Idiopathic Intracranial Hypertension Treatment Trial Research Articles

Classifying and quantifying changes in papilloedema using machine learning

BackgroundMachine learning (ML) can differentiate papilloedema from normal optic discs using fundus photos. Currently, papilloedema severity is assessed using the descriptive, ordinal Frisén scale. We hypothesise that ML can quantify...

Visualization of Optic Nerve Structural Patterns in Papilledema Using Deep Learning Variational Autoencoders.

To visualize and quantify structural patterns of optic nerve edema encountered in papilledema during treatment. A novel bi-channel deep-learning variational autoencoder (biVAE) model was trained using 1498 optical coherence tomography (OCT) scans of 125 subjects over time from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) and 791 OCT scans of 96 control subjects from the University of Iowa. An independent test dataset of 70 eyes from 70 papilledema subjects was used to evaluate the ability of the biVAE model to quantify and reconstruct the papilledema spatial patterns from input OCT scans using only two variables. The montage color maps of the retinal nerve fiber layer (RNFL) and total retinal thickness (TRT) produced by the biVAE model provided an organized visualization of the variety of morphological patterns of optic disc edema (including differing patterns at similar thickness levels). Treatment effects of acetazolamide versus placebo in the IIHTT were also demonstrated in the latent space. In image reconstruction, the mean signed peripapillary retinal nerve fiber layer thickness (pRNFLT) difference ± SD was -0.12 ± 17.34 µm, the absolute pRNFLT difference was 13.68 ± 10.65 µm, and the RNFL structural similarity index reached 0.91 ± 0.05. A wide array of structural patterns of papilledema, integrating the magnitude of disc edema with underlying disc and retinal morphology, can be quantified by just two latent variables. A biVAE model encodes structural patterns, as well as the correlation between channels, and may be applied to visualize individuals or populations with papilledema throughout treatment.

Identification of the characteristic visual field loss patterns in optic neuropathies

Visual fields support physicians in the diagnosis and progression tracking of optic neuropathies, enabling the visualization of the site of the optic nerve or optic pathways damage. Furthermore, the identification of the underlying patterns of different optic neuropathies can strengthen the diagnosis or help the clinicians for the patient's prognosis. Different abnormalities have been described and associated to neuroophthalmological diseases, such as central and ceco‐central scotomas related to hereditary optic neuropathies as Leber and dominant optic atrophy diseases which are mostly affected in the macular retinal ganglion cells and the papillomacular bundle. Altitudinal defects are usually associated with ischemic optic neuropathies, and in the big field of glaucoma the most commonly abnormalities are the arcuate and the nasal step.Related to this topic, artificial Intelligence is gaining traction, implementing, and testing different approaches to the automatic detection of visual field loss patterns in distinct diseases. For example, application of archetype analysis for the detection of glaucoma progression or for the assessment of efficacy in idiopathic intracranial hypertension treatment trial.

Archetypal analysis of longitudinal visual fields for idiopathic intracranial hypertension patients presenting in a clinic setting.

We previously applied archetypal analysis (AA) using visual fields (VF) from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) to derive a model, which quantified patterns (or archetypes [ATs] of VF loss), anticipated recovery, and identified residual VF deficits. We hypothesized that AA could produce similar results using IIH VFs collected in clinical practice. We applied AA to 803 VFs from 235 eyes with IIH from an outpatient neuro-ophthalmology clinic and created a clinic-derived model of ATs, with the relative weight (RW) and average total deviation (TD) for each AT. We also created a combined-derived model from an input dataset containing the clinic VFs and 2862 VFs from the IIHTT. We used both models to decompose clinic VF into ATs of varying percent weight (PW), correlated presentation AT PW with mean deviation (MD), and evaluated final visit VFs considered "normal" by MD ≥ -2.00 dB for residual abnormal ATs. The 14-AT clinic-derived and combined-derived models revealed similar patterns of VF loss previously identified in the IIHTT model. AT1 (a normal pattern) was most prevalent in both models (RW = 51.8% for clinic-derived; 35.4% for combined-derived). Presentation AT1 PW correlated with final visit MD (r = 0.82, p < 0.001 for the clinic-derived model; r = 0.59, p < 0.001 for the combined-derived model). Both models showed ATs with similar patterns of regional VF loss. The most common patterns of VF loss in "normal" final visit VFs using each model were clinic-derived AT2 (mild global depression with enlarged blind spot; 44/125 VFs; 34%) and combined-derived AT2 (near-normal; 93/149 VFs; 62%). AA provides quantitative values for IIH-related patterns of VF loss that can be used to monitor VF changes in a clinic setting. Presentation AT1 PW is associated with the degree of VF recovery. AA identifies residual VF deficits not otherwise indicated by MD.

