Nonmotor complications of Parkinson disease

July 1, 2012|Cleveland Clinic Journal of Medicine

ABSTRACTNonmotor manifestations are integral components of Parkinson disease (PD), and they often have a greater impact on disability and quality of life than the motor features that currently define the illness. Nonmotor features of PD, such as dementia, may be an intrinsic feature of the disorder and persist regardless of the medication state (ie, they continue to manifest in the “on” or “off” state); some nonmotor features, such as psychotic symptoms, may be iatrogenic complications of pharmacologic intervention for the treatment of the motor manifestations of PD. Iatrogenic complications, such as psychosis and impulse control disorders, may respond to modification of the PD treatment regimen at the risk of worsening motor symptoms. Thus, a balance must be struck between controlling nonmotor manifestations and motor features of the disease.

Although the definition of Parkinson disease (PD) is based on the presence of motor features, these are just the “tip of the iceberg.” Nonmotor manifestations are nearly ubiquitous in PD, with behavior problems often being the most malignant. Almost all patients with PD have nonmotor and neuropsychiatric features, including sleep disturbances, compulsive and impulsive behaviors, autonomic dysfunction, and psychosis.

The neuropsychiatric and behavioral features of PD can be classified as intrinsic features, which occur as part of PD, and iatrogenic features, which are complications that arise from treatments used to manage the motor symptoms of PD.

DEMENTIA IN PD

An intrinsic nonmotor feature of PD is dementia, which occurs at a rate four to six times greater in patients with PD than in age-matched controls without PD.¹ The prevalence of dementia in PD varies among studies and depends on the demographics of the population being studied. The cross-sectional prevalence of dementia is 40% in patients with PD.² Seventy-eight percent of a population-based, representative cohort of patients with PD developed dementia during an 8-year study period.³

Dementia is a burden to the caregiver, the patient, and society. Cognitive and behavioral symptoms in patients with PD are the greatest contributors to caregiver distress.⁴ Dementia and associated behavioral symptoms (ie, hallucinations) hasten nursing home placement, contributing to the financial burden of caring for patients with PD.⁵ The risk of mortality is increased when dementia develops.⁶

Figure 1. In a double-blind, placebo-controlled trial that compared rivastigmine with placebo, patients with Parkinson disease dementia who were treated with rivastigmine experienced a 3-point improvement in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) compared with placebo.

At least one medication has shown promise in managing PD dementia. In a pivotal trial of the cholinesterase inhibitor rivastigmine, involving more than 500 patients with PD dementia, the patients randomized to rivastigmine had a 3-point improvement on the primary outcome measure—the mean change from baseline in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale—compared with those randomized to placebo (Figure 1).⁷ This trial led to US Food and Drug Administration approval of rivastigmine for the treatment of PD dementia.

PSYCHOTIC SYMPTOMS IN PD: AN EFFECT OF EXCESS DOPAMINE STIMULATION

Most of the complications observed in PD can be explained by the dopamine effect of medications and by dopamine deficiencies. An excess of dopamine stimulation caused by administration of prodopaminergic agents manifests as dyskinesias, hallucinations, or delusions. Withdrawal of levodopa will reverse these complications but leads to dopamine deficiency and thus a worsening of PD symptoms. Most patients with PD will tolerate mild dyskinesias or hallucinations if their PD symptoms are well controlled.

The hallucinations in PD tend to be visual as opposed to auditory (as in schizophrenia). They are usually benign and involve figures of people, furry animals, or complex scenes. About 10% to 40% of hallucinations in PD are secondary auditory hallucinations, which tend to be nondistinct, non-paranoid, and often incomprehensible (ie, voices in a crowd).

In the same way, the delusions experienced in patients with PD are distinct from those in schizophrenia. The delusions in PD are usually paranoid in nature and involve stereotyped themes (ie, spousal infidelity, feelings of abandonment) rather than the grandiose delusions that are common in schizophrenia.

The reported prevalence of psychotic symptoms in PD, including hallucinations and delusions, ranges from 20% to 50%.^8,9 Auditory hallucinations are a feature in about 10%, and they usually occur with visual hallucinations. Less common are delusions and hallucinations with loss of insight, which are more likely with increasing severity of dementia.

