Abstract text (incl. figure legends and references)

Question

Lowering intracranial pressure (ICP) is the primary rationale of pharmacotherapy in Idiopathic intracranial hypertension (IIH). There is limited evidence behind the use of the leading therapeutics, acetazolamide and topiramate, and how they lower ICP. We assessed the ICP lowering capacity of these drugs in rats and the molecular consequences hereof.

Methods

In a randomized, blinded cross-over study, we assessed the capacity of acetazolamide and topiramate to modulate ICP in female Sprague Dawley rats (N=10) using continuous telemetric ICP monitoring. We assessed single supra-clinical doses over 24 hours, and twice-daily clinically equivalent doses over 10 days. Drugs were delivered via oral gavage. The effects on CSF secretion rates and gene expression at the choroid plexus (CP) for CSF secretory genes were separately evaluated.

Results

Over 24 hours, both acetazolamide and topiramate lower ICP compared to vehicle with peak reduction of 25% at 2 hours. Administering these drugs in combination doubles the ICP lowering effect. Over 10 days, both acetazolamide and topiramate lower daily ICP compared to vehicle with no evidence of tachyphylaxis. Over the course of the day, the effect of acetazolamide wore off overnight whereas the ICP lowering effect of topiramate was sustained overnight relative to control. In accordance, topiramate reduced CSF secretion by 40%. Paradoxically, topiramate increased the expression of CSF secretory genes Slc12a2 and Slc4a10 at CP, whereas acetazolamide has no such effect.

Conclusion

We demonstrate that both acetazolamide and topiramate rapidly lower ICP following administration and that there is an additive lowering ICP effect with combination of the drugs. The ICP lowering effect of these drugs persists with no tachyphylaxis with long term administration. These data thus provides the functional rationale for the clinical use of the combination of acetazolamide and topiramate in IIH and other conditions of raised ICP.