Pure Autonomic Failure: Symptoms, Types, Causes and Treatment

Pure autonomic failure (PAF) is a rare, progressive neurodegenerative disorder that disrupts the body’s autonomic nervous system — the network responsible for automatic functions like blood pressure, temperature regulation, and bladder control. Although PAF is less well-known than related conditions such as Parkinson’s disease or multiple system atrophy, its hallmark symptoms can be life-altering and often require a multidisciplinary approach to management. This article delves into the symptoms, types, causes, and treatment options for pure autonomic failure, providing a comprehensive, evidence-based resource for patients, caregivers, and clinicians.

Symptoms of Pure Autonomic Failure

Pure autonomic failure can affect nearly every aspect of daily life. Symptoms usually develop gradually and are often initially mistaken for other medical conditions. Understanding these symptoms is crucial for timely diagnosis and effective management.

Symptom	Description	Prevalence/Pattern	Source(s)
Orthostatic Hypotension	Drop in blood pressure upon standing	Most common and defining symptom	1 2 3 5 7 13 14
Syncope	Fainting or loss of consciousness	Often triggered by standing; frequent in PAF	1 2 3 7
Dizziness/Lightheadedness	Sensation of spinning or weakness when upright	Highly prevalent; worse in morning or with exertion	1 3 7 13
Visual Disturbances	Blurred or impaired vision	Associated with low blood pressure episodes	1
Neck ("Coat-Hanger") Pain	Ache in the back of the neck/shoulders	Exacerbated by upright posture	1
Genitourinary Dysfunction	Bladder and sexual problems	Urinary incontinence, hesitancy, erectile dysfunction	2 3 5 13
Reduced Sweating	Poor or patchy sweating, heat intolerance	Thermoregulatory failure; patchy pattern	2 3 13 14
Fatigue/Weakness	Generalized lack of energy	Non-specific but very common	1 3
Gastrointestinal Issues	Constipation, delayed gastric emptying	Less common, but significant	3 13

Table 1: Key Symptoms of Pure Autonomic Failure

Understanding the Symptoms

Orthostatic Hypotension and Syncope

The most prominent symptom of PAF is orthostatic hypotension—a sustained drop in blood pressure when standing, which can lead to dizziness, lightheadedness, and sometimes syncope (fainting). This occurs because the nerves that help regulate blood vessel constriction are damaged, preventing normal compensation for gravity when upright. Blood pressure often drops dramatically, and heart rate usually fails to increase adequately as a compensatory response. These episodes are frequently worse in the morning, with exertion, after meals, or in hot environments. Sitting or lying down typically brings rapid relief 1 2 3 5 7 13 14.

Visual Disturbances and Neck Pain

Low blood pressure can also cause visual disturbances (such as blurred vision) and a characteristic 'coat-hanger' pain in the back of the neck and shoulders. The pain is thought to result from reduced blood flow (hypoperfusion) to the neck muscles during upright posture. These symptoms are exacerbated by heat, exercise, straining, or even arm movements 1.

Genitourinary and Thermoregulatory Symptoms

Bladder dysfunction is common, manifesting as urinary hesitancy, incontinence, or even retention. Sexual dysfunction (such as erectile failure in men) also frequently occurs. Reduced or patchy sweating leads to poor temperature regulation and heat intolerance, with some patients experiencing areas of anhidrosis (no sweating) and others with normal or excessive sweating 2 3 5 13 14.

Fatigue, Weakness, and Other Non-Specific Symptoms

Chronic fatigue, weakness, and lethargy are nearly universal, likely due to reduced blood flow to the brain and muscles. Gastrointestinal symptoms, particularly constipation, can also be present, making daily life more challenging 1 3 13.

Types of Pure Autonomic Failure

While PAF is generally considered a single disease entity, clinicians and researchers have recognized different presentations and potential subtypes, particularly as the disorder can sometimes evolve into other related neurodegenerative diseases.

