Psychosis

The onset of psychosis in patients with PD is a serious complication associated with increased risk of nursing home placement, dementia, and death.24 Patients with advanced PD and disease duration of more than 10 years are at highest risk for psychosis; prevalence ranges from 25% to 30% in referral clinics.25 As compared with other psychotic conditions, PD psychosis generally involves well-formed visual hallucinations, presence hallucinations, and paranoid delusions, often about spousal infidelity or abandonment. Hallucinations involving other sensory modalities are much less common and usually occur along with visual hallucinations.26

Psychotic symptoms are intermittent but recurrent and are usually worse at night. Many patients with PD initially report retained insight, and therefore benign hallucinations are diagnosed. However, in most patients, insight is gradually lost and the hallucinations become more threatening.27 Therefore, the term "benign hallucinations" is discouraged because it merely represents the early stages of a progressively disabling course.

The pathophysiology of PD psychosis is not fully understood. Although dopaminergic drugs have long been associated with the development of psychosis, it is hard to assess true causality because psychosis occurs late in the disease when nearly all patients require dopaminergic therapy for motor symptoms. Moreover, an increase in dopaminergic therapy does not always worsen psychosis, and the removal of dopaminergic therapy does not always resolve psychosis. Similarly, other clinical features, such as dementia, are associated with psychosis. These suggest that PD psychosis results from the interaction of PD pathology and medications and is not purely drug-induced.24

Treatment options for PD psychosis are limited. Typical antipsychotics are not recommended in PD because they worsen parkinsonism and may cause acute severe akinesia and rigidity. Clozapine is the only antipsychotic shown to be effective in the treatment of PD psychosis in a randomized, double-blind, placebo-controlled trial.28 Unfortunately, the risk of agranulocytosis requires frequent blood monitoring, which limits the use of clozapine. Despite the lack of definitive evidence of efficacy, quetiapine is often used first because of its favorable safety profile and apparent lack of adverse effects on motor symptoms in PD.29,30 Olanzapine worsens parkinsonism and is not recommended.31,32 Aripiprazole is a partial D2 agonist, with a potentially appealing profile in PD. Despite this, results of studies of aripiprazole in PD have been mixed.33-35 Risperidone is a potent dopamine blocker more similar to the typical antipsychotics in action, but it is generally not recommended despite an open-label study supporting its use.36,37

Because treatment options are limited, management generally begins with the removal of potentially exacerbating medications, such as anticholinergics, monoamine oxidase inhibitors, and dopamine agonists. Levodopa dosing is reduced as much as is tolerated. Subsequently, quetiapine or clozapine is started. Although evidence now links atypical antipsychotics to increased risk of cardiovascular death, this potential risk must be weighed against the poor prognosis associated with psychosis in PD.24

Dementia

In a meta-analysis of prevalence studies, dementia occurred in 30% of patients with PD, and PD dementia accounted for 3% to 4% of all dementia in the general population.38 There is clinical overlap of dementia with Lewy bodies; currently, patients showing dementia before or within 1 year of onset of motor symptoms are considered to have dementia with Lewy bodies.39 Researchers continue to debate whether dementia with Lewy bodies and PD are separate pathological entities or if they represent a continuum of Lewy body disease. Nonetheless, the clinical separation appears helpful from a management and prognostic perspective. Pathologically, converging evidence suggests that Lewy body pathology, not amyloid pathology, underlies PD dementia.40

Currently, donepezil and rivastigmine appear to be modestly effective in delaying time to nursing home placement as well as preserving cognition, with an effect size similar to that seen in Alzheimer disease. In one study of piracetam, researchers found no effect on dementia.29

Sleep disorders

Sleep is disrupted in up to 65% of patients with PD, and sleep disruption is more common in those with PD than in age-matched healthy controls and controls with diabetes mellitus.41 Sleep disturbance is multifactorial, and many patients have multiple sleep problems. As a result, excessive daytime somnolence is one of the most common sleep issues in PD. Autonomic involvement may lead to urinary urgency and frequency with subsequent nocturia. Nocturnal pain can develop from rigidity, akinesia, or dystonia. Comorbid conditions such as restless legs syndrome and rapid eye movement sleep behavior disorder also impair sleep quality. Management generally involves sleep hygiene, maximal treatment of sleep disruptors, and in some cases, modafanil or other stimulants, although these have not been well studied in the PD population.

Impulse control disorders

In the past few years, repetitive, reward-based behaviors have been reported in PD, including pathological gambling, compulsive eating, hypersexuality, punding, and dopamine dysregulation syndrome.42 The causes of these behavioral patterns are not known for certain, but it is thought that they may be related to nonphysiological dopaminergic stimulation altering the frontal-limbic-striatal circuitry. As a group, these conditions are not consistently related to medication doses, disease severity, or disease duration and are only present in a subset of patients; this suggests an idiosyncratic susceptibility modified by PD-specific pathophysiology. Because patients frequently hide or are not distressed by these behaviors, diagnoses may be rare despite a prevalence of 6.1% for all disorders.43 The relationship between impulse control disorders and dopaminergic medications is not clear, but one study noted a prevalence of 0.7% with levodopa versus 13.7% with dopamine agonists as a class.43 No one specific agonist appears to be more closely linked to impulse control disorders. Management of these disorders is not well studied in PD and generally involves removing the suspected offending agent, if possible, and treating any underlying mood disorder.

Summary

PD is a progressive neurodegenerative disorder with symptoms affecting multiple brain areas. The cognitive and behavioral aspects of PD are important because of their impact on the patient and because of their importance to understanding the pathophysiology of this complex disease. Further research is needed to more precisely define and measure nonmotor symptoms, to provide better symptomatic therapies, and to pursue the ultimate goal of protecting or restoring neuronal function.
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