The CSS will remain unchanged so long as you do not upload the default one that comes in the package anyway. and overwrite what you have.
I believe index.php has changed slightly, but putting in all your changes should not be a hassle.
Plugin authors have had plenty of notice about any internal changes in the way WP handles data and variables, so hopefully all is good there.
I certainly don't see it as being any more of an issue than for the multitude of times I have upgraded.
The best advice, as always, for anyone about to upgrade, is to backup your files. Backup the database. Backup your existing installation. If you haven't installed Laughing Lizard's OneClickBackup yet, do it now.
If you do have a heavily modified site, then yes, it will take longer, but then that's the price to pay - after all, the devs cannot know who has done what and engineer the product to work around it.
How do I upgrade ?