α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism.

Oxidative stress and α-synuclein aggregation both drive neurodegeneration in Parkinson's disease, and the protein kinase c-Abl provides a potential amplifying link between these pathogenic factors. Suppressing interactions between these factors may thus be a viable therapeutic approach for this disorder. To evaluate this possibility, pre-formed α-synuclein fibrils (PFFs) were used to induce α-synuclein aggregation in neuronal cultures. Exposure to PFFs induced oxidative stress and c-Abl activation in wild-type neurons. By contrast, α-synuclein - deficient neurons, which cannot form α-synuclein aggregates, failed to exhibit either oxidative stress or c-Abl activation. N-acetyl cysteine, a thiol repletion agent that supports neuronal glutathione metabolism, suppressed the PFF - induced redox stress and c-Abl activation in the wild-type neurons, and likewise suppressed α-synuclein aggregation. Parallel findings were observed in mouse brain: PFF-induced α-synuclein aggregation in the substantia nigra was associated with redox stress, c-Abl activation, and dopaminergic neuronal loss, along with microglial activation and motor impairment, all of which were attenuated with oral N-acetyl cysteine. Similar results were obtained using AAV-mediated α-synuclein overexpression as an alternative means of driving α-synuclein aggregation in vivo. These findings show that α-synuclein aggregates induce c-Abl activation by a redox stress mechanism. c-Abl activation in turn promotes α-synuclein aggregation, in a feed-forward interaction. The capacity of N-acetyl cysteine to interrupt this interaction adds mechanistic support its consideration as a therapeutic in Parkinson's disease.

Bilateral Macular Choroidal Infarction as a Manifestation of Giant Cell Arteritis.

The authors present an unusual case of bilateral macular choroidal infarction as a manifestation of giant cell arteritis (GCA). Due to sequential bilateral presentation, multimodal imaging with spectral-domain optical coherence tomography allows for simultaneous evaluation of progressive stages of outer retinal damage caused by choroidal hypoperfusion seen on fluorescein and indocyanine green angiography. This case report demonstrates that GCA should be considered in the differential diagnosis of placoid maculopathies. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:540-543.].

Spectral-Domain Optical Coherence Tomography, Wide-Field Photography, and Fundus Autofluorescence Correlation of Posterior Ophthalmomyiasis Interna.

Posterior ophthalmomyiasis interna is a rare, potentially devastating infestation of the posterior segment by fly larvae. The authors report the first demonstration of spectral-domain optical coherence tomography (SD-OCT) (Spectralis; Heidelberg Engineering, Heidelberg, Germany), wide-field angiography (Optos, Dunfermline, Scotland) and photography, and fundus autofluorescence with temporal progression during a period of 6 months. A 12-year-old white female presented with acute, painless vision loss with hand motions visual acuity. No larva was visible, so she was treated with oral ivermectin. Visual acuity improved to 20/80. OCT demonstrated hyporeflective spaces of the outer retina and retinal pigment epithelium, which resolved during 1-month period with improved ellipsoid layer by 6 months. Fundus autofluorescence demonstrated linear hypoautofluorescent tracks. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:682-685.].

Consensus on the Diagnosis and Management of Nonparaneoplastic Autoimmune Retinopathy Using a Modified Delphi Approach.

