Nonmotor Symptoms in Parkinson's Disease

ABSTRACT

The recognition and treatment of nonmotor symptoms are increasingly emphasized in the care of Parkinson's disease (PD) patients. This manuscript will review signs and symptoms localized, generally, to the cortex, basal ganglia, brainstem, spinal cord, and peripheral nervous system. Cortical manifestations include dementia, mild cognitive impairment, and psychosis. Apathy, restlessness (akathisia), and impulse control disorders will be linked as basal ganglia symptoms. Symptoms attributed to the brainstem comprise depression, anxiety, and sleep disorders. Peripheral nervous system disturbances may lead to orthostatic hypotension, constipation, pain, and sensory disturbances.

KEYWORDS: :

• impulse control disorder
• nonmotor
• Parkinson
• psychosis

INTRODUCTION

Nonmotor symptoms in Parkinson's disease (PD) patients are increasingly the focus of care in neurology clinics. From a neuroanatomic standpoint, these may be subdivided into cortex (psychosis and cognitive impairment), basal ganglia (impulse control disorders, apathy, and restlessness or akathisia), brainstem (depression, anxiety, and sleep disorders), spinal cord (orthostatic hypotension and urological disturbances), and the peripheral nervous system (pain and constipation) [1–3]. This manuscript will provide an overview of these nonmotor symptoms in PD.

CORTICAL MANIFESTATIONS OF PARKINSON'S DISEASE

Cognitive Disorders

Dementia is reported in more than 30% of PD patients, particularly in those older than 70 years of age [4, 5]. A long-term follow-up study in Norway reports features of dementia in 60.1% of 233 subjects within 12 years of diagnosis [6], while a review of 873 patients in Germany found that 28.6% of this series met the DSM-IV (Diagnostic and statistical manual of mental disorders 4th edition) criteria for dementia [7]. The initial Sydney Multicentre Study reported that more than 80% of end-stage patients developed dementia. More recent reports suggest that the evolution of dementia in PD occurs around 70 years of age, regardless of the time of PD onset [8, 9]. The Movement Disorder Society has recently reviewed the criteria for cognitive assessment in PD [10]. Subcortical dementia is traditionally viewed as the type of cognitive decline seen in advancing PD and affects information processing. Alzheimer's disease (AD) is classically defined as a cortical dementia and affects memory and language [11]. Lewy body disease (LBD) is associated with pathologic changes, typical of PD, occurring throughout the brain, and may have a mixture of cortical and subcortical symptoms. PD with dementia (PDD) is a form of subcortical dementia, dominated by distractibility, passivity, and slow thinking. These disorders differ from a mixed picture of PD and AD, in which patients develop cognitive and language abnormalities early in the course of the illness [12].

Although there is a close relation between motor symptoms and Lewy bodies and neurites with abnormal α-synuclein, nonmotor symptoms are associated with abnormal synpaptic α-synuclein and may affect other neurotransmitter systems [12]. Cholinergic neuronal loss and depletion of choline acetyltransferase are seen early in PDD and dementia with Lewy bodies (DLB) [13], and treatment with cholinesterase inhibitors improves cognition in PD [14]. Interestingly, Caviness et al. have found a 36% increase in α-synuclein concentrations in the motor cortex of PD patients with a history of myoclonus when compared with PD patients without myoclonus; AD pathology was not associated with cortical myoclonus [15].

Treatment of Cognitive Disorders

Cholinesterase inhibitors have been evaluated in the treatment of cognitive impairment in PD. Donepezil at dosages of 5–10 mg/day demonstrated a 2.1 point increase in mean mini-mental state examination (MMSE) score versus a 0.3 point change in the placebo group [16]. However, others warn that cholinergic side effects may worsen parkinsonian symptoms [17, 18]. A placebo controlled study of rivastigmine in PD patients with dementia demonstrated significant benefit in the mean Alzheimer's Disease Assessment Scale-Cognitive subscale and the MMSE [14]. Nausea, vomiting, dizziness, and tremor were more frequent in the rivastigmine group. A cohort of these subjects demonstrated sustained benefit in a 48-week extension study [19]. Rivastigmine (6–12 mg daily) has been also shown to improve attention in PD patients with dementia [20]. However, this agent has been reported to slightly worsen tremor [21]. A 12-week study comparing donepezil and rivastigmine showed similar benefit in cognition, but donepezil was better tolerated [22]. Memantine, titrated to dosages of 20 mg daily, is reported to improve symptoms in moderate cases of AD and PD but is associated with psychosis, perhaps from activation of N-methyl-D-aspartate (NMDA) and dopamine D2 receptors [23].

