Rivastigmine Beneficial in Dementia with Lewy bodies
Abstract & Commentary
Source: McKeith I, et al. Efficacy of rivastigmine in dementia with Lewy bodies: A randomised, double-blind, placebo-controlled international study. Lancet 2000;356:2031-2036.
Dementia with Lewy bodies (DLB) is considered to be the second most common form of neurodegenerative dementia after Alzheimer’s disease. DLB presents in many cases with fluctuating cognitive status, parkinsonism without tremor, delusions, and/or hallucinations. It also expresses increased sensitivity to extrapyramidal side effects of neuroleptics. As yet, no medication has been specifically approved in the United States for the treatment of this condition. Over the past several years, a handful of case series and an open-label trial in Great Britain have suggested that some patients with DLB may respond to treatment with acetylcholinesterase inhibitors. Now, the first randomized, double-blind, placebo-controlled trial of a cholinesterase inhibitor (rivastigmine) to treat DLB has been completed, with positive results.
The 23-week clinical trial involved 120 DLB patients from the United Kingdom, Spain, and Italy with mild to moderately severe dementia (MMSE > 9). The mean age of the test population was 73.9 years, with slightly more males (57%) than females. Rivastigmine 6-12 mg/d or placebo was administered over 20 weeks, followed by a three-week washout period. The primary outcome measure was scores on the Neuropsychiatric Inventory (NPI), which assesses behavioral disturbances in multiple domains based on caregiver reports. Another primary outcome was the speed of response to certain tests in a computerized cognitive assessment battery. Secondary outcome measures included clinician assessments, Minimental scores, and performance on various neuropsychological tests. Changes in motor function were assessed with the United Parkinson’s Disease Rating Scale.
Patients treated with rivastigmine improved both in their reaction time and their behavior as measured by the NPI. Rivastigmine-treated patients tended to respond faster on neuropsychological tests than their counterparts in the placebo group, particularly on tests requiring a greater attentional component. The domains of the NPI that showed the greatest response to rivastigmine were apathy, anxiety, hallucinations, and delusions. There was a higher incidence of side effects in the rivastigmine-treated group, with gastrointestinal upset being the most common adverse occurrence. Three patients in the rivastigmine-treated group and none in the placebo group developed worsened agitation after treatment. Three weeks after discontinuing medication, rivastigmine-treated patients showed comparable reaction times and behavioral disturbances to the placebo group. No significant changes in parkinsonian symptoms were observed within the treatment group as a whole, although four patients who received rivastigmine developed tremor during the trial.
Commentary
Patients with DLB may have an even greater central cholinergic deficit than Alzheimer’s patients, providing a rationale for investigating the use of cholinesterase inhibitors to treat the disease. Both rivastigmine and tacrine have been previously reported to benefit DLB patients in open-label trials. The demonstration in a blinded placebo-controlled trial that rivastigmine has positive effects on DLB patients in terms of reaction time and behavior is a noteworthy finding, and represents an important step towards the possible future acceptance of this class of agents for treating DLB.
Anecdotal evidence suggests that the beneficial effect of cholinesterase inhibition in DLB is not confined to rivastigmine, but may be exhibited by other medications in this class. Presently, rivastigmine is the only cholinesterase inhibitor that has shown significant improvements in a sizable randomized, blinded, controlled trial. While these effects can be rather dramatic in some DLB patients, this study and clinical experience indicate that not every DLB patient responds to this line of therapy. It is unclear how long the benefits in responders can be expected to last, and the optimal dosing in DLB patients remains to be determined for rivastigmine or other drugs in its class.
It is important to note that patients with DLB may be exquisitely sensitive to neuroleptics, particularly high potency antipsychotics such as haloperidol, which may generate severe parkinsonism. Given the relatively benign side effect profile of acetylcholinesterase inhibitors (they do not seem to worsen parkinsonian symptoms in most cases) and the demonstrated efficacy of rivastigmine in reducing delusions and hallucinations in DLB, these agents may be a safer alternative to medications like haloperidol. Cholinesterase inhibitors tend not to be as potent in their anti-psychotic effects as neuroleptics, however, and are not likely to become first-line therapy for severe agitation or aggressive behavior. —Norman R. Relkin
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content