced venous return. ◦ Normal Response: Slight HR increase + peripheral venoconstriction + arteriolar constriction → maintained SBP and increased DBP. ◦ Pathological State (OH): Compensatory mechanism fails. • Baroreflex Impairment: ◦ Associated with autonomic neuropathies or degenerative disorders. ◦ Leads to 'reverse dipping' (supine SBP > morning SBP). ◦ Risk Factor: Supine hypertension is a specific risk for end-organ damage (kidney, cardiac, cerebrovascular). • Renin-Angiotensin-Aldosterone Axis: ◦ Chronic OH → altered axis → pressure diuresis and volume loss during sleep → worse daytime OH.

CLINICAL FEATURES¶

• General Presentation: Symptoms result from decreased function, overactivity, or dysregulation. • Symptoms of Orthostatic Hypotension (OH): ◦ Common: Lightheadedness on standing. ◦ Other: Palpitations, flushing, pallor, fainting/near-fainting. ◦ Indirect/Chronic Symptoms: Dizziness (wobbly), wooziness, orthostatic imbalance, fatigue, tiredness, generalized weakness. • Specific Syndromes: ◦ 'Coat hanger syndrome': Neck and shoulder discomfort due to hypoperfusion of cervical paraspinal/trapezius muscles. ◦ Platypnea: Orthostatic dyspnea due to hypoperfusion of the lung apex. ◦ Orthostatic Angina: Myocardial hypoperfusion. ◦ Orthostatic Headache: May be mistaken for low-pressure CSF headache. • Triggers: Bed rest, food ingestion (large meal + alcohol), fever, heat, exercise, hyperventilation, medications, sepsis, surgery. • Physical Examination Findings: ◦ Vital Signs: Supine and orthostatic (1 and 3 min) BP/HR. ◦ Skin/Limbs: Foot changes (pes cavus/planus), vasomotor color changes, neuropathy, sweat patterns (e.g., 'shotgun' pattern in Figure 1). ◦ Head/Neck: Pupillary exam (symmetry, miosis, mydriasis, reaction to light, redilation rate). ◦ Red Flags for Degenerative Disorders: Impaired olfaction, impaired balance, abnormal movements, dream enactment behavior. ◦ Other Signs: Tongue appearance (macroglossia suggests amyloidosis), skin elasticity, hair distribution.

DIFFERENTIAL DIAGNOSIS¶

• Neurogenic vs. Non-Neurogenic OH: ◦ Non-neurogenic: Compensatory HR increase ≥15 beats/min. ◦ Neurogenic (NOH): ◦ Blunted HR increase <15 beats/min (if no other causes like meds or heart issues). ◦ Precise Metric: ΔHR/ΔSBP ratio <0.5 beats/min/mmHg after 3 min of standing/tilt. ◦ Pathophysiology: NOH involves inadequate release of peripheral norepinephrine → impaired systemic vascular tone. • Syncope Differentiation: ◦ Vasovagal, vasodepressor, and cardiodepressor syncope. ◦ Valsalva Ratio: (Higher HR / Lower HR) measures parasympathetic arm; diminished in autonomic failure. ◦ Adrenergic Index Score: Measures sympathetic arm of baroreflex. ◦ Note: Diminished heart rate variation to deep breathing and Valsalva ratio are seen in autonomic failure, α-synuclein disorders, and anticholinergic use.

