What is dysautonomia?

What is Dysautonomia?

Dysautonomia is a dysfunction of the autonomic nervous system that controls involuntary bodily functions including heart rate, blood pressure, digestion, temperature regulation, and other essential processes. 1, 2

Core Definition and Pathophysiology

Dysautonomia encompasses a broad spectrum of disorders with fundamentally different underlying mechanisms, not a single disease entity. 1, 2 The autonomic nervous system consists of the parasympathetic and sympathetic nervous systems that integrate control of involuntary functions. 1 When dysfunction occurs, defects may appear at various levels—from peripheral nerves, autonomic ganglia, the spinal cord, and/or the brain—resulting in cardiac, respiratory, gastrointestinal, urinary, reproductive, ocular, and sudomotor (sweating) defects. 1

Major Types of Dysautonomia

The term "dysautonomia" bundles fundamentally different disorders that require distinct diagnostic and therapeutic approaches:

Postural Orthostatic Tachycardia Syndrome (POTS)

• Defined in adults as an increase in heart rate of ≥30 beats/min within 10 minutes of upright posture (≥40 beats/min in adolescents) without orthostatic hypotension. 1, 2
• POTS is commonly found in long COVID, with one study finding it in 67% of patients with long COVID. 3
• Associated with G protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies, platelet storage pool deficiency, and small fiber neuropathy. 3

Neurogenic Orthostatic Hypotension (nOH)

• Defined as a reduction of systolic blood pressure of at least 20 mm Hg or 10 mm Hg in diastolic blood pressure within 3 minutes of quiet standing. 2
• Represents a late sign indicating greater severity in the context of dysautonomia. 4
• Must be differentiated from non-neurogenic orthostatic hypotension (nnOH) caused by hypovolemia or medications. 4

Familial Dysautonomia (Riley-Day Syndrome)

• A specific genetic disorder (hereditary sensory and autonomic neuropathy type III) associated with abnormality of sensory and autonomic nerves, decreased sensation of pain, and decreased production of tears. 1, 2

Cardiovascular Autonomic Neuropathy (CAN)

• The term most currently used to define dysautonomia with impairment of the sympathetic and/or parasympathetic cardiovascular autonomic nervous system. 4
• Can be idiopathic (such as multisystemic atrophy or pure autonomic failure) or secondary to systemic pathologies including diabetes mellitus, neurodegenerative diseases, Parkinson's disease, chronic renal failure, and amyloidosis. 4
• Among diabetic patients, 38-44% can develop dysautonomia, with prognostic implications and higher cardiovascular mortality. 4
• In diabetes, autonomic dysfunction typically progresses from involving the parasympathetic system initially, then the sympathetic system, and finally presenting as orthostatic hypotension in advanced stages. 2, 4

Other Forms

• Reflex syncope (neurally mediated syncope): A form where triggers cause disruption of normal circulatory control. 2
• Chronic Fatigue Syndrome: Represents a form of dysautonomia, renamed as systemic disease of exercise intolerance. 4
• Autoimmune autonomic ganglionopathy: Associated with small cell lung cancer, involving antibodies against neuronal acetylcholine receptors in autonomic ganglia. 1

Clinical Manifestations

Cardiovascular Symptoms

• Orthostatic intolerance: Dizziness, lightheadedness, nausea, dyspnea, and vision changes occurring specifically when assuming or maintaining upright position. 1, 2
• Palpitations, exercise intolerance, and syncope or presyncope. 5, 6
• Symptoms are usually relieved by sitting or lying and may be exacerbated by stimuli causing vasodilation, such as food ingestion, exertion, and heat. 6

Gastrointestinal Symptoms

• Nausea, abdominal pain, vomiting, diarrhea, bloating, and severe constipation. 1, 2
• Gastrointestinal dysmotility may occur via mechanisms including COVID-induced angiotensin converting enzyme 2 depletion. 3

Other Systemic Symptoms

• Cognitive dysfunction and fatigue. 5
• Thermoregulatory dysfunction and altered sweating patterns. 6
• Urinary bladder involvement. 6

Common Comorbidities and Associations

Dysautonomia is commonly comorbid with several conditions:

• Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): POTS and small fiber neuropathy are commonly found in both ME/CFS and long COVID. 3
• Mast Cell Activation Syndrome (MCAS): Commonly comorbid with ME/CFS, with histamine receptor antagonists resulting in improvements in the majority of patients. 3
• Hypermobility Spectrum Disorders and Ehlers-Danlos Syndrome: Dysautonomia occurs frequently in these connective tissue disorders. 6, 7
• Migraine: One of the most common comorbidities of POTS, with significant overlap and shared pathophysiology. 7
• Small Fiber Neuropathy (SFN): Characterized by neuropathic symptoms and dysautonomia due to loss of thinly myelinated and unmyelinated nerve fibers, occurring in approximately 40-60% of sarcoidosis patients. 3

Prognostic Implications

The presence of cardiovascular autonomic neuropathy implies greater severity and worse prognosis in various clinical situations:

• Mortality: There is definitive evidence for a predictive value of CAN on overall mortality. 3
• Cardiovascular disease: CAN is a risk marker and likely a risk factor for cardiovascular disease. 3
• Nephropathy progression: CAN independently predicted the progression of diabetic nephropathy, possibly mediated by CAN-induced changes in glomerular hemodynamics. 3
• Orthostatic hypotension: When due to advanced CAN, is associated with an additional increase in mortality risk over that driven by heart rate variability abnormalities. 3

Diagnostic Considerations

Key Clinical Clues

• Typical clinical features such as orthostatic dizziness/lightheadedness, orthostatic intolerance, palpitations, exercise intolerance, cognitive dysfunction, and fatigue should prompt diagnostic investigation for dysautonomia. 5
• Symptoms of orthostatic intolerance are usually relieved by sitting or lying. 6
• The onset of POTS may be linked to an event such as infection, trauma, surgery, or stress. 6

Diagnostic Testing

• An in-office 10-minute stand test or tilt table test in conjunction with other autonomic function tests. 5
• For CAN specifically, Valsalva, Respiratory, and Orthostatic tests (30:15) are the gold standard methods for diagnosis. 4
• The Tilt Test should not be the test of choice for investigating CAN at an early stage, as it detects cases at more advanced stages. 4

Common Pitfall

• Inadequate monitoring of blood pressure when initiating treatment is a common pitfall in managing dysautonomia. 1, 2
• There is often delay in clinicians recognizing the nature of the symptoms and recognizing associated conditions like EDS or HSD, leading to delays in treatment. 6
• These symptoms may be mislabeled with psychiatric disorders. 5

Clinical Context

Dysautonomia is one of the common and under-recognized comorbidities of a wide variety of systemic diseases, including diabetes, autoimmune disorders, vitamin deficiencies, and hormonal dysregulation. 5 Diagnosing and treating dysautonomia is critical to providing comprehensive and personalized medical care to complex patients with chronic illness, who are typically highly symptomatic with multi-systemic complaints as a result of comorbid, and often undiagnosed, dysautonomia. 5