Appropriateness of Ophthalmology Recommendations From an Online Chat-Based Artificial Intelligence Model.

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions. Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty. Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts. Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use.

A Comparative Study of Large Language Models, Human Experts, and Expert-Edited Large Language Models to Neuro-Ophthalmology Questions.

BACKGROUND: While large language models (LLMs) are increasingly used in medicine, their effectiveness compared with human experts remains unclear. This study evaluates the quality and empathy of Expert + AI, human experts, and LLM responses in neuro-ophthalmology. METHODS: This randomized, masked, multicenter cross-sectional study was conducted from June to July 2023. We randomly assigned 21 neuro-ophthalmology questions to 13 experts. Each expert provided an answer and then edited a ChatGPT-4-generated response, timing both tasks. In addition, 5 LLMs (ChatGPT-3.5, ChatGPT-4, Claude 2, Bing, Bard) generated responses. Anonymized and randomized responses from Expert + AI, human experts, and LLMs were evaluated by the remaining 12 experts. The main outcome was the mean score for quality and empathy, rated on a 1-5 scale. RESULTS: Significant differences existed between response types for both quality and empathy (P < 0.0001, P < 0.0001). For quality, Expert + AI (4.16 ± 0.81) performed the best, followed by GPT-4 (4.04 ± 0.92), GPT-3.5 (3.99 ± 0.87), Claude (3.6 ± 1.09), Expert (3.56 ± 1.01), Bard (3.5 ± 1.15), and Bing (3.04 ± 1.12). For empathy, Expert + AI (3.63 ± 0.87) had the highest score, followed by GPT-4 (3.6 ± 0.88), Bard (3.54 ± 0.89), GPT-3.5 (3.5 ± 0.83), Bing (3.27 ± 1.03), Expert (3.26 ± 1.08), and Claude (3.11 ± 0.78). For quality (P < 0.0001) and empathy (P = 0.002), Expert + AI performed better than Expert. Time taken for expert-created and expert-edited LLM responses was similar (P = 0.75). CONCLUSIONS: Expert-edited LLM responses had the highest expert-determined ratings of quality and empathy warranting further exploration of their potential benefits in clinical settings.

Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

OBJECTIVE: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024.

Acute Optic Neuropathy in Older Adults: Differentiating Between MOGAD Optic Neuritis and Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease optic neuritis (MOGAD-ON) and nonarteritic anterior ischemic optic neuropathy (NAION) can cause acute optic neuropathy in older adults but have different managements. We aimed to determine differentiating factors between MOGAD-ON and NAION and the frequency of serum MOG-IgG false positivity among patients with NAION. METHODS: In this international, multicenter, case-control study at tertiary neuro-ophthalmology centers, patients with MOGAD presenting with unilateral optic neuritis as their first attack at age 45 years or older and age-matched and sex-matched patients with NAION were included. Comorbidities, clinical presentations, acute optic disc findings, optical coherence tomography (OCT) findings, and outcomes were compared between MOGAD-ON and NAION. Multivariate analysis was performed to find statistically significant predictors of MOGAD-ON. A separate review of consecutive NAION patients seen at Mayo Clinic, Rochester, from 2018 to 2022, was conducted to estimate the frequency of false-positive MOG-IgG in this population. RESULTS: Sixty-four patients with unilateral MOGAD-ON were compared with 64 patients with NAION. Among patients with MOGAD-ON, the median age at onset was 56 (interquartile range [IQR] 50-61) years, 70% were female, and 78% were White. Multivariate analysis showed that eye pain was strongly associated with MOGAD-ON (OR 32.905; 95% CI 2.299-473.181), while crowded optic disc (OR 0.033; 95% CI 0.002-0.492) and altitudinal visual field defect (OR 0.028; 95% CI 0.002-0.521) were strongly associated with NAION. On OCT, peripapillary retinal nerve fiber layer (pRNFL) thickness in unilateral MOGAD-ON was lower than in NAION (median 114 vs 201 µm, p < 0.001; median pRNFL thickening 25 vs 102 µm, p < 0.001). MOGAD-ON had more severe vision loss at nadir (median logMAR 1.0 vs 0.3, p < 0.001), but better recovery (median logMAR 0.1 vs 0.3, p = 0.002). In the cohort of consecutive NAION patients, 66/212 (31%) patients with NAION were tested for MOG-IgG and 8% (95% CI 1%-14%) of those had false-positive serum MOG-IgG at low titers. DISCUSSION: Acute unilateral optic neuropathy with optic disc edema in older adults can be caused by either MOGAD-ON or NAION. Detailed history, the degree of pRNFL swelling on OCT, and visual outcomes can help differentiate the entities and prevent indiscriminate serum MOG-IgG testing in all patients with acute optic neuropathy.

