Assessment of Cumulative Incidence and Severity of Primary Open-Angle Glaucoma Among Participants in the Ocular Hypertension Treatment Study After 20 Years of Follow-up.

Importance: Ocular hypertension is an important risk factor for the development of primary open-angle glaucoma (POAG). Data from long-term follow-up can be used to inform the management of patients with ocular hypertension. Objective: To determine the cumulative incidence and severity of POAG after 20 years of follow-up among participants in the Ocular Hypertension Treatment Study. Design, Setting, and Participants: Participants in the Ocular Hypertension Treatment Study were followed up from February 1994 to December 2008 in 22 clinics. Data were collected after 20 years of follow-up (from January 2016 to April 2019) or within 2 years of death. Analyses were performed from July 2019 to December 2020. Interventions: From February 28, 1994, to June 2, 2002 (phase 1), participants were randomized to receive either topical ocular hypotensive medication (medication group) or close observation (observation group). From June 3, 2002, to December 30, 2008 (phase 2), both randomization groups received medication. Beginning in 2009, treatment was no longer determined by study protocol. From January 7, 2016, to April 15, 2019 (phase 3), participants received ophthalmic examinations and visual function assessments. Main Outcomes and Measures: Twenty-year cumulative incidence and severity of POAG in 1 or both eyes after adjustment for exposure time. Results: A total of 1636 individuals (mean [SD] age, 55.4 [9.6] years; 931 women [56.9%]; 1138 White participants [69.6%]; 407 Black/African American participants [24.9%]) were randomized in phase 1 of the clinical trial. Of those, 483 participants (29.5%) developed POAG in 1 or both eyes (unadjusted incidence). After adjusting for exposure time, the 20-year cumulative incidence of POAG in 1 or both eyes was 45.6% (95% CI, 42.3%-48.8%) among all participants, 49.3% (95% CI, 44.5%-53.8%) among participants in the observation group, and 41.9% (95% CI, 37.2%-46.3%) among participants in the medication group. The 20-year cumulative incidence of POAG was 55.2% (95% CI, 47.9%-61.5%) among Black/African American participants and 42.7% (95% CI, 38.9%-46.3%) among participants of other races. The 20-year cumulative incidence for visual field loss was 25.2% (95% CI, 22.5%-27.8%). Using a 5-factor baseline model, the cumulative incidence of POAG among participants in the low-, medium-, and high-risk tertiles was 31.7% (95% CI, 26.4%-36.6%), 47.6% (95% CI, 41.6%-53.0%), and 59.8% (95% CI, 53.1%-65.5%), respectively. Conclusions and Relevance: In this study, only one-fourth of participants in the Ocular Hypertension Treatment Study developed visual field loss in either eye over long-term follow-up. This information, together with a prediction model, may help clinicians and patients make informed personalized decisions about the management of ocular hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT00000125.

Risk Factors for Fellow Eye Involvement in Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND: Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in individuals older than 50 years. Demographic, ocular, and systemic risk factors for NAION have been identified, and we sought to determine which, if any, of these factors also increase risk of NAION in the fellow eye. METHODS: We performed a retrospective chart review of patients with "ischemic optic neuropathy" (based on International Classification of Disease [ICD] codes) seen at a single eye center between 2007 and 2017. Patients who met diagnostic criteria for unilateral NAION without fellow eye optic neuropathy at diagnosis were included. Demographic information, ocular comorbidities, and systemic diagnoses were recorded, in addition to whether the fellow eye developed NAION during the follow-up period. Univariate and multivariate Cox proportional hazard regression were used to calculate hazard ratios (HRs) for fellow eye involvement. RESULTS: Three hundred eighteen patients were identified by ICD codes, and 119 were included in the study. Twenty-nine (24%) patients developed NAION in the fellow eye over the mean follow-up period of 3.6 years (range: 1 month-11 years). Significant risk factors for fellow eye NAION included the presence of bilateral optic disc drusen (ODD, HR 2.78, 95% confidence interval [CI] 1.12-6.90, P = 0.02) and noncompliance with continuous positive airway pressure (CPAP) in patients with moderate-to-severe obstructive sleep apnea (HR 4.50, 95% CI 1.79-11.3, P = 0.0015). CONCLUSIONS: Bilateral ODD and noncompliance with CPAP when indicated are associated with increased risk of NAION in the fellow eye. Patients with these risk factors should be counseled on the potentially devastating visual consequences of bilateral NAION, and compliance with CPAP should be stressed when appropriate.

Visual Field Outcomes for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT).

