Levodopa-induced motor complications

Whereas fewer dyskinesias were reported in PD-D patients in a cross-sectional study [60], a longitudinal study found greater mental deterioration in those patients exhibiting dystonic levodopa- induced dyskinesias at baseline [56]. Clissold et al [57] reported fluctuator versus non-fluctuator status in a longitudinal study of levodopa responsiveness in 22 surviving PD patients, in addition to their latest MMSE score. When considering fluctuator status in those subjects with a MMSE score of <24, compared with those above this level (a threshold previously suggested to support a diagnosis of PD-D), only 15% of the fluctuators were classified as PD-D versus 44% of the non-fluctuators. Although these data are insufficient to infer differences in the occurrence of levodopa-induced motor complications in PD-D, they lend some support to the notion that fluctuations may be less frequent.

Neuroleptic sensitivity

Although placebo-controlled studies have previously excluded patients with PD-D, open-label studies with clozapine in PD-related psychosis have included PD-D subjects and found that the drug was similarly well-tolerated in PD-D and PD patients without dementia. Sedation and hypotension are the main side effects described. One study evaluated severe neuroleptic sensitivity reactions (NSRs) according to an operationalized definition, blind to clinical and neuropathological diagnoses, in prospectively studied patients exposed to neuroleptics from two centres [61]. Severe NSR only occurred in patients with DLB—in 53% DLB, 39% PDD, and 27% PD patients— and did not occur in Alzheimer’s disease. No other clinical or demographic features predicted severe NSR. This high frequency of NSR in PD-D clearly has important implications for clinical practice, particularly as even so-called ‘atypical neuroleptics’ such as risperidone, olanzapine, and aripiprazole are not exempt from causing this problem in the closely related DLB [62].

Rate of progression of motor symptoms in PD-D

The development of dementia may be associated with a more aggressive course of motor disease [14, 57, 60]. Jankovic and Kapadia [63] determined the overall rate of functional decline in 297 PD patients, followed up for an average of 6.4 (range 3-17) years. Patients were categorized as having TD or PIGD-dominant PD and the two categories were compared for progression of their total UPDRS scores. Patients with an older age at onset had more rapid progression of PD than those with a younger age at onset, while cognitive deterioration was greater in the older-onset group. Regression analysis of 108 patients whose symptoms were rated during their ‘off’ state showed a faster rate of cognitive decline as age at onset increased, and the annual rate of decline in the UPDRS scores, when adjusted for age at initial visit, was steeper for the PIGD-dominant group compared with the TD group. Dementia at baseline was associated with more rapid motor decline in two studies [64, 65], but this remained significant in only one study after adjusting for other baseline factors, where PD-D patients had a 7.9-point higher annual decline in UPDRS motor scores than those without dementia at baseline [65]. In a longitudinal study, a more rapid decline in UPDRS III scores was reported in PD-D compared with PD patients over 2 years (9.7 versus 5.1 points, respectively) [49]. Although not statistically significant, the absolute deterioration at 2 years was greater in the PIGD than the TD PD subgroup. Rate of motor decline in the PD-D patients was independent of baseline disease duration. In a study of 232 PD patients followed for 8 years, population-averaged logistic regression models were used to describe annual disease progression and to analyse the influence of potential risk factors on functional decline [66]. Age, age at onset, disease duration, and EDS at baseline were strong and independent predictors of greater impairment in motor function and disability, while cognitive impairment at baseline predicted higher disability and a higher Hoehn and Yahr score. Age at disease onset was, however, the main predictor of motor decline, indicating a slower and more restricted pathological process in patients with younger-onset PD.

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