Abstract
Purpose
To determine whether the beneficial effects of acetazolamide (ACZ) in improving vision at 6 months continues to month 12 in participants of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT).
Design
non-randomized clinical study
Methods
In the IIHTT, subjects were randomly assigned to placebo-plus-diet or maximally tolerated dosage of acetazolamide-plus-diet. At 6 months subjects transitioned from study drug to ACZ. This resulted in the following groups 1) ACZ to ACZ; n = 34; 2) placebo to ACZ; n = 35; 3) ACZ to no treatment; n = 16; and 4) placebo to no treatment; n = 11. 96 IIHTT subjects had evaluations at 6 and 12 months. Our main outcome measure was change from month 6 to month 12 in visual field mean deviation with secondary measures being change in papilledema grade, ETDRS scores and quality of life (QoL) measures.
Results
The ACZ to ACZ group improved 0.35 dB , p=0.05; placebo subjects with no ACZ improved 0.81 dB MD, p = 0.07 at 12 mos. The other groups improved 0.35 to 0.46 dB MD. Mean improvements in papilledema grade occurred most markedly in the group that exchanged placebo for ACZ (0.91 units, p < 0.001). QoL and headache disability scores showed significant improvements in the placebo group added ACZ.
Conclusion
Improvements in MD continued from month 6 to month 12 of the IIHTT in all treatment groups –most marked in the placebo group tapered off study drug. Adding ACZ to the placebo group significantly improved papilledema grade, headache and QoL measures.
Introduction
Idiopathic intracranial hypertension (IIH) is a disorder primarily of young overweight women characterized by increased intracranial pressure with its associated signs and symptoms in an alert and oriented patient. Neuroimaging and CSF analysis are normal except for raised intracranial pressure and neuroradiologic findings of intracranial hypertension. Also, no secondary cause of intracranial hypertension is apparent. These features comprise the modified Dandy criteria for IIH used for entry to the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT).1
The IIHTT is a multicenter, double-blind, randomized, placebo-controlled study of acetazolamide in participants with mild visual loss (perimetric mean deviation of −2 dB to −7 dB). All participants received a lifestyle modification program that included weight reduction with a low sodium diet. The trial showed acetazolamide significantly improved visual field function, papilledema grade, CSF pressure and quality of life (QoL) measures at six months.2
At the 6-month visit of the IIHTT, subjects transitioned from study drug to acetazolamide (open label) with the same increasing dosage schedule as the acetazolamide group at the start of the trial. However, subjects with a papilledema grade of less than 1 were tapered off study drug unless they had persisting headaches, pulse synchronous tinnitus or a perimetric mean deviation (MD) that failed to improve. Here, we report the outcomes of 96 subjects followed longitudinally, the Longitudinal Idiopathic Intracranial Hypertension Trial (LIIHT) that completed the Month 6 to Month 12 interventions.
Methods
The study was approved by the Institutional Review Board at each site and individual written informed consent was obtained. Participants age 18–60 were eligible if they met the modified Dandy criteria and had reproducible mild visual loss (−2 dB to −7 dB MD). Participants needed to have bilateral papilledema, have an elevated CSF opening pressure, be untreated with regard to IIH and have no secondary cause of increased intracranial pressure present; other entry criteria are found in prior publications.2;3
Participants were enrolled at 38 sites in North America from March 2010 to November 2012, with the 12 month follow-up ending in December 2013. They were all offered a supervised diet and lifestyle modification program through the New York Obesity Nutrition Research Center. And, they were randomly assigned to receive either acetazolamide or matching placebo.
The study drug was acetazolamide (250 mg) or matching placebo tablets. The initial dosage of study drug was 4 tablets daily in two divided doses followed by dosage increases of 1 tablet every week up to a maximum dosage of 4 grams daily for those receiving acetazolamide. The dosage escalation was stopped if the participant’s papilledema grade (Frisén scale)4;5 became < 1 in both eyes and the MD improved to equal to or better than −1 dB in each eye, unless the presence of other symptoms like headache or pulse synchronous tinnitus suggested that the dosage escalation continue. Participants who were unable to tolerate the study drug could gradually decrease the dosage to a minimum of one-half tablet daily. Participants who discontinued study drug continued to be followed, if willing, for the 12-month duration.
