Idiopathic Parkinson’s disease (PD) is primarily considered a movement disorder.¹ Non-motor symptoms are common, yet often go unrecognised under the shadow of dominating motor symptoms.² However, in recent years non-motor symptoms have gained increasing clinical attention and importance.^2,3 Non-motor symptoms comprise a variety of neuropsychiatric, cognitive, sleep, autonomic and sensory disorders, and their broad-ranging manner represents the wide array of neuropathological changes associated with PD.⁴

Neuropsychiatric symptoms

While overall non-motor symptoms correlate with age and are predominantly found in advanced disease, many of them antedate motor symptoms and can be used as pre-clinical markers of PD.⁵ These non-motor symptoms of PD have massive effects on the patient and may be associated, in their own right, with severe disability, reduced life expectancy, decreased quality of life (QOL), and may indeed precipitate hospitalisation.⁵

The neuropsychiatric symptoms of PD are vast, and include depression, apathy, anxiety, psychosis and impulse control disorders.^5,6

Neuropsychiatric dysfunction has huge implications for the PD patient. Indeed, depression is the most significant predictor of patient QOL while psychosis is a key factor leading to institutionalisation.¹ Not only do the neuropsychiatric symptoms of PD affect the patient’s QOL and life expectancy, they also increase the burden of disease on those close to the patient, with devastating effects on relationships.^7,8,9

Approximately 40% of patients with PD have clinical depression.⁴ While some of the depressive symptoms in PD may occur as a reaction to diagnosis, there is general consensus that a PD-specific pathology plays an integral role in the development with multiple neurotransmitter deficiencies occurring in parallel with Lewy body deposition in connected brainstem loci.^2,5 This hypothesis is supported by the finding that depressive episodes and/or anxiety disorders precede motor symptom onset in up to 30% of patients.^1,2

Parkinson’s sufferers with depression generally exhibit less guilt, sense of failure and self-destructive thoughts when compared with patients with primary major depression.⁶

Apathy is recognised as a distinctive and independent symptom of PD and refers to a set of behavioural, emotional and cognitive features.^5,10 As with depression, it may also have both neurodegenerative and reactive elements.⁵ Anxiety is reported in 20-40% of PD patients and may be related to dopaminergic drug-induced motor fluctuations.^1,2 Manifestations include generalised anxiety disorder, panic attacks, agoraphobia and social phobias.⁴

Psychosis encompasses some of the most challenging non-motor symptoms of PD, occurring in up to 40% of patients.^1,5 Psychotic symptoms are usually mild and include visual hallucinations, illusions, and passage and presence hallucinations. However, in some cases manifestations may be more sinister, including delusions, paranoid ideation and delirium, becoming more frequent with disease progression.^5,10

Hallucinations usually occur in the context of one of two clinical situations: either as a superimposed medical condition following, for example, an infection, or due to the effects of dopaminergic therapy.⁶ Drug-induced hallucinations are more common in elderly and early-onset patients, while late-onset hallucinations are associated with cognitive impairment.⁶ Lewy body deposition and genetic predisposition have also been postulated as potential causes of psychosis.^4,11

Impulse control disorders can also be attributed to adverse drug reactions affecting the mesolimbic pathway.⁵ These include pathological gambling and shopping, punding, binge eating and hypersexuality.

Cognitive decline and dementia

Cognitive impairment occurs frequently in PD, with dementia affecting approximately 40% of PD patients; a rate about six times higher than in the general population.^4,5,6 While mild cognitive dysfunction presents in most patients as bradyphrenia and word-finding difficulties, dementia refers to impairment at a level sufficient to interfere with activities of daily life.⁶ Its nature is progressive and usually becomes apparent after motor symptom onset.⁶

A syndrome of global decline of intellect, memory and personality, it presents mainly as memory and learning impairment, and executive dysfunction and visuospatial deficits.^1,6 It is associated with more rapid progression of disability, increased mortality and an increased risk of institutionalisation, with 90% of affected PD patients placed in nursing homes.^1,6  

Causes include underlying pathologies of neuronal cell degeneration, widespread Lewy body disease and brain atrophy, as well as dopaminergic drug therapy, which may both alleviate and exacerbate symptoms.^1,4,6,10

Sleep disturbances

Sleep disorders are very common in PD, affecting approximately 60-98% of sufferers.¹² Sleep disturbances are attributable to a number of factors, from pathological degeneration of the primary sleep architecture to motor and non-motor symptoms which have a secondary effect on sleep, including nocturia, restless leg syndrome, painful dystonia, nocturnal cramping, nocturnal confusion and hallucinations.^1,5

Obstructive sleep apnoea and rapid-onset sleep with a narcoleptic pattern are also important hidden causes of PD sleep-related morbidity, and are often associated with anti-parkinsonian medications.⁵ Sleep disorders are usually exacerbated with disease progression in conjunction with increased nigrostriatal pathway degradation, increased dopaminergic treatment and worsening motor symptoms.⁵

