I did have a few rare times that a restart didn't work. It took a second restart.
I also noticed that when the ShuttlePro settings don't load; and, whenever I do something that would cause a change in the Machine.ini file, the Machine.ini file would be updated without the ShuttlePro settings. Therefore, the ShuttlePro settings become lost, and additional restarts will not help.
I believe that this is a bug in Mach4. As a workaround, the first thing I do after startup is to verify that the ShuttlePro settings are loaded. I go to Diagnostic > Regfile > Shuttle0 to verify that my Gcode lines are there. It is a hassle, but I would rather do this than have to either reload all of my ShuttlePro settings or load a backup Machine.ini file.