Introduction
When do non-motor symptoms of PD present?
How to detect NMS
What are the NMS of PD?
Sensory symptoms
Sleep disorders
Gastrointestinal symptoms
Neuropsychiatric manifestations of PD
Non-motor symptoms during off periods
NMS secondary to dopaminergic drugs
Other NMS of PD
Conclusion
References

Introduction

Parkinson’s disease (PD) has been long seen as mainly a disease that causes motor symptoms. However non-motor symptoms (NMS) are quite common, may precede the motor symptoms and could be quite disabling. They also impact on patients’ quality of life, increase hospitalisation and cost of care and increase burdens on carers.1

This article will discuss the NMS of PD and how to recognise and manage them.

When do non-motor symptoms of PD present?

NMS symptoms can precede the motor symptoms of PD by many years. They can also present at the onset of the motor symptoms or later on in the disease.

It has been noted that anosmia affects 90% of PD patients long before a diagnosis is made. REM sleep behavioural disorder (RBD) predated motor symptoms of PD in 40% of PD patients. Depression was noted to be present in 9.2% of patients prior to motor symptoms.1

However, there are other NMS of PD that do not usually present until later stages of the disease such as dementia, urinary or faecal incontinence and swallowing problems and their occurrence before the onset of motor symptoms or early in the disease may suggest other diagnosis such as dementia with Lewy body (DLB), multisystem atrophy (MSA) or vascular Parkinsonism.

In one study 109 newly diagnosed untreated PD and 107 controls from Spanish and Austrian centres were assessed for NMS symptoms using a custom-made questionnaire.2

17 out of 31 NMS were more common in patients than in control. They were usually mild and frequently reported at different time span before motor symptoms. Anhedonia, apathy, memory complaints and inattention occurred more frequently during the two years pre-motor period. Smell loss, mood disturbances, taste loss excessive sweating, fatigue and pain occurred more frequently in the 2-10 years premotor period. Constipation, RBD characterised by dream-enacting behaviour, excessive daytime sleepiness (EDS) and postprandial fullness were frequently reported more than 10 years before the onset of motor symptoms

How to detect NMS

A multidisciplinary group of experts including patient group representatives developed a screening tool of 30 items which is called NMS Quest.3

This has been shown to be useful as a screening tool for NMS of PD and does not provide an overall score of disability. It is designed to draw attention to the NMS of PD and initiate further investigation. They advise giving the questionnaire to the patient or caregiver to fill in while waiting to be seen in the clinic. The issues flagged would then be addressed by the clinician.

What are the NMS of PD?

PD is considered as a multisystem disease that affects many body systems such as gastrointestinal, autonomic nervous system and causes neuropsychiatric symptoms in addition to sleep disorders sensory and general symptoms such as weight loss, fatigue and visual disturbances.

How to detect NMS

Anosmia and hyposmia

Many patients with PD when asked directly admit to having lost the sense of smell but may not have been bothered by it and hence would not have sought medical advice. In a systematic review and meta-analysis, they found the olfactory bulb volume on both right and left sides were significantly smaller in PD compared to controls.4

Anosmia and hyposmia predate the onset of motor symptoms of PD by 2-10 years.

Ageusia

Loss of taste sensation is another symptom that can predate motor symptoms. This is not usually distressing to a patient but usually detected when screened with NMS Quest.

Pain

Pain is well recognised in PD, but the mechanism of which is not known. Patients can develop musculoskeletal pain or can develop symptoms of frozen shoulder.5

However, it is important to rule out other causes for any pain before assuming it is an NMS of PD. Patients could also develop paraesthesia with pain and tingling in the extremities. Pain is common during motor fluctuations especially during off periods.

Sleep disorders

This involves RBD, insomnia, excessive daytime sleepiness (EDS) and sudden onset of sleep (SOOS)

RBD

RBD can precede the symptoms of PD. It happens as a result of a loss of atonia during REM sleep resulting into the patients acting out their dreams that is sometimes more distressing to the spouse rather than the patient leading to injuries to the bed partner. However, in some occasions, the patient may vocalise, sleepwalk or fall from bed and may be injured as a result or develop subdural haemorrhage.

