Parkinsonism, Dementia, and Agitation: Clarifying the Diagnosis
Mr. A is a 72-year-old married man with two daughters. He is a native of Puerto Rico who came to the United States at age 20. Mr. A owned a grocery store and worked until 5 years ago, when he developed distressing symptoms of tremor and bradykinesia. He was diagnosed with Parkinson’s disease, but did not receive any treatment until 2 years ago, when his gait became too unsteady for him to walk independently. Levodopa-carbidopa 25/100 mg 1/2 tab 3 times a day was prescribed by his neurologist. Mr. A improved enough to move around in his house, but his wife provided assistance with dressing and grooming. He was able to socialize with his family and friends and continued to provide advice about his grocery store, which one of his daughters was managing.
One year later, Mr. A started to have difficulty remembering names and was very repetitive when discussing finances. Over time, he displayed difficulty with word finding, his attention span was very poor, and he could no longer keep track of time. He would ask for breakfast several times each day and forget that he had eaten meals. His motor function remained stable, and the neurologist continued the levodopa-carbidopa at the same dose. Over the next several months, Mr. A started accusing his wife of cheating on him with other men. He became angry, resistive to care, and agitated in response to these paranoid delusions. Mrs. A was very devoted, but became frightened when her husband started cursing at her and raising his fists in anger. She denied ever having an affair and explained that she only goes out to the store, but this made Mr. A even angrier and physically agitated. Mr. A started refusing to change clothing or bathe because he did not want his wife to help him. Mrs. A asked her daughters for help. They visited with food from the grocery store. Mr. A became aggressive and started throwing dishes at them. The family felt overwhelmed and unable to deal with Mr. A. They brought him to the emergency room for evaluation.
On exam, he appeared thin, was confused, poorly groomed, and disheveled, and had poor eye contact. It was difficult to engage him in a conversation because of his agitation and paranoia. His speech was slow with difficulty finding words. Mr. A’s mood was angry and his affect was flat. He denied perceptual disturbances and exhibited paranoid ideation. He was alert, awake, and oriented only to self. His cognition was impaired; he was not able to do simple tasks that require attention and concentration, such as serial 7’s and spelling, and he could not copy a figure of interlocking pentagons. His judgment and insight were grossly impaired. Mr. A was admitted to the hospital for further evaluation of his cognitive loss and psychotic symptoms, and assessment of his Parkinson’s disease.
Parkinson’s disease (PD) is a chronic neurodegenerative disease that affects approximately 1% of individuals over age 60 years.1 The hallmark of the disease is the slow onset of motor symptoms, which result from the gradual loss of dopaminergic cells in the substantia nigra. The cardinal clinical features are resting tremors, rigidity, and bradykinesia.2,3 Micrographia, a characteristic festinating gait associated with small rapid steps, and a fast, almost mumbling speech pattern are also found in PD. Postural abnormalities with loss of reflexes result in a tendency to fall in a distinct forward or backward pattern, often referred to as propulsion and retropulsion. Although PD is primarily considered a progressive motor disorder, there is a high prevalence of comorbid psychiatric symptoms including mood disturbances, psychosis, and cognitive deficits.4
Progressive cognitive decline occurs in a subgroup of patients with PD.4 The prevalence of dementia among patients with PD ranges from 20% to 40%. Those who develop progressive dementia have an older age of onset, longer duration of PD symptoms, fewer years of formal education level, and a greater severity of motor deficits2,4 (Table I). It is important to differentiate the dementia that occurs over the course of PD from the two more common dementias, Alzheimer’s disease (AD) and Lewy body dementia (DLB)4-8 (Table II). The dementia of PD presents with symptoms of a frontal-subcortical pattern of deficits.5 The spectrum of cognitive impairment in PD includes deficits in executive functioning, attention shifting, recall and retrieval of information, working memory, fluency of speech, word finding, visual discrimination learning and visuospatial reasoning, and relative sparing of memory recognition.2,4,5,7 The pathogenesis of dementia in PD is related to disruption in serotonergic and noradrenergic transmission and cortical Lewy body deposition.4 The nucleus basalis of Meynert is also depleted in patients with PD who have dementia, resulting in cholinergic deficits.9 Dopamine concentrations in the prefrontal and entorhinal cortex were found to be considerably lowered in patients with PD who have dementia as compared with patients with PD without dementia.2
