Sounds like the same issue I am having. One noticeable sound when my mouse stops responding on the League screen is the disconnection/reconnection USB sound when ejecting USB's in Windows 8.
I can rule out dual monitors as I tried it out in single monitor with the same results and I do not believe it is Windows 8 /8.1 charms because the issue occurs usually in the mid top section of the screen and in that general area.
Sometimes when I want to move forward and click my mouse my screen scrolls forward and leaves the view of my champ behind. Other times my mouse click doesn't react when I click it resulting in me missing my combos. Though my screen doesn't drop to the desktop I feel as though it is somehow fused to my desktop in a sort of translucent manner. I see the game but where I click seems to activate the desktop side.
Currently I have no other mouse that I can try to confirm a mouse issue. I will be getting another tomorrow. I am thinking bad cable. Hoping it isn't a bad USB port. Guess I'll confirm that now...
Happened on a different USB port so it looks promising that it is the mouse that is causing this issue.
Played a few games last night. Didn't really notice the issue. One thing I did notice is each game I was purple team (top side). It was a bit more annoying moving the map around. Not related to the issues I was having. Most likely has to do with being used to pulling down on the map on blue side where it is opposite on the purple side.
Going to test the mouse some more but it looks like the mouse was the issue... cross fingers