Introduction

Senile dementia of the Lewy body type is a relatively common variant, representing 15-25% of new cases of dementia. Its diagnostic features have been reviewed on this site (see related link, below). An important aspect of this type of dementia is that it tends to respond to acetylcholinesterase inhibitors, whereas it responds poorly - even adversely - to neuroleptic medications.

Professor Ian McKeith of Newcastle upon Tyne, UK (an acknowledged expert on Lewy-body dementia), together with colleagues from Spain and Italy, has reported recently on a double-blind, placebo-controlled study of a new cholinesterase inhibitor, rivastigmine, in this condition.

Method

Patients with mild to moderately-severe dementia who had a clinical diagnosis of probably Lewy-body dementia were recruited from dementia clinics in Spain, UK, and Italy. They had to be free of any extrapyramidal symptoms, asthma, or a known sensitivity to cholinesterase inhibitors.

120 patients were randomly assigned to receive either rivastigmine or matching placebo, given twice a day for 20 weeks, followed by a 3-week rest period. The rivastigmine doses were 1.5 mg twice daily, escalated by 1.5 mg twice daily for a maximum of 2 weeks at each dose, until 6 mg twice daily or a maximum well-tolerated dose was reached.

Recordings of adverse events, cardiovascular vital signs, electrocardiograms and lab tests were done at frequent intervals during the 20 weeks on drug and after the rest period.

To assess efficacy, the Neuropsychiatric Inventory (NPI) and selected tests from the Cognitive Drug Research Computerized Cognitive Assessment System were done at baseline, at weeks 12 and 20 of treatment, and then 3 weeks after drug discontinuation.

A subscore of the NPI, termed NPI-4, assessed delusions, hallucinations, apathy, and depression, using interviews with the caregiver. The computerized assessment had tests of attention, working memory, and episodic memory. Secondary efficacy measures were the clinical global change, the Minnesota Mini-mental State Exam (MMSE), and other scores from the NPI and the computerized testing system.

Results

The two treatment groups were well balanced with regard to age (mean 73.9 years), sex (52.5% and 60.7% males, respectively) and MMSE (means 17.8 & 17.9, respectively). Of the 120 subjects randomized, 41 rivastigmine and 51 placebo patients completed treatment; 7 in each group experienced adverse events that led to withdrawal, while other reasons for failure to complete were withdrawal of consent (5 rivastigmine, 1 placebo), protocol violations (2,1), treatment failure (1,0), lost to follow-up (2,0), and abnormal ECG (1,0).

Mean rivastigmine doses reached a maximum of 9.4 mg in week 8, and then declined slightly; the maximum daily dose of 12 mg was reached by 56% of the assigned subjects, while 92% reached 6-12 mg daily.

Changes in the mean NPI-4 scores from baseline were all in favor of rivastigmine, being statistically significant at week 20 for two of the analyses done; the intent-to-treat analysis was in favor of rivastigmine, but not significantly so (p=0.088). NPI domains improving most with rivastigmine were apathy, indifference, anxiety, delusions, hallucinations, and aberrant motor behavior.

The computerized assessment speed scores showed that patients on rivastigmine were significantly faster, particularly in tasks focusing on attention. Consistent changes favoring rivastigmine were seen in the total NPI scores, clinical global change, and MMSE scores, although they were not always statistically significant.

At the 3-week follow-up examination, the mean differences from baseline for the rivastigmine group were smaller than those seen at week 20, approaching those of the placebo group.

As many as 92% of patients on rivastigmine and 75% of those on placebo reported mild adverse events; cholinergic effects were predominant - nausea, vomiting, anorexia and sleepiness - and significantly more frequent in the rivastigmine group. Serious adverse events were similar in both groups, with only agitation in 3 subjects ascribed to rivastigmine treatment. There were no relevant rivastigmine-related changes in lab tests, vital signs or ECG results.

Comment

An accompanying editorial in Lancet comments on the findings of this study.¹As patients with dementia with Lewy bodies have a severe cholinergic deficit, it was not unexpected to find that rivastigmine had clear-cut beneficial effects in this disorder. Neuropsychiatric symptoms and reaction times represent novel outcome measures for drug studies in dementias, and may indeed have greater relevance as the more commonly used cognitive assessment scales and clinical global impression scores.

Other conditions with cholinergic deficit include Parkinsons disease with dementia, and patients with mixed Alzheimers and vascular dementia. It is logical to suppose that cholinesterase inhibitors are beneficial in these subjects, too. The use of cholinesterase inhibitors has, to date, been avoided in subjects with parkinsonism, for fear of exacerbation. However, over 90% of the patients in this study exhibited parkinsonism at baseline (a cardinal feature of Lewy-body dementia), without apparent worsening of motor signs during the treatment period. There may well be, therefore, less need for caution in prescribing such agents in patients with parkinsonian symptoms in the future.