Patients with PD who have dementia have been found to have a higher density of Lewy bodies in the neocortex compared with patients with PD without dementia. Severity of the cognitive impairment is significantly correlated with the density and concentration of these Lewy bodies.2 Brain magnetic resonance imaging (MRI) scans of patients with PD who have dementia showed hippocampal atrophy, and single photon emission computed tomography (SPECT) studies have identified hypoperfusion in the superior temporal and parietal regions compared to patients with PD without dementia.2 Cognitive decline in DLB correlates with choline acetyltransferase reduction in presynaptic neurons, and parkinsonian signs correlate with loss of nigrostriatal dopaminergic projections.2,6 Fluctuating cognitive function occurs in 58% of patients with DLB. Visual hallucinations, episodes of syncope, and early visuospatial dysfunction with visuoconstructional apraxia are considered characteristic features of the disorder.6 Assessment of dementia in patients with PD includes: a careful history focusing on the nature of PD; psychiatric history addressing the cognitive, psychotic, and depressive symptoms; and comprehensive mental status examination. (The Mini-Mental State Examination is not sensitive to executive dysfunction, which is common in PD; instead, using the Trail Making Test is more diagnostic.8)
Parkinsonian symptoms that develop in patients with progressive Alzheimer’s dementia are associated with a more rapid progression and marked functional decline. The prevalence of parkinsonian features among patients with AD has been reported with a wide range of 6-50%. In part, this may be related to unrecognized, drug-induced extrapyramidal symptoms secondary to antipsychotic treatment in patients with AD. The presence of neurofibrillary tangles, reduced substantia nigra density, and diminished striatal dopamine activity are suggested to account for parkinsonism in AD.2 Patients with PD dementia perform significantly worse on neuro-psychological tasks that assess executive functions and visuospatial reasoning than patients with AD who display severe deficits in verbal fluency and semantic memory.2 The treatment of dementia in PD creates a major therapeutic challenge because dopaminergic medications used to treat motor symptoms often precipitate hallucinations and confusion.4,6
Pharmacologic approaches to treat psychosis in patients with PD who have dementia should avoid using typical dopamine antagonist neuroleptics because they deteriorate the motor symptoms and cause further physical disabilities.7 Cautious trials of low-dose atypical neuroleptics that affect both the dopamine and serotonin systems may be better tolerated.1 Evidence has been accumulating for the use of cholinesterase inhibitors as an effective treatment that slows the progression of the cognitive decline in patients with PD.9 The cholinesterase inhibitor rivastigmine has been studied extensively in patients with dementia associated with PD with moderate benefits as compared to placebo.10 Dementia in PD complicates the clinical picture of the disease and predicts a more rapid decline, with poor quality of life for the patients and caregivers.4 Early identification and appropriate management of patients with PD at risk of developing dementia would be helpful to reduce morbidity and provide assistance to patients and caregivers. Information for patients and caregivers may be downloaded from the National Parkinson Foundation website at www.parkinson.org.
OUTCOME OF THE CASE PATIENT
Following admission to the hospital, Mr. A underwent a computed tomography scan of his brain, which revealed moderate dilatation of the ventricles and ischemic white matter changes. Laboratory studies including complete blood count, chemistry panel, thyroid profile, Vitamin B12, and folate levels were all within normal limits. He was noted to be taking aspirin 81 mg and losartan 50 mg daily for coronary artery disease in addition to simvastatin 20 mg daily for a history of elevated cholesterol. Quetiapine 25 mg twice daily was started for Mr. A’s psychosis, but it was switched later to ziprasidone due to poor symptom response and worsening motor symptoms. He displayed improvement in his paranoia after the ziprasidone was increased to 40 mg twice daily. He received physical and occupational therapy to maximize his functional status. Donepezil 5 mg daily was started for his dementia. Mr. A was discharged home with his wife. Mrs. A continued to provide most of the care for her husband and was becoming overburdened with his physical needs. The couple eventually moved into a senior housing program that provided meals and a home attendant for Mr. A.
The author reports no relevant financial relationships.