Harish Raja

Effect of Intravitreal Methotrexate and Rituximab on Interleukin-10 Levels in Aqueous Humor of Treated Eyes with Vitreoretinal Lymphoma

Intraocular cytokines are promising diagnostic biomarkers of vitreoretinal lymphoma. Here, we evaluate the utility of IL-10, IL-6 and IL-10/IL-6 for discriminating lymphoma from uveitis and report the effects of intraocular methotrexate and rituximab on aqueous cytokine levels in eyes with lymphoma. This is a retrospective case series including 10 patients with lymphoma and 7 patients with uveitis. Non-parametric Mann-Whitney analysis was performed to determine statistical significance of difference in interleukin levels between lymphoma and uveitis. Compared to eyes with uveitis, eyes with lymphoma had higher levels of IL-10 (U = 7.0; two-tailed p = 0.004) and IL-10/IL-6 (U = 6.0; two-tailed p = 0.003), whereas IL-6 levels were more elevated, although insignificant, in those patients with uveitis than in lymphoma (U = 15.0; two-tailed p = ns). Using a receiver operating characteristic analysis to identify threshold values diagnostic for lymphoma, optimal sensitivity and specificity improved to 80.0% and 100%, respectively, for IL-10>7.025 pg/ml and 90.0% and 100.0%, respectively, for IL-10/IL-6>0.02718. In patients in whom serial interleukin levels were available, regular intravitreal treatment with methotrexate and rituximab was associated with reduction in IL-10 levels over time. In conclusion, optimal IL-10 and IL-10/IL-6 threshold values are associated with a diagnostic sensitivity ≥80% and specificity of 100%. Therefore, these cytokines may serve as a useful adjunct in the diagnosis of lymphoma. While negative IL-10 and IL-10/IL-6 values do not exclude a diagnosis of lymphoma, elevated levels do appear to be consistent with lymphoma clinically. Moreover, elevated levels of IL-10 in the setting of a clinically quiet eye may point to impending disease recurrence. Lastly, once lymphoma is diagnosed, IL-10 levels can be monitored over time to assess disease activity and therapeutic response.

PREVALENCE OF MYD88 L265P MUTATION IN HISTOLOGICALLY PROVEN, DIFFUSE LARGE B-CELL VITREORETINAL LYMPHOMA.

Purpose: Myeloid differentiation primary response gene 88 (MYD88) is a universal adaptor protein in the innate immune system. When associated with a proline for leucine substitution mutation at position 265 (L265P), the protein becomes constitutively activated, amplifying the intracellular pro-inflammatory signal. Recently, we reported two cases of vitreoretinal lymphoma (VRL) that were positive for the mutation. The purpose of this study was to determine prevalence of the MYD88 L265P mutation in a larger series of VRL. Methods: Retrospective chart review of 25 patients with histologically confirmed VRL evaluated at Mayo Clinic, Rochester, between January 2000 and March 2015. Paraffin-embedded blocks from the vitreous were submitted for polymerase chain reaction testing of the L265P mutation. Results: The mutation was positive in 82.4% of all VRL cases and 86.7% of primary VRL cases. The minimum necessary DNA concentration needed for the polymerase chain reaction assay was 4.93 ng/mL. Conclusion: MYD88 gene analysis is a helpful ancillary tool for diagnosing VRL. It often requires fewer cells than flow cytometry or cytology and may be especially useful in early cases where a sufficient number of cells may not be available.

Ocular graft-versus-host disease: A review

Abstract: Hematopoietic stem cell transplantation is important in the management of several lymphoproliferative and bone marrow disorders. Graft-versus-host disease (GVHD) involves inflammatory manifestations that arise after transplant and can affect many organs. Ocular manifestations of GVHD are common, and eye care providers must understand this disease entity. The ocular surface is most commonly involved, but GVHD can affect all parts of the eye. Ocular GVHD can be relapsing and remitting, can decrease quality of life, and can be challenging to diagnose and adequately treat. The diagnostic criteria for and grading of ocular GVHD continue to evolve. This review aims to summarize current definitions, clinical findings, diagnostic criteria, and management of ocular GVHD. The care of patients with ocular GVHD requires a multidisciplinary approach.

Vitreoretinal Lymphoma versus Uveitis: Cytokine Profile and Correlations

Abstract Purpose: To compare the cytokine spectrum of vitreoretinal lymphoma to uveitis and correlate cytokine concentrations with disease activity. Methods: Retrospective case series of 10 patients with vitreoretinal lymphoma and 7 patients with uveitis. Aqueous humor concentration of IFN-γ, TNF-α, TNF-β, IL-1ra, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, MCP-1, G-CSF, GM-CSF, and VEGF-A was determined using a bead-based assay (Luminex). Variance between groups, correlation coefficients, and longitudinal behavior of cytokines were analyzed. Results: No statistically significant difference in cytokines was found when comparing groups. IL-10 was positively correlated with IL-6 and MCP-1. IL-6 was positively correlated with G-CSF, IL-1ra, IL-8, and IL-10. A relationship between concentration of any cytokine, aside from IL-10, and disease activity was not found. Conclusion: IL-10 and IL-6 are good immunologic markers to be used as complementary diagnostic tools. IL-10 is the only IL that could be used for monitoring purposes.

