Combination therapy for PD

To the Editor: Development of motor fluctuations and involuntary movements is the major complication of long-term levodopa (LD) therapy of Parkinson’s disease (PD). Weiner et all report a double-blind, randomized, parallel-group study on the effects of bromocriptine (Br) and LD, alone and in combination, upon the development of motor complications after 4 years of treatment. They conclude that a combination of Br and LD does not postpone the development of such complications and that the longterm therapeutic benefit of combined treatment is not superior to that of LD alone. We were surprised to find in their paper a profound critique of the work done by Rinne. This critique refers to methodologic shortcomings of earlier studies of Rinne’s. Weiner et al, however, fail to refer to a paper by Rinne2 dealing with lisuride. In this 4-year study, 90 patients were randomly allocated to three treatment groups (LD, lisuride, and LD plus lisuride). A fourth group consisted of patients treated primarily with lisuride alone but who received LD in case of a n insufficient therapeutic response. The important results were that (1) patients remaining on lisuride alone did not develop motor complications and (2) a combination of lisuride and LD did reduce wearing-off and peak-dose dyskinesia substantially. Apart from that, the report by Weiner et a1 deserves a number of comments. First, this is another study published as an independent paper although it is only a one-center report of a multicenter study. Such studies are usually planned under criteria that fulfill basic statistical requirements, ie, calculations of the number of patients to be enrolled for appropriate analysis of the results, number of criteria to be tested, etc. A single-center report is not necessarily a representative part of the whole study but rather an undefined fraction. As a result, the statistical methods employed are not adequate for the data. Monte Carlo studies have shown that even one-way ANOVAs give spurious resul ts when used with sample sizes under 10 and unequal cell sizes.3 The results that the authors find most interesting (less frequent dystonia in the Br monotherapy group) is obtained by chi-square test. It is known that chi-square tests with many cell frequencies below five give dubious results. Another point is that eight significant results were obtained from among 142 statistical tests. It is well known that, by such a procedure, the type I error is inflated. In the paper by Weiner e t al, one would expect a t least seven statistically significant (a = 0.05) outcomes by chance. To counteract this problem, an adjustment of the a level is mandatory. Using the Bonferroni method for dependent test procedures, the appropriate a level would be 0.00035, which would leave the authors with one significant result (improvement of the motor examination score of the group treated with LD a t 6 months). The main problem with studies employing a small number of subjects is their lack of statistical power, defined as the likelihood that a real, existing difference between groups is actually detected. To illustrate this point with respect to the study of Weiner et al, we make the following consideration. Assume that the real difference (effect size) is 1.0 times the SD. This is a difference that would be of undoubted clinical importance. With a maximal cell size of n = 9, the power of an ANOVA can be roughly estimated to be below 0.3; actually, the value is so low that it is not given in standard tables. This means that the authors’ main conclusion (that there is no difference between LD and the combination of Br with LD) reflects an error of more than 70%! Our critique is not just a theoretical issue. Because your journal is read by a vast number of clinical neurologists (such as ourselves), an article such as that by Weiner et a1 might lead to changes in therapeutic regimen detrimental to or a t least not optimal for patients.