Causes of Autonomic Dysfunction
Autonomic dysfunction results from three primary categories: primary autonomic failure (degenerative neurological diseases), secondary autonomic failure (damage from systemic diseases), and drug-induced dysfunction, with diabetes being the most common overall cause in clinical practice. 1, 2
Primary Autonomic Failure (Degenerative Neurological Diseases)
Primary autonomic failure comprises degenerative conditions where the autonomic nervous system itself is the primary target of disease 1:
- Multiple System Atrophy (MSA): Characterized by early, severe, and progressive dysautonomia with marked orthostatic hypotension, urinary incontinence, respiratory disturbances including laryngeal stridor and sleep apnea 1, 3
- Parkinson's Disease: Autonomic failure is generally less severe than in MSA, though nearly invariably associated with neuronal loss in the intermediolateral cell columns 1, 3
- Pure Autonomic Failure (PAF): A disorder primarily of postganglionic neurons without central nervous system involvement 1, 3
- Lewy Body Dementia: Associated with autonomic dysfunction as part of the neurodegenerative process 1
The pathophysiology involves degeneration of the intermediolateral cell columns or damage to descending pathways that synapse on these cells 3, 4. MSA can be differentiated from PAF by preserved basal sympathetic activity, decreased CSF neurotransmitter markers, impaired vasopressin response to hypotension, and impaired ACTH/beta endorphin response to hypoglycemia 3.
Secondary Autonomic Failure (Systemic Disease-Related)
Secondary autonomic failure involves autonomic damage by other diseases 1:
Diabetes Mellitus: The most common cause of autonomic dysfunction overall, affecting autonomic innervation through multiple mechanisms including neuropathy, endothelial dysfunction, and vascular disease 5, 2
Amyloidosis: Causes autonomic damage through infiltration of autonomic nerves 1
Peripheral Neuropathies: Various polyneuropathies can cause autonomic dysfunction, particularly those affecting small myelinated and unmyelinated fibers in baroreflex afferents, vagal efferents to the heart, and sympathetic efferent pathways to the mesenteric vascular bed 4
Guillain-Barré Syndrome: Acute demyelination of sympathetic and parasympathetic nerves may cause acute autonomic dysfunction 4
Autoimmune Disorders:
- Autoimmune autonomic ganglionopathy (AAG) with antibodies against ganglionic nicotinic acetylcholine receptors 1, 6
- Paraneoplastic autonomic neuropathy associated with small cell lung cancer (SCLC), with antibodies binding to and blocking ganglionic acetylcholine receptors 1
- Neuromuscular and rheumatologic diseases with autonomic manifestations 6
Spinal Cord Lesions: Traumatic, vascular, inflammatory, demyelinating, or neoplastic lesions involving the autonomic network 3
Cerebrovascular Disease: Can affect descending autonomic pathways 3, 4
Multiple Sclerosis: Demyelinating lesions affecting autonomic pathways 7
Hypermobile Ehlers-Danlos Syndrome (hEDS): Associated with autonomic dysregulation, theorized to involve vascular laxity, peripheral neuropathy, or possible autoimmune etiologies 1
Drug-Induced Autonomic Dysfunction
Drug-induced orthostatic hypotension is the most frequent cause of orthostatic hypotension, representing functional rather than structural autonomic failure 1:
- Antihypertensives: Including beta-blockers, vasodilators, central sympathomimetics, ganglion blockers, and ACE inhibitors 1, 5
- Diuretics: Commonly cause orthostatic hypotension 1
- Tricyclic Antidepressants: Contribute to syncope through orthostatic hypotension and prolonged QT intervals 1, 5
- SSRIs: Associated with autonomic dysfunction 5
- Phenothiazines: Cause orthostatic hypotension 1
- Alpha-blockers: Can induce orthostatic hypotension 1
- Alcohol: Contributes to autonomic dysfunction 1
Pathophysiological Mechanisms
The autonomic nervous system dysfunction can occur at multiple levels 1:
- Peripheral nerves: Damage to autonomic nerve fibers 1, 4
- Autonomic ganglia: Dysfunction at the ganglionic level 1, 6
- Spinal cord: Lesions affecting intermediolateral cell columns 1, 3
- Brain: Central autonomic network disruption 1, 3
In autonomic failure, functional and structural impairments lead to inadequate increase in peripheral resistance and heart rate upon standing, with cardiovascular sympathetic fibers unable to increase total peripheral vascular resistance in the upright posture 1.
Clinical Pitfalls and Diagnostic Considerations
Critical warning: When evaluating autonomic dysfunction, always review the medication list first, as drug-induced dysfunction is the most frequent and reversible cause 1. Discontinuing offending medications should be the initial intervention before pursuing extensive workup 2.
Neurological evaluation should be considered in primary autonomic failure, with warning signs including early impotence, disturbed micturition, and later Parkinsonism and ataxia 1. Referral in secondary autonomic failure depends on which physician treats the underlying disease 1.
Autonomic testing characterizes causes for nonspecific symptoms but is not necessary in patients with classic presentations 2. Treatment focuses on discontinuing offending medications, behavioral modification, and pharmacologic therapy to decrease symptom severity, as autonomic failure has no cure and management aims at improving quality of life 2, 7.