Is there a big difference in the different starting areas you can begin a playthrough in?
Yes. Prison is very hard. Gardens of Midknight is harder than the Briarpatch, and so is Crowl (Sanctuary start), but the sanctuary itself offers significant bonus. Eerie wastes only have random encounters - word is they are hard too, but can be turned off entirely.
Are they all reachable regardless later in the game?
Only Midknight and Briarpatch are reachable (and Briarpatch has an associated location that can't be entered with other starts).
Eerie Wastes provide the most bang for your buck (large unique dungeon full of stuff), but only way later into the game.