The Role of Corticosteroids and Immunomodulatory Therapy in the Management of Infectious Uveitis.

PURPOSE: The index review aims to provide an update on the role of corticosteroids and steroid-sparing immunomodulatory therapy (IMT) in managing patients with infectious uveitis. METHOD: Narrative literature review. RESULTS: Corticosteroids and immunomodulatory therapy (IMT) focus on the host defense system instead of the pathogen, adjusting exaggerated inflammatory reactions to reduce potential harm to ocular tissues. Systemic or local corticosteroids are primarily selected as adjunctive medication for infectious uveitis. Concomitant corticosteroids have also been used in cases of paradoxical worsening in ocular tuberculosis and immune recovery uveitis in cytomegalovirus (CMV) retinitis. While there is no well-established evidence to support the use of IMT in infectious uveitis, it is occasionally used in clinical settings to treat persistent inflammation following resolution of infection such as cases of ocular tuberculosis and ocular syphilis where an insufficient response is observed with corticosteroids. CONCLUSION: There is no consensus on the position of immunomodulatory therapy in the management of infectious uveitis with different etiologies. The index review provides an overview of available adjunctive corticosteroids and IMT options to assist clinicians in managing such disease entities more efficiently.

Birdshot Chorioretinopathy in Early Adulthood: Review of Current Literature and Case Report.

Purpose: We describe the course of a patient diagnosed with birdshot chorioretinopathy (BSCR) in early adulthood and summarize clinical findings from similar BSCR patients reported in the literature. Observations: A 37-year-old male presented to our tertiary uveitis facility with bilateral ocular discomfort, hazy vision, and floaters. Ocular examination was notable for vitritis, optic disc edema, and ovoid hypopigmented chorioretinal lesions, visible on indocyanine green chorioangiography as multiple hypocyanescent spots in the intermediate phase. Full-field electroretinography and visual evoked potential showed global retinal dysfunction and optic nerve dysfunction. Laboratory evaluations were notable only for human leukocyte antigen (HLA)-A29 positivity. The patient was diagnosed with BSCR and started on oral prednisone and eventually managed with infliximab. Conclusions and Importance: BSCR can affect patients in early adulthood. Proper diagnostic work-up, including assessing HLA-A29 positivity, is needed to manage atypical cases.

Evaluation of correlation between Diopsys® NOVA™ fixed-luminance flicker ERG and Diagnosys® Espion 2™ flicker ERG parameters.

PURPOSE: Diopsys® NOVA™ is a novel full-field electroretinography (ffERG) device that can make rapid measurements of retinal electrophysiologic function. Diagnosys® Espion 2™ is a clinical gold-standard ERG device. This study aimed to investigate whether light-adapted Diopsys® NOVA™ fixed-luminance flicker ffERG magnitude and implicit time (converted from phase) measurements correlate with light-adapted Diagnosys® Espion 2™ flicker ffERG amplitude and implicit time measurements, respectively. METHODS: Twelve patients (22 eyes) with various retinal and uveitic diseases underwent light-adapted Diagnosys® Espion 2™ and Diopsys® NOVA™ fixed-luminance flicker testing. Diopsys® magnitude and implicit time (converted from phase) measurements were compared to Diagnosys® amplitude and implicit time measurements, and a Pearson correlation was used to evaluate any existing correlation. Groups were also compared using generalized estimating equations. Bland-Altman plots were utilized to determine agreement between the comparison groups. RESULTS: Age of patients ranged from 14 to 87 years. 58% (n = 7/12) of patients were female. A significant, positive correlation (r = 0.880, P < 0.001) was observed between magnitude (Diopsys®) and amplitude (Diagnosys®) measurements. Amplitude increases by 6.69 µV for each 1 µV increase in Magnitude (p-value < 0.001). A statistically significant, strong positive correlation was observed between Diopsys® implicit time measurements (converted from phase) and Diagnosys® implicit time measurements (r = 0.814, p-value < 0.001). For each 1 ms increase in Diopsys® implicit time, Diagnosys® implicit time increases by 1.13 ms (p-value < 0.001). CONCLUSIONS: There is a statistically significant positive correlation between light-adapted Diopsys® NOVA™ fixed-luminance flicker amplitude and Diagnosys® flicker magnitude values. Additionally, there is a statistically significant positive correlation between Diopsys® NOVA™ fixed-luminance flicker implicit time (converted from phase) and Diagnosys® flicker implicit time values. These results imply that the Diopsys® NOVA™ module, which utilizes the nonstandard shortened International Society for Clinical Electrophysiology of Vision (ISCEV) ERG protocol, can produce reliable light-adapted flicker ffERG measurements.