Psychiatric Disorders

The prevalence of psychotic symptoms may be as high as 60% in the PD population and is associated with poorer disease prognosis [24, 25]. The presence of hallucinations for more than 2 years is a strong predictor of dementia (68%), nursing home placement (42%), or death (25%) [26]. Furthermore, PD patients in nursing care facilities are 16 times more likely to have hallucinations than patients still living at home [27]. Although the diagnosis of Parkinson's disease psychosis (PDP) is controversial, criteria include psychotic symptoms for at least 1 month, with no other cause, with or without dementia, insight and use of dopaminergic medications [28].

Features of Parkinson's Disease With Psychosis

Symptoms of psychosis typically begin 10 years after initial diagnosis of PD, with retained insight and clear sensorium [29]. Prominent hallucinations early in the course of the disease may suggest DLB, AD, or a pre-existing psychiatric disorder [30].

Unlike hallucinations seen in schizophrenia, which are typically auditory and persecutory or grandiose in nature, the hallucinations in PDP are more often visual, with persistent images superimposed upon the natural environment [24]. PD patients often have “presence” or passing (vague images in the peripheral vision) hallucinations and visual illusions early in the evolution to psychosis [29]. With syndrome progression, visual phenomena usually become well formed but appear and vanish suddenly with alerting stimuli [24]. Auditory hallucinations are uncommon and rarely threatening or disturbing. Tactile, olfactory, and gustatory hallucinations are rare.

Delusions occur in a younger age group than hallucinations [31] and may not be as tightly linked to cognitive decline. The types of delusions seen in patients with PD are often paranoid in nature, often centering on marital infidelity. Patients may also report a delusional fear of abandonment, perhaps from worry about nursing home placement. The grandiose, somatic, and religious delusions, common to schizophrenia, are infrequent [32].

Risk factors for psychosis include exposure to dopaminergic medications, advancing age, increasing impairment in executive function, dementia, increasing severity and duration of PD, comorbid psychiatric symptoms such as depression and anxiety, daytime fatigue, sleep disorders, visual impairment, and polypharmacy [33]. Autopsy studies link pathologic changes with parahippocampus, amygdala, and frontal, temporal, and parietal lobes.

Diagnosis of PDP must be distinguished from delirium [34, 35]. Fluctuating levels of consciousness, marked declines in cognitive performance, increased confusion, and disorientation from baseline in the context of medical illness are the hallmark signs of delirium. In psychosis, baseline memory, orientation, and cognition are usually unimpaired.

An initial treatment strategy is to simplify the drug regimen and eliminate nonessential anti-Parkinson medications [35]. If symptoms persist, tapering of anticholinergic agents, amantadine, catechol-O-methyl transferase (COMT) inhibitors, monoamine oxidase type B (MAO-B) inhibitors, and dopamine agonists may also improve symptoms of cognition. If this is not sufficient or cannot be tolerated from declining mobility, atypical antipsychotics are used; traditional antipsychotic agents, or dopamine blocking drugs, should not be used because of the high potential for worsening symptoms of PD. Clozapine, in doses less than 50 mg/day, is safe and effective in reducing PDP symptoms [36]. A four-week, placebo-controlled trial of 60 patients randomized to clozapine showed that 35.7 mg/day significantly reduced psychotic symptoms without worsening motor function [37]. Because agranulocytosis occurs in 1% of patients on clozapine, weekly monitoring of white blood cell counts is required for 6 months and biweekly thereafter. Quetiapine does not require monitoring, but a 3-month study comparing quetiapine with placebo did not show a beneficial effect [38]. Nonetheless, this agent is commonly used as a first line therapy in the treatment of PDP. Therapeutic response is seen usually at much lower dosages than used in patients with schizophrenia, with patients responding from dosages ranging from 12.5 to 150 mg/day. Typically, because of sleepiness, quetiapine is started at bedtime and titrated to symptom relief. In a long-term study of 35 patients, 15 nonresponding patients were switched to clozapine, with a positive response in 12 patients; while 6 of the remaining 20 were controlled with quetiapine for 24 months [39]. Risperidone, aripiprazole, olanzapine, and ziprasidone have not been found effective in treating psychotic symptoms and cause motor worsening. Cholinesterase inhibitors have not produced consistent results for either psychotic or motor symptoms. Memantine, an NMDA receptor antagonist with D2 receptor affinity, may trigger psychosis in some PD patients [23]. Antidepressants may be helpful in patients with comorbid depression but have variable effects on psychotic symptoms. A pilot electroconvulsive therapy (ECT) study with patients refractory to antipsychotic medication demonstrated significant decreases in psychotic symptoms [40].

