The Idiopathic Intracranial Hypertension Treatment Trial: A Long-Time Coming but Worth the Wait.

R andomized clinical trials have served as the foundation for much of the knowledge that we have gained in the last 50 years with regard to efficacy and safety of treatments of various medical conditions. In neuro-ophthalmology, there have been 3 major randomized trials funded by the National Eye Institute. From the Optic Neuritis Treatment Trial (ONTT), we learned about the role of corticosteroids in the treatment of acute optic neuritis (1). From the Ischemic Optic Neuropathy Decompression Trial, we learned about the role of optic nerve sheath decompression as a treatment for anterior ischemic optic neuropathy (2). And now, most recently, from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), we have learned about the effect of acetazolamide on visual function in idiopathic intracranial hypertension (IIH) (3). All 3 trials should be considered landmark studies for neuro-ophthalmology. The IIHTT was a long-time coming. A pilot study funded by the National Eye Institute was conducted between 1989 and 1992 by James Goodwin, James Corbett, and Michael Wall, and there has been a need for a definitive randomized trial since then. With the formation of the Neuroophthalmology Research Disease Investigator Consortium (NORDIC), the framework was in place for the conduct of a major randomized trial, which began in 2010 and published the primary results in JAMA in 2014 (4). The IIHTT enrolled 165 individuals into a placebo-controlled trial at 38 NORDIC sites to answer the question of whether acetazolamide plus a low-sodium weight-reduction diet has a beneficial effect on vision for IIH and mild visual loss compared with diet alone. Eligibility was limited to mild visual loss because of concern about treating patients with more advanced visual loss with a placebo. The trial had a rigorous design and was well conducted with the exception of a higher than desirable dropout rate. However, it seems unlikely that this produced appreciable bias. Overall, there was a modest benefit of acetazolamide seen in the visual field mean deviation, which was the primary outcome. Although the magnitude of the treatment group difference seems small, there was a meaningful treatment group difference found on the quality of life questionnaires favoring the acetazolamide group despite the fact that the treated group, as expected, had substantially more side effects than the placebo group. This suggests that the study participants realized a benefit in their vision that outweighed the negative effect of side effects. Beyond these overall results, what is important in the interpretation of the IIHTT results and application to clinical practice is that there was a strong statistical interaction (P , 0.001) between the degree of baseline papilledema and treatment. The beneficial effect of acetazolamide treatment on visual field was seen solely in participants whose worse eye had Grade 3–5 papilledema at baseline (treatment group difference in mean deviation = 2.27 dB directionally favoring the acetazolamide group) and not present in those with Grade 1–2 papilledema (difference in mean deviation = 20.67 directionally favoring the control group). Epidemiologic dogma would say that in the face of such strong interaction, the overall analysis is not relevant and in fact is misleading because it consists of an overall average effect that does not apply to any patient—for patients with high-grade papilledema, the treatment effect is greater than the overall effect and, for patients with mild papilledema, the treatment effect is less and there may not be visual field benefit at all. This subgroup analysis result has biologic plausibility in the