Unsupervised Machine Learning Shows Change in Visual Field Loss in the Idiopathic Intracranial Hypertension Treatment Trial

We previously reported that archetypal analysis (AA), a type of unsupervised machine learning, identified and quantified patterns of visual field (VF) loss in idiopathic intracranial hypertension (IIH), referred to as archetypes (ATs). We assessed whether AT weight changes over time are consistent with changes in conventional global indices, whether visual outcome or treatment effects are associated with select AT, and whether AA reveals residual VF defects in eyes deemed normal after treatment. Analysis of data collected from a randomized controlled trial. Two thousand eight hundred sixty-two VFs obtained from 165 participants during the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). We applied a 14-AT model derived from IIHTT VFs. We examined changes in individual AT weights over time for all study eyes and evaluated differences between treatment groups. We created an AT change score to assess overall VF change from baseline. We tested threshold baseline AT weights for association with VF outcome and treatment effect at 6 months. We determined the abnormal ATs with meaningful weight at outcome for VFs with a mean deviation (MD) of -2.00 dB or more. Individual AT weighting coefficients and MD. Archetype 1 (a normal VF pattern) showed the greatest weight change for all study eyes, increasing from 11.9% (interquartile range [IQR], 0.44%-24.1%) at baseline to 31.2% (IQR, 16.0%-45.5%) at outcome (P<0.001). Archetype 1 weight change (r= 0.795; P < 0.001) and a global score of AT change (r= 0.988; P < 0.001) correlated strongly with MD change. Study eyes with baseline AT2 (a mild diffuse VF loss pattern) weight of 44% or more (≥ 1 standard deviation more than the mean) showed higher AT2 weights at outcome than those with AT2 weight of < 44% at baseline (P < 0.001). Only the latter group showed a significant acetazolamide treatment effect. Archetypal analysis revealed residual VF loss patterns, most frequently representing mild diffuse loss and an enlarged blind spot in 64 of 66 study eyes with MD of -2.00 dB or more at outcome. Archetypal analysis provides a quantitative approach to monitoring VF changes in IIH. Baseline AT features may be associated with treatment response and VF outcome. Archetypal analysis uncovers residual VF defects not otherwise revealed by MD.

Retinal vessel diameter changes after 6 months of treatment in the Idiopathic Intracranial Hypertension Treatment Trial

Background/AimsPrior studies support an association between increased retinal venule diameter and elevated intracranial pressure (ICP). The purpose of this study was to test the hypothesis that retinal venule diameters decrease...

The Effect of Acetazolamide and Weight Loss on Intraocular Pressure in Idiopathic Intracranial Hypertension Patients.

Acetazolamide (ACZ) lowers intraocular pressure (IOP), acutely in normal eyes and both acutely and chronically in eyes with glaucoma, and cerebrospinal fluid pressure (CSFp), chronically in patients with idiopathic intracranial hypertension (IIH). We hypothesize chronic daily ACZ would significantly reduce IOP and contribute to a translaminar pressure gradient change reflected by alteration in the CSFp-IOP difference and the deformation of the neural canal in patients with IIH and no glaucoma. Before randomization to ACZ or placebo treatment for 6 months, 165 participants in the IIH Treatment Trial had evaluations that included Goldmann applanation, CSFp measurement, and optical coherence tomography determination of the neural canal deformation. These measures were repeated at the 6-month outcome. The IOP was not significantly decreased from baseline at 1, 3, or 6 months in eyes in both treatment groups. At month 6, the amount of ACZ or weight modification did not correlate with any IOP change. The 6-month mean change in neural canal deformation was 0.96 and -0.04 (P=0.001) and in CSFp was -128 and -38 mm H2O (P=0.001), but CSFp-IOP difference change was not significant, in the ACZ and placebo groups, respectively. ACZ does not reduce the IOP in eyes without glaucoma but does decrease the pathologic elevated CSFp, providing evidence that normal systems can compensate for chronic medication effects. The CSFp-IOP is not a direct marker of translaminar pressure gradient and the ACZ normalization of the neural canal deformation appears due to CSFp reduction alone.

