"The majority of the inhabitants knew about the game."
Translation:La plimulto el la loĝantoj sciis pri la ludo.
Well, going by the same distinction between "koni" (kennen) and "scii" (weten) we have in Dutch, I think the distinction here is indeed quite subtle. In fact, I think the use of "koni" also makes sense here. Certainly in Dutch, you would be more likely to say "De meeste inwoners kenden het spel" than "De meeste inwoners wisten van het spel af", although both are possible.
Is la optional? The help text gives me the impression it's optional but that might not mean anything
Does this mean about a specific instance of a game, like the game next Tuesday at 8 in the city stadium, or a game in general, like having heard of baseball?
Would the question above have a different answer if it was koni instead of scii?
There's three "la"s in the sentence, but based on your subsequent questions I take it you're asking about the "la" of "la ludo", correct? I think it's not optional, in the sense that the meaning becomes different if you leave it out (you would still have a grammatically correct sentence; just one with a different meaning).
I think it could both be a specific instance or a game generally as it is written. If it were "koni" rather than "scii" (and without "pri" I guess), I think it would have to be a game generally; it's strange, after all, to know a specific instance of a game in the sense of being (well) acquainted with it. (Some exceptions may be imagined, though. Famous chess games, for instance.)