Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

BACKGROUND: In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. METHODS: A survey was distributed through the secure electronic data collection tool REDCap to neuro-ophthalmology specialists in the North American Neuro-Ophthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained. RESULTS: The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions. CONCLUSION: This study describes the variable neuro-ophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients.

A Case of Bilateral Endogenous Candida dubliniensis Endophthalmitis Treated with Aggressive Local and Systemic Therapy.

Candida dubliniensis is an emerging pathogen implicated in a variety of infections in immunocompromised hosts. A 79-year-old male with autoimmune pancytopenia on chronic oral steroid therapy was admitted for suspected sepsis and started on empirical antibiotics and micafungin. He developed floaters and decreased vision while on this regimen and was diagnosed with bilateral candida endophthalmitis. Blood cultures grew C. dubliniensis.Intravenous therapy was switched to voriconazole and amphotericin B. He also received aggressive intravitreal antifungal therapy consisting of 100 µg/0.1 mL voriconazole (4 OD, 3 OS) and 5 µg/0.1 mL amphotericin B (3 OD, 1 OS) over 2 weeks that resulted in local control of infection. The right eye developed a retinal detachment 1 month after initial presentation that was repaired by 25-gauge pars plana vitrectomy, scleral buckle, laser and silicone oil. At the 15-month follow-up exam, subsequent to silicone oil removal, membrane peel and cataract surgery, OD visual acuity had improved to 20/80. OS was phakic and 20/25. Aggressive intravitreal antifungal therapy combined with intravenous therapy may control endophthalmitis and avoid the risks associated with pars plana vitrectomy during acute infection.

Analysis of the Essential Oils of Five Artemisia Species and Evaluation of their Cytotoxic and Proapoptotic Effects.

BACKGROUND: In this study, the essential oil composition and cytotoxic activities of five Artemisia species were determined. METHODS: The collected plants were water-distilled separately to obtain oils which were then subjected to gas chromatography (GC) and gas chromatography/mass spectrometry GC/MS analyses to identify their compositions. Cancer cells were exposed to different concentrations of samples and cell viability was measured using AlamarBlue® assay. Apoptotic cells were analyzed by propidium iodide (PI) staining and flow cytometry. RESULTS & CONCLUSION: To study the amount of pro-apoptotic proteins and the apoptosis mechanism, Western blot method was used. Although all samples were cytotoxic at the highest concentration, the oil of A. kulbadica showed the strongest activity among other plants. Carvacrol (IC50 21.11 µg/ml) had the most cytotoxic effects among other components. Carvacrol, 1,8-cineole and 4-terpineole caused an increase in the amount of Bax protein and cleaved peroxisome proliferator-activated receptors (PPAR) and caspase proteins in DU 145 cells.

An Incidental Finding of Ecchordosis Physaliphora in a Case of Abducens Nerve Palsy: Case Report.

Ecchordosis physaliphora (EP) is a rare non-malignant mass that originates from remains of the notochord and is typically asymptomatic. A 42-year-old man presented with sudden onset of painless horizontal diplopia and his neurological exam showed sixth cranial nerve palsy. Magnetic resonance imaging (MRI) identified a non-enhanced retroclival mass (EP) with increased signal intensity on T2 and decreased signal intensity on T1-weighted sequences. He was treated with methylprednisolone, completely recovered in four weeks and has remained symptom free. Conservative management should be attempted before surgery in all cases since symptoms can resolve spontaneously and EP could be an incidental finding.

Ipilimumab-induced Adenohypophysitis and Orbital Apex Syndrome: Importance of Early Diagnosis and Management.

Ipilimumab is a novel anti-melanoma agent known to infrequently cause multi-organ autoimmunity. We report a case of pituitary hypophysitis and orbital inflammation followed by an orbital apex syndrome. A 64-year-old woman with a history of skin melanoma, receiving ipilimumab treatment, was seen for near total loss of vision in the right eye and proptosis. Headache of 3-month duration preceded the onset of diplopia followed by severe loss of vision in the right eye. Neuro-ophthalmologic examination was consistent with an orbital apex syndrome. Extensive blood work and magnetic resonance imaging of the brain and orbit suggested an inflammatory process, rather than a metastatic lesion. Accordingly, the patient received high-dose methylprednisolone followed by tapering oral prednisone. At the 6-month follow-up visit, visual acuity on the right eye had significantly improved but diplopia remained, associated with large amplitude esotropia that improved incompletely though while on prednisone. The favourable outcome supported a final diagnosis of ipilimumab-induced inflammatory orbital apex syndrome and clinically silent pituitary adenohypophysitis. The case presented herein highlights unexpected ipilimumab-associated adverse effects and proposes the possibility of and interaction between inflammatory and immune mechanisms.