Neuro-Ophthalmology Landmark Studies

---

Start with IV and you’ll be full of glee; go straight to PO and you’ll be saying “No!”  The Optic Neuritis Treatment Trial (ONTT) sought to determine the optimal treatment for acute optic neuritis. Patients with acute optic neuritis (aged 18-46), excluding those with previous optic neuritis in the same eye, were randomized to three groups: placebo (n = 150), IV methylprednisolone x3 days followed by oral prednisone x11 days (n = 151), and oral prednisone x14 days (n = 156).

Key Points:

• The IV methylprednisolone group had quicker recovery compared to the placebo (and oral prednisone group), though there was no large difference in visual acuity at 6 months
• The oral prednisone group had an increased risk of repeat optic neuritis (RR 1.79 vs. placebo)
• At 15 years, the cumulative probability of developing MS after an episode of optic neuritis was 50%; 25% if no MRI lesions at baseline, 72% if there were.  

Overall, the ONTT is a landmark study because led to a major shift in the treatment of optic neuritis. Before the trial, there was no clear treatment protocol, and the use of corticosteroids was questioned. The study clearly showed that treatment should start with IV methylprednisolone and should avoid starting with oral prednisone. It also showed that the presence of MRI lesions was a key prognostic indicator for the development of MS.

Sometimes doing nothing is really better than doing something. The ischemic optic neuropathy decompression trial (IONDT) in the 1990s was meant to evaluate the safety and efficacy of treating nonarteritic anterior ischemic optic neuropathy (NAION) with optic nerve decompression surgery (ONDS) versus careful follow-up. Prior to this study the natural progression of NAION had not been defined, and therefore needed to be established prior to establishing if a treatment such as ONDS was efficacious. The multicenter randomized, single-masked, controlled clinical trial enrolled 244 NAION patients and visual acuity equal to or less than 20/64. Patients were randomized into careful follow-up (n=125) or ONDS (n=119). The primary outcome was visual acuity at 6 months.

Key Points:  

• Patients who received surgery did not have significantly better visual acuity at 6 months than those who did not receive surgery
• Patients who received surgery had a significantly higher likelihood of losing 3 or more lines of vision at six months than those who didn't receive surgery
• Patients who received surgery had increased rates of intra- and post-operative adverse events

Overall, the IONDT is a landmark study because it entirely changed the management and understanding of NAION. Not only did the study demonstrate new clinical characteristics of NAION by evaluating the natural progression of the disease, but it showed that treatment of NAION with ONDS was not effective and detrimental to the patient.

What feels like a brain tumor, acts like a brain tumor, but isn’t a brain tumor? Pseudotumor cerebri! The Idiopathic Intracranial Hypertension Trial (IIHT) sought to determine the effect of acetazolamide in reducing visual loss symptoms after 6 months of treatment, in conjunction with the standard diet and weight loss. Patients with a new diagnosis of IIH by modified Dandy criteria (aged 18-60 years), excluding those with previous IIH or IIH for more than 2 weeks, were randomized to two groups: placebo (n = 79) or acetazolamide (n = 86) for 6 months.

Key Points:  

• Acetazolamide group had greater improvement in perimetric mean deviation (+1.24) versus placebo (+0.71), with P = 0.050
• Both the acetazolamide group and placebo group improved intracranial pressures and papilledema grade, but the acetazolamide group improved more ( -1.31 versus -0.61, P < 0.001)
• The acetazolamide group had increased adverse effects (most notably paresthesia and nausea), but no permanent side effects

The IIHT showed that acetazolamide is effective medical therapy, both for lowering intracranial pressure and for treating the visual field defect of moderate idiopathic intracranial hypertension vision loss/papilledema. Normally the limitation to high doses are the side effects, and the side effects seen in this trial were known, such as paresthesia of the extremities, a metallic taste in the mouth, fatigue, and frequent urination. Acetazolamide, as well as weight loss, is the first-line treatment for IIH.