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.

Urothelial cell carcinoma presenting with rapid visual deterioration, a case of rare brain metastases with unique clinical presentation.

BACKGROUND: Urothelial cell carcinoma (UCC), the most common cancer of the urinary system, rarely metastasizes to the brain. 1-3 More rare still is the subset of patients with urothelial carcinoma brain metastases whose UCC primary is first diagnosed at the same time as their CNS metastatic disease, with oncologic workup prompted by CNS clinical manifestations.4 Paraneoplastic optic neuropathy (PON) is likewise a rare clinical entity, which has not yet been described in association with UCC brain metastases. CASE DESCRIPTION: Herein, we present the sentinel case of UCC believed to be of endometrial origin in an 81 year old woman initially presenting with symptoms of fatigue, nausea, vertigo, and rapidly deteriorating vision over the course of 1 month. Visual deterioration prompted neuro imaging remarkable for multiple supratentorial and infratentorial metastases as well as likely neoplastic inflammatory involvement of the bilateral optic nerves. The patient underwent a right temporal open brain biopsy, with pathology findings consistent with UCC. Subsequent PET scanning demonstrated a heavy burden of disease including an FDG-avid uterine mass with local and distal extension of disease including bilateral hydroureteronephrosis with obstruction of the distal ureters. The patient and her family elected to pursue home hospice without further workup or intervention. CONCLUSIONS: While this is the first such case presented, it is possible that UCC of the uterine wall represents a particularly aggressive form of the disease more prone to presenting with CNS metastases and PON.

Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status.

PURPOSE: Inherited optic neuropathy is genetically heterogeneous, and genetic testing has an important role in risk assessment and counseling. The purpose of this study is to determine the prevalence and spectrum of mutations in a group of patients referred for genetic testing to a tertiary center in the United States. In addition, we compared the clinical features of patients with and without mutations in OPA1, the gene most commonly involved in dominantly inherited optic atrophy. METHODS: Clinical data and genetic testing results were reviewed for 74 unrelated, consecutive patients referred with a history of insidious, relatively symmetric, bilateral visual loss secondary to an optic neuropathy. Patients were evaluated for disease-causing variants in OPA1, OPA3, WFS1, and the entire mitochondrial genome with DNA sequencing and copy number variation (CNV) testing. RESULTS: Pathogenic DNA variants were found in 25 cases, with the majority (24 patients) located in OPA1. Demographics, clinical history, and clinical features for the group of patients with mutations in OPA1 were compared to those without disease-causing variants. Compared to the patients without mutations, cases with mutations in OPA1 were more likely to have a family history of optic nerve disease (p = 0.027); however, 30.4% of patients without a family history of disease also had mutations in OPA1. OPA1 mutation carriers had less severe mean deviation and pattern standard deviation on automated visual field testing than patients with optic atrophy without mutations in OPA1 (p<0.005). Other demographic and ocular features were not statistically significantly different between the two groups, including the fraction of patients with central scotomas (42.9% of OPA1 mutation positive and 66.0% of OPA1 mutation negative). CONCLUSIONS: Genetic testing identified disease-causing mutations in 34% of referred cases, with the majority of these in OPA1. Patients with mutations in OPA1 were more likely to have a family history of disease; however, 30.4% of patients without a family history were also found to have an OPA1 mutation. This observation, as well as similar frequencies of central scotomas in the groups with and without mutations in OPA1, underscores the need for genetic testing to establish an OPA1 genetic diagnosis.

Metachronous Involvement, Diagnostic Imprecision of Serum Immunoglobulin G4 Levels, and Discordance Between Clinical and Radiological Findings in Immunoglobulin G4-Related Pachymeningitis: A Longitudinal Case Report.

Immunoglobulin G4-related disease is an increasingly recognized, idiopathic systemic disorder that might be associated with elevated serum IgG4 level and tissue infiltration by IgG4-positive plasma cells. We describe the clinical features and biopsy findings in a patient who presented with features suggestive of pachymeningitis and multiple cranial neuropathies. Meningeal biopsy and other laboratory studies established the diagnosis of IgG4-related hypertrophic pachymeningitis. Despite treatment with corticosteroids and mycophenolate mofetil, the patient exhibited a fluctuating progressive course, which stabilized with rituximab, although the radiological findings persisted over 2½ years of follow-up. Our case highlights many important evolving concepts in the disorder, including unusual pathologic features, lack of correlation between serum IgG4 levels and the clinical course, and posttreatment clinicoradiological discordance. We provide potential explanations for this discrepancy, highlight the validity of novel cerebrospinal fluid studies and progressive systemic involvement despite use of immune-suppressive treatments, and emphasize the usefulness of rituximab as a disease-stabilizing agent.

