What is pure autonomic failure in older adults, particularly those with a history of neurological disorders such as Parkinson's disease or multiple system atrophy?

What is Pure Autonomic Failure?

Pure autonomic failure (PAF) is a rare, progressive neurodegenerative disorder characterized by isolated dysfunction of the autonomic nervous system, manifesting primarily as severe orthostatic hypotension without other neurological deficits such as parkinsonism, cerebellar signs, or cognitive impairment. 1, 2

Pathophysiology

• PAF results from degeneration of postganglionic sympathetic and parasympathetic neurons in the thoracic spinal cord and paravertebral autonomic ganglia 2
• It is classified as an α-synucleinopathy with Lewy bodies and α-synuclein deposits found in autonomic neural structures, placing it in the same disease spectrum as Parkinson's disease, multiple system atrophy, and Lewy body dementia 2, 3
• Unlike multiple system atrophy where α-synuclein accumulates in oligodendroglia, PAF involves neuronal deposition of α-synuclein, predominantly in peripheral autonomic ganglia and nerves 3, 4

Clinical Presentation

Cardinal Features

• Neurogenic orthostatic hypotension is the defining feature: sustained drop in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg within 3 minutes of standing 1, 5
• Symptoms include severe lightheadedness, visual blurring, generalized weakness, fatigue, leg buckling, and the characteristic "coat hanger" headache (triangular pain at the base of the neck from trapezius ischemia) 1
• Bladder dysfunction (urinary retention, incontinence), erectile dysfunction, and sudomotor abnormalities (sweating disorders, regional anhydrosis) are common 5, 2
• Gastrointestinal autonomic dysfunction may occur 2, 3

Key Distinguishing Features

• Absence of other neurological deficits distinguishes PAF from other synucleinopathies—no parkinsonism, ataxia, cognitive impairment, or pyramidal signs at presentation 1, 2
• Symptoms are provoked or exacerbated by prolonged standing, exertion, meals (postprandial hypotension), and increased ambient temperature 1
• Disease onset is typically in adulthood with slow, progressive course 2, 3

Diagnostic Evaluation

Autonomic Testing

• Low circulating norepinephrine levels confirm sympathetic dysfunction 5
• Abnormal cardiovagal response and sweating abnormalities on autonomic function testing 5
• Preserved basal sympathetic activity helps differentiate from multiple system atrophy 4
• Normal electrophysiologic studies exclude peripheral somatic neuropathies with autonomic involvement 5

Neurological Assessment

• Referral for autonomic evaluation is reasonable (Class IIa recommendation) in patients with known or suspected neurodegenerative disease presenting with orthostatic hypotension to improve diagnostic and prognostic accuracy 1
• Look for early warning signs that suggest progression beyond PAF: early impotence, disturbed micturition, and later development of parkinsonism or ataxia 1
• DaTscan imaging may reveal subclinical nigrostriatal dopaminergic degeneration even without clinical parkinsonism, potentially indicating early central nervous system involvement 6

Differential Diagnosis

Primary Autonomic Failure Syndromes

• Multiple system atrophy (MSA): Distinguished by early, severe dysautonomia plus parkinsonism (MSA-P), cerebellar ataxia (MSA-C), or predominant autonomic dysfunction (MSA-A/Shy-Drager syndrome) with pyramidal signs 1
• Parkinson's disease: Autonomic failure is generally less severe than in MSA; presence of resting tremor, bradykinesia, and rigidity 1
• Lewy body dementia: Cognitive impairment and visual hallucinations predominate 1

Secondary Autonomic Failure

• Diabetes mellitus, amyloidosis, kidney/liver failure, alcohol abuse cause secondary autonomic nervous system damage 1
• Various polyneuropathies and autoimmune autonomic neuropathies 1

Drug-Induced Orthostatic Hypotension

• Most frequent cause of orthostatic hypotension: antihypertensives, diuretics, tricyclic antidepressants, phenothiazines, levodopa, MAO inhibitors, and alcohol 1
• This represents functional rather than structural autonomic failure 1

Prognosis and Phenoconversion

• Critical caveat: A significant proportion of PAF patients will eventually convert to another synucleinopathy with central nervous system involvement—Parkinson's disease, multiple system atrophy, or dementia with Lewy bodies 3
• Prognosis for survival in PAF is better than for other synucleinopathies when it remains isolated 2
• Risk factors for phenoconversion include abnormal DaTscan imaging, male sex, shorter disease duration, and more severe genitourinary symptoms 6

Management Approach

• No disease-modifying therapy exists; treatment focuses on symptomatic management of orthostatic hypotension and supine hypertension 2
• Fludrocortisone and midodrine improve orthostatic tolerance 5
• Avoid medications that worsen orthostatic hypotension; however, disruption of psychiatric drug regimens should not be undertaken without relevant psychiatric expertise due to potential severe consequences 1
• Monitor for development of central neurological features suggesting phenoconversion to Parkinson's disease, multiple system atrophy, or Lewy body dementia 3