What are the signs, symptoms, and diagnosis of Pure Autonomic Failure (PAF)?

Pure Autonomic Failure: Signs, Symptoms, and Diagnosis

Pure Autonomic Failure (PAF) is characterized by orthostatic hypotension, widespread autonomic dysfunction, and absence of central neurological deficits, with diagnosis requiring demonstration of neurogenic orthostatic hypotension and exclusion of other causes of autonomic failure.

Clinical Presentation

Cardinal Signs and Symptoms

• Orthostatic Hypotension:

  • Sustained decrease in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg within 3 minutes of standing 1
  • May present with severe drops in BP upon standing, causing significant disability 2

• Orthostatic Intolerance Symptoms:

  • Dizziness, lightheadedness, weakness upon standing
  • Visual disturbances (blurring, tunnel vision)
  • Hearing disturbances (impaired hearing, tinnitus)
  • Neck and shoulder pain ("coat hanger pain"), low back pain
  • Fatigue and exercise intolerance 1

Other Autonomic Manifestations

• Cardiovascular:

  • Blunted heart rate response to standing (typically <10 bpm increase) 1
  • Absence of compensatory tachycardia with orthostatic stress
  • Supine hypertension (may be present in some patients)

• Sudomotor Dysfunction:

  • Anhidrosis (reduced or absent sweating) 3
  • May initially present as regional anhidrosis before becoming widespread 4
  • Can manifest as Harlequin syndrome (unilateral anhidrosis with contralateral facial flushing) in early stages 4

• Genitourinary Dysfunction:

  • Erectile dysfunction in men
  • Urinary retention or incontinence
  • Neurogenic bladder 2, 3

• Gastrointestinal Dysfunction:

  • Constipation
  • Early satiety
  • Impaired gastrointestinal motility 3

Diagnostic Approach

Key Diagnostic Criteria

1. Orthostatic BP Measurement:

   • Measure BP in supine position and after 3 minutes of standing
   • Diagnostic criterion: drop in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg 1
   • In cases of supine hypertension, a drop ≥30 mmHg should be considered significant 1

2. Autonomic Function Testing:

   • Valsalva Maneuver: Reveals absence of phase IV BP overshoot and blunted heart rate response 1
   • Deep Breathing Test: Shows reduced heart rate variability (E/I index <15 bpm) 1
   • 24-hour Ambulatory BP Monitoring: Often shows "non-dipping" or "reverse-dipping" BP pattern 1

3. Laboratory Tests:

   • Low plasma norepinephrine levels in supine position
   • Minimal or absent increase in plasma norepinephrine upon standing 2

Differential Diagnosis

PAF must be distinguished from other causes of autonomic failure:

1. Multiple System Atrophy (MSA):

   • Presence of cerebellar ataxia, parkinsonism, or pyramidal signs indicates MSA rather than PAF 3

2. Parkinson's Disease with Autonomic Failure:

   • Presence of motor symptoms (tremor, rigidity, bradykinesia) suggests Parkinson's disease 5

3. Secondary Causes of Autonomic Failure:

   • Diabetes mellitus
   • Amyloidosis
   • Autoimmune autonomic neuropathy
   • Paraneoplastic autonomic neuropathy 1

4. Drug-Induced Orthostatic Hypotension:

   • Antihypertensives, antidepressants, antiparkinsonian medications, diuretics 5

Pathophysiology

PAF is characterized by:

• Peripheral sympathetic denervation with impaired vasoconstrictor response 1
• Alpha-synuclein deposition in peripheral autonomic neurons (though cases without synucleinopathy have been reported) 6, 7
• Cell loss in intermediolateral columns and sympathetic ganglia 6
• Lewy bodies may be found in sympathetic ganglia and distal autonomic axons 6

Important Considerations

• PAF typically presents in middle-aged or elderly individuals 3
• The condition is progressive, with symptoms worsening over years 2
• Patients may initially present with focal autonomic symptoms before developing generalized autonomic failure 4
• PAF can convert to other synucleinopathies (Parkinson's disease, MSA, dementia with Lewy bodies) in some patients, requiring ongoing monitoring 3
• Symptoms are typically worse in the morning, with heat exposure, after meals, or with exertion 1

Diagnostic Pitfalls to Avoid

1. Failing to distinguish from initial or delayed OH: Unlike initial OH (resolves within 30 seconds) or delayed OH (occurs after 3 minutes), classical OH in PAF occurs within 3 minutes of standing and persists 1

2. Overlooking non-orthostatic autonomic symptoms: Focus only on orthostatic hypotension may miss important diagnostic clues like sudomotor, genitourinary, or gastrointestinal dysfunction 3

3. Misattributing symptoms to medication effects: While medications can cause or worsen orthostatic hypotension, persistent symptoms after medication adjustment suggest an underlying autonomic disorder 5

4. Inadequate follow-up: Given the potential for PAF to convert to other synucleinopathies, regular neurological assessment is essential even after diagnosis 3