BASAL GANGLIA SYMPTOMS

Impulse Control Disorders

Behavioral disturbances in PD associated with dopaminergic therapy have been recognized for over 40 years. Hypersexuality and hyperlibidinous behavior are listed in early literature on levodopa, and pathological gambling, compulsive shopping, and binge eating are now well recognized [41]. Patients may also develop compulsive motor behaviors, called punding. Dopamine dysregulation syndrome is seen in patients taking excessive dopamine replacement therapy, who exhibit severe dyskinesia, cyclical mood disorder, and impairment of social and occupational functioning. Impulse control disorder (ICD) is the term used for a constellation of symptoms and maladaptive behaviors that emerge with PD progression and increasing anti-Parkinson medications. These include disruptive behaviors (e.g., punding), destructive behaviors (e.g., compulsive spending or gambling, binge eating, or hypersexuality), and addictive behaviors (e.g., excessive use and abuse of anti-Parkinson medications) [41]. Not surprisingly, 17.5% of 103 newly diagnosed PD patients screened positive for at least one ICD, suggesting that these behaviors are not simply a side effect of increasing dopaminergic therapy [42].

Treatment of Impulse Control Disorders

Symptoms of ICD most often respond to reduction or withdrawal of dopaminergic therapy, particularly dopamine agonists. Others have suggested the addition of selective serotonin re-uptake inhibitors (SSRIs), quetiapine, valproic acid, naltrexone, or topiramate [43]. In addition, successful treatment has been shown with donezepil and clozapine [43]. There are also reports of improvement after deep brain stimulation surgery, in the context of dopaminergic therapy reduction [44]. However, some also report worsening or emergence of ICD behaviors after surgery [43].

BRAINSTEM SYMPTOMS

Depression

In PD, the average prevalence of major depressive disorder is 17%, while dysthymia occurs in 13%, and minor depression in 22% [45]. If depression is suspected, inquiry about early morning awakening, low mood with diurnal variation, apathy, crying, withdrawal, and suicidal tendencies is important [46]. Unique features attributed to depression in a PD population include increased dysphoria, irritability, sadness, anxiety, brooding, cognitive deficits, pessimism, and suicidal ideation without action. In addition, PD patients appear to have less guilt and self-blame than other populations [47].

Treatment of Depression

Between 15% and 20% of PD patients are prescribed antidepressant medications [48]. The tricyclic antidepressants, such as amitriptyline or nortriptyline, are beneficial but may produce cognitive compromise. The SSRIs are also helpful in the treatment of depression and better tolerated [49]. Sertraline has low selectivity for serotonin relative to dopamine reuptake and a highly favorable profile, improving quality of life, particularly activities of daily living (ADL), mobility, and stigma [50]. Although there are reports of the antidepressant benefit of dopaminergic therapy, a recent review of 19 reports failed to find sufficient evidence to recommend dopamine agonists in treating this condition [51].

Anxiety Syndromes

Up to 40% of patients experience clinically significant anxiety, including panic disorder, generalized anxiety, and phobic disorders [50]. This rate is higher than that in the general population and in other patients with similar disabilities. Concerns about and fear of institutionalization, of going insane or of dying, are unique features of anxiety associated with PD. Symptoms of anxiety difficult to distinguish from parkinsonism include numbness, tingling sensations, breathlessness, chest discomfort, sweating, abdominal discomfort, restlessness, and dizziness and may be more prominent in the “off-state” [52, 53].

Apathy

Apathy has been reported in about half of all patients with PD [54] and may be noted by the patient or family members even prior to motor symptoms. It is characterized by an isolated lack of motivation, hopelessness, and low mood, but not necessarily anhedonia. Apathy is believed to result from deficits in implementing efficient cognitive strategies, perhaps from fronto-striatal circuit impairment, but has no known treatment [55].

Sleep Disorders

Sleep difficulties are estimated to occur in the majority of PD patients, and nighttime awakenings are three times more frequent than in healthy age-matched controls [56]. Polysomnographic investigation in PD patients documents less total sleep time, less sleep efficiency, more frequent awakenings, and greater overall waking time compared with controls [57]. Dopaminergic therapy was the strongest predictor of sleep disturbance [58].

Excessive Daytime Sleepiness

Excessive daytime sleepiness (EDS) is associated with advancing disease, increased medication dosage, longer duration of disease, and male gender. Daytime sleepiness in PD is associated with both neuropathological changes and anti-PD therapy [56]. Studies while off medication revealed normal multiple sleep latency tests [57], while rapid eye movement suppression occurs with levodopa infusion [59, 60].

