For me it's the disorientation. I lose my sense of distance when I don't have the ground nearby. The feeling I get is a lot like when I play a different game, or different class, and I no longer know what the ranges look like, whether for spells or aggro. But it gets worse. Up-Down is hard to tell unless I'm very close and I level my camera. Until then, no clue.
I have no elegant ideas for the distance issue. A distance indicator on portraits could help, but it would seem a bit odd that my paladin can, just by looking, tell the distance of an enemy down to the tenth of a yard, especially when I as the player am completely lost.
But the height, that I can fix. Around, or possibly inside, the target circle (the green or red thing on the ground that indicates your target), add another circle which indicates relative position on the z-axis. If they are above you, white; below you, black; even, grey; with gradual lighter or darker for positions in-between. Being a color-based system it isn't going to be especially accurate, but it could help quite a bit to at least know in advance that an enemy is much higher than you.
EVE Online is dying
2 hours ago