Electroretinographic findings in retinal vasculitis.

AIM: To describe and correlate electroretinographic responses with clinical and angiographic findings in retinal vasculitis (RV). METHODS: Medical records of patients with diagnosis of RV at a tertiary eye centre from December 2017 to May 2021 were reviewed. Cases in which fluorescein angiography (FFA) and full field electroretinography (ffERG) were done within 1 month were included. FFAs were graded according to the Angiography Scoring for Uveitis Working Group from 0 to 40, where 0 is normal. A novel ffERG grading system was implemented where individual waves were graded for timing and amplitude and general ffERG score was determined with 6 being a perfect score. RESULTS: 20 patients (34 eyes) were included. Mean age was 43.9±19.8 years; 70% were female. Median best-corrected visual acuity was 0.8 (0.08-1). Mean FFA score was 12.6±6.5. Median general ffERG score was 5 (0-6). 68% and 91% of eyes had responses with general ffERG scores ≥5 and 4, respectively. Flicker timing was most commonly affected.FFA scores weakly correlated with delayed photopic cone b-wave and flicker timing (p=0.03 and 0.016, respectively). Vitreous haze moderately correlated with delayed cone b-wave timing (p<0.001), delayed flicker timing (p=0.002) and weakly correlated with lower flicker amplitude (p=0.03). Underlying systemic disease was associated with poor ffERG responses. CONCLUSION: In this study, RV was not frequently associated with severe global retinal dysfunction Higher FFA scores, and vitreous haze grading were weakly, but significantly, correlated with cone-generated ffERG responses.

Multifocal electroretinographic findings in angiographic macular leakage in the setting of intermediate, posterior, or panuveitis.

OBJECTIVE: To evaluate the functional implications of angiographic macular leakage without the presence of intraretinal fluid on optical coherence tomography (OCT) in eyes with intermediate, posterior, or panuveitis. METHODS: Retrospective study on patients with a diagnosis of intermediate, posterior, or panuveitis. Patients who had fluorescein angiography, OCT, and multifocal electroretinography (mfERG) within a predetermined time frame were included. Demographic and clinical data including types of ocular inflammation and best-corrected visual acuity (BCVA), in addition to OCT, fluorescein angiography, and mfERG data were collected. The study cohort was divided into 2 groups based on the presence of angiographic macular leakage and macular edema (ME): group 1 (no ME and no macular leakage) and group 2 (presence of macular leakage without ME). RESULTS: A total of 29 patients (43 eyes) were included in the study, with 13 patients (17 eyes) in group 1 and 16 patients (26 eyes) in group 2. No statistically significant differences in age, sex, anterior-chamber cells, lens status, vitreous cells, vitreous haze, BCVA, or mean central subfoveal thickness were found between groups 1 and 2. All mfERG values, including N1 and P1 response densities and timings for rings 1-5, did not show any statistically significant difference between group 1 and 2. No correlation was found between either BCVA or central subfoveal thickness and any of mfERG values for rings 1-3. CONCLUSIONS: In absence of ME, angiographic macular leakage in eyes with uveitis might not be associated with worse macular function when compared with eyes without angiographic macular leakage.

Effect of Pupil Size on Fixed-Luminance Flicker Full-Field Electroretinogram Magnitude.

Purpose: Diopsys® NOVA fixed-luminance flicker full-field electroretinogram (ffERG) device is a potential adjunct to conventional flicker ffERG testing for assessing cone cell function. Magnitude of measured electrical response is known to vary with pupil size in conventional ffERG testing. The index study characterizes the relationship between magnitude of measured electrical activity and pupil size, both pupil diameter and pupil area, for this device. Methods: Seventeen patients (34 eyes) with no known ocular diseases were enrolled in the study. Electrophysiologic function of cone cells was evaluated using fixed-luminance flicker ffERG before and after dilation. Linear regression models, with inter-eye correlations controlled as fixed-effects, were used to characterize the effect of pupil dilation on the magnitude of the measured responses. Results: Mean age of study patients was 33.5 (standard deviation 7.4 years), and 35.3% of the subjects were female. Mean value of electrical response magnitude was 10.07±2.79µV before dilation and 15.30±4.08µV after dilation. The correlations of ERG magnitude with pupil diameter and with pupil area were not significant for either dilated or undilated eyes considered separately but were highly significant (p<0.001) for dilated and undilated eyes considered in aggregate. ERG magnitude tended to increase by 1.08 µV for every 1 mm increase in pupillary diameter. Conclusion: An increase in pupil size, both pupil diameter and pupil area, is significantly associated with an increase in flicker ffERG magnitude recorded by the Diopsys device, suggesting that pupil size should be measured and considered when making clinical judgments based on the flicker ffERGs recorded by the device, and that pupil size-specific reference ranges could improve the clinical utility of the device.

Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses.

Gene therapy has emerged as a research topic of choice in recent years. The eye in particular is one of few organs of the body for which gene therapy has received Food and Drug Administration approval, and it remains a field of great interest for gene therapy development. However, its associated immune and inflammatory reactions may render the treatment ineffective or harmful, which are of particular concern for the eyes due to their susceptibility to inflammation. The severity of immune and inflammatory reactions depends on the choice of vector and its route of administration. Furthermore, most preclinical and clinical studies have shown that the dose of vectors is correlated with the degree of humoral response and ocular inflammation. The route of administration directly impacts the degree of immune and inflammatory reaction. Subretinal delivery produces a weaker humoral response than the intravitreal route. However, some studies have demonstrated that the subretinal delivery induces a stronger inflammatory reaction. On the other hand, several instances of vision loss due to severe late onset intraocular inflammation were reported in a clinical trial involving intravitreal delivery of viral vectors. When compared with the intravitreal route, suprachoroidal gene delivery has been shown to produce weaker humoral response. However, unlike the subretinal space, the suprachoroidal space is not known to have immune privilege status. Inflammatory reactions following ocular gene therapy are typically mild and most clinical and preclinical studies have shown that they can be controlled with topical, local or systemic steroids. However, severe inflammatory responses may occur and require aggressive management to avoid permanent vision loss. Further investigations are required to elucidate and expand our knowledge of inflammatory reactions, and their optimal management, following ocular gene therapy.

Safety of Intravenous Methylprednisolone in Refractory and Severe Pediatric Uveitis.

Purpose: To evaluate the safety of intravenous high-dose pulse methylprednisolone succinate (IVHDM) in the management of severe or refractory non-infectious pediatric uveitis. Methods: We reviewed all uveitis patients who were ≤16 years of age and who received IVHDM with a dose of ≥500 mg per day (1-3 days a month) for at least 3 months during their management at a tertiary care eye hospital. Results: Twenty pediatric patients with severe or refractory uveitis who received IVHDM were identified. Six patients received IVHDM either once, as a preoperative medication, or at a lower dose than 500 mg, and were excluded. The remaining 14 patients received IVHDM for at least 4 months. Age (mean±SD) was 11.9±2.4 years and 50% were female. Duration of treatment was 14.2±7.5 months. Thirteen patients received IVHDM in combination with other immunomodulatory therapy (IMT). Except for two outliers, IVHDM was given at a dose of 8-25 mg/kg per infusion. Three major adverse events (AEs) occurred in two patients: a single episode of bradycardia, compression fracture following minor trauma and adrenal insufficiency. The number of AEs (major and minor) strongly correlated with duration of treatment (p=0.004) and moderately correlated with the cumulative dose/weight (p=0.051). Weight gain was associated with the use of concomitant oral steroids and not with duration of treatment or cumulative dose. Conclusion: IVHDM may be a valid therapeutic option for aggressive/refractory pediatric uveitis. The reported AEs in this series can also be attributed to the concurrent IMT or the underlying disease itself.

Yet another case of ocular sarcoidosis.

PURPOSE: To report a case of bilateral pan-uveitis resembling fungal and viral endophthalmitis in a patient who was ultimately diagnosed with sarcoidosis. OBSERVATION: A 64-year-old female presented with a four-day history of painless vision loss in the right eye. She presented with multiple concurrent systemic complaints, including a history of oral and genital sores, patches of hypopigmented skin on her forearms, and occasional shortness of breath. Upon further examination, she was noted to have bilateral pan-uveitis, which was more severe in the right than left eye. Posterior pole examination of the right eye revealed dense vitritis with multiple large whitish round balls that seemed suggestive of fungal or viral endophthalmitis. Initial therapies included intravitreal (IVT) foscarnet and intravenous (IV) acyclovir, followed by IV amphotericin B and oral voriconazole, which did not improve ocular signs and symptoms. Further evaluations ruled out infectious etiologies and lymphoma. Chest computerized tomography (CT) scan revealed findings suggestive of sarcoidosis, which was confirmed with lung biopsy. Anti-viral and -fungal treatments were discontinued, and the patient was started on IV methylprednisolone followed by oral prednisone and mycophenolate mofetil. Ocular symptoms improved, and the patient remained stable after treatment. CONCLUSION AND IMPORTANCE: The index report illustrates a case of ocular sarcoidosis that imitated the presentation of infectious endophthalmitis. Though ocular sarcoidosis is known to masquerade as a range of disorders and constitutes part of the differential diagnosis for infectious endophthalmitis, sarcoidosis has not been reported in recent literature to imitate the presentation of fungal endophthalmitis. The index case suggests that ocular sarcoidosis should be considered in the differential diagnoses of fungal endophthalmitis.

