NeurologyTier 1Disease (DEADMAN)

Parkinson disease and related conditions - progressive supranuclear palsy

Description

4-repeat tauopathy - an atypical parkinsonian syndrome (Parkinson-plus)
Core: early postural instability with backward falls + vertical supranuclear gaze palsy + axial rigidity + early cognitive/behavioural change

The cardinal features

Vertical gaze palsy, downgaze first, later horizontal
- Supranuclear = voluntary saccades impaired, oculocephalic (doll's head) reflex preserved -> the lesion is above the nuclei
- Earliest sign is slowing of vertical saccades, before any range restriction
Falls within the first year, backwards - the single most useful discriminator from Parkinson disease
Axial > limb rigidity, extended neck posture (retrocollis)
Frontal/subcortical dementia - apathy, disinhibition, impulsivity ("motor recklessness" - rises from a chair without warning)
Applause sign - cannot stop after 3 claps (frontal, not specific)
Staring, reduced blink (~3/min), procerus sign (furrowed brow, "astonished" facies)
Pseudobulbar palsy - spastic dysarthria, dysphagia, emotional lability
Symmetrical from onset, poor/absent levodopa response, no tremor (or minimal)

Clinical subtypes (MDS criteria)

Subtype	Dominant feature
PSP-Richardson (classic)	Falls + gaze palsy + cognitive change; fastest decline
PSP-parkinsonism (PSP-P)	Asymmetric, tremor, initial levodopa response - misdiagnosed as PD for years; slower course
PSP-PGF (progressive gait freezing)	Pure freezing, minimal rigidity
PSP-CBS / PSP-SL / PSP-F	Corticobasal, speech-language (apraxia of speech), frontal presentations

Epidemiology

Prevalence ~5-7 per 100,000 (likely underestimated - often misdiagnosed as PD)
Commonest atypical parkinsonian syndrome
Onset typically 60-70 yrs; onset before 40 essentially excludes it
M slightly > F
Almost always sporadic; MAPT H1 haplotype is the major genetic risk factor
~5% of parkinsonism in specialist clinics

Aetiopathogenesis

4R tau aggregation (exon 10 inclusion) -> neurofibrillary tangles, tufted astrocytes, oligodendroglial coiled bodies
- Contrast: Alzheimer = 3R+4R; Pick disease = 3R; CBD = 4R (tufted astrocytes vs astrocytic plaques distinguish PSP from CBD)
Distribution: globus pallidus, subthalamic nucleus, substantia nigra, superior colliculus, periaqueductal grey, dentate nucleus, brainstem tegmentum
- Superior colliculus/rostral interstitial MLF involvement -> vertical gaze palsy
- Pedunculopontine nucleus -> postural instability and falls
Dopaminergic denervation is postsynaptic (striatal D2 loss) as well as presynaptic
- This is why levodopa fails - there is no intact receptor target downstream
MAPT H1/H1 genotype over-represented
Mimic to exclude: vascular parkinsonism, NPH, Whipple disease (oculomasticatory myorhythmia), anti-IgLON5 disease, niemann-Pick type C in the young, midbrain tumour

Diagnosis

Clinical. Definite PSP requires neuropathology.

MDS diagnostic domains

Four functional domains, each graded by certainty:
- O - ocular motor dysfunction (vertical supranuclear gaze palsy > slow vertical saccades > frequent macro square-wave jerks / lid apraxia)
- P - postural instability (falls within 3 yrs > tendency to fall on pull test > pull test retropulsion)
- A - akinesia (progressive gait freezing within 3 yrs > parkinsonism, akinetic-rigid, levodopa-resistant > parkinsonism with tremor or levodopa-responsive)
- C - cognitive dysfunction (speech/language disorder > frontal behavioural presentation > corticobasal syndrome)
Mandatory: sporadic, age >=40 at onset, gradually progressive

Examination

Test saccade speed, not just range - ask for fast up-down and left-right refixation
Doll's head manoeuvre: full eye movements return -> confirms supranuclear
Square-wave jerks on fixation, apraxia of eyelid opening, blepharospasm
Pull test - unguarded, en-bloc retropulsion
Axial vs appendicular tone; retrocollis
Frontal release signs, applause sign, verbal fluency
Speech and swallow

Imaging

MRI midsagittal: hummingbird/penguin sign (midbrain tegmental atrophy), Mickey Mouse sign on axial, third ventricle widening
Midbrain:pons ratio <0.52, or MR parkinsonism index elevated - supportive, not diagnostic
Rule out vascular disease, hydrocephalus and structural lesions - the main reason to image
DAT scan abnormal but does not separate PSP from PD

Adjuncts

Formal neuropsychology - frontal-executive pattern
Videofluoroscopic swallow study - aspiration risk frequently silent
CSF and blood biomarkers (NfL raised, p-tau) - research/supportive only
Levodopa challenge to a genuine dose (e.g. up to 1000 mg/day equivalent for 1-3 months) before declaring non-response

Management

No disease-modifying therapy. Management is symptomatic, anticipatory and multidisciplinary - and the MDT is where the benefit actually comes from.