Paraneoplastic vision loss.

Paraneoplastic vision loss, which represents a small percentage of paraneoplastic neurologic syndromes, can be a blinding disease. Presenting visual symptoms are variable, making diagnosis challenging. History of the presenting illness, ocular examination, and utilization of various modalities, such as automated perimetry, ocular coherence tomography, and electroretinogram allow for localization of vision loss to the optic nerves or retina, guiding in diagnosis and management. Paraneoplastic vision loss is often painless, bilateral, and subacute, and accompanies other neurologic symptoms but can be the first presenting symptom. Paraneoplastic optic neuropathy has been described in association with several antibodies, but most commonly anti-CRMP5. Cancer-associated retinopathy is the most common paraneoplastic autoimmune retinopathy; however, melanoma-associated retinopathy and bilateral diffuse uveal melanocytic proliferation have also been described to be associated with a paraneoplastic process affecting the retina. Paraneoplastic visual loss is an expanding field and advances in research have improved phenotypic characterization; however, further work is needed to identify more reliable biomarkers of disease and to better understand the underlying mechanisms and management.

Fluorescein Angiography Findings in Susac Syndrome: A Multicenter Retrospective Case Series.

BACKGROUND: Susac syndrome is a vasculopathy, resulting in the classic triad of branch retinal artery occlusion (BRAO), inner ear ischemia, and brain ischemia. In this retrospective chart review, we characterize fluorescein angiography (FA) findings and other ancillary studies in Susac syndrome, including the appearance of persistent disease activity and the occurrence of new subclinical disease on FA. METHODS: This multicenter, retrospective case series was institutional review board-approved and included patients with the complete triad of Susac syndrome evaluated with FA, contrasted MRI of the brain, and audiometry from 2010 to 2020. The medical records were reviewed for these ancillary tests, along with demographics, symptoms, visual acuity, visual field defects, and findings on fundoscopy. Clinical relapse was defined as any objective evidence of disease activity during the follow-up period after initial induction of clinical quiescence. The main outcome measure was the sensitivity of ancillary testing, including FA, MRI, and audiometry, to detect relapse. RESULTS: Twenty of the 31 (64%) patients had the complete triad of brain, retinal, and vestibulocochlear involvement from Susac syndrome and were included. Median age at diagnosis was 43.5 years (range 21-63), and 14 (70%) were women. Hearing loss occurred in 20 (100%), encephalopathy in 13 (65%), vertigo in 15 (75%), and headaches in 19 (95%) throughout the course of follow-up. Median visual acuity at both onset and final visit was 20/20 in both eyes. Seventeen (85%) had BRAO at baseline, and 10 (50%) experienced subsequent BRAO during follow-up. FA revealed nonspecific leakage from previous arteriolar damage in 20 (100%), including in patients who were otherwise in remission. Of the 11 episodes of disease activity in which all testing modalities were performed, visual field testing/fundoscopy was abnormal in 4 (36.4%), MRI brain in 2 (18.2%), audiogram in 8 (72.7%), and FA in 9 (81.8%). CONCLUSIONS: New leakage on FA is the most sensitive marker of active disease. Persistent leakage represents previous damage, whereas new areas of leakage suggest ongoing disease activity that requires consideration of modifying immunosuppressive therapy.

Visual Outcomes Following Plasma Exchange for Optic Neuritis: An International Multicenter Retrospective Analysis of 395 Optic Neuritis Attacks.

