Case Report: Long-term Structural and Functional Effects of Ethambutol Optic Neuropathy.

SIGNIFICANCE: This case report demonstrates reduction in the retinal nerve fiber layer (RNFL) thickness and an abnormal electroretinogram after toxic optic neuropathy from ethambutol, more than 1 year after improvements in visual acuity (VA) and visual fields (VFs) were seen. Although many studies have described complications of ethambutol, continuing reduction in RNFL thickness 2 years after discontinuation has not been described elsewhere. PURPOSE: It is well known that ethambutol can cause optic nerve toxicity, visual impairment, and VF loss. Visual acuity can be regained after stopping the drug; however, the amount and time frame are variable. There are few data on long-term follow-up of these cases to direct clinicians how to proceed once VA has stabilized. Here we present a case with 2 years of follow-up for a patient with ethambutol toxicity, showing the condition change even after VA becomes normal. CASE REPORT: A 61-year-old man presented shortly after discontinuing ethambutol for Mycobacterium avium complex. Visual acuity values were 20/70 in the right eye and 20/125 in the left eye with cecocentral VF scotomas. Optical coherence tomography showed normal RNFL. Visual-evoked potentials were significantly reduced and delayed. Over the course of 2 years, the patient became asymptomatic as VA and VF returned to normal and visual-evoked potential improved. However, the optical coherence tomography RNFL was reduced from each visit to the next, and the electroretinogram showed decreased scotopic and photopic amplitudes. CONCLUSIONS: Signs of ethambutol toxicity may remain or worsen years after discontinuation, even in the absence of patient symptoms and with normal VA and VF.

SEQUENTIAL CHANGES IN HYDROXYCHLOROQUINE RETINOPATHY UP TO 20 YEARS AFTER STOPPING THE DRUG: Implications for Mild Versus Severe Toxicity.

PURPOSE: To characterize the stability or progression of different stages of hydroxychloroquine (HCQ) retinopathy up to 20 years after stopping the drug. METHODS: We reviewed findings from 13 patients with initial HCQ retinopathy classified as early (patchy photoreceptor damage), moderate (ring of photoreceptor thinning or scotoma), or severe (retinal pigment epithelial [RPE] damage). Patients had been off HCQ for as many as 14 years at initial examination and were subsequently followed for 5 years to 8 years with repeated fundus autofluorescence and spectral domain optical coherence tomography. RESULTS: Early and moderate cases stabilized in fundus autofluorescence appearance, foveal thickness, ellipsoid zone line length, and visual acuity for up to 9 years after stopping HCQ. By contrast, severe cases demonstrated a continual loss of these parameters for up to 20 years off the drug. The presence of RPE damage at initial examination predicted progressive retinopathy over many years. CONCLUSION: The steady progression of severe HCQ retinopathy in eyes showing RPE damage after drug cessation suggests a metabolic insult that chronically destabilizes rather than destroys cellular function, with a clinical course resembling that of genetic dystrophies. Our findings stress the importance of early detection to minimize progression and visual loss.

Perifoveal interdigitation zone loss in hydroxychloroquine toxicity leads to subclinical bull's eye lesion appearance on near-infrared reflectance imaging.

PURPOSE: To characterize the ultrastructural and functional correlates of hydroxychloroquine (HCQ)-induced subclinical bull's eye lesion seen on near-infrared reflectance (NIR) imaging. METHODS: An asymptomatic 54-year-old male taking HCQ presented with paracentral ring-like scotoma, abnormal multifocal electroretinography (mfERG) and preserved ellipsoid zone on optical coherence tomography (OCT). Dense raster OCT was performed to create en face reflectivity maps of the interdigitation zone. Macular Integrity Assessment (MAIA) microperimetry and mfERG findings were compared with NIR imaging, en face OCT, retinal thickness profiles and wave-guiding cone density maps derived from flood-illumination adaptive optics (AO) retinal photography. RESULTS: The bull's eye lesion is an oval annular zone of increased reflectivity on NIR with an outer diameter of 1450 µm. This region corresponds exactly to an area of preserved interdigitation zone reflectivity in en face OCT images and of normal cone density on AO imaging. Immediately surrounding the bull's eye lesion is an annular zone (3°-12° eccentricity) of depressed retinal sensitivity on MAIA and reduced amplitude density on mfERG. Wave-guiding cone density at 2° temporal was 25,400 per mm2. This declined rapidly to 12,900 and 1200 per mm2 at 3° and 4°. CONCLUSION: Multimodal imaging illustrated pathology in the area surrounding the NIR bull's eye, characterized by reduced reflectance, wave-guiding cone density and retinal function. Further studies are required to investigate whether the bull's eye on NIR imaging and en face OCT is prominent or consistent enough for diagnostic use.