Once a PD patient experiences hallucinations, they are likely to continue. In a 6-year longitudinal study, the prevalence of hallucinations increased from 33% at baseline to 55% at 72 months.¹⁰ Persistent psychosis was found in 69% of participants in the Psychosis and Clozapine in PD Study (PSYCLOPS) with 26 months of follow-up.¹¹

High caregiver burden

Psychotic symptoms in PD are associated with high caregiver stress and increased rates of nursing home placement. Goetz et al¹² showed that PD patients with psychosis had a much greater risk of nursing home placement than those without psychosis. The prognosis for PD patients in extended-care facilities is worse for those with psychotic symptoms.¹³

Management of psychotic symptoms

The first step in managing psychosis in PD is to rule out other causes of changes in mental status, such as infection, electrolyte imbalance, or introduction of new medications.

Adjusting anti-PD medications to a tolerable yet effective dose may help to reduce the incidence and severity of psychotic complications. If necessary, selective discontinuation of anti-PD medications may be tried in the following sequence: anticholinergics, amantadine, monoamine oxidase B inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, and levodopa/carbidopa.

If motor symptoms prevent dosage minimization or discontinuation of some medications, then the addition of an atypical antipsychotic medication should be considered. Before the advent of atypical antipsychotics, the management of psychosis and hallucinations in PD was unsatisfactory, reflected by a mortality of 100% within 2 years among psychotic PD patients placed in nursing homes compared with 32% among age-matched community dwellers.¹³ The introduction of atypical antipsychotics has improved survival among PD patients with psychosis. In one study, mortality over 5 years was 44% among PD patients taking long-term clozapine for the treatment of psychosis.¹⁴ Recurrence of psychosis is rapid (within 8 weeks) even when PD patients are slowly weaned from atypical antipsychotics.¹⁵

Receptor affinities differ among antipsychotics. Because dopamine has been implicated as the principal neurotransmitter in the development of PD psychosis, atypical antipsychotics, with milder dopamine-blocking action, have played a central role in the treatment of PD psychosis. The dopamine D₂ receptor is the main target for conventional antipsychotic drugs to exert their clinical effects. Atypical antipsychotics have different affinities for the D₂ receptors.¹⁶ Occupancy of D₂ receptors with atypical antipsychotics is 40% to 70% (risperidone and olanzapine have higher affinity for the D₂ receptor than clozapine and quetiapine), and affinity for 5-HT_2A receptors can be as high as 70%. This affinity for 5-HT_2A receptors relative to D₂ receptors may be important for therapeutic efficacy of the atypical antipsychotics. Antagonism of muscarinic, histaminergic, noradrenergic, and other serotonergic receptors also differs among the atypical antipsychotics.

Clozapine remains the gold standard atypical antipsychotic agent, based on results from three relatively small (N = 6 to 60) double-blind, placebo-controlled studies in PD patients with dopaminergic drug-induced psychosis.^17–19 Quetiapine improved psychotic symptoms associated with PD in several open-label studies, but has not demonstrated the same success in double-blind clinical trials.^20,21

Loss of cholinergic neurons and implications for treatment. In autopsy studies, the loss of cholinergic neurons is more profound in PD than in Alzheimer disease, which suggests that procholinergic drugs may improve symptoms of PD dementia, a major risk factor for hallucinations. In open-label studies, acetylcholinesterase inhibitors have reduced the frequency of hallucinations in patients who have dementia with Lewy bodies (DLB) and in patients with PD dementia. Double-blind trials of patients with DLB and PD dementia concentrated on the effect of cholinesterase inhibitors on dementia and not hallucinations. One concern with the use of a procholinergic drug in patients with PD has been worsening of parkinsonism, but studies of acetylcholinesterase inhibitors have shown no worsening of parkinsonism and only transient worsening of tremor.

Ondansetron, a 5-HT₃ receptor antagonist used as an antinausea medication, produced moderate improvements in hallucinations and delusions in an open-label trial for the treatment of psychosis in advanced PD.²² For PD patients with psychosis and comorbid depression, antidepressant therapy and electroconvulsive therapy may be effective options.^23,24

References

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