Circadian rhythm disruption is common in advancing PD, and advanced sleep phase syndrome is common in PD. Other causes of sleep disruption include bradykinesia, rigidity, nocturnal immobility, and, rarely, a low amplitude tremor [56]. Choreiform dyskinesia are rarely associated with increased awakenings but have been correlated with delay in sleep return.

Sleep attacks were initially described in eight PD patients taking pramipexole and one receiving ropinirole who fell asleep while driving [61]. In the initial description, the “attack” is a clinical phenomenon of an unavoidable and abrupt transition from wakefulness to sleep. Similar case histories for almost all dopaminergic therapies have been reported [56], and there appears to be a greater sleep risk during dosage up titration [62]. Sleep apnea is common in multiple system atrophy and other parkinsonism-plus syndromes but does not appear to be more frequent in PD than in controls.

Treatment of Excessive Daytime Sleepiness

Modafinil 200–400 mg/day is effective in reversing the EDS and the sedative effects of anti-PD medications [63]. Despite the subjective improvement in daytime drowsiness reported by a substantial percentage of PD patients, no objective benefit in any of the traditional measures of sleep could be demonstrated in a double-blind, placebo-controlled study [64]. Nocturnal administration of sodium oxybate has been found in an open-label polysomnographic study involving 38 subjects to improve EDSs and fatigue in patients with PD [65].

AUTONOMIC DYSFUNCTION

Higher age, greater disease severity, and increasing doses of dopaminergic medication are associated with autonomic dysfunction. Autonomic symptom severity was associated with more motor dysfunction, depressive symptoms, cognitive dysfunction, psychiatric complications, nighttime sleep disturbances, and EDS [66].

Gastrointestinal Disturbances

Nausea and loss of appetite are seen with all antiparkinsonian medications. Most often these symptoms begin with the initiation of levodopa, secondary to the bloodstream metabolism of this amino acid to dopamine and stimulating the area postrema, the emesis center of the brain, not protected by the blood–brain barrier [67]. Prolonged gastrointestinal (GI) transit time is seen in the vast majority of PD patients [68]. Paralytic ileus affects 7.1% of PD patients and may cause bloating, pain, nausea, vomiting, and distension. Anismus, or an inability to relax the external anal sphincter for defecation, is seen in off periods [69]. Physiological mechanisms associated with GI transit result from loss of myenteric neurons and vagal nerve cells, which affect the peristaltic reflex. In addition, proximal peristalsis declines with striatal microinjection of dopamine or substance P [70].

Urological Dysfunction

Lower urinary tract symptoms in PD range from 38% to 71%, usually from the loss of the dopaminergic inhibitory effect on micturition [71]. Bladder detrusor overactivity causes urge episodes (53%), urge incontinence (27%), and detrusor overactivity (46%) [72]. Bladder contraction is mediated through cholinergic, parasympathetic fibers, while relaxation results from noradrenergic sympathetic receptors at the hypogastric nerve [73]. Urinary storage depends on autonomic sacral spinal cord segments. The pontine storage center is influenced by the hypothalamus, cerebellum, basal ganglia, and frontal cortex [2]. Voiding is initiated by the hypothalamus and prefrontal cortex. Stimulation of the SNpc inhibits micturition, and striatal dopamine increases urinary storage [2].

Sexual Dysfunction

Sexual dysfunction ranges from 12% to 60% in men with PD [73]. In a review of sexual functioning of 32 women and 43 men with PD, women reported difficulties with arousal (87.5%), reaching orgasm (75.0%), and sexual dissatisfaction (37.5%) [74]. Men reported erectile dysfunction (68.4%), sexual dissatisfaction (65.1%), premature ejaculation (40.6%), and difficulties reaching orgasm (39.5%). Associated illnesses, medication use, motor difficulties, depression, anxiety, and advancing PD all contribute to sexual dysfunction [36]. More recently, hypothalamic impairment has been suggested to play a major role in decreased libido and erectile dysfunction in PD, via altered dopamine-oxytocin pathways [73].

Excessive Sweating

Excessive sweating is related to plasma levodopa fluctuations with peak dose dyskinesia associated with mild increased sweating, and drenching sweats being associated with an end-of-dose, off period [36]. Treatment of sweating hinges on achieving stable plasma levodopa levels.

Orthostatic Hypotension

Orthostatic hypotension is reported in 10%–20% of patients and increases with age and severity of PD; if unrecognized, it may lead to emergency evaluations for dizziness or syncope [36]. Symptoms include light-headedness or dizziness when standing, fatigue, and aching across the back of the shoulders and neck. Frequent monitoring with standing and sitting blood pressures are helpful in following this problem and may often be done by caregivers.