Case Report: Hydroxychloroquine Retinopathy.

SIGNIFICANCE: Hydroxychloroquine retinopathy causes irreversible central visual loss and can progress despite medication discontinuation. Appropriate dosing and recognition of early disease are important to minimize adverse visual sequelae. In 2016, the American Academy of Ophthalmology updated its 2011 recommendations for dosing, screening, and monitoring of hydroxychloroquine retinopathy. PURPOSE: The aim of this study was to report a case of hydroxychloroquine retinopathy in a patient who developed toxicity on a dose meeting safety thresholds from the 2011 guidelines (i.e., 6.5 mg/kg ideal body weight and cumulative dose <1000 g), but exceeding that from the 2016 revised recommendations (i.e., 5.0 mg/kg real body weight). CASE REPORT: A 61-year-old woman with rheumatoid arthritis treated with 400 mg/kg hydroxychloroquine daily for 6 years (daily dose, 5.72 mg/real body weight or 6.5 mg/kg ideal body weight; cumulative dose, 876 g) experienced progressive central vision loss and a scotoma affecting her reading ability and was referred to the Retina service. Prior yearly examination with only Ishihara color vision and Amsler grid testing was normal. On examination, visual acuity was 20/40 in the right eye and 20/30 in the left eye. A fundus examination showed bilateral bull's-eye maculopathy, a classic finding of hydroxychloroquine retinal toxicity. Fundus autofluorescence showed a parafoveal ring of speckled hypoautofluorescence and an external ring of increased signal. There were characteristic structural changes on spectral domain-optical coherence tomography, including parafoveal loss of the ellipsoid zone and outer nuclear layer. Humphrey visual field testing of the central 10-2 revealed incomplete paracentral annular scotoma. Subsequently, hydroxychloroquine was switched to sulfasalazine. CONCLUSIONS: The 2016 American Academy of Ophthalmology guidelines for hydroxychloroquine retinopathy were revised to reflect new dosing and care guidelines for early detection of retinal toxicity and to minimize the extent of irreversible vision loss.

Central scotoma in tobacco-alcohol toxic optic neuropathy measured with semi-automated kinetic perimetry.

PURPOSE: To measure the area of central scotoma obtained with semi-automated kinetic perimetry (SKP) in patients suffering from tobacco-alcohol toxic neuropathy (TATN). METHODS: Twelve eyes of six patients with TATN were examined with SKP. Area of central scotoma was measured in square degrees (deg2). Additionally, static automated perimetry (SAP) within 60° was performed in each patient. RESULTS: Area of central scotoma was 41.8 deg2 for III4e isopter, 22.9 deg2 for I4e isopter and 16.1 deg2 for I2e isopter in TATN patients. SAP revealed central scotoma in all patients. There was 100% of accordance between two methods. CONCLUSION: SKP is comparable with SAP in assessing central scotoma. SKP offers advantage of measuring central scotoma and assessing remaining peripheral visual field in TATN, even with low incidence and prevalence of this clinical entity.

Spectral domain optical coherence tomography findings in long-term silicone oil-related visual loss.

PURPOSE: To investigate spectral domain optical coherence tomography findings in long-term silicone oil-related visual loss. METHODS: Four symptomatic patients were reviewed 4 years to 9 years after vitrectomy with silicone oil tamponade for macula-on retinal detachment. Three lost vision with oil in situ, with one at the time of oil removal. Eleven control eyes with good vision were included. Patients underwent assessment of best-corrected visual acuity, contrast sensitivity, Farnsworth-Munsell 100 Hue testing, static perimetry, and spectral domain optical coherence tomography imaging of the macula and disk. RESULTS: Long-term best-corrected visual acuity was significantly reduced in affected eyes (range, 0.44-1.02), as was contrast sensitivity (0.75-1.35) and color discrimination (Farnsworth-Munsell-100 Hue score, 151-390). Static perimetry showed a central scotoma in all affected eyes. Optical coherence tomography revealed microcystic macular changes in the inner nuclear layer of all affected eyes associated with severe loss of the papillofoveal retinal nerve fiber layer. In one patient, serial optical coherence tomography images showed development of microcystic macular changes 18 months after oil removal. Control eyes lacked these features, except two asymptomatic eyes that showed microcystic changes on optical coherence tomography with a corresponding paracentral scotoma. CONCLUSION: We have demonstrated microcystic macular changes in the inner nuclear layer of affected eyes, as well as focal severe loss of the papillofoveal projection. These changes share significant morphologic features reported in multiple sclerosis-associated optic neuritis and Leber hereditary optic neuropathy.