PURPOSE: To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON). METHODS: We conducted an international multicenter retrospective study evaluating the outcomes of ON following PLEX. Outcomes were compared to raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset. RESULTS: A total of 395 ON attack treated with PLEX from 317 patients were evaluated. The median age was 37 years (range 9-75), and 71% were female. Causes of ON included multiple sclerosis (108), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (92), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (75), seronegative-NMOSD (34), idiopathic (83), and other (3). Median time from onset of vision loss to PLEX was 2.6 weeks (interquartile range [IQR], 1.4-4.0). Median visual acuity (VA) at the time of PLEX was count fingers (IQR, 20/200-hand motion), and median final VA was 20/25 (IQR, 20/20-20/60) with no differences among etiologies except MOGAD-ON, which had better outcomes. In 81 (20.5%) ON attacks, the final VA was 20/200 or worse. Patients with poor outcomes were older (P = .002), had worse VA at the time of PLEX (P < .001), and longer delay to PLEX (P < .001). In comparison with the ONTT subset with severe corticosteroid-unresponsive ON, a final VA of worse than 20/40 occurred in 6 of 50 (12%) PLEX-treated ON vs 7 of 19 (37%) from the ONTT treated with intravenous methylprednisolone without PLEX (P = .04). CONCLUSION: Most ON attacks improved with PLEX, and outcomes were better than attacks with similar severity in the ONTT. The presence of severe vision loss at nadir, older age, and longer delay to PLEX predicted a worse outcome whereas MOGAD-ON had a more favorable prognosis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Clinical Reasoning: An 80-Year-Old Woman With a Homonymous Hemianopsia.

An 80-year-old woman who was experiencing visual symptoms for 2 years was found to have a left homonymous hemianopsia (HH). On further evaluation the following month, she was noted to have simultanagnosia and alexia. MRI of the brain did not reveal a structural etiology for the symptoms. [18F]-fluorodeoxyglucose (FDG) PET-CT was performed to aid in the diagnostic investigation. This case of posterior cortical atrophy highlights the differential diagnosis of a HH in the absence of a structural lesion on MRI and the role of FDG PET-CT imaging in such patients.

Frequency of Asymptomatic Optic Nerve Enhancement in a Large Retrospective Cohort of Patients With Aquaporin-4+ NMOSD.

BACKGROUND AND OBJECTIVES: Asymptomatic or persistent optic nerve enhancement in aquaporin-4 (AQP4)-immunoglobulin G (IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) is thought to be rare. Improved understanding may have important implications for assessment of treatment efficacy in clinical trials and in clinical practice. Our objective was to characterize NMOSD interattack optic nerve enhancement. METHODS: This was a retrospective cohort study performed between 2000 and 2019 (median follow-up 5.5 [range 1-35] years) of patients with AQP4-IgG-positive optic neuritis (ON) evaluated at Mayo Clinic. MRI orbits were reviewed by a neuroradiologist, neuro-ophthalmologist, and neuroimmunologist blinded to the clinical history. Interattack optic nerve enhancement (>30 days after attack) was measured. The correlation between interattack enhancement and Snellen visual acuity (VA), converted to logarithm of the minimum angle of resolution (logMAR), at attack and at follow-up were assessed. RESULTS: A total of 198 MRI scans in 100 patients with AQP4-IgG+ NMOSD were identified, with 107 interattack MRIs from 78 unique patients reviewed. Seven scans were performed before any ON (median 61 days before attack [range 21-271 days]) and 100 after ON (median 400 days after attack [33-4,623 days]). Optic nerve enhancement was present on 18/107 (16.8%) interattack scans (median 192.5 days from attack [33-2,943]) of patients with preceding ON. On 15 scans, enhancement occurred at the site of prior attacks; the lesion location was unchanged, but the lesion length was shorter. Two scans (1.8%) demonstrated new asymptomatic lesions (prior scan demonstrated no enhancement). In a third patient with subjective blurry vision, MRI showed enhancement preceding detectable eye abnormalities on examination noted 15 days later. There was no difference in VA at preceding attack nadir (logMAR VA 1.7 vs 2.1; p = 0.79) or long-term VA (logMAR VA 0.4 vs 0.2, p = 0.56) between those with and without interattack optic nerve enhancement. DISCUSSION: Asymptomatic optic nerve enhancement occurred in 17% of patients with NMOSD predominantly at the site of prior ON attacks and may represent intermittent blood-brain barrier breakdown or subclinical ON. New asymptomatic enhancement was seen only in 2% of patients. Therapeutic clinical trials for NMOSD require blinded relapse adjudication when assessing treatment efficacy, and it is important to recognize that asymptomatic optic nerve enhancement can occur in patients with ON.

