If you can copy/paste the window layout (right click on the window layout and select copy to clipboard, paste here it shows up as XML) I'd like to see why the focus follows mouse option doesn't work for you. I tested it in different ways before release and it worked wonderfully.

As of ISBoxer 36, Window Layouts now apply when you export; those required a restart in 35 or earlier. If you make changes to WoW Macros through ISBoxer, then you will need to /reloadui on the affected windows so the ISBoxer Addon (generated when you Export) can reapply the macros.

There's a few specific settings that might require a restart of the game, like if you change the IS console hotkey or the FPS indicator (2 settings in your Character Set) while playing. Nothing that you'd notice that I can think of though.