Ocular manifestations of tick-borne diseases.

Tick-borne illnesses are a significant disease burden worldwide. Diagnosis is challenging and requires a high level of clinical suspicion. Ocular manifestations reported in association with tick-borne disease are mostly as case reports and small case series because of the relative infrequency with which they occur; however, given the global nature of health care and increase in travel in the 21st century, it is important for ophthalmologists to be aware of ocular manifestations of these diseases because early diagnosis may reduce morbidity and mortality. Here, we review of the literature of tick-borne diseases with reported ophthalmic findings. All known human tick-borne diseases are discussed, including a brief description of the causative agent, region of endemicity, vector, systemic symptoms, and any reported eye findings. When possible, we also address the strength of the evidence for these ocular associations.

Mighty MyD88 in Health and Disease.

In 2012, Treon et al,1 in their study of patients with IgM lymphoplasmacytic lymphoma and the associated clinical syndrome Waldenstrom macroglobulinemia (WM), found that a single nucleotide somatic mutation in the myeloid differentiation primary response 88 (MYD88) gene, leading to substitution

The diagnosis and treatment of primary vitreoretinal lymphoma: a review

BackgroundTo describe the recent diagnostic and treatment options for the most predominant form of primary vitreoretinal lymphoma (PVRL), namely diffuse large B cell lymphoma. This is mainly based on the experience at the Mayo Clinic as well as a partial review of the literature. MYD88 L265P mutation is seen in about 80% of cases; therefore, a polymerase chain reaction for this mutation helps in making the diagnosis that has been notoriously difficult to make. Local therapy using intravitreal methotrexate and rituximab has been very helpful in the treatment of the local disease. Systemic high-dose intravenous methotrexate is helpful in treating bilateral disease in conjunction with intravitreal therapy. Whether it is helpful in preventing or delaying the development of central nervous system lymphoma (CNSL) is still in dispute. If there is development of CNSL or recurrent ocular disease, alternatives to high-dose methotrexate under investigation include pomalidomide, stem cell transplantation, or ibrutinib, with or without local therapy. Vitrectomy alone might be helpful as a debulking procedure. Because of the risks of redevelopment of disease, local radiation should be given if other options are not possible. Aqueous levels of IL10 are helpful in following the redevelopment of local disease.ConclusionAlthough PVRL is still a difficult disease to diagnose and treat, new advances are helping to make these easier. Larger collaborative studies will be helpful in determining better treatments.

USE OF FIBEROPTIC-GUIDED CO2 LASER IN THE TREATMENT OF UVEAL EFFUSION.

Background/Purpose: To report a new technique for treating patients with uveal effusion syndrome by the fiberoptic-guided CO2 laser. Methods: Interventional case report. A 74-year-old man presented with exudative detachment of the choroid secondary to uveal effusion syndrome. Partial-thickness sclerotomy and full-thickness sclerotomy were performed to treat the disease using a fiberoptic-guided CO2 laser. Results: After the surgery, the patients visual acuity improved and choroidal folds disappeared. Conclusion: This technique allows concomitant coagulation and cutting, thereby reducing the risk of bleeding and providing better depth control.

Macular edema is a rare finding in untreated vitreoretinal lymphoma: small case series and review of the literature

AbstractBackground To determine the occurrence of macular edema (ME) in vitreoretinal lymphoma (VRL).MethodsRetrospective analysis of 17 patients (31 eyes) with VRL. A review of the literature was done as well.Results Nine patients (15 eyes) had fluorescein angiography and/or optical coherence tomography at presentation. In the ME group (six eyes of four patients), three patients (five eyes) had prior chemotherapy and radiation. Excluding eyes with radiation retinopathy (three eyes), rate of ME was 25% (3/12). When two unirradiated fellow eyes of eyes with radiation retinopathy were also excluded, ME rate was 10% (1/10). Excluding the eyes with intraocular surgery, the rate of ME was 0%. In the group without ME (nine eyes of six patients), one patient (one eye) was treated with chemotherapy and radiation and three patients (five eyes) with chemotherapy. Review of the literature showed that the ME was found between 2 and 60% of cases, but most of the cases with ME had prior interventions.ConclusionsMacular edema in VRL is not uncommon but usually related to prior interventions. Macular edema as an initial presentation of VRL is rare.

Presumed Posterior Uveitis Related To Ehrlichia Exposure

PURPOSE To describe a case of posterior uveitis with retinal vasculitis related to Ehrlichia exposure. PATIENTS AND METHODS Single case report of a 68-year-old woman with posterior uveitis, steroid-induced glaucoma, and retinal holes. RESULTS Ehrlichia titers were elevated 4-fold (1:256; normal <1:64) with an otherwise normal laboratory workup. The patients cystoid macular edema responded to sub-Tenons triamcinolone and oral doxycycline. CONCLUSION To our knowledge, this is the first case of posterior uveitis associated with Ehrlichia reported in humans.