Intracranial hypertension: a current review.

To provide a current review of recent publications with regards to intracranial hypertension. Attempts were made to provide pediatric data; however, the recent completion of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) has provided a wealth of data with regards to adult intracranial hypertension.The pediatric incidence of intracranial hypertension ranges between 0.63 and 0.71 per 100 000 children. A majority of pediatric cases responded to acetazolamide, with resolution of headache averaging 3.8 weeks. Most patients require less than 1 year of treatment with male sex, older age at diagnosis, primary intracranial hypertension, and lack of headache being predictors of good response. Fluorescein angiography has the highest accuracy in distinguishing true papilledema from pseudopapilledema. The IIHTT found Frisen grade of papilledema was within 1 grade in 92.8% of patients. Monitoring of potassium levels is not required and aplastic anemia was not seen in patients taking acetazolamide. Although the newer pediatric studies report incidence rates in pediatric intracranial hypertension are lower than seen in adults, intracranial hypertension is still a concern in pediatrics. There has been a wealth of information with regards to symptomatology, treatment, and outcomes from the IIHTT that will hopefully assist with management in the pediatric population.

An update of idiopathic intracranial hypertension.

We aim to provide a comprehensive and updated review on idiopathic intracranial hypertension (IIH), including the most current studies and treatment options. Special focus will be put on recent theories about the pathophysiology, and on newer prospective studies on treatment modalities. The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) provided evidence supporting acetazolamide as a well tolerated first-line therapy in IIH patients with mild vision loss. Recent studies have shown venous sinus stenting as a well tolerated and effective surgical alternative for patients with refractory IIH. Idiopathic intracranial hypertension is a vision-threatening disorder that predominantly affects obese women of childbearing age. This disorder is becoming more prevalent as the obesity epidemic continues to increase. As our understanding of this disorder continues to evolve, diagnosis and management approaches have changed over time. However, the pathogenesis for IIH remains unclear. Several theories have been proposed, including abnormalities in cerebrospinal dynamics, metabolic causes and genetics. The diagnostic criteria are based on the revised Dandy criteria. Traditionally, treatment was based on clinical experiences and retrospective studies. However, a new, prospective, randomized, controlled trial, the IIHTT, provided evidence-based data to help guide medical therapy. Additionally new, prospective studies are underway for the different surgical alternatives to treat IIH.

The Relationship Between Optic Disc Volume, Area, and Frisén Score in Patients With Idiopathic Intracranial Hypertension

To compare measurements of papilledema using fundus photography, optical coherence tomography (OCT), and Frisén score in patients with idiopathic intracranial hypertension (IIH). Retrospective, noncomparative analysis of randomized controlled trial data. The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) evaluated weight management and treatment with acetazolamide compared with placebo in patients with IIH and mild visual loss. Among the 126 subjects in the IIHTT OCT substudy, fundus photographs and OCT scans of the optic disc were taken at baseline and at 6 and 12months after enrollment. Trained readers scored each eye using a modified Frisén scale and measured the area of disc elevation. OCT scans assessed optic nerve head (ONH) volume. Correlations between volume and area were computed for both study and nonstudy eyes. Disc area and ONH volume were positively correlated at baseline (R2= 0.77 in study eyes, P < .001). Correlations between area and volume were similar in the treatment groups at baseline, but were weaker in the acetazolamide group compared with the placebo group at 6months (R2= 0.25 vs R2= 0.76 in study eyes) and 12months (R2= 0.19 vs R2= 0.65 in study eyes). At 6 and 12months after enrollment, there was no consistent relationship between Frisén score, disc area, and ONH volumes in the acetazolamide group. Frisén score fails to reflect the photographic area and OCT volume of papilledema after treatment with acetazolamide. Clinicians should use caution when using the Frisén scale to monitor the effect of treatment on papilledema over time.