The Versatile Teaching Eye: an affordable, 3D-printed model eye for simulating ophthalmic examination.

Purpose: To describe the Versatile Teaching Eye (VT Eye), a 3D-printed model eye designed to provide an affordable examination simulator, and to report the results of a pilot program introducing the VT Eye and an ophthalmic training curriculum at a teaching hospital in Ghana. Methods: TinkerCAD was used to design the VT Eye, which was printed with ABS plastic. The design features an adapter that permits use of a smartphone as a digital fundus. We developed a set of digital flashcards allowing for an interactive review of a range of retinal pathologies. An analog fundus was developed for practicing traditional slit lamp and indirect examinations as well as retinal laser practice. The model was used for a period of 2 weeks by ophthalmic trainees at Komfo Anokye Teaching Hospital, Kumasi, Ghana, to practice indirect ophthalmoscopy, slit lamp biomicroscopy, smartphone funduscopy, and retinal image drawing. Results were assessed at by means of a pre-/post-training survey of 6 residents. Results: The VT Eye accommodates diverse fundus examination techniques. Its 3D-printed design ensures cost-effective, high-quality replication. When paired with a 20 D practice examination lens, the digital fundus provides a comprehensive, interactive training environment for <$30.00 (USD). This device allows for indirect examination practice without requiring an indirect headset, which may increase the amount of available practice for trainees early in their careers. In the Ghana pilot program, the model's use in indirect examination training sessions significantly boosted residents' confidence in various examination techniques. Comparing pre- and post-session ratings, average reported confidence levels rose by 30% for acquiring clear views of the posterior pole, 42% for visualizing the periphery, and 141% for capturing important pathology using personal smartphones combined with a 20 D lens (all P < 0.05). Conclusions: The VT Eye is readily reproducible and can be easily integrated into ophthalmic training curricula, even in regions with limited resources. It offers an effective and affordable training solution, underscoring its potential for global adoption and the benefits of incorporating innovative technologies in medical education.

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study.

OBJECTIVE: To characterize patients misdiagnosed with multiple sclerosis (MS). METHODS: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. RESULTS: Of 110 misdiagnosed patients, 51 (46%) were classified as "definite" and 59 (54%) "probable" misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. CONCLUSIONS: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Ocular flutter as the presenting sign of lung adenocarcinoma.

Ocular flutter is a rare ophthalmic finding that could represent paraneoplastic phenomena. In adults it is most commonly associated with small cell lung cancer (SCLC). Most patients also present with other neurological defects. We report the case of a 75-year-old woman who presented with isolated ocular flutter. The ensuing workup was significant for an early lung adenocarcinoma that would not have been biopsied otherwise due to its small size. To our knowledge, this is the first reported case of isolated ocular flutter as the presenting symptom of non-SCLC.

An anatomical classification of the variations of the inferior phrenic vein.

The majority of anatomical textbooks of gross anatomy offer very little information concerning the anatomy and distribution of the inferior phrenic vein (IPV). However, in the last decade, an increasing number of reports have arisen, with reference to the endoscopic embolization of esophageal and paraesophageal varices, as well as venous drainage of hepatocellular carcinomas (HCC). The IPV is one of the major sources of collateral venous drainage in portal hypertension and HCC. The aim of this study was to identify the origin and distribution of the IPVs (right and left), both in normal and (selective) pathological cases. We have examined 300 formalin-fixed adult cadavers, without any visible gastrointestinal disease, and 30 cadavers derived from patients with HCC. The right IPV drained into the following: the inferior vena cava (IVC) inferior to the diaphragm in 90%, the right hepatic vein in 8%, and the IVC superior to the diaphragm in 2%. The left IPV drained into the following: the IVC inferior to the diaphragm in 37%, the left suprarenal vein in 25%, the left renal vein in 15%, the left hepatic vein in 14%, and both the IVC and the left adrenal vein in 1% of the specimens. The IPVs possessed four notable tributaries: anterior, esophageal, lateral and medial. The right IPV served as one of the major extrahepatic draining veins for all 30 cases of HCC. These findings could have potential clinical implications in the transcatheter embolization of esophageal and paraesophageal varices, as well as in mobilizing the supradiaphragmatic segment of IVC.