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IIHTT

The Idiopathic Intracranial Hypertension Treatment Trial

Year of Publication: 2014

Authors: The NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee (Michael Wall, Michael P. McDermott, Karl D. Kieburtz, ..., Mark J. Kupersmith)

Journal: JAMA

Citation: JAMA. 2014;311(16):1641-1651. doi:10.1001/jama.2014.3312

Link: https://journals.lww.com/jneuro-ophthalm...reatment.2.aspx

PDF: https://journals.lww.com/jneuro-ophthalm...load-,PDF,-EPUB

Clinical Question

Does acetazolamide improve visual function when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss?

Bottom Line

Acetazolamide combined with a low-sodium weight-reduction diet resulted in modest but statistically significant improvement in visual field function compared to diet alone in patients with IIH and mild visual loss, though the clinical importance remains uncertain

        Major Points
        First multicenter, double-blind, randomized controlled trial of acetazolamide for IIH
Primary outcome showed 0.71 dB greater improvement in visual field (PMD) with acetazolamide vs placebo (P=0.050)
Significant improvements in secondary outcomes: papilledema grade (P<0.001), vision-related quality of life (VFQ-25, P=0.003), and weight loss (4 kg greater, P<0.001)
Treatment effect was greater in patients with more severe papilledema (grade 3-5) compared to milder papilledema
Common adverse events included paresthesia (48%), dysgeusia (15%), fatigue (16%), and GI symptoms
19% withdrawal rate with similar reasons between groups; more acetazolamide patients discontinued drug (9 vs 1)
Mediation analysis showed weight loss did not explain the visual benefit of acetazolamide

      

Design

Study Type: Interventional, randomized controlled trial

Randomization: 1

Blinding: Double-masked (participants, investigators, outcome assessors)

Enrollment Period: March 2010 to November 2012

Follow-up Duration: 6 months

Centers: 38

Countries: United States, Canada

Sample Size: 165

Analysis: Intention-to-treat using ANCOVA with multiple imputation for missing data, adjusted for center, baseline PMD, and papilledema grade; secondary analysis used MMRM; statistical analysis performed with SAS version 9.3

Inclusion Criteria

Age 18-60 years
Diagnosis of IIH meeting modified Dandy criteria
Reproducible mild visual loss (PMD between -2 and -7 dB)
Bilateral papilledema
Elevated CSF opening pressure
Untreated with regard to IIH
No secondary cause of increased intracranial pressure

Exclusion Criteria

Visual loss more severe than -7 dB PMD (lack of clinical equipoise for randomization)
Visual loss less than -2 dB (insufficient room for improvement)
Secondary causes of intracranial hypertension
Prior treatment for IIH
Other exclusions detailed in trial supplement

Baseline Characteristics

Characteristic	Acetazolamide	Placebo
Sample size	86	79
Age (years)	28.2 ± 6.9	30.0 ± 8.0
Female (%)	97.7	97.5
White (%)	62.8	68.4
Black (%)	29.1	20.3
Weight (kg)	108.1 ± 25.6	107.3 ± 24.5
BMI	40.0 ± 8.5	39.9 ± 8.1
PMD study eye (dB)	-3.5 ± 1.2	-3.5 ± 1.1
PMD fellow eye (dB)	-2.3 ± 1.1	-2.3 ± 1.1
Papilledema grade study eye (mean)	2.76	2.76
Papilledema grade 1 (%)	9.3	15.2
Papilledema grade 2 (%)	37.2	29.1
Papilledema grade 3 (%)	23.3	25.3
Papilledema grade 4 (%)	27.9	26.6
Papilledema grade 5 (%)	2.3	3.8
CSF pressure (mm H2O)	348.9 ± 94.1	342.0 ± 70.7
VFQ-25 total score	83.8 ± 14.1	82.1 ± 13.4
VFQ-25 neuro supplement	75.8 ± 15.4	75.0 ± 13.7
SF-36 Physical	45.4 ± 9.8	46.3 ± 8.2
SF-36 Mental	45.2 ± 11.8	44.0 ± 13.3
HIT-6 score	60.3 ± 8.7	59.1 ± 9.3
Headache (%)	81.4	87.3