PURPOSE: To develop diagnostic criteria for nonparaneoplastic autoimmune retinopathy (AIR) through expert panel consensus and to examine treatment patterns among clinical experts. DESIGN: Modified Delphi process. METHODS: A survey of uveitis specialists in the American Uveitis Society, a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of expert panel surveys were used in a modified Delphi process. The expert panel consisted of 17 experts, including uveitis specialists and researchers with expertise in antiretinal antibody detection. Supermajority consensus was used and defined as 75% of experts in agreement. RESULTS: There was unanimous agreement among experts regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including cancer-associated retinopathy and melanoma-associated retinopathy. Diagnostic criteria and tests essential to the diagnosis of nonparaneoplastic AIR and multiple supportive criteria reached consensus. For treatment, experts agreed that corticosteroids and conventional immunosuppressives should be used (prescribed) as first- or second-line treatments, though a consensus agreed that biologics and intravenous immunoglobulin were considered appropriate in the treatment of nonparaneoplastic AIR patients regardless of the stage of disease. Experts agreed that more evidence is needed to treat nonparaneoplastic AIR patients with long-term immunomodulatory therapy and that there is enough equipoise to justify randomized, placebo-controlled trials to determine if nonparaneoplastic AIR patients should be treated with long-term immunomodulatory therapy. Regarding antiretinal antibody detection, consensus agreed that a standardized assay system is needed to detect serum antiretinal antibodies. Consensus agreed that an ideal assay should have a 2-tier design and that Western blot and immunohistochemistry should be the methods used to identify antiretinal antibodies. CONCLUSIONS: Consensus was achieved using a modified Delphi process to develop diagnostic criteria for nonparaneoplastic AIR. There is enough equipoise to justify randomized, placebo-controlled trials to determine whether patients with nonparaneoplastic AIR should be treated with long-term immunomodulatory therapy. Efforts to develop a standardized 2-tier assay system for the detection of antiretinal antibodies have been initiated as a result of this study.

Tattoo-associated uveitis.

PURPOSE: To describe the clinical presentation of uveitis with coincident onset of raised and indurated tattooed skin. DESIGN: Case series. METHODS: Seven consecutive patients were evaluated at a tertiary ophthalmologic facility with coincident uveitis and cutaneous tattoo induration over an 18-month period. All subjects underwent complete ophthalmic examination and a focused systemic medical evaluation including serologic testing and imaging studies. Two participants underwent biopsy of their tattoos. The patients' clinical courses and responses to treatment over a follow-up period of 1-20 months are reported (mean follow-up = 9 months). Main outcome measures included degree of intraocular inflammation, ocular complications, visual acuity, clinically observable tattooed skin changes, and biopsy results. RESULTS: Five of 7 patients had bilateral nongranulomatous anterior uveitis: 4 with chronic and 1 with recurrent disease. The remaining 2 patients had bilateral chronic granulomatous panuveitis. Biopsies of raised and indurated tattoos were performed in 2 patients and demonstrated noncaseating granulomatous inflammation surrounding tattoo ink in the dermis. The skin changes resolved in all patients, with a faster response noted in those treated with high-dose oral prednisone for intraocular inflammation. Five patients subsequently experienced recurrent flares of intraocular inflammation in conjunction with the recurrence of raised and indurated tattoos. CONCLUSIONS: These cases represent a subset of patients in whom skin tattooing may have incited an immune response leading to simultaneous inflammation of the eyes and tattooed skin.

Clinical features and incidence rate of ocular complications in punctate inner choroidopathy.

PURPOSE: To study the clinical features and incidence rate of ocular complications in patients with punctate inner choroidopathy. METHODS: This is a retrospective cohort study conducted in a single-center academic practice setting. Patients diagnosed with punctate inner choroidopathy at the Wilmer Eye Institute, Johns Hopkins University from 1984 to 2012 were identified. Demographics and clinical features including the presence of choroidal neovascularization (CNV) and structural complications were collected. Main outcome measures, including visual impairment and incidence rate of ocular complications, were analyzed. RESULTS: Thirty-one patients (59 eyes) were included in the study. Follow-up data were available for 24 patients (47 eyes) with a mean follow-up time of 3.4 years (range, 2 months to 8.7 years). In the affected eyes with follow-up, the incidence rate of visual impairment to 20/50 or worse was 0.06 per eye-year (EY) (95% confidence interval, 0.022/EY-0.114/EY). The incidence rate of visual loss to 20/200 or worse was 0.006/EY (95% confidence interval, 0.0001/EY-0.034/EY). Thirty-six eyes (77%) had an ultimate visual acuity of 20/40 or better. All of the 13 patients with more than ≥ 3 years of follow-up had a visual acuity of ≥ 20/40 in at least 1 eye at 3 years after presentation. Two thirds of the follow-up patients (67%) on immunomodulatory drug therapy did not have new or recurrent CNV. However, this was not a statistically significant difference. Three eyes with follow-up had recurrence of CNV for an incidence rate of 0.04/EY (95% confidence interval, 0.008/EY-0.12/EY). Two eyes developed new CNV during follow-up for an incidence rate of 0.02/EY (95% confidence interval, 0.002/EY-0.066/EY). CONCLUSION: The visual prognosis in most cases of punctate inner choroidopathy is very good. The incidence rate of new CNV and recurrent CNV was 0.02/EY and 0.04/EY, respectively.

