Non-motor symptoms of Parkinson's disease

Non-motor symptoms (NMS) are common in PD and, in the geriatric population, contribute more to disability, institutionalisation and carer burden than the motor features.

Pathy's lists them as bradyphrenia (slowness of mental function), depression, memory problems and dementia, constipation, bladder dysfunction and autonomic dysfunction (gastrointestinal, sexual, cardiovascular). Essentials adds psychosis, anxiety and sleep disturbance.

They can be grouped as neuropsychiatric, cognitive, autonomic, sleep and sensory.

Neuropsychiatric symptoms are dominated by anxiety and depressive syndrome. The anxiety disorders encountered are mainly generalised anxiety disorder and obsessive–compulsive disorder.

Major depressive episodes are frequent — about 50% of patients may be affected during the course of the disease. Diagnosis is difficult because fatigue, sleep disorders and lack of interest occur in PD in the absence of overt depression.

Cognitive impairment is never a sign of early PD and is observed only after several years of evolution (PD-related dementia). Dementia occurring within a few months of parkinsonism indicates dementia with Lewy bodies instead.

Visual hallucinations, delusions and delirium occur in advanced disease and are frequently dose-related adverse effects of levodopa rather than the disease itself.

Autonomic disorders are dominated by orthostatic hypotension and constipation.

Orthostatic hypotension is directly related to autonomic dysfunction and is often worsened by antiparkinsonian drugs. It is defined as a fall in systolic BP of 20 mmHg or diastolic BP of 10 mmHg within three minutes of standing from supine. It is often asymptomatic but can cause discomfort or syncope. Repeated search for orthostatic hypotension is part of the monitoring of any parkinsonism patient.

Constipation is found in about 50% of PD patients, related to impaired bowel motility, sphincter dysfunction and poor physical activity. It arises from dyssynergic defecation due to incoordination of the pelvic floor musculature and from the constipating effect of PD medication.

Constipation is a key symptom that must be actively elicited — it causes abdominal discomfort, nausea and reduced appetite, and is associated with reduced efficacy of medications due to reduced absorption.

Gastric emptying is delayed in at least 70% of PD patients, causing nausea and bloating and impairing nutrition and drug absorption. Small-intestinal, colonic and anorectal dysmotility are also common, with prolonged oro-caecal transit.

Other autonomic symptoms: sweating, drooling, sexual dysfunction and urinary frequency, urgency and dysuria. Urinary symptoms may be attributed to PD only after excluding urinary infection, bladder or prostate disease and anticholinergic drugs.

Swallowing: heartburn is common from impaired acid clearance. The effects of levodopa and anticholinergics on swallowing are inconsistent — either may improve or worsen dysphagia. Limited data indicate benefit from subcutaneous apomorphine infusion.

Impaired olfaction is an early sign, reflecting early involvement of the olfactory pathways by α-synuclein pathology. Hyposmia and visual hallucination are supportive criteria in the Queen Square Brain Bank criteria.

REM sleep behaviour disorder — loss of normal REM atonia with acting-out of dreams — results from brainstem circuit dysfunction and is strongly associated with neurodegenerative disease; melatonin is used in treatment.

In advanced PD, patients experience insomnia, pain, sweats, orthostatic hypotension, dysphagia, dysarthria, drooling of saliva, urinary dysfunction, and cognitive or psychiatric disorders including depression, anxiety, visual hallucinations and dementia.

The governing rule (Pathy's Table 53.4): every non-motor treatment is considered only after adjusting levodopa therapy, because levodopa itself does not improve non-motor symptoms, posture or gait, and many non-motor problems are levodopa side effects.

Best-evidence treatments: domperidone for nausea and vomiting (ECG monitoring for QT prolongation; metoclopramide is contraindicated); venlafaxine for depression; clozapine or pimavanserin for hallucinations and delusions; rivastigmine for dementia and for apathy; droxidopa for orthostatic hypotension; sleep hygiene for insomnia; probiotics, prebiotic fibre, hydration and macrogol for constipation; botulinum toxin into salivary glands for severe drooling; sildenafil for erectile dysfunction.

Other options: SSRIs, cognitive-behavioural therapy or rTMS for depression; SSRIs or CBT for generalised anxiety (no best-evidence treatment exists); donepezil for dementia; midodrine, fludrocortisone and elastic venous compression for orthostatic hypotension; melatonin for insomnia; lubiprostone or psyllium for resistant constipation; solifenacin (low brain penetration) for urinary urgency. Pramipexole is effective for PD depression but may induce delirium and should not be first choice in older patients. No effective treatment exists for mild cognitive impairment in PD.

Clozapine practicalities: start 12.5 mg daily, titrate in five-day increments to a usual 25–50 mg; contraindicated in neutropenia; blood count weekly for two months then twice monthly; discontinue permanently if the neutrophil count falls below 1500/mm3. Pimavanserin, a 5-HT2A inverse agonist, is effective and safe without haematological monitoring.

Timed toileting every 2–4 hours and 30 minutes after meals improves continence and prevents constipation, particularly in patients with coexisting cognitive impairment.