Arms

Field	Acetazolamide + Diet	Control
Intervention	Acetazolamide 250 mg tablets; initial dose 4 tablets daily (1 g/d) in 2 divided doses, escalated by 1 tablet weekly to maximum 16 tablets (4 g/d); plus low-sodium weight-reduction diet from New York Obesity Nutrition Research Center	Matching placebo tablets; same escalation schedule as acetazolamide arm; plus identical low-sodium weight-reduction diet
Duration	6 months	6 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change in perimetric mean deviation (PMD) from baseline to month 6 in the eye with the most severe visual loss at baseline (study eye), measured by Humphrey Field Analyzer SITA Standard 24-2	Primary	0.71 dB improvement (from -3.53 to -2.82 dB)	1.43 dB improvement (from -3.53 to -2.10 dB)		0.050
Change in PMD in fellow eye	Secondary	0.42 dB improvement	0.87 dB improvement		0.045
Change in papilledema grade (study eye, fundus photography)	Secondary	-0.61 (from 2.76 to 2.15)	-1.31 (from 2.76 to 1.45)	Treatment effect -0.70	<0.001
Change in papilledema grade (fellow eye, fundus photography)	Secondary	-0.52 (from 2.50 to 1.98)	-1.14 (from 2.50 to 1.36)	Treatment effect -0.62	<0.001
VFQ-25 total score	Secondary	+1.98 (from 82.97 to 84.95)	+8.33 (from 82.97 to 91.30)	Treatment effect 6.35	0.003
VFQ-25 10-item neuro-ophthalmic supplement	Secondary	+1.59 (from 75.45 to 77.04)	+9.82 (from 75.45 to 85.27)	Treatment effect 8.23	<0.001
SF-36 Physical Component Summary	Secondary	+2.82 (from 45.82 to 48.64)	+5.84 (from 45.82 to 51.66)	Treatment effect 3.02	0.03
SF-36 Mental Component Summary	Secondary	+2.17 (from 44.61 to 46.78)	+5.62 (from 44.61 to 50.23)	Treatment effect 3.45	0.03
HIT-6 total score	Secondary	-9.11 (from 59.70 to 50.59)	-9.56 (from 59.70 to 50.14)	Treatment effect -0.45	0.77
Visual acuity in study eye (number of correct letters)	Secondary	+2.64	+2.65	Treatment effect 0.01	0.99
Weight change	Secondary	-3.45 kg (from 107.72 to 104.27 kg)	-7.50 kg (from 107.72 to 100.22 kg)	Treatment effect -4.05 kg	<0.001
CSF pressure change (n=85: 47 acetazolamide, 38 placebo)	Secondary	-52.4 mm H2O (from 357.2 to 304.8)	-112.3 mm H2O (from 357.2 to 244.9)	Treatment effect -59.9 mm H2O	0.002
Presence of headache at month 6	Secondary	68%	69%	Adjusted OR 1.10	0.80
Treatment failure	Secondary	6 participants	1 participant		0.06
Paresthesia	Adverse	5 (6.3%)	41 (47.7%)		<0.001
Dysgeusia	Adverse	0 (0%)	13 (15.1%)		<0.001
Fatigue	Adverse	1 (1.3%)	14 (16.3%)		<0.001
Decreased CO2	Adverse	0 (0%)	9 (10.5%)		0.003
Nausea	Adverse	10 (12.7%)	26 (30.2%)		0.008
Vomiting	Adverse	3 (3.8%)	12 (14.0%)		0.03
Diarrhea	Adverse	3 (3.8%)	12 (14.0%)		0.03
Tinnitus	Adverse	3 (3.8%)	11 (12.8%)		0.05
Serious Adverse Events	Adverse	3 participants (2 rapidly failing vision requiring optic nerve sheath fenestration, 1 pneumonia)	6 participants (renal impairment, transaminitis, elevated lipase with pancreatitis, diverticulitis, allergic reaction, hypokalemia)
Drug Discontinuation	Adverse	1 (1.3%)	9 (10.5%)

Subgroup Analysis

Treatment effect on primary outcome was substantially greater in participants with baseline papilledema grade 3-5 (2.27 dB) compared to those with grade 1-2 (-0.67 dB). Interactions examined with age, race, baseline PMD, papilledema grade, weight change in previous 6 months, and constant visual loss

Criticisms

19% withdrawal rate, though similar between groups
More participants discontinued acetazolamide (9) than placebo (1), which may have attenuated the treatment effect
Estimated treatment effect (0.71 dB) was only about half of the pre-specified minimal clinically important difference (1.3 dB)
Minimal clinically important difference was based on small pilot study and did not incorporate patient input
Clinical significance of 0.71 dB improvement in PMD remains uncertain
Only 47% (85/165) agreed to repeat lumbar puncture at month 6 for CSF pressure measurement
Results apply only to patients with mild visual loss (PMD -2 to -7 dB), not more severe cases
Unable to separate effect of acetazolamide from effect of diet, as all received dietary intervention
Relatively short 6-month follow-up period
Mean final dose was 2.5 g/d in acetazolamide group vs 3.5 g/d in placebo group
Predominantly female population (97.6%) limits generalizability

