Enhanced regional cerebral perfusion following acetazolamide: Preliminary oral dose-escalation results

Background: Cerebral perfusion is altered early in multiple sclerosis (MS). Acetazolamide (ACZ) has a good safety and tolerability profile. The perfuseMS trial (NCT02466074) is a placebo‐controlled trial to evaluate the effect of long‐term ACZ therapy on lesion evolution in MS patients. Objectives: Determine feasibility and tolerability of twice‐daily oral ACZ and identify the optimal dose for the planned perfuseMS trial. Methods: Eligible patients have stable MS, either treatment naïve or on platform therapies. Absolute cerebral blood flow (CBF) was measured using pseudo‐continuous arterial spin labeling (pCASL). Five MS patients received twice‐daily oral ACZ. Every two weeks the dose was increased and CBF determined using pCASL. pCASL was performed with a single shot gradient echo EPI sequence (TR/TE of 4300 ms/16 ms, voxel 3 × 3 × 5 mm, 70 dynamics, 1900 MS label duration, 2000 MS post label delay). Data were analyzed with FMRIB Software Library and FreeSurfer v5.3.0. After partial volume correction, CBF maps were registered to 3D‐MPRAGE images using boundary‐based registration. Brain regions were segmented using semi‐automated methods into cortex, normal‐appearing white matter (NAWM), deep gray matter (DGM) and T2‐hyperintense lesions. Results: Patients generally tolerated doses of ACZ up to 4000 mg daily with tolerable side effects consistent with those previously reported in the literature. Increased CBF was observed in various brain regions. These typically plateaued at the 2000 mg daily dose. CBF in the cortex increased by a maximum of 13.6%, DGM by 21.6% and NAWM by 13.7%. Pair‐wise analysis showed significant increase in CBF (mean/100 ml/min [SD]) at 2000 mg daily ACZ vs 0 mg ACZ in the cortex (69.3 [12.0] vs 61.0 [10.7]; p=0.005) and DGM (39.4 [3.7] vs. 32.4 [6.0]; p=0.03). As expected, absolute CBF in NAWM was lowest pretreatment with an observed numeric, but not significant, increase in perfusion on ACZ (16.6 [1.7] vs. 14.6 [3.0]; p=0.34). Conclusion: We report for the first time the feasibility and tolerability of adjunct therapy with daily oral ACZ in MS patients. Despite the small sample size, we found significant increases in regional cerebral perfusion on ACZ therapy. These results show that blood flow can be increased in brain tissue in MS patients and support further investigation of our hypothesis that cerebral hypoperfusion may be important to lesion evolution and improving cerebral perfusion might impact tissue preservation/repair.