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Using ChE-Is in practice: predictors of outcome, side effects, and discontinuation

Visual hallucinations are known from post-mortem studies to be associated with more severe cholinergic deficits in the Lewy body dementias [22], and patients with hallucinations might therefore be expected to benefit more from cholinergic enhancement. This was demonstrated to be the case in both the DLB [23] and the PD-D studies with rivastigmine [24]. The presence of visual hallucinations in Lewy body disease is also associated with a greater degree of impairment in attentional performance and a faster rate of cognitive decline, the common factor probably being greater cholinergic deficit—the activity of enzyme butyryl-cholinesterase may play a role [25] which may increase in functional importance as acetylcholinesterase levels diminish with disease progression. Other clinical indicators suggestive of central cholinergic failure, and therefore potentially predictive of a good ChE-I response, include apathy and daytime drowsiness. In practice the majority of PD-D and DLB patients will have such symptoms, visual hallucinations, or both. Given the lack of any demonstrable alternatives, a trial of a ChE-I seems to be the preferred action for any PD-D or DLB patient with significant cognitive impairments.

The side-effect profile of ChE-Is in Lewy body dementias is broadly similar to that reported in the AD population, but there are additional effects to be considered which probably reflect the pre-existing impact of the disease on cholinergic autonomic activity. The drugs are generally well tolerated at doses in the usual AD range, with dropout rates from 10 to 31% being reported. In addition to the well-recognized gastrointestinal side effects, troublesome hypersalivation, rhinorrhoea, and lachrymation occurred in about 15% of DLB and PD-D patients treated with donepezil, and postural hypotension, falls, and syncope in up to 10% [26]. The same open- label study found no difference in treatment responsiveness or side-effect profile when PD-D and DLB patients were compared. Worsening parkinsonism occurred in 9% of patients on 10 mg of donepezil, but this was rarely clinically significant and it could usually be improved by dose reduction. Abrupt withdrawal of ChE-Is may be associated with rapid return of neuropsychiatric symptoms and cognitive decline in DLB and PD-D [27]. Although reinstatement of treatment may reverse such deterioration, it is recommended that patients with Lewy body-related dementias who are assessed as responding to ChE-Is are maintained on treatment for the long term. Since attempts at switching from one ChE-I to another may be associated with clinically significant withdrawal effects [28], this treatment strategy should be considered carefully and patients who are switched should be closely monitored. A preliminary comparison of datasets from treatment studies in DLB using different ChE-Is suggests that there are no major differences between the available agents [29].

Rivastigmine has a marketing approval for treatment of patients with mild to moderate PD-D, both in the European Union and the Unites States. Licensing approval has not been obtained for any of the other ChE-Is in PD-D, nor for the use of any of them in DLB. Much prescribing is therefore ‘off label’, creating difficulties for those drafting good practice guidelines and dealing with reimbursement issues. Given the scale of the clinical problem and the lack of safe alternatives, this is an unsatisfactory situation and there is a good case for investment in more clinical trials, particularly those measuring longer-term outcomes, cost-effectiveness, and practical aspects of drug administration.

 
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