The most recent referendums in Spain and Italy is a clear signal that mid-sized European economies are subject to disintegration because their nation-states give no benefits anymore to their most developed parts. Two biggest states, Germany and France, (the Great Britain is out of the EU processes) have to retain their nation-states (despite separatism of some regions within these countries) because of potential loss of power in EU and global processes. To some extent these two countries are equal to the EU by political power  - France is one of five permanent UN Security Council members and Germany is the largest exporting economy.  

Smaller states have no influence on the most important decisions but may take all advantages of financial and labor redistribution and enjoy safety. Moreover, many of them are single-nation and have no social and historical cracks to disintegrate.  

The disintegration of Spain and Italy is predetermined by the internal mechanisms and structures of the EU, where the overall payment into the EU funds would be smaller for the separated highly developed regions than the payment to the capitals of their mother-states. At the same time, the EU provides the full spectrum of services of a nation-state. Hence, there are less economic/social/national/ethnic/… reasons to keep formal links in a current state - the EU replaces them and it is its goal. The biggest countries are also interested in such disintegration giving them more power. The smallest countries might have own benefits due to stronger lateral links with like. 

In addition, such disintegration is actually not disintegration at all. This is reintegration. One needs only a soft mechanism to this.