An Up to Date Review of Pseudotumor Cerebri Syndrome

Idiopathic intracranial hypertension (IIH), pseudotumor cerebri syndrome (PTCS), and benign intracranial hypertension are all terms that have been used for a neurologic syndrome consisting of elevated intracranial pressure (ICP), headache and vision loss without mass lesion or underlying infection or malignancy. In this review article, categorization, diagnostic criteria, symptom management strategies, and disease treatment options for pseudotumor cerebri syndrome will be discussed. The Idiopathic Intracranial Hypertension Treatment Trial has now proven that acetazolamide should be the first line therapy in primary PTCS, but other treatment options exist in patients who cannot tolerate acetazolamide or in selected cases, which requires surgical intervention for PTCS which acutely threatens vision. Headache has also been shown to require focused treatment beyond therapies that lower ICP, specifically targeting coexistent primary headache disorders and medication overuse. Advances in treatment and diagnostic modalities have improved understanding of PTCS types and their treatment. The pathophysiology of primary PTCS, however, remains incompletely understood, but continued evaluation of cerebrospinal fluid flow dynamics, aquaporins, hormones, natriuretic peptides, and the link with female gender and obesity may lead to future answers.

Idiopathic Intracranial Hypertension in Children and Adolescents: An Update.

Idiopathic intracranial hypertension (IIH), previously known as pseudotumor cerebri syndrome (PTC) is a serious neurological disorder that can lead to irreversible visual loss. Predominantly a disorder affecting women in reproductive years, the pediatric population is not spared. In the past few years, the condition has been redefined, due to new accepted values for opening pressure in children and advances in neuroimaging. Emerging techniques in ophthalmology are being increasingly used to monitor disease in these patients. And, although the treatment tools have not changed in several years, important evidence for efficacy for acetazolamide finally came to light in recent years in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). This review article provides an overview on recent advances in diagnosis, evaluation and treatment of IIH.

The Idiopathic Intracranial Hypertension Treatment Trial: A Review of the Outcomes

The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) was the first large, randomized study on the use of acetazolamide and weight loss for treatment of idiopathic intracranial hypertension-associated vision loss. The multicenter trial also examined a number of secondary outcomes. This review summarizes all available results of the study published in the literature since 2014. Prior to the IIHTT, clinicians managed idiopathic intracranial hypertension based on data from small, unmasked trials, expert opinion, and clinical experience. Due to the lack of empiric evidence, there were no official treatment protocols to guide treatment of the disorder. We performed a PubMed literature search for all articles with data from the IIHTT Study Group. After review of each article and any relevant supporting literature, the results were compiled into a summary of the literature. The PubMed search identified 14 articles with primary and/or secondary outcome data from the IIHTT. We summarized the findings for the primary outcome of visual field outcomes in the acetazolamide treatment group compared to the placebo group, as well as secondary outcomes for the safety and tolerability of acetazolamide, cerebrospinal fluid opening pressure, quality of life, fundus photography, and optical coherence tomography. While both groups demonstrated improvement on most outcomes, acetazolamide had a greater effect even when controlling for its effect on weight loss. As the first large, randomized, prospective trial, the IIHTT extensively expanded the available data on idiopathic intracranial hypertension treatment. Most importantly, it provided support for the safe use of acetazolamide up to 4 g daily with weight loss for effective treatment of mild vision loss in IIH, with associated improvements in papilledema, increased intracranial pressure, and quality of life.

Headache in Idiopathic Intracranial Hypertension: Findings From the Idiopathic Intracranial Hypertension Treatment Trial.

To characterize the phenotype, headache-related disability, medical co-morbidities, use of symptomatic headache medications, and headache response to study interventions in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Patients with untreated IIH and mild vision loss enrolled in the IIHTT and randomized to acetazolamide (ACZ) and weight loss or placebo (PLB) and weight loss had prospective assessment of headache disability using the Headache Impact Test-6 (HIT-6) questionnaire. Subjects with headache at the baseline visit were assigned a headache phenotype using the International Classification for Headache Disorders version 3 beta (ICHD-3b). Medication overuse was determined using the participants' reported medication use for the preceding month and ICHD-3b thresholds for diagnosing medication overuse headache. We investigated relationships between headache disability and various other clinical characteristics at baseline and at 6 months. Headache was present in 139 (84%) of the 165 enrollees at baseline. The most common headache phenotypes were migraine (52%), tension-type headache (22%), probable migraine (16%), and probable tension-type headache (4%). Fifty-one (37%) participants overused symptomatic medications at baseline, most frequently simple analgesics. A similar amount of improvement in the adjusted mean (± standard error) HIT-6 score occurred in the ACZ (-9.56 ± 1.05) and PLB groups (-9.11 ± 1.14) at 6 months (group difference -0.45, 95% CI -3.50 to 2.60, P = .77). Headache disability did not correlate with any of the studies, variables of interest, which included: the lumbar puncture opening pressure at baseline or at 6 months, body mass index, the amount of weight lost, papilledema grade, perimetric mean deviation, or the use of hormonal contraception. Headache disability was significantly associated with patient-reported quality of life in the physical, mental, and visual domains. Headache was common, of varied character, disabling, and associated with poorer quality of life in our cohort of patients with mild visual impairment. The lack of correlation between headache disability and cerebrospinal fluid (CSF) pressure at baseline and at the end of the randomized phase of the study implies that headache in IIH may be related to factors other than intracranial hypertension, and that specific headache treatment is needed in addition to therapies directed at lowering CSF pressure.