Type/Variant	Distinguishing Feature	Risk/Progression Pattern	Source(s)
Classic PAF	Isolated peripheral autonomic dysfunction	Slow progression, no motor/cognitive symptoms	2 5 7 13
Converting PAF	PAF that evolves into MSA, PD, or DLB	10-25% risk over years	4 6 9 10
PAF without Synucleinopathy	No α-synuclein/Lewy body pathology	Extremely rare, may involve different mechanism	8

Table 2: Types and Progression of Pure Autonomic Failure

Differentiating Types and Risk of Progression

Classic PAF

Classic PAF is marked by autonomic failure without evidence of central nervous system (CNS) involvement. Patients experience only autonomic symptoms, and the disease is typically slow to progress. Most patients remain stable for many years 2 5 7 13.

PAF with Phenoconversion

A significant minority (10-25%) of patients develop new neurological symptoms over time, a process called phenoconversion. This means PAF can evolve into multiple system atrophy (MSA), Parkinson’s disease (PD), or dementia with Lewy bodies (DLB), all of which are considered synucleinopathies—diseases characterized by the abnormal accumulation of α-synuclein protein in the nervous system 4 6 9 10. Predictors of progression include severe bladder dysfunction, subtle motor symptoms at onset, dream enactment behavior (REM sleep behavior disorder), and certain laboratory findings (e.g., supine norepinephrine levels, patterns of anhidrosis) 4 6.

PAF without Synucleinopathy

Rarely, some individuals meet the clinical criteria for PAF but lack the typical pathological findings of α-synuclein or Lewy bodies. These cases suggest there might be other, as yet unidentified, disease mechanisms at play 8.

The Importance of Monitoring

Given the risk of progression, regular follow-up is crucial for people with PAF to detect early signs of motor or cognitive involvement. This enables timely diagnosis and management of evolving conditions such as MSA or PD 4 6 9 10.

Causes of Pure Autonomic Failure

Pinpointing the underlying causes of PAF has been the subject of extensive research. While many details are still being unraveled, recent discoveries have shed light on the biological underpinnings of this complex disorder.

Cause/Mechanism	Description	Evidence/Notes	Source(s)
α-Synucleinopathy	Deposition of α-synuclein in autonomic neurons	Found in PAF, MSA, PD, DLB	2 3 5 7 13
Peripheral Autonomic Degeneration	Degeneration of pre- and postganglionic sympathetic/parasympathetic nerves	Main pathological finding	3 13 14
Lewy Body Pathology	Neuronal cytoplasmic inclusions (Lewy bodies)	Seen in most, but not all, cases	3 5 7 13
Sympathetic Noradrenergic Denervation	Loss of nerve fibers that release norepinephrine	Causes failure to regulate blood pressure	7 8 13 14
Unknown/Idiopathic	Some cases lack synucleinopathy or clear pathology	Very rare	8

Table 3: Underlying Causes and Mechanisms in Pure Autonomic Failure

The Role of α-Synuclein and Lewy Bodies

Synucleinopathy Explained

The majority of PAF cases are now understood to be α-synucleinopathies. This means they are marked by the misfolding and accumulation of the protein α-synuclein in neurons and glial cells within the autonomic nervous system. These protein clumps—called Lewy bodies—are also found in the brains of people with Parkinson’s disease, multiple system atrophy, or dementia with Lewy bodies, linking these disorders at a molecular level 2 3 5 7 13.

Peripheral Autonomic Degeneration

In PAF, degeneration primarily affects the peripheral autonomic nervous system. Both the preganglionic and postganglionic sympathetic and parasympathetic neurons may be involved, especially in the thoracic spinal cord and paravertebral ganglia. This results in defective synthesis and release of norepinephrine, a neurotransmitter crucial for blood pressure regulation 3 13 14.

Sympathetic Noradrenergic Denervation

A defining feature of PAF is sympathetic noradrenergic denervation—the loss of nerve fibers that release norepinephrine. This causes a failure to raise blood pressure upon standing. Laboratory tests often show markedly reduced plasma norepinephrine levels and impaired responses to stimuli 7 8 13 14.

Exceptions: PAF without Synucleinopathy

Not all patients with the clinical features of PAF have detectable α-synuclein or Lewy bodies. These rare exceptions suggest alternative disease mechanisms may exist, though they remain poorly understood 8.

