Laird Harrison

February 27, 2015

CORONADO, California — The effects of diet and acetazolamide (Diamox) on idiopathic intracranial hypertension stimulated controversy here at the North American Neuro-Ophthalmology Society 2015 Annual Meeting.

In the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), vision and other symptoms improved in patients treated with both acetazolamide and diet, said principle investigator Michael Wall, MD, from the University of Iowa in Iowa City.

However, improvements were also seen in patients treated with diet and placebo, he reported.

Although improvements in vision were greater in the acetazolamide group, the fact that those patients lost a mean of about 6% of their body weight — twice that lost in the placebo group — led the investigators to ask whether "the acetazolamide effect" is simply the result of better weight loss.

This study was not designed to detect the effects of diet, Dr Wall cautioned, and the statistical analysis suggests that the acetazolamide effect is independent of weight loss. The weight loss continued for 6 months, whereas most of the vision improvement occurred in the first 2 months, he explained.

"We can speculate that we have two effects here. We have an initial effect from acetazolamide, and then an improvement from diet," he said. "But we really need to design a study to prove that."

The patient population in this trial, the largest-ever prospective study of the disorder, was described by Dr Wall's team last year (JAMA Neurol. 2014;71:693-701).

The study outcomes were reported here during a 2-hour symposium.

Trial Outcomes

"We've learned a lot," said Dr Wall. "We learned that acetazolamide led to significantly improved visual-field function, papilledema grade, quality-of-life measures, and cerebrospinal fluid pressure."

The trial involved 165 newly diagnosed untreated patients. All met the modified Dandy criteria for the disorder, and all had a perimetric mean deviation from −2 to −7 dB. All but four of the patients were women. Mean body mass index was 39.9 kg/m².

All study participants were prescribed a low-calorie diet, provided with a weight-loss counselor, and randomly assigned to either daily acetazolamide up to 4 g or placebo.

Headache, the most common symptom, affected 84.2% of the patients, and 32.1% experienced vision loss.

Improvements in transient visual obscurations were more pronounced in the acetazolamide group than in the placebo group, as were improvements in pulsatile tinnitus, dizziness, photophobia, neck pain, and visual loss.

Improvements in cognitive dysfunction and radicular pain were more common in the placebo group than in the acetazolamide group, although the percent of patients affected by these symptoms at baseline was small.

The improvement in headache was larger in the placebo than the acetazolamide group, but difference was not statistically significant.

The primary indicator of vision loss was perimetric mean deviation, which provides an average loss per test location weighted for the central points.

Improvement on this measure was seen in both groups, but was 0.71 to 1.19 dB greater in the acetazolamide group.

For patients with a perimetric mean deviation at baseline of 3 to 5 dB, there was a 2 dB increase in the acetazolamide group but a decrease in the placebo group. The difference of 2.27 dB between the two groups was significant (P < .001).

There were fewer patients whose condition worsened in the acetazolamide group than in the placebo group (9 vs 17).

Early Treatment Diabetic Retinopathy (ETDRS) scores improved in both groups; the difference was not significant. When the Frisén scale for grading papilledema was used, however, the improvement was much better in the acetazolamide group. Declines in optic disc volume and cerebral spinal fluid were also significantly greater in the acetazolamide group than in the placebo group.

Adverse Events

There were 676 adverse events during the study, so the benefits of the treatment came at a cost for many, said investigator Martin ten Hove, MD, from Queen's University in Kingston, Ontario, Canada.

"This was not powered to be a safety study, but it does represent the first database that actually has detailed investigations for adverse events in acetazolamide, which is a powerful thing," he explained.

Dr ten Hove pointed out that all signs and symptoms of ill health were counted as adverse events, whether or not the investigators considered them to be related to treatment.

Two-thirds of the adverse events were in the acetazolamide group. Half of the subjects reported at least five events. Parageusia, dysgeusia, paresthesia, fatigue, and diarrhea were all statistically significant.

The daily acetazolamide dose was escalated every seventh day, up to 4 g, which took a mean of 12 weeks. Lab values were checked frequently, and the escalation was halted when there was a severe adverse event or a decrease in function or quality of life. The dose was decreased in nine patients, Dr ten Hove reported.

"I was a little bit surprised by how well tolerated the protocol was," he said. In fact, 44% of the patients were able to tolerate 4 g, and 90% were able to tolerate at least 1 g.

Metabolic and renal events did not reach significance, but 44 lab values were interpreted as adverse events. White blood cell counts declined in two patients, and six patients were hospitalized.

Two patients developed renal calculi. "This is an issue that we may need to monitor if we decide to use these doses going forward," said Dr ten Hove.

We didn't study weight loss, we studied acetazolamide.

The findings cannot be generalized beyond the study population, and the follow-up in this study was short. However, "we can conclude that for this population, acetazolamide has a reasonable tolerance profile and a reasonable safety profile," he reported.

Dr ten Hove recommended that clinicians consider risk factors for renal calculi on these doses, and monitor complete blood counts.

"Is it proper to say that acetazolamide made the weight loss work better?" asked an audience member after the presentation.

Dr Wall clarified: "We didn't study weight loss, we studied acetazolamide."

"You are comparing apples with oranges instead of apples with apples," said another audience member. He pointed out that it would be useful to separate out a subset of patients from the acetazolamide group whose mean weight loss was the same as that of patients in the placebo group.

Dr Wall said he would discuss that with the study statistician. "We can look at it and see if there's anything there."

This study was funded by the National Institutes of Health. Dr Wall and Dr ten Hove have disclosed no relevant financial relationships.

North American Neuro-Ophthalmology Society (NANOS) 2015 Annual Meeting. Presented February 25, 2015.


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