DIAGNOSTIC APPROACH¶

Basic Screening: CBC, CMP, ESR; check Iron, Ferritin, B12, D, and Folic Acid.
Nutritional/Metabolic (if GI distress/weight loss): Thiamine, B6, Niacin, Riboflavin, Vitamin C, Copper, CoQ10, Carnitine.
Endocrine Screening: Thyroid, Adrenal (Cortisol), Medullary (Catecholamine), 5-HIAA (Carcinoid).
Small Fiber Evaluation: If HbA1c is normal → perform 2-h glucose tolerance test.
Autonomic Specific Testing: ◦ Catecholamines: Supine vs. Upright (Normal = double or more; Autonomic failure = no significant rise). ◦ Serology: Sjögren's, Scleroderma, MCTD. ◦ Paraproteinemia: Serum free light chains and protein electrophoresis (for early amyloid). ◦ Autoimmune Markers: Ganglionic ACh nicotinic receptor, P/Q channel, plexin, GAD. ◦ Paraneoplastic: anti-Hu, anti-CRMP5, anti-amphiphysin. ◦ Infection: HIV, EBV, HSV, VZV, CMV. ◦ Genetic/Treatable: Porphyria, Fabry's disease.
Autonomic Evaluation Tests (Table 4): ◦ Heart Rate Variation to Deep Breathing: Diminished in autonomic failure. ◦ Valsalva Maneuver: Measures parasympathetic arm; diminished in autonomic failure. ◦ Tilt Table Testing: Differentiates vasovagal, vasodepressor, and cardiodepressor syncope. ◦ Sudomotor Function (QSART): Identifies postganglionic sudomotor axon lesions. ◦ Thermoregulatory Sweat Test (TST): Qualitative measure of global sweat production.

MANAGEMENT & TREATMENT¶

Non-Pharmacologic Management: ◦ [Note: Specific actions not detailed in source text, but listed as a management category].
Pharmacologic Management: ◦ Fludrocortisone: ◦ Dose: 0.1–0.2 mg/d. ◦ Mechanism: Expands plasma volume. ◦ Monitoring: Watch for supine hypertension, pedal edema, and hypokalemia. ◦ Midodrine: ◦ Dose: 2.5 mg 3 times daily. ◦ Mechanism: Direct α-adrenoceptor agonist. ◦ Timing: Last dose must be before 6:00 p.m. to avoid nocturia and supine hypertension.

COMPLICATIONS & PROGNOSIS¶

• Neurogenic OH (NOH) Prognosis: ◦ Mortality rate ≈ 44% over 30 months. ◦ Mortality rate >60% over 10 years. • Supine Hypertension Risks: ◦ Risk of end-organ damage: Kidney, cardiac, or cerebrovascular.

SPECIAL POPULATIONS¶

• Pediatric/Adolescent: ◦ POTS definition in adolescents: HR increase >40 beats/min within 10 min of standing. • Geriatric: ◦ OH prevalence increases with age (up to 20% in those >70 years).

KEY PEARLS & HIGH-YIELD POINTS¶

• Diagnostic Thresholds: ◦ OH: SBP ≥20 mmHg or DBP ≥10 mmHg (3 min). ◦ NOH: HR increase <15 beats/min OR ΔHR/ΔSBP <0.5. ◦ POTS: HR increase >30 (or >40 in adolescents) without SBP drop. • Clinical Markers: ◦ 'Shotgun' pattern of sweat (Fig 1) = autonomic dysfunction. ◦ 'Hot cross bun' sign (Fig 6) = MSA-C. ◦ Valsalva ratio ↓ = parasympathetic failure. • Critical Risk Factor: Supine hypertension is a key indicator for baroreflex impairment and potential end-organ damage.

Reference Tables¶

TABLE 451-1 Effects of Sympathetic and Parasympathetic Systems on Various Effector Organs Pupil Accommodation Heart¶

Harrison's 22e, p.3540

	SYMPATHETIC	PARASYMPATHETIC
Pupil	Pupillodilation (alpha)	Pupilloconstriction
	Decreased
Heart	Positive chronotropic effect (beta) Positive inotropic effect (beta)	Negative chronotropic effect Negative inotropic effect
	Vasoconstriction (alpha) Vasodilation (beta)
Veins	Vasoconstriction (alpha) Vasoconstriction (beta)
	Bronchodilation (beta)
Gastrointestinal tract	Decreased motility (beta) Contraction of sphincters (alpha)	Increased motility Relaxation of sphincter
	Detrusor relaxation (beta) Contraction of sphincter (alpha)
Salivary glands	Scant, thick, viscid saliva (alpha)	Copious, thin, watery saliva
	Piloerection (cutis anserina)
Sweat glands	Increased secretion (cholinergic)	Decreased secretion
	Ejaculation
Adrenal medulla	Catecholamine release
	Glycogenolysis (alpha and beta) Lipolysis (alpha and beta)

