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Hello Hans: Your responses are very thought provoking - I have responded below: JAR said>>>Yes, levodopa causes dyskinesias in advanced PD WHEN YOU INSIST IN USING > inappropriately HIGH DOSES OF LEVODOPA despite the dyskinesias. HvdG replied>The alternative is more OFF-periodes when you reduce the doses of levodopa. JAR now replies: No! A better alternative is that when you arrive at this juncture you keep the levodopa levels below those which produce dyskinesias and add another medication. JAR said> >> You yourself indicate that "patients with advanced Parkinsonism that > reduce the use of levodopa have less dyskinesias." << > HvdG replied> I mean that if at a certain moment a PWP HAS dyskinesias, AT THAT MOMENT > dyskinesias can be reduced by using less levodopa. JAR now replies: Which only proves my point that the dyskinesias are DOSE related. It does not prove that early exposure brings on the dyskinesias any sooner. JAR said> >> That last statement is NOT the same as what you wish to imply, that > patients who delay the use of levodopa have less dyskinesias. << > HvdG replied> PWP that delay the use of levodopa, do not have LESS dyskinesias, but will > experience the dyskinesias a few years LATER. JAR now replies: Neither LESS nor LATER. I strongly disagree and challenge you to produce ANY scientific evidence to prove this point. This is the crux of the matter. Indeed, in the theoretical situations you presented, you present a scenario which is very consistent with my interpretations. In Situation 3 you indicate that the dyskinesias experienced are related to the dosage, and reversible when the dosage is reduced. One large benefit of Situation 3 (my favorite) is that you were able to achieve 10 years of treatment with MONOTHERAPY, while Situation 2 was already on two drugs after three years!!!! The only reason you saw dyskinesias in situation 3 before you saw them in situation 2 was that you were using too high a dose of levodopa at that time - since you yourself stated that cutting the dose of levodopa improved the dyskinesias. I suggest that a better model is to attribute the dyskinesias to the duration or stage of the DISEASE, not to the duration of TREATMENT. Unfortunately these are difficult to separate, because they are measured in parallel and overlapping time coordinates. The net result, however, is that, as the disease progresses, the patient is more sensitive to the induction of dyskinesias (in much the same way that levodopa can bring out LATENT chorea in a person with presymptomatic Huntington's Chorea.) Indeed, this fits in remarkably well with some of Brian Collins' observations and hypotheses. Indeed, this model predicts that there is a point in the progression of the disease in which the sensitivity to dyskinesias sets the ceiling to the levodopa dosage. This ceiling gradually descends and approaches the curve which defines the level of levodopa necessary for a beneficial response, which is gradually increasing during the progression of the disease. The convergence of the declining ceiling for dyskinesias, and the rising floor for beneficial response provides for the well known observation of a gradually narrowing therapeutic window. Notice that this model is consistent with all of the following clinical observations: 1) as the disease progresses, the response declines 2) as the response declines, some additional response can be obtained by increasing the levels (the rising floor) 3) the levels of levodopa must be kept below a ceiling level above which dyskinesias occur. 4) the ceiling to avoid dyskinesias slowly comes down with progressing disease, and becomes a limiting factor by narrowing the therapeutic window. 5) it is the narrowing of the therapeutic window that requires the more frequent administration of medication to avoid high peaks (dyskinesias) and deep troughs (freezing). Earlier in the disease, a wider therapeutic window provides for greater tolerance of level fluctuations. This is why I favor early treatment with levodopa: 1) easier titration 2) longer stability 3) longer monotherapy (which, by the way, reduces the cost!!!!) Eventually, most patients will be on two drugs, one of which will be levodopa. Why not use levodopa first if it provides easier and quicker titration, longer period of clinical stability, simpler monotherapy, and lower cost? Hard to beat!!! Jorge A Romero, MD Jorge A Romero, MD