Characterization of Autonomic Dysfunction Among Migraineurs With and Without Complaints of Orthostatic Intolerance

Purpose and Hypothesis: To identify and distinguish central autonomic dysfunction from peripheral autonomic dysfunction (or both) in migraineurs suffering from orthostatic intolerance (OI) compared to migraineurs not suffering from OI. We hypothesize that OI manifests from a predominantly central autonomic component. Methods: We studied two populations of migraineurs, one group complaining of symptoms of OI for 6 months or longer and a group without OI symptoms, using a 70-degree, 45-minute passive head-up tilt-table test (HUT), R-R interval measurements during deep breathing, blood pressure and heart rate monitoring during Valsalva maneuver and release, Quantitative Sudomotor Axon Reflex Test (QSART), and skin biopsy for intraepidermal nerve fiber density. Categorical differences between the two populations were compared using exact likelihood ratio chi-square tests, and 95% confidence intervals for sensitivity, specificity, positive and negative predictive values were calculated. Results: Thirty-seven migraineurs with OI (Group 1) and 22 migraineurs without (Group 2) were studied and were demographically similar except for a greater representation of migraines with brainstem auras in Group 1 (27% v 5%; p= 0.032). Ninety-seven percent of Group 1 patients, versus 68% Group 2, manifested abnormal 45-minutes HUT, a significant difference (p=0.020, Fisher’s exact test). The first 5-minute evaluation of the HUT exhibited high specificity (1.00; 95% CI: 0.85-1.00) for the diagnosis of postural tachycardia syndrome (POTS) with a positive predictive value of 1.00 (0.59, 1.00; p=0.037). The HUT extended to 45-minutes however showed greater sensitivity compared with the 10-minute HUT (0.95; 95% CI:0.82-0.99; p=0.020). We found no differences between groups in autonomic laboratory or skin biopsy findings. Fifty-seven percent of Group 1 and 50% of Group 2 exhibited biopsy-proven small fiber neuropathy (SFN), a difference that did not reach statistical significance. Conclusions: We failed to confirm our hypothesis that OI is a manifestation of a central autonomic dysfunction in migraineurs. The finding of SFN in a majority of subjects points to peripheral autonomic contributions and raises the possibility of an underlying systemic disorder. Extending HUT table testing to 45-minutes increases diagnostic sensitivity and better reflects life events. Funding Statement: This study was supported by a grant from the Bakken Heart-Brain Institute, Cleveland Clinic, Cleveland, Ohio, USA. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study was approved by the Cleveland Clinic’s Institutional Review Board. Informed consent was obtained from all participants in the study.