TABLE 451-2 Classification of Clinical Autonomic Disorders I. Autonomic Disorders with Brain Involvement A. Associated…¶

Harrison's 22e, p.3541

I. Autonomic Disorders with Brain Involvement
A. Associated with multisystem degeneration 1. Multisystem degeneration: autonomic failure clinically prominent a. Multiple-system atrophy (MSA) b. Parkinson’s disease with autonomic failure c. Diffuse Lewy body disease with autonomic failure 2. Multisystem degeneration: autonomic failure clinically not usually prominent a. Parkinson’s disease without autonomic failure b. Other extrapyramidal disorders (inherited spinocerebellar atrophies, progressive supranuclear palsy, corticobasal degeneration, Machado-Joseph disease, fragile X syndrome [FXTAS]) B. Unassociated with multisystem degeneration (focal CNS disorders) 1. Disorders mainly due to cerebral cortex involvement a. Frontal cortex lesions causing urinary/bowel incontinence b. Focal seizures (temporal lobe or anterior cingulate) c. Cerebral infarction of the insula 2. Disorders of the limbic and paralimbic circuits a. Limbic encephalitis b. Autonomic seizures c. Shapiro’s syndrome (agenesis of corpus callosum, hyperhidrosis, hypothermia)	3. Disorders of the hypothalamus a. Thiamine deficiency (Wernicke-Korsakoff syndrome) b. Diencephalic syndrome c. Neuroleptic malignant syndrome d. Serotonin syndrome e. Fatal familial insomnia f. Antidiuretic hormone (ADH) syndromes (diabetes insipidus, inappropriate ADH secretion) g. Disturbances of temperature regulation (hyperthermia, hypothermia) h. Disturbances of sexual function i. Disturbances of appetite j. Disturbances of BP/HR and gastric function k. Horner’s syndrome 4. Disorders of the brainstem and cerebellum a. Posterior fossa tumors b. Syringobulbia and Arnold-Chiari malformation c. Disorders of BP control (hypertension, hypotension) d. Cardiac arrhythmias e. Central sleep apnea f. Baroreflex failure g. Horner’s syndrome h. Vertebrobasilar and lateral medullary (Wallenberg’s) syndromes i. Brainstem encephalitis
II. Autonomic Disorders with Spinal Cord Involvement
A. Traumatic quadriplegia B. Syringomyelia C. Subacute combined degeneration D. Multiple sclerosis and neuromyelitis optica	E. Amyotrophic lateral sclerosis (mild, late) F. Tetanus G. Stiff-person syndrome H. Spinal cord tumors
III. Autonomic Neuropathies
A. Acute/subacute autonomic neuropathies a. Subacute autoimmune autonomic ganglionopathy (AAG) b. Subacute paraneoplastic autonomic neuropathy c. Guillain-Barré syndrome d. Botulism e. Porphyria f. Drug-induced autonomic neuropathies—stimulants, drug withdrawal, vasoconstrictor, vasodilators, beta-receptor antagonists, beta-agonists g. Toxin-induced autonomic neuropathies h. Subacute cholinergic neuropathy	B. Chronic peripheral autonomic neuropathies 1. Small fiber neuropathy, including cryptogenic sensory polyneuropathy (CSPN) 2. Combined sympathetic and parasympathetic failure a. Amyloid b. Diabetic autonomic neuropathy c. AAG (paraneoplastic and idiopathic) d. Sensory neuronopathy with autonomic failure e. Fabry’s disease f. Diabetic, uremic, or nutritional deficiency g. Familial dysautonomia (Riley-Day syndrome) h. Hereditary sensory and autonomic neuropathy i. HIV-related autonomic neuropathy j. Geriatric dysautonomia (age >80 years) 3. Disorders of orthostatic intolerance: OH; POTS; reflex syncope; prolonged bed rest; space flight; chronic fatigue