NeurologyTier 1Disease (DEADMAN)

Parkinson disease and related conditions - multiple systems atrophy

Description

Sporadic, progressive alpha-synucleinopathy - autonomic failure + parkinsonism and/or cerebellar ataxia
Pathology: glial cytoplasmic inclusions (Papp-Lantos bodies) of alpha-synuclein in oligodendrocytes
- *An oligodendroglial synucleinopathy - Parkinson disease and DLB are neuronal. That is the defining pathological distinction*

Subtypes

	Predominant	Notes
MSA-P	Parkinsonism	~2/3 in Western populations; rigid-akinetic, symmetric, jerky postural tremor rather than pill-rolling rest tremor
MSA-C	Cerebellar	~1/3 (higher in Japan); gait and limb ataxia, scanning dysarthria, nystagmus

Both develop autonomic failure - it is obligatory for the diagnosis

The atypical parkinsonian syndromes - place MSA among them

	Discriminating feature
MSA	Early, severe autonomic failure; cerebellar signs; stridor; poor/short-lived levodopa response
PSP (Steele-Richardson-Olszewski)	Early falls (backwards) in the first year, vertical supranuclear gaze palsy (down more than up), axial > limb rigidity, frontal behavioural change, "surprised" stare
Corticobasal degeneration	Markedly asymmetric, apraxia, alien limb, cortical sensory loss, myoclonus, dystonia
Dementia with Lewy bodies	Dementia within 1 year of parkinsonism, fluctuating cognition, visual hallucinations, RBD, neuroleptic sensitivity
Drug-induced parkinsonism	Symmetric, exposure to dopamine blockers (antipsychotics, metoclopramide, prochlorperazine), may take up to 12 months to resolve after cessation
Vascular parkinsonism	Lower-body predominant, gait apraxia, pyramidal signs, stepwise course, white matter disease
Idiopathic Parkinson disease	Asymmetric onset, rest tremor, excellent and sustained levodopa response

Epidemiology

Incidence ~0.6-3 per 100,000/yr; prevalence ~2-5 per 100,000
Mean onset ~55-60 yrs - younger than idiopathic Parkinson disease
M=F (some series show a slight male excess)
~5-10% of parkinsonism in movement disorder clinics
Almost always sporadic - familial cases are exceptional (COQ2 variants)

Aetiopathogenesis

Misfolded alpha-synuclein accumulates in OLIGODENDROCYTES -> glial cytoplasmic inclusions
-> oligodendroglial dysfunction, loss of trophic support (dec GDNF), demyelination, and secondary neuronal loss
Prion-like cell-to-cell propagation of pathological synuclein; neuroinflammation and microglial activation
Selective vulnerability determines the phenotype
- Striatonigral degeneration (putamen, SNpc) -> MSA-P
- Olivopontocerebellar degeneration -> MSA-C
- Intermediolateral cell columns of the cord, Onuf's nucleus, medullary catecholaminergic nuclei -> autonomic failure
- *Post-synaptic striatal degeneration is why levodopa fails* - the receptor target is lost, not just the dopamine
Risk factors are poorly defined; no established environmental cause

Diagnosis

A clinical diagnosis (MDS criteria 2022) - clinically established, clinically probable, and possible prodromal MSA (research use only)
Definite MSA requires neuropathology

Core features

Autonomic failure - severe and early. The single most useful discriminator
- Cardiovascular: severe orthostatic hypotension (a drop of >=20/10 mmHg within 3 min, and the criteria require a substantial drop), supine hypertension, syncope
- Urogenital: erectile dysfunction (often the first symptom in men, years before), urinary urgency and frequency, then incomplete bladder emptying with a raised post-void residual, incontinence
- Also: constipation, anhidrosis, dry mouth/eyes
- *Autonomic failure that appears early and out of proportion to the motor disease is MSA until proven otherwise*
Parkinsonism - symmetric, rigid-akinetic, rapidly progressive, with a poor or transient levodopa response
Cerebellar - gait and limb ataxia, cerebellar dysarthria, downbeat or gaze-evoked nystagmus

Supportive clinical features - the "red flags" of MSA

Stridor and inspiratory sighing - vocal cord abductor paresis; predicts sudden death
Severe dysarthria and dysphagia disproportionate to the motor disease
Antecollis (disproportionate neck flexion) and Pisa syndrome; camptocormia
REM sleep behaviour disorder - very common, often the earliest feature
Orofacial dystonia induced by levodopa ("risus sardonicus")
Cold, dusky, violaceous hands with poor capillary return
Jerky, irregular postural/action tremor rather than a classical rest tremor
Emotional incontinence (pathological crying/laughing)
Preserved cognition until late - marked early dementia argues against MSA and for DLB or PSP

Investigations

Test	MSA
Brain MRI	"Hot cross bun" sign in the pons (pontocerebellar fibre degeneration); putaminal atrophy with a hyperintense putaminal rim; middle cerebellar peduncle hyperintensity and atrophy; cerebellar and pontine atrophy
Cardiac MIBG (123I-metaiodobenzylguanidine) scintigraphy	Uptake PRESERVED in MSA (pre-ganglionic lesion) but REDUCED in Parkinson disease (post-ganglionic cardiac sympathetic denervation) - the key discriminating test
Autonomic function testing	Head-up tilt, Valsalva, sweat testing - confirms neurogenic orthostatic hypotension (absent compensatory tachycardia)
Urodynamics + post-void residual	Detrusor overactivity then raised residual >100 mL
Sleep study	Stridor, RBD, obstructive and central apnoea
Levodopa challenge	Poor or unsustained response (though up to 1/3 respond initially, and the response then fades)
Skin biopsy / seed amplification assay	Phosphorylated alpha-synuclein - increasingly used, not yet routine

Exclude: Wilson disease, structural lesions, normal pressure hydrocephalus, hereditary ataxias (SCA1/2/3/6/7, fragile X tremor-ataxia syndrome, Friedreich), paraneoplastic and autoimmune cerebellar disease, coeliac, B12, thyroid

Management

No disease-modifying therapy. Management is symptomatic, anticipatory, and multidisciplinary - and autonomic symptoms usually cause more disability than the motor ones.