Optic chiasm involvement in AQP-4 antibody-positive NMO and MOG antibody-associated disorder.

BACKGROUND: Optic neuritis (ON) is often the presenting symptom in inflammatory central nervous system demyelinating disorders. OBJECTIVE: To compare the frequency and pattern of optic chiasm involvement in patients with aquaporin-4-immunoglobulin G (AQP4-IgG)-associated ON to patients with myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated ON. METHODS: Retrospective review of all patients evaluated at Mayo Clinic, Stanford University and Ramathibodi Hospital who were found to have: (1) ON, (2) either MOG-IgG or AQP4-IgG by cell-based assay, and (3) magnetic resonance imaging (MRI) at the time of ON. MRI was reviewed for contrast enhancement of the optic chiasm and the pattern of involvement. RESULTS: One hundred and fifty-four patients (74 AQP4-IgG and 80 MOG-IgG) were included. Among patients with AQP4-IgG-ON, 20% had chiasmal involvement, compared with 16% of patients with MOG-IgG-ON (p = 0.66). In patients with chiasmal involvement, longitudinally extensive optic nerve enhancement (from orbit extending to chiasm) was identified in 54% of MOG-IgG-ON patients, compared with 7% of AQP4-IgG-ON patients (p = 0.01). CONCLUSION: Chiasmal involvement of MOG-IgG-ON and AQP4-IgG-ON occur at more similar frequencies than previously reported. Furthermore, MOG-IgG-ON chiasmal involvement is more likely to be part of a longitudinally extensive optic nerve lesion.

Proceedings of the 43nd Annual Upper Midwest Neuro-Ophthalmology Group Meeting, July 23, 2021 and Second Virtual Upper Midwest Neuro-Ophthalmology Group Meeting.

The 43rd meeting of the Upper Midwest Neuro-Ophthalmology Group (UMNOG) took place on July 23, 2021. For the second sequential year, the meeting was held virtually due to the COVID-19 pandemic. The meeting was held in the honour of the late Ivy Dreizin MD. Ninety people attended virtually marking the highest UMNOG meeting attendance on record. There were 23 podium presentations interspersed with numerous personal testimonials recognising Dr Dreizin and her immense contributions to the UMNOG community.

Clinical Characteristics and Treatment of MOG-IgG-Associated Optic Neuritis.

PURPOSE OF REVIEW: Antibodies against myelin oligodendrocyte glycoprotein (MOG) are associated with a unique acquired central nervous system demyelinating disease-termed MOG-IgG-associated disorder (MOGAD)-which has a variety of clinical manifestations, including optic neuritis, transverse myelitis, acute disseminating encephalomyelitis, and brainstem encephalitis. In this review, we summarize the current knowledge of the clinical characteristics, neuroimaging, treatments, and outcomes of MOGAD, with a focus on optic neuritis. RECENT FINDINGS: The recent development of a reproducible, live cell-based assay for MOG-IgG, has improved our ability to identify and study this disease. Based on contemporary studies, it has become increasingly evident that MOGAD is distinct from multiple sclerosis and aquaporin-4-positive neuromyelitis optica spectrum disorder with different clinical features and treatment outcomes. There is now sufficient evidence to separate MOGAD from other inflammatory central nervous system demyelinating disorders, which will allow focused research on understanding the pathophysiology of the disease. Prospective treatment trials are needed to determine the best course of treatment, and until then, treatment plans must be individualized to the clinical manifestations and severity of disease.

CXCL9 compensates for the absence of CXCL10 during recurrent Herpetic stromal keratitis.