Treatment of Autonomic Dysfunction

Orthostatic hypotension may be treated with increased fluid intake, salt, fludrocortisone, and midodrine [1, 36]. In 2007, the Food and Drug Administration (FDA) approved DOPS (Droxidopa; Chelsea Therapeutics) for the treatment of orthostatic hypotension [75]. Effective treatments for constipation include psyllium, polyethylene glycol, and bisacodyl, magnesium sulphate [76]. Lubiprostone, an intestinal ClC-2 chloride channel activator that increases intestinal fluid secretion, and tegaserod maleate, a serotonin receptor type-4 [5-HT(4)] partial agonist both stimulate GI motility [77, 78]. Macrogol, an isosomotic electrolyte, has been found to significantly increase frequency of bowel movements and improve stool consistency [79]. Other remedies include neostigmine, symbiotic yogurt, subcutaneous methylnaltrexone in opioid-related constipation, botulinum toxin injections, and sacral nerve stimulation [80].

Increased urinary frequency due to overactive bladder often improves with levodopa [81], oxybutynin, tolterodine, solifenacin or darifenacin [82], and botulinum toxin injections into the bladder wall [83]. Sildenafil citrate has been found to be safe and effective in the treatment of erectile dysfunction associated with PD but may unmask orthostatic hypotension [84].

SENSORY DISTURBANCES

Visual Disturbances

Impaired visual acuity, contrast sensitivity, color discrimination, temporal sensitivity, motion perception, peripheral visual field sensitivity, visual processing, ocular surface irritation, altered tear film, decreased blink rate, and decreased convergence amplitudes are common in PD [85, 86]. Electrophysiologic testing suggests that retinal ganglion cell impairment plays a role in the loss of acuity and prolonged visual evoked potentials and abnormal electroretinographic patterns are seen [87]. Interestingly, both of these neurophysiologic assessments respond to levodopa [88, 89]. Motor disturbances have been attributed to visual hallucinations, double vision, and estimating spatial relations and most often produced freezing of gait [90].

Pain and Paresthesia

Shoulder pain is recognized as an early and sometimes initial symptom of PD [91]. Later in the disease, pain may be subdivided into dystonic or nondystonic varieties. In a report of 402 PD patients versus 317 healthy age-matched controls, the rates of nondystonic pain (arthralgia and neuropathic) were similar, while dystonic and cramping pain occurred only in PD subjects [92]. In the PD group, dystonic pain occurred in 7% of patients, with symptoms distributed to the leg or foot (5.5%), neck or shoulder (2.2%), and arm (1%). In addition, more PD patients experienced pain for at least 3 months (69% vs. 63%, p = .04). A review of 450 consecutive PD patients at 25 centers has found chronic pain, attributed to PD, to be present in 167 patients (37%) [93]. Patients with pain had younger onset, higher depression, and more motor complications.

While the mechanism of central or peripheral pain symptoms in PD is unknown, there appears to be a change in pain threshold when studying patients in the on or off states [93, 94].

Restless legs syndrome (RLS) and PD overlap in some features including response to dopaminergic drugs, but whether the two disorders are pathogenically linked is controversial [95, 96]. Akathisia is an inability to sit still and, unlike RLS, involves the entire body. This symptom is most often associated with dopamine receptor blocking drugs, such as metoclopramide or haloperidol, and is characterized by stereotyped and repetitive crossing of legs or pacing in place and inner feelings of restlessness.

CONCLUSION

Nonmotor symptoms in PD are increasingly recognized as a significant cause of disability and may involve almost any aspect of the nervous system. Autonomic nervous system dysfunction includes GI disturbances, urogenital dysfunction, orthostatic hypotension, and thermoregulatory difficulties. Peripheral nervous system involvement is seen with changes in olfaction, vision, and sensory decline. Higher cortical dysfunction results in symptoms of cortical or subcortical dementia, while basal ganglia disturbances may result in impulsive or compulsive behaviors. Brainstem involvement may result in sleep dysfunction.

Declaration of interest: Dr. Mark Stacy receives grant support from Ceregene, IMPAX, Michael J. Fox Foundation, Neuraltus, Novartis, Parkinson Study Group, and Schering-Plough. He has served as a consultant for Allergan, Biogen, General Electric, Novartis, Osmotica, Schering-Plough, and Synosia. He has also served on protocol steering committees or safety monitoring boards for Biogen, Neurologix, and EMD Serono and receives royalties from Informa Press for the Handbook of Dystonia.