The focus in Parkinson’s disease (PD) has traditionally centred on motor symptoms such as resting tremor, rigidity and bradykinesia. PD has long been considered a disease of dopaminergic neurons of the substantia nigra. But degeneration in PD is widespread throughout the brainstem and even affects the peripheral nervous system. The result is a broad range of non-motor manifestations that can significantly impact patients’ quality of life. Despite their importance, these symptoms often go unrecognized by patients or physicians, leading to an important unmet need.

We’ll discuss the most important, treatable non-motor manifestations, and summarize others in Table 1 (see sidebar).

Constipation

Constipation is probably the commonest dysautonomic feature of PD. Severe and disabling symptoms occur in a third of constipated PD patients — complications can include megacolon, pseudo-obstruction or volvulus. In addition to increased colonic transit time, PD patients often feel unable to completely evacuate their bowel. Manometric studies have shown that PD patients have hypercontraction of the anal sphincters during bowel movements (anismus), which leads to incomplete bowel emptying.

Autonomic manifestations including constipation are mainly due to degeneration of peripheral autonomic neurons and vagal nuclei in the brainstem. Constipation is frequently blamed on parkinsonian drugs, but in fact it occurs regardless of medication. Indeed, constipation can predict development of PD — in prospective studies, people with < 1 bowel movement daily have a 3-4 times increased risk of PD.

Treatment of constipation in PD is similar to that in the general population. Stool softeners, bulking agents such as Metamucil, bran fibre, prunes or dried apricots can be useful. But many, if not most patients will need additional stimulant laxatives or enemas. Senokot is often effective; it comes in pill form or as a tea. Although theoretical concerns about overuse and habituation exist, we’ve rarely encountered this in practice and generally treat patients as much as needed to provide comfort.

Bladder dysfunction

Bladder dysfunction in PD most often involves detrusor hyperreflexia, resulting in nocturia, frequency and urgency. These symptoms can be confused with prostatic hyperplasia in men. The basal ganglia normally inhibits micturition, so when substantia nigra neurons degenerate, this inhibition is lost. Less commonly, some develop hyporeflexic bladder with difficulty initiating, incomplete voiding and urinary leakage.

Urgency can be controlled by anticholinergic medications. These include oxybutynin (5 mg bid-tid), tolteridine (2 mg qd) and trospium chloride (20 mg qhs). Tricyclic antidepressants may also help because of their anticholinergic properties. With any anticholinergic medication in PD, patients should be monitored for hallucinations or worsening of memory loss. Nocturia can be treated with desmopressin nasal spray (10 μg qhs, increasing as needed) — this requires monitoring of electrolytes.

Orthostatic hypotension (OH)

Impaired baroreflex cardiovagal function and loss of sympathetic innervation in the heart and peripheral veins result in orthostatic symptoms. Normally, concentrations of norepinephrine increase from supine to standing but this response is blunted in PD. Dopaminergic drugs also can exacerbate OH. OH
can be dangerous, as it doubles the risk for falls. Classic symptoms (lightheadness with standing) predominate, but OH can present atypically with postural confusion, headache, or shoulder/neck pain.

Non-pharmacologic measures such as raising the bed angle, increasing salt intake and compression stockings can be considered, but are often poorly tolerated. If taking levodopa, the first line therapy is domperidone, a dopamine antagonist that doesn’t cross the blood-brain barrier (10-20 mg with each levodopa dose). Domperidone may even help in patients not on levodopa. Other treatment options involve medications that raise blood pressure, including the mineralocorticoid fludrocortisone (0.1-0.2 mg/qd) or the α1-agonist midodrine (2.5-10 mg tid). Physostigmine 30-60 mg qid has shown efficacy and it has the advantage of simultaneously treating constipation (Arch Neurol 2006;63:512-8).

REM sleep behaviour disorder (RBD)

RBD is characterized by the loss of normal muscle tone during REM sleep and is up to 100 times more prevalent in PD patients than in the general population. Patients act out their dream content and may punch, kick, talk, shout and fall out of bed. Injuries are quite common. RBD is most frequent in the early morning (when REM sleep predominates) and men are more often affected than women.

RBD can predate the diagnosis of PD and over 40% of patients with idiopathic RBD will have been diagnosed with a neurodegenerative disease such as PD after 10 years. The exact pathological mechanism is unclear but animal models implicate deficits in brainstem (especially pontine) nuclei controlling REM sleep. Clonazepam (0.25-1 mg qhs) or melatonin (3-12 mg qhs) often completely suppress RBD.

Excessive daytime
sleepiness (EDS)

Excessive somnolence is common in PD, affecting up to 40%. In mild cases, patients fall asleep when inactive but when severe, patients fall asleep even in stimulating conditions such as eating, walking or working. Sudden sleep attacks while driving have been reported. EDS can precede PD — people with somnolence are 3 times more likely to subsequently develop PD in prospective studies.

The etiology of EDS is multifactorial. Daytime somnolence can be caused by insomnia and fragmented sleep due to restless legs syndrome, but on average patients with EDS sleep more deeply than those without. Medications, particularly dopaminergic drugs, commonly exacerbate somnolence, and all patients starting dopaminergic meds need to be aware of this side effect. The leading cause of EDS, however, is degeneration of central sleep regulation centres in the brainstem — that is, EDS is a primary feature of PD.

