Atypical parkinsonism: MSA, PSP and corticobasal degeneration

At a glance

• Atypical parkinsonism is parkinsonism with features that don't fit Parkinson disease: early falls, early autonomic failure, cerebellar signs, gaze palsy, apraxia, symmetry and a poor or fading levodopa response.
• Multiple system atrophy (MSA) is a synucleinopathy. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are four-repeat (4R) tauopathies.
• All three progress faster than Parkinson disease. Median survival is about 6 to 10 years from symptom onset, and aspiration pneumonia is the commonest cause of death.
• No drug changes the course. Care is symptom-led, multidisciplinary and palliative early.
• See Parkinson disease for the MDS red flags that should prompt this differential.

Comparison

Feature	MSA	PSP	Corticobasal syndrome
Pathology	Alpha-synuclein glial cytoplasmic inclusions in oligodendrocytes	4R tau: tufted astrocytes, globose tangles	4R tau: astrocytic plaques (CBD), but many other pathologies
Onset	50s to 60s	60s	60s
Parkinsonism	Symmetric or asymmetric, early falls, poor response	Axial more than limb rigidity, neck extended, symmetric	Strikingly asymmetric limb rigidity and dystonia
Hallmark	Early severe autonomic failure, cerebellar ataxia, stridor	Vertical gaze palsy, backward falls in the first year, frontal syndrome	Apraxia, cortical sensory loss, alien limb, myoclonus
Cognition	Usually preserved early	Dysexecutive, apathy, slowed thinking	Apraxia, aphasia, frontal change
MRI	Putaminal atrophy with iron-sensitive signal loss; hot cross bun pons; middle cerebellar peduncle atrophy	Midbrain atrophy (hummingbird sign), reduced midbrain to pons ratio	Asymmetric frontoparietal atrophy

Multiple system atrophy

Subtypes

• MSA-P (parkinsonian): commoner in Western populations.
• MSA-C (cerebellar): gait and limb ataxia, scanning speech, nystagmus; commoner in Japan. See Cerebellar disorders.
• Both have autonomic failure. The parkinsonian and cerebellar features usually merge over time.

MDS criteria (2022)

• Sporadic, progressive, onset after age 30.
• Clinically established MSA: autonomic dysfunction plus poorly levodopa-responsive parkinsonism or a cerebellar syndrome, plus at least 2 supportive features and at least 1 MRI marker.
• Clinically probable MSA: at least 2 of autonomic dysfunction, parkinsonism (any levodopa response) and cerebellar syndrome, plus at least 1 supportive feature. No MRI needed.
• Autonomic dysfunction means post-void residual 100 mL or more, unexplained urge incontinence, or neurogenic orthostatic hypotension of at least 20/10 mmHg within 3 minutes. The 2008 criteria needed 30/15, which older texts still quote. These are the thresholds for clinically established MSA.
• For clinically probable MSA the autonomic bar is lower: any post-void residual, or neurogenic orthostatic hypotension within 10 minutes of standing or tilt.
• MRI markers (putaminal, pontine, middle cerebellar peduncle or cerebellar atrophy, hot cross bun sign) can appear in either subtype. The putaminal rim sign was left out of MDS 2022 because healthy people often show it on 3 T MRI.
• Supportive features: rapid progression, severe dysphagia or dysarthria within 3 years, early postural instability, inspiratory stridor or sighs, disproportionate antecollis or Pisa syndrome, levodopa-induced craniocervical dystonia without limb dyskinesia, jerky postural tremor, Babinski sign, cold blue hands and feet, erectile dysfunction under 60, pathological laughter or crying.
• Prodromal clues: erectile dysfunction, urinary symptoms and REM sleep behaviour disorder years before motor onset.

Pitfall: in a man with urinary retention and parkinsonism, a prostatectomy often fails because the bladder problem is neurogenic. Urodynamics first.

Management

• Orthostatic hypotension: stop vasodilators and diuretics, salt and fluid loading, compression garments, head-up bed tilt of about 10 degrees, midodrine or fludrocortisone. Check for supine hypertension, which treatment worsens.
• Bladder: measure post-void residual. Intermittent self-catheterisation when residual exceeds 100 mL; mirabegron for urgency rather than anticholinergics if cognition is a concern.
• Stridor and sleep-disordered breathing: laryngoscopy, CPAP, tracheostomy in selected patients. Nocturnal stridor is linked to sudden death.
• Levodopa trial in everyone with parkinsonism, up to about 1,000 mg/day if tolerated. Orthostatic hypotension often limits the dose.