Rituximab therapy for refractory orbital inflammation: results of a phase 1/2, dose-ranging, randomized clinical trial.

IMPORTANCE: Orbital inflammation is a potentially blinding and disfiguring disease process that is often treated with systemic corticosteroids and immunosuppression; better treatments are needed. OBJECTIVE: To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory orbital inflammation. DESIGN, SETTING, AND PARTICIPANTS: A dose-ranging, randomized, double-masked phase 1/2 clinical trial was conducted at a tertiary referral ophthalmology clinic. Ten individuals with orbital inflammation refractory to systemic corticosteroids and at least 1 other immunosuppressive agent were enrolled from January 2007 to March 2010. INTERVENTIONS: Rituximab infusions were administered on study days 1 and 15 at doses of either 500 mg or 1000 mg. Initial responders with recurrent inflammation after week 24 were permitted reinfusion with an additional cycle of 2 open-label 1000-mg rituximab infusions. MAIN OUTCOMES AND MEASURES: The primary outcomes were reduction of inflammation measured with a validated orbital disease grading scale and corticosteroid dose reduction by at least 50%. The secondary outcomes were visual acuity, reduction in pain, and participant- and physician-reported global health assessment. RESULTS: Of 10 enrolled patients, 7 demonstrated improvement on the orbital disease grading scale at the 24-week end point with rituximab therapy. Of these 7 individuals, 4 were receiving corticosteroids at study inception and all achieved successful dose reduction. For the secondary outcome measures in the 10 participants, 7 patients and 8 patients improved in self-rated and physician global health scores, respectively, and 7 patients had reduction in pain by 25% or more at 24 weeks. Four patients who were positive responders at the week 24 end point experienced breakthrough inflammation after week 24 and received reinfusions between 24 and 48 weeks. Vision remained stable in all participants. Three of 10 patients had short-term objective or subjective worsening 2 to 8 weeks after receiving rituximab infusions, which was averted in subsequent patients with oral corticosteroids administered during the infusion and did not affect the eventual positive treatment outcome. No significant differences with regard to efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. CONCLUSIONS AND RELEVANCE: Rituximab was safe and effective in 7 of 10 patients with noninfectious orbital disease, although 4 required reinfusion with rituximab to maintain control of orbital inflammation. Substantial toxicity was not noted. Rituximab should be considered in the treatment of refractory orbital inflammation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00415506.

Sclerouveitis associated with Rosai-Dorfman disease in an HIV-infected patient.

PURPOSE: To describe a case of Rosai-Dorfman-associated sclerouveitis in an HIV-infected patient. DESIGN: Case report. METHODS: A 49-year-old man with HIV had bilateral eye pain, redness, photophobia, and multiple systemic complaints. He underwent serial ocular examinations, abdomen/pelvis CT scan, and lymph node biopsy. RESULTS: Ophthalmologic evaluation revealed bilateral, nongranulomatous anterior uveitis and anterior scleritis. Biopsy of a retroperitoneal lymph node identified on CT revealed mixed inflammatory infiltrate composed of histiocytes, lymphocytes, and plasma cells involving fibroadipose tissue, indicating Rosai-Dorfman disease. CONCLUSIONS: This is the first report of sclerouveitis in Rosai-Dorfman disease. Rosai-Dorfman is typically self-limiting, occurring rarely in HIV.

Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial.

OBJECTIVE: Tumour necrosis factor (TNF) blockers have been demonstrated to be effective in the treatment of systemic and ocular inflammatory diseases. We conducted a prospective, multicentre, open-label Phase II clinical trial to assess the effectiveness and safety of adalimumab, a fully human anti-TNF monoclonal antibody, in treating refractory uveitis. METHODS: Subjects with non-infectious uveitis refractory to corticosteroids and at least one other immunosuppressive medication were enrolled. Treatment outcome was ascertained by a composite endpoint comprised of visual acuity, intraocular inflammation, ability to taper immunosuppressives, and posterior segment imaging. Clinical response was defined by improvement in at least one parameter, worsening in none, and well controlled intraocular inflammation. Week 10 responders were permitted to continue receiving adalimumab for the study duration of 50 weeks. RESULTS: Twenty-one of 31 patients (68%) were characterised as clinical responders at 10 weeks, of whom 12 patients (39%) exhibited durable response after 50 weeks. The most common reason for study termination was primary or secondary inefficacy. No patients experienced treatment-limiting toxicity clearly related to study therapy. CONCLUSIONS: Adalimumab was safe and effective in 68% of refractory uveitis patients 10 weeks after study enrolment, and maintained in 39% after 1 year. Ongoing study is required to determine the place of adalimumab and other TNF blockers in the treatment of uveitis.

Interferon alpha 2b in the treatment of uveitic cystoid macular edema.

PURPOSE: To determine the efficacy of interferon alpha 2b in the treatment of refractory, uveitic cystoid macular edema (CME). METHODS: Retrospective chart review of 4 patients attending the uveitis clinic at the Casey Eye Institute, Oregon Health & Science University. RESULTS: All 4 patients had uveitis and refractory CME, resistant to a variety of immunosuppressants. All patients, except one with severe scleral thinning, had tried and failed therapy with locally injected corticosteroids. Treatment with systemic interferon alpha 2b produced dramatic improvement in CME (central macular thickness: 563 to 267 µm, p = .002) and visual acuity (logMAR: +0.81 to +0.45, p = .0004) in all 4 cases. All patients have been able to reduce the interferon dosage, but none has discontinued it completely. All patients had some mild adverse response that did not necessitate stopping therapy. CONCLUSIONS: Interferon alpha 2b is an effective option to treat refractory CME secondary to uveitis.

Bystander effect produced by radiolabeled tumor cells in vivo.

The bystander effect, originating from cells irradiated in vitro, describes the biologic response(s) of surrounding cells not directly targeted by a radiation insult. To overcome the limitations of in vitro tissue culture models and determine whether a bystander effect that is initiated by the in vivo decay of a radionuclide can be demonstrated in an animal, the ability of 5-[(125)I]iodo-2'-deoxyuridine ((125)IUdR)-labeled tumor cells to exert a damaging effect on neighboring unlabeled tumor cells growing s.c. in nude mice has been investigated. When mice are injected with a mixture of human colon LS174T adenocarcinoma cells and LS174T cells prelabeled with lethal doses of DNA-incorporated (125)I, a distinct inhibitory effect on the growth of s.c. tumor (derived from unlabeled cells) is observed. Because (i) the (125)I present within the cells is DNA-bound, (ii) approximately 99% of the electrons emitted by the decaying (125)I atoms have a subcellular range (<0.5 microm), and (iii) the overall radiation dose deposited by radiolabeled cells in the unlabeled cells within the growing tumor is <10 cGy, we conclude that the results obtained are a consequence of a bystander effect that is generated in vivo by factor(s) present within and/or released from the (125)IUdR-labeled cells. These in vivo findings significantly impact the current dogma for assessing the therapeutic potential of internally administered radionuclides. They also call for reevaluation of the approaches currently used for estimating the risks to individuals and populations inadvertently exposed internally to radioactivity as well as to patients undergoing routine diagnostic nuclear medical procedures.