Meta-analysis showed that RBD is a marker for the development of neurodegenerative disease in particular synucleinopathy. Patients with RBD were followed up for many years. The risk of developing neurodegenerative disorder was 33.5% at five years, 82.4% at 10.5 years, 96.6% at 14 years.6

The majority who converted developed PD (43%) followed by DLB (25%).

Treatment of distressing RBD would be with clonazepam at night or melatonin.7

EDS and sudden onset of sleep (SOOS)

These are other sleep disorders that may impact on patient’s ability to drive. It is important to ask PD patients about EDS and SOOS and if they do drive and are likely to fall asleep whilst driving then they should be advised not to drive unless this can be resolved by adjusting medications as dopamine agonists (DA) are more likely to cause sleepiness than levodopa and it may be worth considering reducing DA or switching to Levodopa. Other sedative drugs should be stopped if possible such as anxiolytics or antipsychotics or sedative antihistamines.

Physical methods in the form of sleep hygiene should be used such as exercise during the day to improve night time sleepiness and limiting naps to maximum 30 minutes. If these measures fail consider modafinil.7

Insomnia and fragmentation of sleep is another sleep disorder in PD and can be managed by sleep hygiene. Restless leg syndrome (RLS) and periodic limb movements (PLM) can occur in PD and may cause insomnia as the patient has persistent need to move his legs and this could be managed by DA in a small dose like pramipexole or ropinirole or rotigotine two hours before bedtime. Iron supplements can help even in the presence of normal serum ferritin or iron studies as it is thought that low iron level in the CNS rather than the serum is a contributing factor.8

Gastrointestinal symptoms

Constipation

Constipation is the commonest NMS of PD and may precede motor symptoms by many years.

However, it is important to rule out any other cause of constipation before assuming it is purely secondary to PD. If there is a recent change in bowel habit then investigating the lower GI tract should be considered.  Hypothyroidism and iatrogenic causes for constipation such as anticholinergic drugs and opiate analgesics should be looked for and addressed. Non-pharmacological measures include encouraging mobility, regular exercises, increasing the fibre content of food and fluid intake would help. 

It has been shown that macrogols are more effective than lactulose for constipation in PD.9

Constipation due to anorectal dysfunction can be difficult to treat. Laxatives may worsen the condition and cause soiling.  Dopaminergic drugs may help and measures such as regular faecal training, botox injection of puborectalis or sacral nerve stimulation can be used. In resistant constipation where two maximum doses of laxatives have been used the selective serotonin 5HT4-receptor agonist with prokinetic properties, procalupride can be tried. This drug can theoretically improve gastric emptying.

Delayed gastric emptying

This is another GI NMS of PD. It causes upper GI symptoms and may delay the absorption of PD medications resulting into “delayed on” or “no on” when the patient remains bradykinetic early on in the day.

Dopamine antagonist like metoclopramide cannot be used to treat this condition in PD patients but domperidone could be used at a maximum dose of 10mg tds with monitoring of QT interval as it may cause QT interval prolongation. Macrolides can be used but not on a long-term basis.

Dysphagia

Dysphagia is a late NMS of PD. If it occurs early in the disease then it would point out to other parkinsonian syndromes.

In PD, dysphagia occurs in both oral and pharyngeal stages of swallowing. Increasing the dose of PD medication can improve swallowing. Involvement of speech and language therapist (SALT) earlier at the onset of symptoms is important. They can advise on using thickened fluids and alteration of the consistency of food and frequency of swallowing. They would also refer to Videofluoroscopy if necessary. If the above measures fail and a patient is at risk of aspiration then insertion of a gastrostomy feeding tube (PEG) may be indicated if appropriate.10

Patient’s opinion or prior advanced directives should be taken into consideration. The presence of severe dementia or when the disease is in the palliative stage, insertion of a PEG tube may not be appropriate.

Drooling

Drooling is a common NMS of PD. It is not caused by excessive salivary production but by delayed patient’s swallowing. SALT can advise about non-pharmacological measures to prevent drooling.