We were interested in the effects on our primary and secondary outcomes from adding acetazolamide treatment to the subjects in the placebo group. Therefore, at the 6 month visit, to reduce bias, subjects were not told which study drug they had been taking. They were all “transitioned” to acetazolamide (open label) with the same increasing dosage schedule as at the onset of the IIHTT. However, subjects with a papilledema grade of <1 (based on the Site Investigator examination) were tapered off acetazolamide unless they had persisting headaches or pulse synchronous tinnitus or a MD that failed to improve. If so, they were placed on acetazolamide regardless of the low papilledema grade. Also, they were not tapered off acetazolamide if they refused to go off. Beginning the day following the 6-month visit, on days 1–6, subjects exchanged 2 tablets of study drug with 2 tablets of acetazolamide (250 mg/tablet) twice daily. Beginning on day 7, subjects increased the dosage by 1 pill every week until the maximum dosage for that patient was reached or side effects prohibited increasing the dosage further. Thus, subjects who were able to tolerate the maximum dosage of 16 tablets per day (4gm acetazolamide) reached the maximum dosage of acetazolamide 84 days after the 6-month visit.
Participants had visits at screening, baseline, and 1, 2, 3, 4.5, 6, 9 and 12 months and then yearly after baseline. At the month 6 and 12 visits, participants had automated perimetry in both eyes using Humphrey Field Analyzer SITA Standard program 24-2. The testing was performed by a technician certified by the Visual Field Reading Center (VFRC). The papilledema grade (Frisén scale) 4;5 was documented by a team of three experienced neuro-ophthalmologist study investigators using fundus photographs; values range from 0 (normal) to 5 (severe papilledema). A best corrected visual acuity using trial lenses mounted in spectacles was measured using ETDRS charts. The eye designated as the study eye, defined at the time of randomization was the eye with the worst MD; this eye was used for all analyses. Vision-related quality of life was assessed using the NEI VFQ-25 and its 10-item neuro-ophthalmic supplement;6;7 a 4- to 6-point change in NEI VFQ-25 scores represents a clinically meaningful change.8 Generic health-related quality of life was assessed with the SF-36.9 Quality of life scores range from 0 to 100, with higher scores indicating better quality of life. The HIT-6 Inventory10 was used to assess headache impact; scores range from 13 to 78, with higher scores indicating worse headache severity. Here we analyze the changes from month 6 to 12.
There were 4 groups identified based on the treatment at IIHTT entry and after 6 months: group 1) acetazolamide to acetazolamide, n = 34; 2) placebo to acetazolamide, n = 35; 3) acetazolamide to no treatment, n = 16; and 4) placebo to no treatment, n = 11. For each of these four groups, results are reported as mean and standard deviation of each outcome by visit (i.e. Month 6 and Month 12) along with the associated change in outcome and p-value. Paired T-tests were used to compare mean values between Month 6 and Month 12 separately for each group. P-values < 0.05 were considered statistically significant. Mediation analyses were performed to determine if acetazolamide’s effect on weight change is mediating its effects on the clinical outcomes.
Results
96 subjects had site evaluations at both 6 months and one year and met criteria for study entry. Their mean (SD) age was 29.9 (7.9) years. 98% were female. Their BMI at the month 6 visit was 37.9 (8.9) kg/m2. eTable 1 shows the baseline IIHTT characteristics comparing subjects in study vs. not in study at 12 months. The table shows no significant differences in demographic, neuro-ophthalmological, nor vision and general health related quality of life characteristics between those that were enrolled in the study at baseline and those that dropped out (all p>0.05). Those initially randomized to placebo and in study (n=46) were slightly older than those randomized to placebo and not in study (n=33) (mean 31.7 vs 27.5 years, p=0.01), however the other characteristics were similar between these two groups as well as comparing those initially randomized to acetazolamide. 34 subjects met criteria for possible treatment failure (worsening of either eye of 2 or 3 dB of MD depending on initial mean deviation). During the second six months of the trial none of the subject’s visual field worsening was confirmed on repeat testing, i.e, there were no subjects that met criteria for treatment failure as defined by study protocol.3 These subjects were classified by the study Adjudication Committee as “performance failures” and not true worsening of IIH.11
Our results can be found in Tables 1–8 and eTables 2 and 3. The ACZ to ACZ group improved 0.35 dB, p=0.05; and placebo subjects that improved to the point that they could stop medication at six months (group 4) continued their improvement by 0.81 dB, p = 0.07 at 12 mos (Table 1). The other two groups improved 0.41 and 0.46 dB MD but neither change reached significance. ETDRS acuity scores also improved in group 4 (placebo to no acetazolamide) but the other groups had minimal worsening of their ETDRS acuity (eTable 2).