Sleep attacks can be sudden, so all patients with EDS must be counselled to never drive while drowsy. Since dopaminergic agents may increase somnolence, reducing medications may help (although effects on motor state must be balanced). Sleep hygiene can help relieve insomnia. Increasing caffeine consumption during the day seems to benefit many patients. Finally, modafinil (100-400 mg/qd), a psychostimulant with an unknown mechanism of action, has been shown to aid EDS in randomized trials.

Drooling

Drooling in PD isn't caused by salivary hypersecretion, but is secondary to impaired swallowing, decreased spontaneous mouth movements, and flexed head posture. Complications include choking and aspiration pneumonia.

Improvement of motor symptoms can alleviate sialorrhea by facilitating swallowing and mouth movements. Anticholinergics are also of benefit by decreasing salivary production — we commonly use atropine 1% solution with 1-2 drops under the tongue. Caution is needed in patients with baseline memory dysfunction or hallucinations. Injections of botulinum toxin into the parotid and/or submandibular glands reduce salivary production as well, and are often quite effective.

Depression and anxiety

Depression in PD differs from non-PD depression in that there's less self-blame, guilt, sense of failure or self-destructive thoughts, and suicides are rare. Rather, PD depression is characterized by anhedonia, pessimism and anxiety. Depression occurs in approximately 30-40% of PD patients — family members often notice this before the patient (although masked facial expression and monotone voice can be misinterpreted as depression). Depression in PD isn’t purely a reaction to disability — mesocortical monoaminergic deficits have been implicated and depressed patients have decreased CSF concentrations of 5-hydroxyindolacetic acid (a serotonin metabolite).

PD patients also commonly develop anxiety. As with depression, anxiety can be a preclinical marker of PD and can present as panic attacks, phobia or generalized anxiety disorder. In those who have fluctuations in motor state, anxiety is very common in the ‘off’ state, and medication adjustment may alleviate this ‘off’ period anxiety.

Treatment of depression in PD may differ from other forms of depression. Randomized trials have also confirmed benefit of citalopram for PD depression, but there's no evidence that other, newer SSRIs or SNRIs help depression in PD. A recent trial found that a tricyclic antidepressant (nortriptyline 30-75 mg qhs) was effective, whereas a serotonin reuptake inhibitor (paroxetine) was not (Neurology 2009(March 10);72(10):886-92). Again, many patients with memory dysfunction or hallucinations may be unable to tolerate tricyclic antidepressants due to their anticholinergic effects.

Impulse control disorders (ICD)

PD patients on dopaminergic medications are at risk of developing impulse control disorders (ICD) such as pathological gambling, hypersexuality, binge eating, compulsive shopping, punding (repetitive performance of meaningless tasks) or compulsive medication use. Pathological gambling and hypersexuality are the most common impulse control disorders. They can have devastating consequences on patients’ lives. These side effects are much more common with dopamine agonist medications (such as pramipexole and ropinirole), although they occasionally occur in patients on levodopa monotherapy. A history of alcohol abuse, gambling and addictions prior to PD indicates increased risk for impulse control disorders.

The most important “treatment” is to warn sufferers of these behaviours when starting dopamine agnonists, and to monitor for them in patients already on agonists (patients rarely disclose them spontaneously). If they occur, reduction of dopamine agonists almost always relieves the symptoms.

Hallucinations and psychosis

Hallucinations usually occur after years of disease. They may be due to degeneration of cortical areas involved in perception but are increased by parkinsonian medications as well. Hallucinations in PD tend to occur in the evening and during changes from sleep to wake. They often begin as minor, non-threatening visual images — these include “animating illusions” (e.g. a spot on a wall becomes an insect) or fleeting “sense of presence.” Common fully-formed hallucinations include children, animals and Lilliputian figures, frequently at first appearing in corners of rooms. Initially, insight is retained but as they progresses, insight is lost and patients may develop paranoid delusions. Distrust is often directed at family members and delusions of spousal infidelity or theft aren’t uncommon. Psychosis is a major risk factor for nursing home placement and increased mortality.

If a patient experiences sudden onset of severe hallucinations or agitations, suspect a secondary cause such as sepsis. In general, treatment of hallucinations involves reduction of low-potency parkinsonian medications (e.g. amantadine, dopamine agonists). If removal worsens motor state, the other options include atypical antipsychotics (clozapine 12.5-25 mg hs or quetiapine 25-50 mg hs, increasing as needed). If there’s associated cognitive impairment, acetylcholinesterase inhibitors may resolve hallucinations completely.

Cognitive impairment & dementia

Dementia is the commonest cause of institutionalization in PD and almost exclusively affects patients aged over 65. PD dementia is characterized by memory difficulties that respond to external cues (subcortical dementia), difficulty with planning, attention deficits, and bradyphrenia (slowed thinking). Even in the absence of frank dementia, abnormal verb generation and impaired visuospatial processing can be observed in early PD. Dementia in PD may represent a heterogenous condition with a spectrum of pathological changes — the commonest underlying pathology is Lewy body deposition in the cortex, and rapid fluctuations in cognition and hallucinations are signs of this.

Treatment options for PD dementia are similar to dementia from other causes. Sedative medications must be avoided, and sudden onset dementia indicates need for a general medical workup. Cholinesterase inhibitors (rivastigmine 1.5-6 mg bid and donepezil 5-10 mg qd) are usually helpful, although gastroinstestinal side effects are common.

To sum up

PD is much more than just a pure motor disorder. In many cases, the connection of these non-motor symptoms to PD isn’t obvious, so vigilance is needed. These manifestations are generally very treatable, and recognizing them can make a big difference to a patient’s quality of life.