Peripapillary Retinal Pigment Epithelium Layer Shape Changes From Acetazolamide Treatment in the Idiopathic Intracranial Hypertension Treatment Trial.

PurposeRecent studies indicate that the amount of deformation of the peripapillary retinal pigment epithelium and Bruch's membrane (pRPE/BM) toward or away from the vitreous may reflect acute changes in cerebrospinal fluid pressure. The study purpose is to determine if changes in optic-nerve-head (ONH) shape reflect a treatment effect (acetazolamide/placebo + weight management) using the optical coherence tomography (OCT) substudy of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) at baseline, 3, and 6 months.MethodsThe pRPE/BM shape deformation was quantified and compared with ONH volume, peripapillary retinal nerve fiber layer (pRNFL), and total retinal (pTR) thicknesses in the acetazolamide group (39 subjects) and placebo group (31 subjects) at baseline, 3, and 6 months.ResultsMean changes of the pRPE/BM shape measure were significant and in the positive direction (away from the vitreous) for the acetazolamide group (P < 0.01), but not for the placebo group. The three OCT measures reflecting the reduction of optic disc swelling were significant in both treatment groups but greater in the acetazolamide group (P < 0.01).ConclusionsChange in the pRPE/BM shape away from the vitreous reflects the effect of acetazolamide + weight management in reducing the pressure differential between the intraocular and retrobulbar arachnoid space. Weight management alone was also associated with a decrease in optic nerve volume/edema but without a significant change in the pRPE/BM shape, implying an alternative mechanism for improvement in papilledema and axoplasmic flow, independent of a reduction in the pressure differential. (ClinicalTrials.gov number, NCT01003639.)

Current concepts and strategies in the diagnosis and management of idiopathic intracranial hypertension in adults.

Since obesity has become an epidemic in industrialized nations, idiopathic intracranial hypertension (IIH) is now a more common neuro-ophthalmic disorder that causes visual loss and headaches. This review highlights the new diagnostic criteria for IIH and the new insights into the pathophysiologic mechanisms of IIH. Key diagnostic and monitoring techniques for papilledema include not only neuroimaging and the measurement of cerebrospinal fluid (CSF) pressure, but also perimetry, optical coherence tomography, and ocular sonography. The main findings of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) support acetazolamide as the mainstay for medical therapy. CSF diversion procedures, endovascular venous sinus stenting, and optic nerve sheath fenestration are all surgical options when IIH is refractory to medical treatment or when it presents fulminantly. Future clinical trials comparing these procedures will help develop better paradigms in the surgical management of IIH.

Optic disc haemorrhages at baseline as a risk factor for poor outcome in the Idiopathic Intracranial Hypertension Treatment Trial

BackgroundThe risk of optic disc haemorrhages on visual outcome in idiopathic intracranial hypertension (IIH) is unknown. We report the type and frequency of optic disc haemorrhages and other funduscopic abnormalities...

