System.NullReferenceException Error

[matthew.221135]

I keep getting this error on my layer manager (refer attached), after which, the layer manager will not work.
It only seems to occur on one particular set of drawings ( External Reference and all drawings that reference it)
The X-REF is approx 3.2Mb yet takes approx 2 minutes to save and 1 min to reload, all drawings referencing it are only about 150Kb and still take about 1 min to save.
Xref does utilise annotative objects, would this account for time to save?
I have searched Internet for System.NullReferenceException keywords and can only get responses from programming forums regarding programs I do not use.
Does anyone have any ideas?

[RobertB]

Have you audited all drawings and purged the annotation scales? Have you purged RegApps?

[matthew.221135]

I have purged all RegApps, audited and performed recover on drawings, have also wblocked out all entities into blank drawing. all to no avail. seems to be happening more and more often, may need to reinstall my ACAD, Have had to restart 4 times today, I suppose tis better to restart than have crash.