The only difference for a dead-is-dead play-style is that you have to cover your bases carefully. So choose skills that fill in the gaps in your defenses, as well as providing you with fighting abilities. You'll need either Alteration (Shield spells) or Alchemy. You'll need to manage your health carefully, which probably means hot-keyed healing potions. I always make sure to have one ranged attack method and (at least) one close-up fighting method. Don't overlook Restoration; the Absorb Health spell effect, which works only in Touch spells, is a good way of healing yourself while killing.
Difficulty? That's up to you, but I doubt that you'll get far in a d-i-d with the slider all the way right.