The Longitudinal Idiopathic Intracranial Hypertension Trial: Outcomes From Months 6–12

To determine whether the beneficial effects of acetazolamide (ACZ) in improving vision at 6months continues to month 12 in participants of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Nonrandomized clinical study. In the IIHTT, subjects were randomly assigned to placebo-plus-diet or maximally tolerated dosage of acetazolamide-plus-diet. At 6months 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. Ninety-six IIHTT subjects had evaluations at 6 and 12months. Our main outcome measure was change from month 6 to month 12 in visual field mean deviation (MD) with secondary measures being change in papilledema grade, ETDRS scores, and quality-of-life (QoL) measures. The ACZ to ACZ group improved 0.35 dB, P= .05; placebo subjects with no ACZ improved 0.81 dB MD, P= .07 at 12months. The other groups improved 0.35-0.46 dB MD. Mean improvements in papilledema grade occurred most markedly in the group that exchanged placebo for ACZ (0.91 units, P<.001). QoL and headache disability scores showed significant improvements in the placebo group with added ACZ. 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 QoLmeasures.

Role of vitamin A metabolism in IIH: Results from the idiopathic intracranial hypertension treatment trial

IntroductionVitamin A and its metabolites (called retinoids) have been thought to play a role in the development of idiopathic intracranial hypertension (IIH). The IIH Treatment Trial (IIHTT) showed the efficacy of acetazolamide (ACZ) in improving visual field function, papilledema grade, quality of life and cerebrospinal fluid (CSF) pressure. We postulated that IIH patients would demonstrate elevated measures of vitamin A metabolites in the serum and CSF. MethodsComprehensive measures of serum vitamin A and its metabolites were obtained from 96 IIHTT subjects, randomly assigned to treatment with ACZ or placebo, and 25 controls with similar gender, age and body mass index (BMI). These included retinol, retinol binding protein, all-trans retinoic acid (ATRA), alpha- and beta-carotenes, and beta-cryptoxanthin. The IIHTT subjects also had CSF and serum vitamin A and metabolite measurements obtained at study entry and at six months. ResultsAt study entry, of the vitamin A metabolites only serum ATRA was significantly different in IIHTT subjects (median 4.33nM) and controls (median 5.04nM, p=0.02). The BMI of IIHTT subjects showed mild significant negative correlations with serum ATRA, alpha- and beta-carotene, and beta-cryptoxanthin. In contrast, the control subject BMI correlated only with serum ATRA. At six months, the serum retinol, alpha-carotene, beta-carotene, and CSF retinol were increased from baseline in the ACZ treated group, but only increases in alpha-carotene (p=0.02) and CSF ATRA (p=0.04) were significantly greater in the ACZ group compared with the placebo group. No other vitamin A measures were significantly altered over the six months in either treatment group. Weight loss correlated with only with the change in serum beta-carotene (r=−0.44, p=0.006) and the change in CSF retinol (r=−0.61, p=0.02). ConclusionVitamin A toxicity is unlikely a contributory factor in the causation of IIH. Our findings differ from those of prior reports in part because of our use of more accurate quantitative methods and measuring vitamin A metabolites in both serum and CSF. ACZ may alter retinoid metabolism in IIH patients.

Quality of life at 6 months in the Idiopathic Intracranial Hypertension Treatment Trial.

To examine the changes in vision-specific and overall health-related quality of life (QOL) at 6 months in participants with idiopathic intracranial hypertension (IIH) and mild visual loss enrolled in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) and to determine the signs and symptoms of IIH that mediate the effect of acetazolamide on QOL. We assessed QOL using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25), the 10-Item NEI-VFQ-25 Neuro-Ophthalmic Supplement, and the 36-Item Short Form Health Survey (SF-36). We examined associations among changes in QOL measures over 6 months, treatment status, and changes in signs and symptoms using linear and structural equation models. Among the 165 participants with IIH (86 randomized to acetazolamide, 79 to placebo), beneficial effects of acetazolamide were seen on all QOL scales evaluated, as well as on the Near Activities (5.60 points, p = 0.03), Social Functioning (3.85 points, p = 0.04), and Mental Health (9.82, p = 0.04) subscales of the NEI-VFQ-25. Positive acetazolamide-related effects on QOL appeared to be primarily mediated by improvements in visual field, neck pain, pulsatile tinnitus, and dizziness/vertigo that outweighed the side effects of acetazolamide. The marked reductions in baseline QOL seen among patients with mild visual loss from IIH are improved by treatment with acetazolamide. When combined with acetazolamide-associated improvements in visual field and other aspects of IIH, our findings with respect to QOL provide further support from the IIHTT in favor of acetazolamide to augment a dietary intervention in the treatment of IIH with mild visual loss (clinicaltrials.gov: NCT01003639).