When you alt tab out of the game with two monitors, and you come back, and then swing your mouse in the direction of your other monitor quickly and click (to attack, often in panic), you click off the game.
The game pauses so this is minor but it is annoying. Might be something wrong with keeping the mouse in the border at quick speeds, through all my testing no amount of slow movement will take the mouse off the screen and replicate this, just a quick burst of speed. My second monitor is to the left, pretty sure it doesn't matter but when bug shooting having all the variables in place helps.