Episodic recognition memory and the hippocampus in Parkinson's disease: A review.

Parkinson's disease is a progressive neurodegenerative disorder of aging. The hallmark pathophysiology includes the development of neuronal Lewy bodies in the substantia nigra of the midbrain with subsequent loss of dopaminergic neurons. These neuronal losses lead to the characteristic motor symptoms of bradykinesia, rigidity, and rest tremor. In addition to these cardinal motor symptoms patients with PD experience a wide range of non-motor symptoms, the most important being cognitive impairments that in many circumstances lead to dementia. People with PD experience a wide range of cognitive impairments; in this review we will focus on memory impairment in PD and specifically episodic memory, which are memories of day-to-day events of life. Importantly, these memory impairments severely impact the lives of patients and caregivers alike. Traditionally episodic memory is considered to be markedly dependent on the hippocampus; therefore, it is important to understand the exact nature of PD episodic memory deficits in relation to hippocampal function and dysfunction. In this review, we discuss an aspect of episodic memory called recognition memory and its subcomponents called recollection and familiarity. Recognition memory is believed to be impaired in PD; thus, we discuss what aspects of the hippocampus are expected to be deficient in function as they relate to these recognition memory impairments. In addition to the hippocampus as a whole, we will discuss the role of hippocampal subfields in recognition memory impairments.

The effects of dopamine on digit span in Parkinson's disease.

BACKGROUND: Parkinson's disease patients are at an elevated risk of developing cognitive impairment. Although cognitive impairment is one of the strongest predictors of quality of life, dopaminergic anti-parkinsonian medications are designed to target motor symptoms. However, there is substantial evidence that dopamine also impacts cognition, in particular working memory. It is therefore critical for movement disorders physicians to understand the potential dopaminergic effects on working memory when prescribing these medications. Verbal digit span tasks offer a potentially straightforward and quick assessment of baseline working memory. Moreover, Digit Span Backward was recently validated as a screening tool for mild cognitive impairment in Parkinson's disease when participants were medicated. Research indicates that the interaction between dopamine and working memory follows an Inverted-U shaped curve, but the effect of dopamine on Digit Span has not been well studied. Our study seeks to: (1) determine the validity of verbal Digit Spans for detecting cognitive impairment in Parkinson's disease patients both ON and OFF medications; and (2) ascertain the effects of dopaminergic medications on verbal Digit Span. METHODS: We recruited 64 Parkinson's disease patients and 22 age-and education-matched controls. Parkinson's patients completed Digit Span Backward and Digit Span Forward ON and OFF medications, while healthy controls completed them once. All participants were categorized by cognitive diagnosis using level-II consensus criteria. RESULTS: Digit Span Backward successfully identified mild cognitive impairment in Parkinson's disease, both ON and OFF medications. Combining patients with and without cognitive impairment, we found that dopamine significantly improved performance on Digit Span Backward, but not Forward. In a secondary analysis, we found this dopaminergic improvement was restricted to the Low baseline working memory group; the High baseline working memory group was unaffected. CONCLUSIONS: This study provides evidence for Digit Span Backward as a screening tool for working memory impairment in Parkinson's disease and for its utility in measuring baseline working memory. Moreover, it reveals a partial beneficial effect of dopamine on Digit Span in Parkinson's disease patients.

Accessory lateral rectus in a patient with normal ocular motor control.

Although supernumerary extraocular muscles are common in monkeys and other species, they are relatively rare in humans and typically are noted in the context of childhood strabismus. We present a case of an incidentally found unilateral accessory lateral rectus muscle in a 51-year-old woman with normal ocular motor control. In this patient, the accessory lateral rectus was approximately 10% the size of a normally sized lateral rectus muscle. It originated from the orbital apex, traveled between the optic nerve and the lateral rectus and attached to the superolateral aspect of the globe. This unique case demonstrates that accessory lateral rectus in humans may have no impact on eye movement and ocular alignment.