Acetazolamide, Low-Cal Diet Help Intracranial Hypertension

Pauline Anderson

July 03, 2014

LOS ANGELES — Patients with idiopathic intracranial hypertension (IIH) who are treated with acetazolamide and follow a weight-loss diet have significantly improved visual field function, papilledema grade, quality of life, and cerebrospinal fluid pressure, and the treatment is well tolerated, according to results of new multicenter, randomized, placebo-controlled study.

Although patients following this treatment regimen lost an average of 7.5 kg over the course of 6 months, the effect of the drug was independent of the amount of weight loss, said lead author Deborah I. Friedman, MD, professor of neurology and ophthalmology, University of Texas Southwestern Medical Center in Dallas.

However, patients in the study did not get significant relief from headaches.

Dr. Deborah I. Friedman

"We recommend using the maximum tolerated dosage, up to 4 g a day, of acetazolamide plus diet to treat IIH patients with mild visual loss," said Dr. Freidman.

She presented the results here at the American Headache Society (AHS) 56th Annual Scientific Meeting.

Vision Loss

IIH is characterized by papilledema, which often leads to vision loss. About 80% of patients with IIH have some type of permanent visual field defect, and 5% have blindness.

The study included 165 patients, all but 4 of them women, with an average age of 29.2 years. Almost 88% of the participants were obese, with a mean body mass index of 39.9 kg/m2.

All participants had newly diagnosed IIH, meeting the modified Dandy criteria. In addition to papilledema, these criteria include signs and symptoms of increased intracranial pressure (ICP), normal level of alertness (other than increased ICP), normal neurodiagnostics (except elevated ICP), and no other cause of increased ICP.

Participants also had to have mild visual field loss (a perimetric mean deviation [PMD] of −2 to −7 dB in the worse eye). PMD is a global indication of visual loss; the closer the number is to zero, the better the vision; the more negative the number, the worse the vision.

Patients were randomly assigned to receive either placebo or acetazolamide, starting with 1 g daily and gradually increasing this every 6 days to a maximum of 4 g a day. The average dose of the drug during the study was 2.5 g a day (the equivalent of placebo was 3.5 g a day).

All patients were told to follow a low-sodium, weight-reduction diet.

Role of Diet

The role of diet in IIH dates back 40 years, when researchers reported that papilledema resolved with a very low calorie diet, although "unfortunately, they didn't do any visual testing," said Dr. Friedman. Other than this and 1 other study that found that a low-calorie diet decreased cerebrospinal fluid pressure, most of the reports looking at diet and acetazolamide are "anecdotal," she said.

Although physicians have been using acetazolamide to treat IIH for a long time, the evidence of its efficacy is scarce. According to the Cochrane Review (in 2005 and again in 2009), existing studies "don't allow for the quantification of either the relative or absolute benefit of any of the treatments and there is a desperate need for large studies that can provide this information."

The primary question for this new study was whether the drug plus diet was superior to placebo plus diet in improving visual field function over the course of 6 months. Secondary outcomes were changes in optic disc edema, quality of life, and cerebrospinal fluid pressure.

The study found that for the primary outcome — change in PMD in the worse affected eye — there was a statistically significant difference (P = .05) benefiting the drug over placebo. The therapeutic gain, or the difference in PMD between the 2 groups, was 0.71 dB.

This did not meet the predetermined level of clinical efficacy, which was 1.3 dB, said Dr. Friedman.

However, the treatment seemed to work better in patients with a more severe papilledema grade. Although the most common grade at study entry was a relatively mild 2, when researchers looked at participants with grades 3 to 5 at baseline, the effect size was quite large (2.27 dB; P ˂ .001).

"It may be that acetazolamide confers better benefit in patients who have more severe papilledema," commented Dr. Friedman

The target weight loss for study participants was 6%, which was based on previous studies showing that this amount of weight loss seems to improve papilledema. Those who took the drug lost more weight than those receiving placebo (a mean of −7.50 kg vs a mean of −3.45 kg, with a treatment effect of −4.05 kg; 95% confidence interval, −6.27 to −1.83 kg; P < .001)

Further analysis found that the effect of acetazolamide was independent of the amount of weight loss, said Dr. Friedman

Quality of life, both generally and related to vision, improved for patients in both groups, but more so in the drug group. "This was kind of surprising to me, given all the side effects with the acetazolamide that we see in our practices," said Dr. Friedman.

In this study, there were more serious adverse events in the drug than in the placebo group (9 vs 3). There were also 2 patients with renal stones, 1 with transaminitis, 1 with pancreatitis, and cases of diverticulitis, allergic reactions, nausea, vomiting, diarrhea, and tinnitus, among other adverse events, in the drug group.

Although quite a few patients (19%) were withdrawn from the study, the number was similar in both groups. Of the 7 treatment failures, 6 occurred in the placebo group.

No Effect on Headache

There was no difference in scores on the Headache Impact Test. Dr. Friedman said this was not surprising, as even after the IIH is "treated and gone," headache tends to continue to be a problem for these patients.

"So when we're treating patients who have IIH, probably acetazolamide is not enough to make a difference, and their headache needs to be treated separately."

Session cochair Meredith Barad, MD, assistant professor, anesthesia, at the Stanford Headache Center, Palo Alto, California, wondered whether topiramate could be used instead of acetazolamide in IIH patients.

"We don't know the proposed mechanisms of acetazolamide, but if it's related to its carbonic anhydrase inhibition, topiramate certainly doesn't have that property," said Dr. Friedman. "My personal recommendation is to use topiramate for the headache and acetazolamide to treat the disease. I do use them in combination."

Researchers measured cerebrospinal pressure in about 50% of patients. The study found a reduction in pressure that was greater in the drug group (effect size, −59.9 mm H2O; 95% confidence interval, −96.4 to −23.4 mm H2O; P = .002).

The researchers also collected a significant amount of laboratory data, including levels of sodium, chloride, and potassium. Although there has been concern that patients with IIH might develop aplastic anemia or hypokalemia, "we saw none of those problems," said Dr. Friedman.

Dr. Friedman acknowledged that the results may not apply to those whose visual field is more (or less) severe than PMD −2 to −7dB. Patients with more visual field loss are typically referred for surgery, "which should be the next trial" topic, she said.

Asked by Vincent Martin, MD, codirector, University of Cincinnati Headache and Facial Pain Program, Ohio, about how patients were able to comply with such a difficult-to-follow diet, Dr. Friedman reported that all patients were assigned a weight loss coach with whom they spoke weekly by telephone. As well, there was a Web-based mechanism set up where patients could confer with each other and discuss their progress.

"I think we were all surprised at how much weight they were able to lose," she said. "Our patients often tell us that they can't lose weight regardless of what they do, and clearly they can."

The investigators have disclosed no relevant financial relationships.

American Headache Society (AHS) 56th Annual Scientific Meeting. Presented Saturday, June 28, 2014.

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