Funding

National Eye Institute (NEI) grants 1U10EY017281-01A1, DCBC 1U10EY017387-01A1, ARRA supplements

Based on: IIHTT (JAMA, 2014)

Authors: The NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee (Michael Wall, Michael P. McDermott, Karl D. Kieburtz, ..., Mark J. Kupersmith)

Citation: JAMA. 2014;311(16):1641-1651. doi:10.1001/jama.2014.3312

Reviewed by: Keiko Ihara, MD

Content summarized and formatted by NeuroTrials.ai.

IIHTT

(2014)

Objective

To determine whether acetazolamide improves visual function when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss

Study Summary

• Acetazolamide plus diet showed modest improvement in visual field function compared to diet alone (treatment effect 0.71 dB, P=0.050)
• Significant improvements in papilledema grade, quality of life measures, and weight loss
• More frequent adverse events with acetazolamide including paresthesia, dysgeusia, and GI symptoms

Intervention

Acetazolamide (up to 4 g/d) or placebo, both with low-sodium weight-reduction diet

Inclusion Criteria

Adults 18-60 years with IIH meeting modified Dandy criteria and mild visual loss (PMD -2 to -7 dB)

Study Design

Arms: Acetazolamide + diet (n=86) vs Placebo + diet (n=79)

Patients per Arm: 86 acetazolamide, 79 placebo

Outcome

• Primary: Acetazolamide improved PMD by 1.43 dB vs 0.71 dB with placebo (difference 0.71 dB, 95% CI 0 to 1.43, P=0.050)
• Papilledema grade improved more with acetazolamide (treatment effect -0.70, P<0.001)
• Quality of life improved significantly with acetazolamide (VFQ-25: +6.35 points, P=0.003)

Bottom Line

Major Points

First multicenter, double-blind, randomized controlled trial of acetazolamide for IIH
Primary outcome showed 0.71 dB greater improvement in visual field (PMD) with acetazolamide vs placebo (P=0.050)
Significant improvements in secondary outcomes: papilledema grade (P<0.001), vision-related quality of life (VFQ-25, P=0.003), and weight loss (4 kg greater, P<0.001)
Treatment effect was greater in patients with more severe papilledema (grade 3-5) compared to milder papilledema
Common adverse events included paresthesia (48%), dysgeusia (15%), fatigue (16%), and GI symptoms
19% withdrawal rate with similar reasons between groups; more acetazolamide patients discontinued drug (9 vs 1)
Mediation analysis showed weight loss did not explain the visual benefit of acetazolamide

Study Design

Study Type: Interventional, randomized controlled trial
Randomization: Yes
Blinding: Double-masked (participants, investigators, outcome assessors)
Sample Size: 165
Follow-up: 6 months
Centers: 38
Countries: United States, Canada

Primary Outcome

Definition: Change in perimetric mean deviation (PMD) from baseline to month 6 in the eye with the most severe visual loss at baseline (study eye), measured by Humphrey Field Analyzer SITA Standard 24-2

Control	Intervention	HR/OR	P-value
0.71 dB improvement (from -3.53 to -2.82 dB)	1.43 dB improvement (from -3.53 to -2.10 dB)	- (0 to 1.43 dB)	0.050

Limitations & Criticisms

19% withdrawal rate, though similar between groups
More participants discontinued acetazolamide (9) than placebo (1), which may have attenuated the treatment effect
Estimated treatment effect (0.71 dB) was only about half of the pre-specified minimal clinically important difference (1.3 dB)
Minimal clinically important difference was based on small pilot study and did not incorporate patient input
Clinical significance of 0.71 dB improvement in PMD remains uncertain
Only 47% (85/165) agreed to repeat lumbar puncture at month 6 for CSF pressure measurement
Results apply only to patients with mild visual loss (PMD -2 to -7 dB), not more severe cases
Unable to separate effect of acetazolamide from effect of diet, as all received dietary intervention
Relatively short 6-month follow-up period
Mean final dose was 2.5 g/d in acetazolamide group vs 3.5 g/d in placebo group
Predominantly female population (97.6%) limits generalizability

Citation

JAMA. 2014;311(16):1641-1651. doi:10.1001/jama.2014.3312

View Original Publication →

IIHTT

The Idiopathic Intracranial Hypertension Treatment Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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