Herpetic stromal keratitis (HSK) is a disease that is typically associated with reactivation of a latent HSV-1 infection. This disease is driven, in part, by chemokines that recruit leukocytes to the cornea. Surprisingly, neutralization of CXCL10 significantly reduced disease, while B6-CXCL10-/- mice exhibited worse disease compared with similarly infected wild-type controls. We hypothesized that compensatory up-regulation of CXCL9 occurs in the absence of CXCL10. Analysis of CXCL9 expression in HSV-1-infected B6 mice and B6-CXCL10-/- mice revealed significantly more CXCL9 in B6-XCL10-/- mice. Treatment of B6 and B6-CXCL10-/- mice with neutralizing antibodies to CXCL9 reduced HSK scores in B6-CXCL10-/-, but not B6 mice. We conclude that CXCL10 production worsens HSK and that CXCL9 may compensate in CXCL10-deficient animals. These studies identify the critical role that CXCL10 plays in the pathogenesis of recurrent HSK, and that CXCL9 displays its importance when CXCL10 is absent.

Herpes simplex keratitis: challenges in diagnosis and clinical management.

Herpes simplex virus is responsible for numerous ocular diseases, the most common of which is herpetic stromal keratitis. This is a recurrent infection of the cornea that typically begins with a subclinical infection of the cornea that establishes a latent infection of sensory ganglia, most often the trigeminal ganglia. Recurring infections occur when the virus is reactivated from latency and travels back to the cornea, where it restimulates an inflammatory response. This inflammatory response can lead to decreased corneal sensation, scarring, and blindness. The diagnosis of these lesions as the result of a recurrent herpes simplex virus infection can at times be problematic. Currently, herpetic stromal keratitis is diagnosed by its clinical presentation on the slit-lamp examination, but the literature does not always support the accuracy of these clinical findings. Other diagnostic tests such as polymerase chain reaction assay, enzyme-linked immunosorbent assay, immunofluorescent antibody, and viral cultures have provided more definitive diagnosis, but also have some limitations. That said, accurate diagnosis is necessary for proper treatment, in order to prevent serious consequences. Current treatment reduces the severity of lesions and controls further viral spread, but does not provide a cure.

Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea.

Racecadotril (acetorphan) is a neutral endopeptidase (NEP) inhibitor with known antidiarrheal activity in animals and humans; however, in humans, it suffers from shortcomings that might be improved with newer drugs in this class that have progressed to the clinic for nonenteric disease indications. To identify potentially superior NEP inhibitors with immediate clinical utility for diarrhea treatment, we compared their efficacy and pharmacologic properties in a rat intestinal hypersecretion model. Racecadotril and seven other clinical-stage inhibitors of NEP were obtained or synthesized. Enzyme potency and specificity were compared using purified peptidases. Compounds were orally administered to rats before administration of castor oil to induce diarrhea. Stool weight was recorded over 4 hours. To assess other pharmacologic properties, select compounds were orally administered to normal or castor oil-treated rats, blood and tissue samples collected at multiple time points, and active compound concentrations determined by mass spectroscopy. NEP enzyme activity was measured in tissue homogenates. Three previously untested clinical NEP inhibitors delayed diarrhea onset and reduced total stool output, with little or no effect on intestinal motility assessed by the charcoal meal test. Each was shown to be a potent, highly specific inhibitor of NEP. Each exhibited greater suppression of NEP activity in intestinal and nonintestinal tissues than did racecadotril and sustained this inhibition longer. These results suggest that newer clinical-stage NEP inhibitors originally developed for other indications may be directly repositioned for treatment of acute secretory diarrhea and offer advantages over racecadotril, such as less frequent dosing and potentially improved efficacy.

Murine corneal transplantation: a model to study the most common form of solid organ transplantation.

Corneal transplantation is the most common form of organ transplantation in the United States with between 45,000 and 55,000 procedures performed each year. While several animal models exist for this procedure and mice are the species that is most commonly used. The reasons for using mice are the relative cost of using this species, the existence of many genetically defined strains that allow for the study of immune responses, and the existence of an extensive array of reagents that can be used to further define responses in this species. This model has been used to define factors in the cornea that are responsible for the relative immune privilege status of this tissue that enables corneal allografts to survive acute rejection in the absence of immunosuppressive therapy. It has also been used to define those factors that are most important in rejection of such allografts. Consequently, much of what we know concerning mechanisms of both corneal allograft acceptance and rejection are due to studies using a murine model of corneal transplantation. In addition to describing a model for acute corneal allograft rejection, we also present for the first time a model of late-term corneal allograft rejection.