Table 1.
Mean deviation change over 6 months by group. The first mean deviation value is at 6 months and the second value is at 12 months. Mean deviation values are in decibels.
| Group | MD | St Dev | MD Improvement | P value |
|---|---|---|---|---|
| ACZ to open-label ACZ | −2.34 | 1.64 | ||
| −1.99 | 1.47 | 0.35 | 0.05 | |
| PLB to open-label ACZ | −2.44 | 1.61 | ||
| −2.03 | 1.06 | 0.41 | 0.10 | |
| ACZ tapered off ACZ | −2.32 | 1.27 | ||
| −1.86 | 1.91 | 0.46 | 0.30 | |
| PLB to no ACZ | −1.57 | 1.59 | ||
| −0.76 | 1.33 | 0.81 | 0.07 |
MD = mean deviation; ACZ = acetazolamide, PLB = placebo, dB = decibels
Table 8.
Subject change in weight by group from six to 12 months.
| Group | Weight | St Dev | Weight Change | P value |
|---|---|---|---|---|
| ACZ to open-label ACZ | 205.96 | 40.74 | ||
| 205.23 | 40.17 | −0.73 | 0.71 | |
| PLB to open-label ACZ | 220.40 | 53.33 | ||
| 214.60 | 54.87 | −5.80 | 0.02 | |
| ACZ tapered off ACZ | 259.24 | 73.17 | ||
| 266.58 | 75.86 | 7.34 | 0.03 | |
| PLB to no ACZ | 226.30 | 64.84 | ||
| 221.15 | 62.77 | −5.16 | 0.15 |
ACZ = acetazolamide, PLB = placebo
Mean improvements in papilledema grade also occurred in all groups but most markedly in the group that exchanged placebo for acetazolamide (0.91 Frisén grade units, p < 0.001; Table 3). The other groups either did not change (group that tapered off acetazolamide) or improved 0.46 Frisén scale units.
Table 3.
Quality of life measures showing Short Form-36 Physical Component scores by group at six and 12 months.
| Group | SF-36 score | St Dev | SF improvement | P value |
|---|---|---|---|---|
| ACZ to open-label ACZ | 51.7 | 7.51 | ||
| 52.28 | 8.08 | 0.58 | 0.67 | |
| PLB to open-label ACZ | 49.51 | 8.69 | ||
| 51.56 | 8.48 | 2.05 | 0.05 | |
| ACZ tapered off ACZ | 52.38 | 5.76 | ||
| 53.51 | 8.60 | 1.13 | 0.53 | |
| PLB to no ACZ | 55.26 | 4.66 | ||
| 57.11 | 3.71 | 1.85 | 0.26 |
ACZ = acetazolamide, PLB = placebo, SF = short form
With regard to QoL scores, there was improvement in most groups but the only significant improvement was in the group that transitioned from placebo to acetazolamide. The PLB group that did not receive ACZ actually had mild worsening in the SF-36 mental components scores but this change was not significant. Headache disability scores (HIT-6 total score) also improved in all groups except the placebo group that did not transition to acetazolamide (group 4). In contrast, the largest and significant improvement headache disability was in the group that transitioned from placebo to acetazolamide (p = 0.01).
Weight change occurred in those transitioning from placebo to ACZ who lost about 6 pounds (p = 0.02) while those tapered off acetazolamide gained about 7 pounds (p = 0.03). The other two groups continued to lose weight with the least amount of the weight loss in the group that continued acetazolamide throughout the 12 month period. Mediation analyses showed acetazolamide’s effect on weight change was not being mediated by its effects on the clinical outcomes.
