White matter hyperintensities: from medical comorbidities to bipolar disorders and back.

White matter hyperintensities (WMHs) are among the most replicated neuroimaging findings in studies of patients with bipolar disorders (BD). Despite the high rates of WMHs, their role and etiology in BD are not well understood. WMHs occur in multiple other conditions frequently co-morbid with BD. From the available studies it seems that WMHs are not a primary risk factor/endophenotype for BD. More likely, these lesions indicate the presence of medical co-morbidities with specific links to BD. Furthermore, the etiology of the WMHs in BD may represent different processes depending on age. In certain forms of BD, such as pediatric BD, WMHs may represent co-morbidity with developmental disorders. High frequency of migraine in BD and high prevalence of WMHs in migraine may suggest that a substantial proportion of WMHs in early adulthood to midlife BD subjects may be related to co-morbidity with migraine. Among elderly subjects with BD, or those with late-onset BD, WMHs are likely related to the presence of cardiovascular/metabolic disorders. With further research WMHs may enhance our knowledge about various pathological pathways involved in BD, help in decreasing the etiological heterogeneity of BD, and become useful as markers of severity or subtype of BD.