Disparity between visual fields and optical coherence tomography in hydroxychloroquine retinopathy.

PURPOSE: American Academy of Ophthalmology recommendations for screening for hydroxychloroquine (HCQ) retinopathy advise objective measures, such as spectral-domain optical coherence tomography (SD-OCT) and multifocal electroretinography (mfERG) along with visual fields. However, the relative sensitivity and specificity of screening tests have not been fully resolved. We characterize a subset of patients with toxicity who show unusual disparity between fields and SD-OCT and thus have implications for screening practice. DESIGN: Review of charts and clinical data. PARTICIPANTS: Patients at Stanford and Kaiser Permanente who had used HCQ with greater than 1000 g cumulative exposure. There were more than 2000 such individuals, among whom 150 had clear evidence of toxicity. METHODS: Patients were evaluated by visual fields (10-2 white Swedish Interactive Threshold Algorithm pattern deviation plots), SD-OCT, and sometimes mfERG or fundus autofluorescence. MAIN OUTCOME MEASURES: Relative findings on visual fields in comparison with SD-OCT. RESULTS: There were 11 patients among those with HCQ toxicity who had parafoveal ring scotomas but a normal-appearing SD-OCT. None had a history of macular disease or evidence for any other cause of bull's eye maculopathy. Conversely, all cases with a clear degree of parafoveal damage on SD-OCT showed at least some focal spots of parafoveal field loss. CONCLUSIONS: Approximately 10% of patients with early HCQ toxicity showed prominent ring scotomas on field testing without obvious SD-OCT abnormality. This should encourage the inclusion of visual fields as a key screening tool, even when SD-OCT (a more specific and objective test) also is performed. The combination of visual fields and SD-OCT gives both sensitivity and specificity while avoiding unnecessary stoppage of the drug.

[Visual loss under silicone oil]. / Visusminderung unter Silikon.

Silicone oil is used as intravitreal tamponading agent in surgery for rhegmatogenous retinal detachment (RRD) cases complicated with proliferative vitreoretinopathy (PVR). Recently, a number of case series have appeared where profound central visual loss has been found in eyes after uncomplicated vitrectomy with silicone tamponade for RRD in eyes with seemingly good visual potential. Several reports have demonstrated the migration of silicone oil droplets into the retina and the optic nerve, others the widespread loss of myelinated optic nerve fibres. These reports are reviewed, and it is concluded that caution is warranted when silicone oil is used in eyes with good visual potential. Finally the additional danger of central visual loss should be taken into consideration when deciding to use silicone oil or gas as intravitreal tamponade.

Macular sensitivity changes for detection of chloroquine toxicity in asymptomatic patient.

PURPOSE: To describe the efficacy of microperimetry (MP-1) in detecting early retinal toxicity as a result of chronic use of chloroquine and in monitoring the changes in macular sensitivity in an asymptomatic patient with best-corrected visual acuity of 20/20 bilaterally. METHODS: A 60-year-old woman presented for routine ocular examination with a medical history of severe rheumatoid arthritis, for which she had been receiving 3 mg chloroquine (CQ) per kilogram for the past 17 years. The patient was asymptomatic with best-corrected visual acuity of 20/20 bilaterally. RESULTS: Microperimeter showed loss of sensitivity in the macular region with a dense scotoma within the central 12 degrees (2.80 +/- 4.7 dB right eye and 2.84 +/- 4.7 dB left eye). CQ treatment was discontinued and substituted by Plaquenil. CONCLUSIONS: Chloroquine retinal toxicity can be recognized in a subclincal form by the presence of early changes in macular sensitivity, detected by MP-1.

Risk factors for ethambutol optic toxicity.

CONTEXT: Optic neuropathy is a well-known complication of ethambutol therapy and usually manifests as a decrease in visual acuity, cecocentral scotomas, and deficits in color vision. OBJECTIVE: To support or disprove the hypothesis that a significant majority of patients who develop ocular toxicity while undergoing treatment for a mycobacterium infection do so after experiencing either a prolonged course or unusually high serum levels of ethambutol. DESIGN: Retrospective chart review (16 cases) and literature meta-analysis (54 cases). RESULTS: Many cases lacked important data, but none countered the hypothesis. Age, duration of ethambutol, and dose of ethambutol were positively correlated with risk of toxicity. CONCLUSIONS: Given an understanding of the risk factors for ethambutol optic toxicity, there exists a rationale for an optimization of ethambutol dosing protocols that can maximize the therapeutic effect while minimizing the incidence of optic toxicity.

Changes in retinal sensitivity from retained subretinal perfluorocarbon liquid.