PURPOSE: The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) showed that acetazolamide provided a modest, significant improvement in mean deviation (MD). Here, we further analyze visual field changes over the 6-month study period. METHODS: Of 165 subjects with mild visual loss in the IIHTT, 125 had perimetry at baseline and 6 months. We evaluated pointwise linear regression of visual sensitivity versus time to classify test locations in the worst MD (study) eye as improving or not; pointwise changes from baseline to month 6 in decibels; and clinical consensus of change from baseline to 6 months. RESULTS: The average study eye had 36 of 52 test locations with improving sensitivity over 6 months using pointwise linear regression, but differences between the acetazolamide and placebo groups were not significant. Pointwise results mostly improved in both treatment groups with the magnitude of the mean change within groups greatest and statistically significant around the blind spot and the nasal area, especially in the acetazolamide group. The consensus classification of visual field change from baseline to 6 months in the study eye yielded percentages (acetazolamide, placebo) of 7.2% and 17.5% worse, 35.1% and 31.7% with no change, and 56.1% and 50.8% improved; group differences were not statistically significant. CONCLUSIONS: In the IIHTT, compared to the placebo group, the acetazolamide group had a significant pointwise improvement in visual field function, particularly in the nasal and pericecal areas; the latter is likely due to reduction in blind spot size related to improvement in papilledema. (ClinicalTrials.gov number, NCT01003639.).

Factors Affecting Visual Field Outcomes in the Idiopathic Intracranial Hypertension Treatment Trial.

BACKGROUND: To determine the prevalence of visual field (VF) performance failures (PF) and treatment failures (TFs), and identify factors associated with PFs in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: A total of 165 participants from 38 sites with idiopathic intracranial hypertension (IIH) and mild visual loss were randomized to either acetazolamide-plus diet or placebo-plus diet. The IIHTT Visual Field Reading Center evaluated 2950 Swedish Interactive Threshold Algorithm Standard 24-2 VFs from the enrolled participants. A TF was defined when the participant's VF mean deviation (MD) worsened ≥2 to 3 dB from the average baseline MD (range of -2 to -7 dB) with a second retest confirming the visual deterioration. A PF was determined when the participant's: 1) VF results met TF criteria but were not confirmed on retest, 2) deterioration was confirmed on retest but the IIHTT Adjudication Committee concluded a TF was clinically unlikely. RESULTS: TF was detected in 7/165 (4%) of the participants and PF was detected in 35/165 (21%) of the participants on at least 1 examination. Four of the 35 PFs were adjudicated for TF, however based on clinical review by the adjudication committee and a third retest, they were judged as PFs. Of the 2,950 total IIHTT VF examinations, 2.7% met PF criteria. CONCLUSIONS: PF was confirmed in 21% of subjects and in 2.7% of the total number of VF examinations and was reversible on repeat testing. We recommend retesting when perimetric worsening occurs in otherwise clinically stable or improving IIH patients.

Positive Auto-Antibody Activity With Retina and Optic Nerve in Smokers and Non-Smokers: The Controversy Continues.

Auto-antibodies assist with the diagnosis of ocular paraneoplastic syndromes and autoimmune ocular conditions; however, the frequency of positive test results as a possible precursor to future disease is unknown. The frequency of positive antibodies in heavy smokers who may be at risk for autoimmune-related retinopathy and optic neuropathy was evaluated. Serum antibody activity was evaluated through the use of Western blot reactions from pig retina and optic nerve extract. Fifty-one patients were included: 35 patients were smokers (average: 40.9 pack-year history) and 26 patients had no past smoking history. None of the patients had any visual complaints or known eye disease. Of the patients studied, 76.5% (39 patients: 18 smokers, 21 non-smokers) had positive antiretinal antibodies, and 19.6% (10 patients: 3 smokers, 7 non-smokers) had positive antioptic nerve antibodies. Anti-retinal antibodies were seen in a majority of randomly selected patients with and without a past smoking history. Anti-optic nerve bodies were less common, but more prevalent in those who never smoked. The specificity of these antibodies remains greatly uncertain and clinical correlation is warranted.

Perimetry, retinal nerve fiber layer thickness and papilledema grade after cerebrospinal fluid shunting in patients with idiopathic intracranial hypertension.

BACKGROUND: To investigate the effect of cerebrospinal fluid (CSF) shunting on quantitative perimetry and papilledema in patients with uncontrolled idiopathic intracranial hypertension (IIH). METHODS: We retrospectively reviewed all cases of IIH with CSF shunting at our institution between 2004 and 2011. Perimetry was performed before and after surgery in 15 patients, and the mean deviation (MD) was compared before and after surgery to assess the effect of the intervention. RESULTS: Fourteen of the IIH patients were female and 1 was male. The average age was 34 years. CSF shunting resulted in significant improvement in the perimetric results with an increase in the MD of 5.63 ± 1.19 dB (P < 0.0001). Additionally, average retinal nerve fiber layer (RNFL) thickness measurement by optical coherence tomography decreased by 87.27 ± 16.65 µm (P < 0.0001), and Frisen papilledema grade decreased by 2.19 ± 0.71 (P < 0.0001). CONCLUSIONS: Our results suggest that CSF shunting results in improvement in perimetry, RNFL swelling, and papilledema grade in patients with IIH.