If they fail then sublingual atropine drops can be used as they are less likely to cause systemic side effects, alternatively, ipratropium spray could be applied sublingually. Systemic antimuscarinic drugs could be used such as glycopyrrolate. In severe cases, referral to a specialist for botulinum toxin type A or B salivary gland injection can be considered.7

Neuropsychiatric manifestations of PD

Depression

This is the commonest psychiatric symptom of PD that may precede PD long before the onset of motor symptoms. Parmipexole has been proven to be efficacious in treating depression in PD.11

SSRI’s such as paroxetine or citalopram can be used to treat depression. SNRI’s such as venlafaxine extended release. Tricyclic antidepressants nortriptyline and desipramine have been shown in some studies to be likely efficacious in treating depression in PD and are recommended by movement disorder society.11

Psychosis

Psychosis is a late symptom of PD and can be mild in the form of visual hallucinations which could be non-distressing and may not warrant treatment to sever distressing visual hallucinations and paranoid delusions which could be very serious especially to the spouse and may lead to institutionalisation.

Risk factors for psychosis include old age, cognitive impairment, depression history of vivid dreams and RBD.

Patients who develop acute psychosis should be screened for delirium to exclude any other causative factors before assuming it is PD related psychosis. If other causes of delirium are excluded then Parkinson’s medications should be adjusted stopping anticholinergics first then amantadine second then gradually reducing DA then stopping monoamine oxidase inhibitors (MAOI) especially if the patient is on selegiline.

Levodopa is less likely to precipitate psychosis but could do that especially in higher doses. One should accept some worsening of motor symptoms by dose reduction or omission of certain dopaminergic drugs. Doses of all PD medications should be down titrated gradually and not stopped completely.

If the above measures fail, low dose of atypical antipsychotics should be used. Clozapine is the licensed drug for this indication but its use is restricted as the initiating clinician should be registered to use it and regular check of white cell count is required as it may cause idiosyncratic agranulocytosis which could be fatal.

Alternatively, quetiapine can be used in small doses and increased gradually if necessary. Quetiapine is less likely to cause worsening of motor PD symptoms than other antipsychotics. It is important to do an ECG to monitor QT interval as all antipsychotics can cause prolongation of QT interval.

Acetyl cholinesterase inhibitors (AChI) can be used to treat visual hallucinations and rivastigmine is preferable to other AChI’s

Dementia

PD dementia (PDD) is a late feature of PD. Patients who develop dementia preceding motor symptoms or within one year of their onset is not classed as PDD but as Dementia with Lewy Body (DLB). Risk factors for PDD are older age, severe Parkinsonism, especially the akinetic rigid type, postural instability and gait disorder, male gender and other psychiatric problems like depression, psychosis and mild cognitive impairment (MCI)

Rivastigmine has been shown in studies to improve cognition and activity of daily living.12

If rivastigmine is not tolerated other cholinesterase in inhibitors or memantine could be used instead.

Non-motor symptoms during off periods

Patients who experience motor fluctuations with off periods can also develop NMS off symptoms in the form of fatigue, pain, inner restlessness, sensory symptoms, dyspnoea depression, anxiety and unclear thinking.13

Treatment would include alleviating motor off periods with antiparkinsonian medications like spreading the dosage of levodopa to prevent wearing off symptoms or adding cCatechol-O-methyl transferase inhibitors (COMT inhibitor) such as entacapone or the new drug opicapone or using modified release DA or MAOI. In severe cases, apomorphine injection can be used to alleviate off period symptoms.

Dysautonomia

Autonomic neuropathy in PD is quite common and can present in orthostatic hypotension (OH), Sexual disorder and urinary incontinence.

Orthostatic hypotension

Orthostatic hypotension (OH) is common in PD due to the disease itself as well as a side effect of the medications especially dopamine agonists. It is present in 48% of PD patients and is asymptomatic in 60% of patients.14

All patients with PD should be screened for OH with lying and standing BP on each clinic visit.

A drop of systolic BP >20mm Hg or diastolic BP >10mm Hg or supine BP <90 would be consistent with OH. OH can cause dizziness on standing up and falls leading to injuries and possible hospitalisation with increased morbidity and mortality.

Treatment would be to eliminate any iatrogenic cause of OH such as antihypertensives including diuretics. Patients should be advised to avoid sudden standing up and sit by the edge of the bed after waking up for a few minutes before rising. Patients should be encouraged to drink fluids especially on waking up in the morning when OH is at its peak. Using full-length compression stocking/abdominal bandage can be helpful as well head up tilt of bed to 30as this increases renal artery pressure and causes increased renin secretion.