PURPOSE: To study the effect of retained subretinal perfluorocarbon liquid (PFCL) on retinal function. METHODS: Scanning laser ophthalmoscope microperimetry was performed on four eyes with retained subretinal PFCL after vitreoretinal surgery for complicated retinal detachments with and without proliferative vitreoretinopathy. RESULTS: Scotomas to the highest intensity stimulus were noted in the area of the subretinal PFCL in all four eyes. All scotomas encompassed approximately the same area as the retained PFCL droplets. In the area vacated by a migrating PFCL droplet in one eye, the highest intensity stimulus could be perceived, but a relative scotoma (to a lower intensity stimulus) was present. CONCLUSIONS: There is a local reduction in retinal function in the area of retained subretinal PFCL. There may be partial recovery of retinal function in an area vacated by the subretinal PFCL. Subretinal PFCL beneath the fovea or at risk for migration beneath the fovea should be considered for removal.

[Optic atrophy subsequent to epiretinal triamcinolone deposits in an eye following inner limiting membrane peeling]. / Optikusatrophie nach epiretinalen Triamcinolon-Ablagerungen in einem Auge mit entfernter Membrana limitans interna.

BACKGROUND: Although current in vitro studies show local cytotoxicity of triamcinolone (TA) crystals if they are in direct contact with cells, a toxic effect of epiretinal TA deposits has not been reported yet clinically. For the first time, we present a case of potential cytotoxicity of epiretinal TA deposits in vivo. CASE REPORT: A 68-year old patient underwent a re-vitrectomy with peeling of a macular pucker and the internal limiting membrane (ILM) combined with an intravitreal injection of 25 mg TA due to a secondary macular pucker with cystoid macular edema. Postoperatively, pronounced epiretinal deposits of TA crystals were identified in the area of the posterior pole. Two months after the injection a consecutive optic atrophy with central visual field defect and severe reduction of the visual acuity to hand movements was apparent. CONCLUSION: Our case report indicates possible in-vivo toxicity of TA deposits in eyes subsequent to vitrectomy and peeling of the ILM. This is in accordance with previous in-vitro studies showing ILM and vitreous to be protective biological factors, but demonstrate pronounced cytotoxicity if TA crystals are allowed to directly adhering to denuded ganglion cells. Hence, we consider that TA injection should be carefully weighed in those patients with prior ILM removal.

Optical coherence tomography in a patient with chloroquine-induced maculopathy.

We herein report the optical coherence tomography (OCT) findings in a case of chloroquine-induced macular toxicity, which to our knowledge, has so far not been reported. A 53-year-old lady on chloroquine for treatment of rheumatoid arthritis developed decrease in vision 36 months after initiation of the treatment. Clinical examination revealed evidence of retinal pigment epithelial (RPE) disturbances. Humphrey field analyzer (HFA), fundus fluorescein angiography (FFA) and OCT for retinal thickness and volume measurements at the parafoveal region were done. The HFA revealed bilateral superior paracentral scotomas, FFA demonstrated RPE loss and OCT revealed anatomical evidence of loss of ganglion cell layers, causing marked thinning of the macula and parafoveal region. Parafoveal retinal thickness and volume measurements may be early evidence of chloroquine toxicity, and OCT measurements as a part of chloroquine toxicity screening may be useful in early detection of chloroquine maculopathy.

Retinal toxicity secondary to Plaquenil therapy.

BACKGROUND: Hydroxychloroquine sulfate (Plaquenil; Sanofi-Aventis, Bridgewater, New Jersey) is an antimalarial agent, which is sometimes used for the treatment of certain autoimmune disorders. Its use has been associated with ocular side effects; the most concerning is toxic maculopathy. CASE REPORT: A 71-year-old arthritic white woman requested a second opinion regarding retinal Plaquenil toxicity. The patients history was significant for seronegative rheumatoid arthritis diagnosed 6 years prior. She had taken Plaquenil 400 mg a day for about 5 years but had discontinued the drug 6 months before when bilateral central scotomas were first noted. At the consultation visit, her visual acuities were 20/20 in both eyes. SITA-Standard 10-2 disclosed a dense scotoma with 4 degrees of central sparing in each eye. Fundus examination found retinal pigment epithelium changes bilaterally; no "bulls eye" retinopathy was observed. CONCLUSION: Withdrawal of the medication is the only effective treatment for Plaquenil toxicity and, even then, the toxic effects may progress because of the slow clearance of the drug. Though controversy exists regarding screening recommendations, a baseline ophthalmic examination should be performed on all patients before initiating Plaquenil. If a patient is considered low risk, examinations can be scheduled annually. For high-risk patients, 6-month progress visits are strongly recommended.