A. Motor

Levodopa trial in every patient - titrate to a genuine dose before abandoning
- ~20-40% show a modest, transient benefit (higher in PSP-P)
- Withdraw slowly if ineffective; no benefit from dopamine agonists, and they worsen confusion and hallucinations
Amantadine - occasionally helps gait freezing
Physiotherapy: balance, gait, eye-movement and "stop-look" training
Falls prevention is the central intervention: weighted walker (a light frame accelerates backward falls), home modification, remove loose rugs, hip protectors
Botulinum toxin for blepharospasm, apraxia of eyelid opening, focal dystonia, sialorrhoea

B. Bulbar and nutrition

Early speech pathology review, repeated as swallow deteriorates
Diet texture modification, thickened fluids
PEG discussion early, while the patient can participate - does not prevent aspiration of saliva or prolong survival, but may ease burden
Sialorrhoea: glycopyrrolate, botulinum toxin to salivary glands (avoid oral anticholinergics - worsen cognition)

C. Vision

Prisms for downgaze restriction (reading, stairs); high-contrast tape on step edges
Ocular lubricants for reduced blink and exposure
Lid surgery rarely

D. Cognitive and behavioural

Cholinesterase inhibitors do not help and may worsen gait - avoid
Non-pharmacological behaviour strategies first
SSRIs for depression and pseudobulbar affect
Avoid antipsychotics where possible; quetiapine at low dose if essential

E. Anticipatory and palliative

Discuss prognosis, advance care planning and enduring guardianship early - decision-making capacity declines
Continence, constipation, pressure area and pain management
Carer support and respite - carer burden in PSP exceeds that in Parkinson disease
Palliative care referral well before the terminal phase
Driving cessation is required early - impaired downgaze, falls, impulsivity and slowed executive function together
Brain donation discussion for definitive diagnosis

Associations

Other 4R tauopathies: corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, some FTD-MAPT
MAPT H1 haplotype
Frontotemporal dementia spectrum - overlapping behavioural and language presentations
Guadeloupean and Guamanian atypical parkinsonism (annonacin-containing fruit)
Depression, apathy and pseudobulbar affect
Sleep: insomnia, REM sleep behaviour disorder (far less common than in synucleinopathies - its presence favours MSA/DLB/PD)
Aspiration pneumonia, malnutrition
Autonomic failure is NOT a feature - prominent early orthostatic hypotension or urinary failure points to MSA

Natural history & complications

Relentlessly progressive; median survival ~6-9 years from symptom onset (PSP-P longer, ~9-12; PSP-Richardson shorter, ~6-7)
Milestones: falls within 1 year -> wheelchair by ~3-4 years -> dysphagia by ~3-5 years
Early dysphagia and early falls are the strongest predictors of shorter survival
Aspiration pneumonia is the usual cause of death

Complications

Fall-related injury: hip fracture, subdural haematoma (a sudden deterioration in a faller is a subdural until imaged)
Aspiration pneumonia, malnutrition, weight loss
Immobility - pressure injury, contracture, VTE
Urinary incontinence, constipation
Depression, carer burnout

Distinguishing the atypical parkinsonian syndromes

	PSP	MSA	CBD	DLB
Hallmark	Early backward falls, vertical gaze palsy	Autonomic failure, cerebellar or parkinsonian	Asymmetric apraxia, alien limb	Visual hallucinations, fluctuation, RBD
Symmetry	Symmetric	Symmetric	Markedly asymmetric	Symmetric
Levodopa	Poor	Partial, wanes	Poor	Poor, worsens hallucinations
Pathology	4R tau	alpha-synuclein (glial cytoplasmic inclusions)	4R tau	alpha-synuclein (Lewy bodies)
MRI	Hummingbird sign	Hot cross bun, putaminal rim	Asymmetric parietal atrophy	Often normal

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