If these measures fail and the patient is still symptomatic, NICE recommends using midodrine as first-line.7

This drug is given in three divided doses; the last dose should not be less than four hours before bedtime as it may cause supine hypertension. The patient should have blood pressure checked at bedtime while supine and if supine hypertension is detected then a small dose of short-acting calcium channel blocker or GTN patch at night could be used. Alternatively, fludrocortisone could be used in a dose of 50 microgram once daily in the morning, increased gradually up to a maximum of 400 microgram per day. This drug can cause leg oedema or worsening of pre-existing heart failure. Potassium level should be checked with higher doses as it can cause hypokalaemia.

Other drugs which can be used are pyridostigmine, which is a cholinesterase inhibitor, droxidopa which is a prodrug of adrenaline and noradrenaline.

OH can be caused by all dopaminergic drugs used to treat PD symptoms and can be associated with starting treatment, increasing dosage or adding a new drug. Domperidone has been shown in some studies to be useful in preventing OH with concomitant PD medications, especially with apomorphine.15

Caution should be experienced with domperidone as it can prolong QT interval.

Genito-urinary symptoms

Detrusor instability and incontinence is common in PD and would best be managed with antimuscarinic drugs that do not cross blood-brain barrier such as trospium rather than oxybutynin.

Mirabegron is a β3 noradrenergic agonist that has no cognitive side effects and can be useful to use in a patient who is at risk of developing cognitive impairment.

Erectile dysfunction is common in PD and can be treated with sildafinil without the occurrence of side effects like OH.16

NMS secondary to dopaminergic drugs

ICD is a rare but serious side effect of dopamine agonists. Symptoms include pathological gambling, binge eating and hyper sexuality. It is important to warn patients who are started on DA of these serious side effect and to inquire specifically about ICD symptoms from patients who are on DA and relatives as sometimes patients may not admit to having them and may end up with financial, legal or marital problems. Treatment involves gradually reducing and stopping DA and replacing them with levodopa. Cognitive behavioural therapy could also be useful.

Other NMS of PD

Fatigue is a common symptom of PD which is worse during off periods.

Weight loss and weight gain are common in PD the former could be due to severe dyskinesias in patients with motor fluctuations while the latter could be drug induced. However, patients with weight loss should be properly assessed for other causes of weight loss before assuming it is due to PD as otherwise other causes of weight loss could be missed.

Excessive sweating can occur in PD especially in patients with motor fluctuations or with dyskinesias. This could be managed by adjusting medications to control off motor symptoms.

Visual disturbances with poor visual acuity and blurred vision to colour stimuli and diplopia can also occur in PD patients. Poor visual acuity is postulated to be due to lack of dopamine in the retina.

Conclusion

NMS of PD are symptoms that could precede the motor symptoms of PD. They can be as disabling as motor symptoms and may affect the quality of life with increasing cost of care. It is often overlooked unless the clinician actively looks for them by using screening tools such as NMS Quest.

Early identification and management of NMS would reduce morbidity and mortality and prevent hospitalisation and institutionalisation.

A multidisciplinary approach should be used including involving speech and language therapist, PD nurse specialist, movement disorder specialist and a neuropsychologist to manage NMS of PD.

 

Farid Munim
Consultant Physician and Geriatrician at Frimley Park hospital

 

Conflict of interest: none declared

 

References

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3. Chaudhuri R, et al. International Multicenter Pilot Study of the First Comprehensive Self-Completed Nonmotor Symptoms Questionnaire for Parkinson’s Disease: The NMS Quest  Study. Movement Disorders 2006; 21 (7): 916–923

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13. Fackrell R, Hindle V, Chaudhuri KR. Non-Motor Symptoms in Parkinson’s disease https://www.rcplondon.ac.uk/file/9251/download?token=4z3FqSky.

14. Munim. Management of Inpatients with Parkinson’s disease in the acute setting. Journal of Geriatric Medicine 2017; 27-31

15. Bachi, et al. Domperidone for Hypotension in Parkinson's Disease: A Systematic Review. J Parkinsons Dis 2017; 7(4): 603-617

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