Autonomic dysfunction - Parkinson disease

Description

Autonomic failure is a core, non-motor feature of Parkinson disease - not a complication of treatment
Often precedes motor onset by years (constipation, erectile dysfunction) and is a major determinant of quality of life and institutionalisation

The domains

Domain	Manifestation
Cardiovascular	Orthostatic hypotension, supine hypertension, postprandial hypotension
Genitourinary	Urinary frequency, urgency, nocturia; erectile dysfunction
Gastrointestinal	Constipation, gastroparesis, dysphagia, sialorrhoea
Thermoregulatory	Hyperhidrosis (often "off" periods), heat intolerance
Pupillomotor	Impaired accommodation

The three named in most exam stems: orthostatic hypotension, urinary frequency and constipation**

Autonomic symptoms in >70-90% of PD patients over the disease course
Constipation in ~60-80% - may precede motor symptoms by 10-20 years and is a recognised prodromal marker
Orthostatic hypotension in ~30-60%, rising with disease duration and levodopa dose
Erectile dysfunction in ~60% of men; urinary symptoms in ~40-70%
Severe, early autonomic failure should prompt reconsideration of multiple system atrophy rather than PD

Alpha-synuclein (Lewy) pathology is not confined to the substantia nigra
Braak staging: pathology begins in the dorsal motor nucleus of the vagus and olfactory bulb (stage 1-2) before reaching the substantia nigra (stage 3)
- -> explains why constipation and hyposmia precede tremor by years
Peripheral autonomic denervation
- Lewy bodies in the enteric nervous system -> slowed colonic transit, gastroparesis
- Cardiac sympathetic denervation -> loss of noradrenergic tone -> neurogenic OH with a blunted heart rate response
- This is the key contrast with MSA, in which the lesion is preganglionic/central and cardiac postganglionic innervation is preserved - the basis of MIBG scintigraphy
Drug contribution: levodopa and dopamine agonists cause vasodilatation and worsen OH; anticholinergics worsen constipation, retention and cognition

Ask directly - patients rarely volunteer these

Lying and standing BP at 1 and 3 minutes at every clinic visit - and note whether the pulse rises (it should not in neurogenic OH)
Bowel frequency and consistency; bloating and early satiety (gastroparesis)
Urinary frequency, urgency, nocturia, incomplete emptying
Sexual function; sweating; drooling; swallowing

Confirm and exclude alternatives

Orthostatic hypotension: >=20/10 mmHg fall within 3 min; blunted HR response confirms neurogenic
Urinary symptoms: post-void residual and uroflowmetry
- In men, exclude prostatic obstruction before attributing to PD - and before starting an anticholinergic
Gastroparesis: gastric emptying scintigraphy after excluding mechanical obstruction
- Delayed emptying also causes erratic levodopa absorption and unpredictable "off" periods
Constipation: exclude colorectal malignancy where red flags exist

When to doubt the diagnosis of PD

Severe autonomic failure within the first 1-2 years, poor levodopa response, early falls, cerebellar or pyramidal signs, stridor -> multiple system atrophy
Early prominent visual hallucinations and fluctuating cognition -> dementia with Lewy bodies

Review the drug list first - much of this is iatrogenic or drug-aggravated.

A. Orthostatic hypotension

Reduce or reschedule antihypertensives; consider reducing dopamine agonist dose
Salt and fluid liberalisation, abdominal binder, head-up bed tilt, counter-manoeuvres, bolus cold water
Fludrocortisone 0.1-0.2 mg daily or midodrine 2.5-10 mg tds (last dose >=4 h before bed)
Pyridostigmine where supine hypertension coexists
Do not treat supine hypertension aggressively at the cost of daytime falls

B. Constipation

Adequate fluid and fibre, mobility
Macrogol (osmotic laxative) is first-line; add a stimulant if needed
Review anticholinergics (benztropine, oxybutynin, TCAs) - cease where possible
Severe constipation impairs levodopa absorption and worsens motor control

C. Urinary symptoms

Detrusor overactivity is the usual pattern - urgency, frequency, nocturia
Timed voiding, fluid timing, treat constipation first
Prefer mirabegron (beta-3 agonist) over antimuscarinics - anticholinergics worsen cognition, constipation and retention in PD
- If an antimuscarinic is unavoidable, use trospium or darifenacin (poor CNS penetration)
Nocturia: head-up tilt, evening fluid restriction, desmopressin with sodium monitoring
Intravesical botulinum toxin or intermittent catheterisation for refractory disease
Exclude prostatic obstruction and check post-void residual before any antimuscarinic

D. Gastroparesis and levodopa absorption

Small frequent low-fat meals
Domperidone - the antiemetic/prokinetic of choice (does not cross the blood-brain barrier; QT prolongation - ECG and avoid with other QT-prolonging drugs**)
*Never metoclopramide or prochlorperazine - central D2 blockade worsens parkinsonism*
Dispersible or intestinal-gel levodopa formulations for erratic response

E. Other

Sialorrhoea: glycopyrronium (poor CNS penetration), sublingual atropine drops, botulinum toxin to salivary glands
Erectile dysfunction: sildenafil - caution, it worsens orthostatic hypotension
Hyperhidrosis: usually "off"-related - optimise dopaminergic cover
Dysphagia: speech pathology assessment; aspiration is a leading cause of death

Autonomic features progress with disease duration and correlate with disease stage and cumulative levodopa exposure
Orthostatic hypotension is an independent predictor of falls, cognitive decline and mortality in PD
Constipation and hyposmia may precede motor onset by >10 years
Aspiration pneumonia from dysphagia is the leading cause of death in advanced PD
Non-motor features, not motor features, are the main determinants of quality of life and nursing home placement in advanced disease

Monitor

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