A. Neurogenic orthostatic hypotension - the highest-yield problem

Non-pharmacological first, and never abandon them
- Stop or reduce antihypertensives, alpha blockers, diuretics, nitrates, tricyclics
- Increase salt and fluid (2-3 L/day); rapid ingestion of 500 mL of cold water raises BP within 20-30 min - a genuinely useful pre-meal manoeuvre
- Compression stockings to waist level and an abdominal binder (the abdominal binder is more effective than stockings)
- Slow positional change, counter-manoeuvres (leg crossing, squatting), avoid large carbohydrate meals, alcohol, heat and straining
- Head-up tilt of the bed at night - reduces nocturnal pressure natriuresis and morning hypotension
Drugs
- Fludrocortisone 0.1-0.2 mg daily - monitor potassium, oedema, supine hypertension
- Midodrine 2.5-10 mg up to three times daily - last dose at least 4 h before bed
- Droxidopa where available (not marketed in Australia); pyridostigmine for milder cases
- Consider desmopressin at night for nocturnal polyuria
*Supine hypertension is the constant trade-off* - avoid lying flat during the day, elevate the head of the bed, consider a short-acting nocturnal agent (GTN patch removed in the morning)
Target symptom relief and standing time, not a blood pressure number

B. Parkinsonism

Trial levodopa to at least 1000 mg/day (with carbidopa or benserazide) for 3 months before declaring failure
- ~1/3 respond initially; the response usually fades within 1-2 years
- Watch for worsening orthostatic hypotension and orofacial dystonia
Amantadine occasionally helps; dopamine agonists are poorly tolerated (hypotension, hallucination)
*Deep brain stimulation is NOT effective and is contraindicated*
Physiotherapy, exercise and falls prevention have the best evidence of anything

C. Urogenital

Post-void residual measurement in everyone - the management diverges completely above and below ~100 mL
Storage symptoms: antimuscarinic (cognitive load) or mirabegron; intradetrusor botulinum toxin
Retention: clean intermittent self-catheterisation - the standard, and far preferable to an indwelling catheter
Erectile dysfunction: sildenafil - warn about profound hypotension; give with the patient supine and BP known

D. Bulbar and respiratory - where the risk of sudden death sits

Stridor: refer to ENT and sleep medicine urgently. CPAP is first-line; tracheostomy for severe or refractory stridor
- *Nocturnal stridor is a marker of sudden death - it must be asked about at every visit*
Speech pathology and dietitian; texture modification, thickened fluids
Discuss PEG early, as part of advance care planning
Sialorrhoea: glycopyrronium, atropine drops, botulinum toxin to salivary glands

E. Other

RBD: melatonin first (clonazepam worsens OSA and falls); bedroom safety
Constipation: fluid, fibre, macrogol
Depression, emotional incontinence, pain, spasticity
Early palliative care, advance care planning, enduring guardianship
Driving cessation (falls, syncope, cognitive and visual issues)
Carer support; MSA Australia / Parkinson's Australia; occupational therapy home assessment

Associations

REM sleep behaviour disorder - a prodromal marker in most; conversion from idiopathic RBD to MSA is much less common than to Parkinson disease or DLB
Nocturnal stridor and vocal cord abductor paresis
Sleep-disordered breathing - obstructive and central
Neurogenic orthostatic hypotension with supine hypertension
Neurogenic bladder - recurrent UTI, hydronephrosis
Depression, anxiety, emotional incontinence
Cold discoloured extremities
Not associated with: significant early dementia, hallucinations, or a sustained levodopa response - each of those points elsewhere

Natural history & complications

Relentlessly progressive - median survival 6-10 years from symptom onset (roughly half that of idiopathic Parkinson disease)
Median time to walking aid ~3 years; to wheelchair ~5 years; to bed-bound ~6-8 years
Worse prognosis: early autonomic failure, stridor, MSA-P subtype, older onset, early falls, rapid motor progression

Causes of death

Bronchopneumonia and aspiration (commonest)
Sudden death - nocturnal, related to stridor, laryngeal obstruction or central apnoea
Urosepsis, pulmonary embolism, cachexia

Complications

Recurrent falls and fracture; syncope and head injury
Aspiration pneumonia; malnutrition
Urinary retention, recurrent UTI, renal impairment
Pressure injury, contracture, immobility
Supine hypertension -> end-organ damage
Carer burden, depression in patient and carer

Monitor

Lying and standing BP at every visit (and supine BP overnight if drug-treated)
Ask about stridor, choking, falls, and post-void residual at every visit
Swallow safety and weight
Levodopa response - and stop it if there is no benefit
Advance care planning revisited as the disease progresses

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