Baseline visual field findings in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT).

PURPOSE: To characterize visual field (VF) loss at the baseline visit and to evaluate VF quality control (QC) procedures in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: The Visual Field Reading Center (VFRC) evaluated 660 baseline VFs (1320 hemifields) from 165 enrolled patients. Three readers independently classified each superior and inferior hemifield and identified any abnormalities. A subset (20%) of the hemifields was reread to evaluate within- and between-reader agreements. The QC system addressed test parameters, patient data, and shipment errors. RESULTS: The majority (60%) of the baseline hemifields consisted of localized nerve fiber bundle-type VF loss. Approximately one-third (31.5%) of all the classifications consisted of partial arcuate defects combined with an enlarged blind spot, making this the most common type of hemifield classification. Inferior hemifield loss was greater than superior loss for both study and nonstudy eyes. Reader agreements were >90% for both inferior and superior hemifields for two out of three readers. Test-retest reliability agreement for individual readers was 95% for both hemifields. There were few QC errors with only 5.48 error points per 100-point VF. CONCLUSIONS: The most common type of IIHTT baseline hemifield abnormality was a localized nerve fiber bundle-like defect. Localized inferior hemifield loss was more common than superior hemifield loss. Quality control and within- and between-reader agreement were excellent for the IIHTT (ClinicalTrials.gov number, NCT01003639).

The idiopathic intracranial hypertension treatment trial: clinical profile at baseline.

IMPORTANCE: To our knowledge, there are no large prospective cohorts of untreated patients with idiopathic intracranial hypertension (IIH) to characterize the disease. OBJECTIVE: To report the baseline clinical and laboratory features of patients enrolled in the Idiopathic Intracranial Hypertension Treatment Trial. DESIGN, SETTING, AND PARTICIPANTS: We collected data at baseline from questionnaires, examinations, automated perimetry, and fundus photography grading. Patients (n = 165) were enrolled from March 17, 2010, to November 27, 2012, at 38 academic and private practice sites in North America. All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation between -2 dB and -7 dB. All but 4 participants were women. MAIN OUTCOMES AND MEASURES: Baseline and laboratory characteristics. RESULTS: The mean (SD) age of our patients was 29.0 (7.4) years and 4 (2.4%) were men. The average (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 39.9 (8.3). Headache was the most common symptom (84%). Transient visual obscurations occurred in 68% of patients, back pain in 53%, and pulse synchronous tinnitus in 52%. Only 32% reported visual loss. The average (SD) perimetric mean deviation in the worst eye was -3.5 (1.1) dB, (range, -2.0 to -6.4 dB) and in the best eye was -2.3 (1.1) dB (range, -5.2 to 0.8 dB). A partial arcuate visual field defect with an enlarged blind spot was the most common perimetric finding. Visual acuity was 85 letters or better (20/20) in 71% of the worst eyes and 77% of the best eyes. Quality of life measures, including the National Eye Institute Visual Function Questionnaire-25 and the Short Form-36 physical and mental health summary scales, were lower compared with population norms. CONCLUSIONS AND RELEVANCE: The Idiopathic Intracranial Hypertension Treatment Trial represents the largest prospectively analyzed cohort of untreated patients with IIH. Our data show that IIH is almost exclusively a disease of obese young women. Patients with IIH with mild visual loss have typical symptoms, may have mild acuity loss, and have visual field defects, with predominantly arcuate loss and enlarged blind spots that require formal perimetry for detection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01003639.

The idiopathic intracranial hypertension treatment trial: design considerations and methods.

BACKGROUND: The objectives of this study were to present the rationale for the main aspects of the study design and describe the trial methodology for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: Eligible candidates with mild visual field loss (automated perimetric mean deviation [PMD] -2 to -7 dB) were randomized to receive either acetazolamide or matching placebo tablets. Randomized participants were offered participation in a supervised dietary program. The primary outcome variable, PMD, was measured at 6 months. Additionally, cerebrospinal fluid from subjects and serum from study participants and matched controls were collected for genetic analysis and vitamin A studies. An ancillary optical coherence substudy was added to investigate the changes of papilledema in the optic nerve head and retina that correlate with Frisén grading, visual field deficits, and low-contrast visual acuity. RESULTS: The randomized trial entered 165 participants from March 17, 2010, through November 27, 2012, from the United States and Canada. The primary outcome (month 6) visits were successfully completed by June 15, 2013. Blood specimens were obtained from 165 controls without IIH to investigate vitamin A metabolism and genetic markers of potential risk factors for IIH. CONCLUSIONS: The IIHTT is the first randomized, double-masked placebo-controlled trial to study the effectiveness of medical treatment for patients with IIH.