Progressive supranuclear palsy

Recognition

• Richardson syndrome (PSP-RS), the classic form: unexplained backward falls in the first year, axial rigidity with neck extension, and vertical gaze palsy.
• Eye signs: slowed vertical saccades first (downgaze before upgaze), square wave jerks, reduced blink rate, then supranuclear palsy overcome by the doll's eye manoeuvre. Apraxia of eyelid opening and blepharospasm.
• Face: "astonished" stare with procerus contraction.
• Frontal features: apathy, dysexecutive syndrome, perseveration, the applause sign (keeps clapping after being asked to clap three times), pseudobulbar affect.
• Dysphagia and dysarthria come early, and aspiration is the usual cause of death.

MDS criteria (2017)

Domain	Highest-certainty feature
Ocular motor	O1 vertical supranuclear gaze palsy; O2 slow vertical saccades
Postural instability	P1 repeated unprovoked falls within 3 years; P2 tendency to fall on pull test
Akinesia	A1 progressive gait freezing within 3 years; A2 axial, levodopa-resistant parkinsonism
Cognitive dysfunction	C1 speech or language disorder; C2 frontal behavioural change; C3 corticobasal syndrome

• Probable PSP-RS = O1 or O2 plus P1 or P2.
• Other phenotypes: PSP-parkinsonism (asymmetric, tremor, partial levodopa response, often mistaken for Parkinson disease for years), progressive gait freezing, PSP-corticobasal syndrome, PSP-speech and language (non-fluent aphasia) and PSP-frontal.

Management

• Levodopa trial; benefit, if any, is modest and short-lived. Amantadine occasionally helps.
• Falls prevention: physiotherapy, a weighted walker, hip protectors, home modification. Patients lack insight into risk ("motor recklessness").
• Botulinum toxin for blepharospasm, apraxia of eyelid opening and dystonia.
• Speech pathology early; discuss feeding tubes before the crisis.
• The anti-tau antibodies gosuranemab and tilavonemab failed in phase 2 trials (2021).

Corticobasal syndrome and corticobasal degeneration

• Corticobasal syndrome (CBS) is the clinical picture. Corticobasal degeneration is the pathology, and the two match only about half the time. CBS can be caused by Alzheimer disease, PSP or frontotemporal lobar degeneration.
• Armstrong 2013 criteria, probable CBS: asymmetric presentation of 2 of limb rigidity or akinesia, limb dystonia and limb myoclonus, plus 2 of orobuccal or limb apraxia, cortical sensory deficit and alien limb phenomena.
• Bedside: a stiff, useless, dystonic arm held flexed; stimulus-sensitive myoclonus; cannot copy gestures or mime using a tool (ideomotor apraxia); agraphaesthesia and astereognosis with intact primary sensation; the hand wanders and grasps on its own.
• Can present as a non-fluent aphasia or frontal behavioural syndrome. See Dementia syndromes.
• Investigations: MRI with asymmetric frontoparietal atrophy, FDG-PET with asymmetric hypometabolism, and CSF Alzheimer biomarkers or amyloid PET to identify Alzheimer pathology.
• Management: levodopa rarely helps; clonazepam or levetiracetam for myoclonus; botulinum toxin for painful dystonia; occupational therapy for the useless limb.

Investigations across the group

• MRI brain is the most useful test. Ask for iron-sensitive sequences and midsagittal views of the midbrain.
• DaT SPECT is abnormal in all three and in Parkinson disease, so it does not separate them.
• Cardiac MIBG (limited availability): reduced in Parkinson disease and Lewy body dementia, usually normal in MSA.
• Alpha-synuclein seed amplification in CSF or skin is positive in Parkinson disease and MSA and negative in the tauopathies. It is still a research or specialist tool in Australia.
• Autonomic testing: lying and standing BP at 1 and 3 minutes, bladder scan for residual, tilt table.

Care in Australia

• Multidisciplinary clinics: neurologist, movement disorder nurse, physiotherapy, speech pathology, dietitian, continence and palliative care. Telehealth helps rural patients.
• NDIS if the access request is made before 65; My Aged Care afterwards.
• Driving: Austroads Assessing Fitness to Drive applies its neurological conditions standards (check the current edition for exact criteria). The licensing authority decides, and a conditional licence with periodic review may be possible on the treating doctor's advice while driving isn't impaired. Assess motor, cognitive, visual (gaze palsy) and orthostatic symptoms, and advise patients to notify the licensing authority.
• Advance care planning soon after diagnosis, covering feeding tubes, tracheostomy and preferred place of death.
• In hospital, as with Parkinson disease, give levodopa on time and avoid dopamine antagonists such as haloperidol and metoclopramide.

Pitfalls

• Calling early falls "Parkinson disease with poor balance". Falls in the first year suggest PSP.
• Missing orthostatic hypotension because BP was measured only sitting.
• Treating MSA urinary retention with prostate surgery.
• Using DaT SPECT to "confirm Parkinson disease" over MSA or PSP.
• Assuming CBS means CBD pathology; Alzheimer disease underlies a substantial minority and changes counselling.
• Abandoning levodopa after a low-dose trial. Give at least 600 mg/day, and up to about 1,000 mg/day if tolerated, before calling it a failure.