Discussion
Improvements in visual field function in IIHTT participants continued from month 6 to month 12 of the IIHTT regardless of their original treatment group. The only group where this improvement reached significance was in the subjects who continued on ACZ, which was also the largest group in the observational study (35% of LIIHT subjects). However, the effect of visual field MD improvement was most marked in magnitude with borderline significance was in the 12% of LIIHT subjects that were never treated with ACZ. This was an unexpected finding but supported by the related improvement in visual acuity scores . Interestingly, this group continued to lose weight (5 pounds per subject on average) which may be, in part, responsible for their improvement. This supports one of the current hypotheses for successful therapy – having had an excellent response to the lifestyle management / weight loss program, is beneficial for IIH subjects for at least one year. Alternatively, it is possible for this group, their IIH was a self-limited disease and they improved spontaneously.
It should be noted that the IIHTT cohort of subjects with mild visual loss did not have a large range to improve, especially in the acetazolamide group after six months of regimented therapy. This is reflected in the small improvements present in the two groups that took acetazolamide for the first six months. While we were not surprised to find the placebo-plus diet that did not receive acetazolamide group continued to improve, we cannot explain why there was not at least as much improvement in the group that went from placebo to acetazolamide. Presumably, those that were switched to acetazolamide had worse underlying disease at six months. Both of these groups that initially took placebo had improvement in papilledema grade, more so (almost two times as much) in the placebo to acetazolamide group. This is in concert with the statistically significant effect of acetazolamide on lowering papilledema grade at six months in the IIHTT.2
We have reported that in the IIHTT, IIH patients QoL at time of diagnosis is affected, even in patients with mild visual impairment.12 This included vision-specific QoL measures.12 In addition, we found at six months, the acetazolamide-treated participants experienced significant improvement in quality of life measures, including the VFQ-25 total score and its 10- item neuro-ophthalmic supplement as well as the SF-36 Physical Component Summary and Mental Component Summary scores.2 In the LIIHT subjects at 12 months we found significant improvement in QoL only in the placebo group that started open-label acetazolamide. On the contrary, the PLB group that did not receive ACZ had mild worsening in the SF-36 mental components scores but this change did not reach statistical significance. These findings add to the evidence that acetazolamide treatment for IIH improves QoL in spite of having a variety of side effects.
At the month 6 primary outcome time point, both treatment groups had improvement in headache disability but no effect of acetazolamide was appreciated. At month 12, after the acetazolamide exchange, the only significant improvement in headache disability scores was in the placebo-plus diet group that started acetazolamide. Therefore it appears acetazolamide may have a beneficial effect on headache in this subgroup. This may be mediated by the lowering of CSF pressure that accompanies acetazolamide treatment in IIH.2;13
The IIHTT was designed primarily to determine benefits of acetazolamide over the first six months of treatment. The LIIHT was conducted to address other questions. Although protocols were followed for the first three months of the LIIHT, in many respects, this follow-up cohort should be considered an observational study. A study weakness is that by year one only 58% of subjects remained although participants in the study compared to those that dropped out were similar with regard to baseline IIHTT demographic, neuro-ophthalmological, and vision and general health related quality of life characteristics and we expect the impact of excluding those that dropped out to be minimal. In addition, reasons for dropping out were similar in the groups. Another weakness is the placebo-plus diet subjects were not randomized during the LIIHT so there is no true control group. Therefore, it is possible some of the effects represent the natural history of IIH, with some subjects improving spontaneously rather than from an effect of weight loss or ACZ. While all outcomes were preplanned and were the same as the primary study outcomes at month six, we did evaluate multiple outcomes and multiple groups within each outcome. Therefore, our primary outcome of change in MD should be considered stronger than the significant findings in the secondary outcomes, which should be considered suggestive, possibly meriting further research.
In conclusion, the 12 month results support the six month conclusions. Acetazolamide again significantly reduced papilledema grade and it significantly improved quality of life measures when added to subjects originally in the placebo group. A new finding is the significant positive effect on headache disability in the group that transitioned from placebo to acetazolamide. Visual field function as measured by perimetric mean deviation continued to improve in all groups and improved most in the placebo group whose IIH symptoms and signs had resolved at six months. We conclude acetazolamide has a beneficial effect on a variety of IIH outcomes.
Supplementary Material
Table 2.