REM sleep behaviour disorder (RBD) affects approximately one-third of PD patients.¹³ RBD is characterised by loss of normal muscle atonia during REM sleep, thus enabling patients to physically act out their dreams.¹¹ RBD can appear early in the course of PD and may antedate motor symptoms by several years.^2,5

Although the pathogenesis is unknown, there is speculation that RBD arises due to lower brain stem degeneration including the pedunculopontine and subcoeruleus nuclei, corresponding with its early onset.⁵

Involuntary dozing, or excessive daytime sleepiness (EDS), is another sleep disorder affecting PD patients.⁵ With a prevalence of up to 50%, it has a strong effect on QOL yet often remains unidentified.^4,5 It is probably related to myriad factors, including disease process, sleep disruption and drug treatments.⁵

Dysautonomia

Dysautonomia, abnormal functioning of the autonomic nervous system, occurs with varying severity in PD.¹⁴ The pathophysiology is complex, involving degeneration of medullary centres that mediate autonomic function, as well as monoaminergic, cholinergic and serotoninergic nuclei, which cause abnormalities within the central autonomic system.^5,11

This combination of multiple-system atrophy and peripheral sympathetic failure results in many autonomic disturbances, including nausea, constipation, urogenital problems, orthostatic hypotension and hyperhidrosis.⁴

Constipation and increased intestinal transit time are among the most common non-motor symptoms.¹ Several studies have reported an increased prevalence of constipation in PD patients of between 28-61%, as compared with controls (6-33%).¹ Constipation may even precede PD development; one prospective study found initial constipation to be associated with a threefold increased development risk.⁵ Other gastrointestinal symptoms which overlap with autonomic symptoms include drooling, ageusia, dysphasia, choking, reflux, vomiting, unsatisfactory voiding of bowel and faecal incontinence.⁵

Urogenital dysautonomia in PD presents with urinary and sexual dysfunction. Urinary dysfunction lies among the most common non-motor presenting complaints, occurring in 27-39% of patients.^2,15 While nocturia and urgency are ‘classic’ early complaints, others, such as incomplete bladder emptying and double micturition, may present as later features.^1,2

Sexual dysfunction can present with erectile and ejaculatory dysfunction in men, and impaired vaginal lubrication and anorgasmia in women. Both an increase and reduction in sexual drive have also been reported.^2,16

Indeed, dopaminergic drug treatments can themselves be culpable in sexual dysfunction where aberrant sexual behaviour and increased sexual drive form part of a dopamine dysregulation syndrome.⁵ Orthostatic hypotension, a late feature of PD, correlates with both disease duration and severity as well as dopaminergic medication dose.⁵

Clinical presentations include somnolence, light-headedness, syncope, coat-hanger pain and falls. Hyperhidrosis, resulting from thermoregulatory dysautonomia, affects mainly the face, neck and trunk regions. It is a function of plasma levodopa fluctuations where peak-dose dyskinesias are associated with increased sweating, and drenching sweats with end-of-dose off periods.^4,15

Sensory changes

Sensory complaints are another non-motor aspect of PD. These bizarre and wide-ranging symptoms include visual changes, olfactory dysfunction, restless leg syndrome (RLS) and pain.^4,5

Visual changes include changes in visual acuity, contrast sensitivity, temporal sensitivity, colour discrimination, motion perception, image-processing speed and peripheral visual field sensitivity.⁴

Olfactory dysfunction affects up to 90% of PD patients. Although generally marked when tested, patients do not usually notice or complain of olfactory dysfunction.⁵ It is considered to be among the earliest PD symptoms and has potential as a pre-clinical marker for motor symptom onset.⁵

Its pathology is consistent with its early presentation involving degeneration of extranigral neurons in the olfactory bulb and anterior olfactory nucleus.⁵ RLS is commonly reported in conjunction with PD due to a common nigrostriatal dopaminergic pathophysiology.⁴ It can be difficult to distinguish between true RLS and ‘wearing off’ symptoms of levodopa-treated PD.⁵ Other non-motor symptoms can also be confused with ‘wearing off’, including anxiety, tingling, unclear thinking and cold limbs.⁵

Pain (dystonic and non-dystonic) is a common complaint in PD with both primary and secondary causes. It is more prevalent in younger-onset patients and in those with advanced disease, greater depressive symptoms and more motor complications.^2,5,18 Lewy body deposition in areas of the central pain processing system accounts for some of these symptoms.⁴

Conclusion

Contrary to original beliefs surrounding PD, the non-motor symptoms associated with the disease are many and broad-ranging. Early recognition and clinical focus on these symptoms is vital and will not only aid patient identification and improve treatment strategies, but will enhance patient outcomes and overall QOL. With the increasing age and life expectancy of the PD population, the need for affordable, high-quality care has never been more pertinent, and future focus on non-motor symptoms of PD will be integral to achieving these objectives.

References

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