How to differentiate between clinical phenotypes and make a definite diagnosis of Progressive Supranuclear Palsy (PSP)?

Differentiating Clinical Phenotypes and Making a Definitive Diagnosis of Progressive Supranuclear Palsy (PSP)

The definitive diagnosis of Progressive Supranuclear Palsy (PSP) requires identification of specific clinical features across four functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction, with vertical saccade abnormalities being the most specific diagnostic feature. 1, 2

Key Clinical Phenotypes of PSP

PSP presents with distinct clinical phenotypes that can be differentiated based on symptom patterns:

Richardson's Syndrome (RS) - Classical PSP

• Key features:
  • Early postural instability and falls (within first year)
  • Vertical supranuclear gaze palsy (especially downward)
  • Rapid disease progression (mean duration 5.9 years)
  • Poor response to levodopa
  • Early cognitive dysfunction/frontal dementia
  • More common in males (2:1 ratio)
  • Earlier age at death (mean 72.1 years) 3

PSP-Parkinsonism (PSP-P)

• Key features:
  • Asymmetric onset of symptoms
  • Presence of tremor
  • Initial moderate response to levodopa
  • Slower disease progression (mean duration 9.1 years)
  • Even sex distribution
  • Later age at death (mean 75.5 years)
  • Often misdiagnosed as Parkinson's disease 3

Diagnostic Algorithm

Step 1: Evaluate for Core Clinical Features Across Four Domains

1. Ocular Motor Dysfunction (highest specificity)

   • Test for decreased velocity of vertical saccades (especially downward)
   • Assess for absence of vertical optokinetic nystagmus
   • Look for square-wave jerks 1

2. Postural Instability

   • Document early falls (within first 3 years)
   • Assess for lurching gait and axial dystonia 4

3. Akinesia/Parkinsonism

   • Evaluate for bradykinesia and rigidity
   • Note asymmetry vs. symmetry of symptoms
   • Document response to levodopa (typically poor) 4, 3

4. Cognitive Dysfunction

   • Test for frontal executive dysfunction
   • Assess verbal fluency deficits
   • Evaluate for apathy and impulsivity 5

Step 2: Apply Movement Disorder Society Diagnostic Criteria

Based on combinations of features in these domains, classify as:

• Probable PSP: Highest certainty, requires most specific features
• Possible PSP: Intermediate certainty
• Suggestive of PSP: Lower certainty 2

Step 3: Obtain Supportive Imaging

• MRI Brain: Look for midbrain atrophy ("hummingbird sign")
• FDG-PET/CT: Assess for hypometabolism in medial frontal cortex, anterior cingulate, striatum, and midbrain
• DaTscan (Ioflupane SPECT/CT): Evaluate for decreased striatal uptake 1

Differential Diagnosis

Differentiate PSP from other parkinsonian syndromes:

• Parkinson's Disease (PD): Asymmetric onset, resting tremor, good levodopa response, later postural instability
• Multiple System Atrophy (MSA): Early autonomic dysfunction, cerebellar signs (MSA-C), striatonigral degeneration (MSA-P)
• Corticobasal Degeneration (CBD): Asymmetric limb apraxia, alien limb phenomenon, cortical sensory deficits
• Dementia with Lewy Bodies: Early visual hallucinations, fluctuating cognition
• Vascular Parkinsonism: Stepwise progression, vascular risk factors 4, 1

Common Pitfalls and Caveats

1. Misdiagnosis as Parkinson's Disease: PSP-P variant is frequently misdiagnosed due to asymmetric onset and initial levodopa response. Look for early falls and vertical gaze abnormalities to differentiate. 3

2. Delayed Recognition of Ocular Signs: Vertical supranuclear gaze palsy may develop later in the disease course. Early subtle slowing of vertical saccades is more sensitive than complete gaze palsy. 1, 6

3. Overreliance on Single Clinical Features: No single feature is pathognomonic; diagnosis requires constellation of findings across multiple domains. 2

4. Failure to Recognize Phenotypic Evolution: PSP variants may evolve throughout disease course, with patients developing features of different phenotypes over time. 7

5. Inadequate Ocular Examination: Proper testing of saccades and optokinetic nystagmus is essential but often overlooked or performed incorrectly. 1

Current diagnostic approaches have improved sensitivity but remain insufficient for early diagnosis. The 2017 Movement Disorder Society criteria represent the most up-to-date approach to clinical diagnosis, though biomarker development remains an active area of research. 7, 2