Frisén papilledema grade change over month 6 to month 12 of the Longitudinal Idiopathic Intracranial Hypertension Trial by group. The first Frisén grade value is at six months and the value below it is at 12 months.
| Group | Frisén Grade | St Dev | Frisén Grade Improvement | P value |
|---|---|---|---|---|
| ACZ to open-label ACZ | 0.50 | 0.66 | ||
| 0.38 | 0.60 | 0.12 | 0.10 | |
| PLB to open-label ACZ | 1.61 | 1.37 | ||
| 0.70 | 0.73 | 0.91 | <0.001 | |
| ACZ tapered off | ACZ | 0.47 | 0.52 | |
| 0.47 | 0.74 | 0.0 | 0.99 | |
| PLB to no ACZ | 0.73 | 0.47 | ||
| 0.27 | 0.47 | 0.46 | 0.02 |
ACZ = acetazolamide, PLB = placebo
Table 4.
Quality of life measures showing Short Form-36 Mental Component scores by group at six and 12 months.
| Group | 2SF-36 score | St Dev | SF improvement | P value |
|---|---|---|---|---|
| ACZ to open-label ACZ | 50.82 | 6.71 | ||
| 50.92 | 8.04 | 0.1 | 0.95 | |
| PLB to open-label ACZ | 45.04 | 11.97 | ||
| 49.42 | 10.08 | 4.38 | 0.03 | |
| ACZ tapered off ACZ | 51.16 | 5.83 | ||
| 51.21 | 8.27 | 0.06 | 0.98 | |
| PLB to no ACZ | 53.48 | 5.70 | ||
| 50.13 | 12.67 | −3.35 | 0.33 |
ACZ = acetazolamide, PLB = placebo, SF = short form
Table 5.
Quality of life measures showing Visual Function Questionairre-25 scores by group at six and 12 months.
| Group | VFQ-25 score | St Dev | VFQ improvement | P value |
|---|---|---|---|---|
| ACZ to open-label ACZ | 91.95 | 8.75 | ||
| 91.64 | 6.03 | −0.31 | 0.78 | |
| PLB to open-label ACZ | 86.05 | 12.27 | ||
| 88.64 | 10.7 | 2.59 | 0.01 | |
| ACZ tapered off ACZ | 93.13 | 8.60 | ||
| 93.69 | 7.78 | 056 | 0.82 | |
| PLB to no ACZ | 92.36 | 6.21 | ||
| 94.27 | 2.20 | 1.92 | 0.2 |
ACZ = acetazolamide, PLB = placebo, VFQ = Visual Function Questionairre
Table 6.
Visual Function Questionairre-25 10-Item Supplement total scores by group at six and 12 months.
| Group | VFQ-10 score | St Dev | VFQ improvement | P value |
|---|---|---|---|---|
| ACZ to open-label ACZ | 85.06 | 11.36 | ||
| 85.13 | 8.89 | 0.07 | 0.97 | |
| PLB to open-label ACZ | 79.51 | 12.59 | ||
| 82.91 | 12.24 | 3.4 | 0.05 | |
| ACZ tapered off ACZ | 86.03 | 13.49 | ||
| 87.13 | 12.10 | 1.09 | 0.75 | |
| PLB to no ACZ | 84.73 | 9.90 | ||
| 85.36 | 8.25 | 0.64 | 0.72 |
ACZ = acetazolamide, PLB = placebo, VFQ = Visual Function Questionnaire
Table 7.
Headache Impact Test total scores by group at six and 12 months.
| Group | HIT-6 score | St Dev | HIT-6 improvement | P value |
|---|---|---|---|---|
| ACZ to open-label ACZ | 51.70 | 8.52 | ||
| 50.80 | 9.26 | −0.90 | 0.63 | |
| PLB to open-label ACZ | 53.26 | 9.31 | ||
| 49.56 | 9.40 | −3.70 | 0.01 | |
| ACZ tapered off ACZ | 46.63 | 7.80 | ||
| 45.06 | 10.62 | −1.56 | 0.56 | |
| PLB to no ACZ | 47.82 | 7.37 | ||
| 48.45 | 6.33 | 0.64 | 0.74 |
ACZ = acetazolamide, PLB = placebo, HIT-6 = Headache Impact Test
Footnotes
Date Trial was Registered: 10/28/2009
Date Trial Began: 2/6/2009
NORDIC 1U10EY017281-01A1
Trial Registration: clinicaltrials.gov identifier: NCT01003639
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