Treatment of Pure Autonomic Failure

Managing PAF is focused on relieving symptoms and improving quality of life. While no cure currently exists, a combination of non-pharmacological and pharmacological treatments can significantly reduce the burden of symptoms.

Approach	Main Strategies	Notes/Effectiveness	Source(s)
Lifestyle & Non-Pharmacological	Increased fluid/salt, compression garments, physical counter-maneuvers	First-line, effective for many	11 12 13 14
Medication: Volume Expansion	Fludrocortisone, recombinant erythropoietin	Retain salt/water, increase blood volume	11 12 13 14
Medication: Pressor Agents	Midodrine, atomoxetine, yohimbine, pyridostigmine	Raise blood pressure, as needed	11 12 13 14
Management of Comorbidities	Address post-prandial hypotension, supine hypertension, constipation, bladder dysfunction	Multidisciplinary approach needed	11 12 13
Monitoring & Education	Regular follow-up, patient education	Essential for detecting progression	4 6 9 13

Table 4: Management and Treatment Options in Pure Autonomic Failure

Non-Pharmacological Approaches

Lifestyle Modifications

The first step in managing PAF involves lifestyle changes that help maintain blood pressure and reduce symptoms:

• Increase fluid and salt intake: This expands blood volume and helps prevent drops in blood pressure.
• Compression garments: Waist-high compression stockings or abdominal binders reduce blood pooling in the legs and abdomen.
• Physical counter-maneuvers: Leg crossing, squatting, or tensing leg muscles before standing can help prevent fainting.
• Elevate the head of the bed: Helps minimize overnight drops in blood pressure and reduce supine hypertension 11 12 13 14.

Patient Education

Teaching patients to recognize early signs of orthostatic hypotension and avoid triggers (such as hot environments or large meals) is key for safety and well-being 11 12 14.

Pharmacological Treatments

Volume Expansion

• Fludrocortisone: A mineralocorticoid that helps the kidneys retain salt and water, thereby increasing blood volume.
• Recombinant erythropoietin: Used if anemia is present, to increase red blood cell mass 11 12 13 14.

Pressor Agents

• Midodrine: A direct-acting vasoconstrictor, often used before upright activities.
• Atomoxetine, yohimbine, pyridostigmine: These medications enhance sympathetic activity or support neurotransmitter action to help maintain blood pressure. Short-acting agents are preferred and can be used “as needed” 11 12 13 14.

Tailoring Treatment and Managing Complications

Addressing Comorbidities

• Supine hypertension: Some patients with PAF may develop high blood pressure when lying down, which requires careful management to avoid complications.
• Post-prandial hypotension: Blood pressure can fall after meals; smaller, more frequent meals may help.
• Constipation and bladder dysfunction: Dietary adjustments, bowel regimens, and urological interventions may be needed 11 12 13.

Multidisciplinary Care

Given the wide range of symptoms, patients may need care from neurologists, cardiologists, urologists, gastroenterologists, and physical therapists 13.

Monitoring for Disease Progression

Regular clinical assessments help detect early signs of progression to other synucleinopathies, allowing for prompt intervention and support 4 6 9 13.

Conclusion

Pure autonomic failure is a rare but impactful disorder that challenges both patients and healthcare providers. Through a combination of vigilance, lifestyle changes, and targeted therapy, many people with PAF can achieve meaningful improvements in their quality of life.

Key takeaways:

• PAF is primarily characterized by orthostatic hypotension, syncope, and a spectrum of other autonomic symptoms.
• While most patients have “classic” PAF, a significant minority may progress to multiple system atrophy, Parkinson’s disease, or dementia with Lewy bodies.
• The main pathological driver is peripheral autonomic degeneration—often, but not always, involving α-synuclein deposition (synucleinopathy).
• Management focuses on relieving symptoms through a mix of non-pharmacological strategies and medications.
• Multidisciplinary care and regular monitoring are essential for patient safety and early detection of disease progression.

By staying informed and proactive, patients and their care teams can navigate the complexities of pure autonomic failure with greater confidence and effectiveness.