Cerebrospinal Fluid Cytokine and Chemokine Profiles in Central Nervous System Sarcoidosis: Diagnostic and Immunopathologic Insights.

OBJECTIVE: To evaluate the cerebrospinal fluid (CSF) cytokine/chemokine profile of central nervous system (CNS) neurosarcoidosis (NS), and its utility in differential diagnosis, treatment, and prognostication. METHODS: In this case-control study, we validated 17 cytokines/chemokines (interleukin [IL]-1-beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and tumor necrosis factor [TNF]-alpha) in a multiplexed automated immunoassay system (ELLA; Bio-Techne, Minneapolis, MN, USA), and assessed them in CSF and serum of symptomatic patients with probable or definite CNS NS (01/2011-02/2023) with gadolinium enhancement and/or CSF pleocytosis. Patients with multiple sclerosis, primary CNS lymphoma, aquaporin-4 immunoglobulin G positivity, non-inflammatory disorders, and healthy individuals were used as controls. RESULTS: A total of 32 NS patients (59% women; median age, 59 years [19-81]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin-4 immunoglobulin G positive, and 34 patients with non-inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL-2, IL-6, IL-10, IL-13, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and TNF-alpha levels were significantly higher in NS patients compared with non-inflammatory controls (p ≤ 0.02); elevations were more common in CSF than serum. Concurrent elevation of IL-6, CXCL9, CXCL10, GM-CSF, interferon-gamma, and TNF-alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL-6, IL-10, IL-13, CXCL9, CXL10, GM-CSF, and TNF-alpha associated with measures of disease activity. INTERPRETATION: NS CSF cytokine/chemokine profiles suggest T cell (mainly T helper cell type 1), macrophage, and B-cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. ANN NEUROL 2024.

Neurological autoimmunity in patients with non-pulmonary neuroendocrine neoplasms: clinical manifestations and neural autoantibody profiles.

BACKGROUND AND PURPOSE: Paraneoplastic neurological autoimmunity is well described with small-cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs). METHODS: Adult patients with histopathologically confirmed non-pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116). RESULTS: Thirty-four patients were identified (median age 68 years, range 31-87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non-ICI-treated patients. The most frequent neurological phenotypes (non-ICI-treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q-type voltage-gated calcium channel [seven], muscle-type acetylcholine receptor [three], anti-neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non-ICI-treated) and neural autoantibody positivity was associated with poor neurological outcome. DISCUSSION: Neurological autoimmunity associated with non-pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment.

Development of an intravitreal peptide (BQ123) sustained release system based on poly(2-hydroxyoctanoic acid) aiming at a retinal vasodilator response.

PURPOSE: Development of a novel formulation for intravitreal administration, in which the endothelinA receptor antagonist BQ123 is incorporated in a biodegradable and injectable polymer drug delivery system, poly(2-hydroxyoctanoic acid), aiming at a prolonged retinal vasodilator response. METHODS: BQ123 was incorporated in poly(2-hydroxyoctanoic acid), leading to an easily injectable, homogenous mixture. In vitro release profiles were obtained in porcine vitreous humor (n=6). The ex vivo biocompatibility was studied by placing the formulation in contact with porcine retinal tissues and performing histology. In a pilot in vivo study, the change in retinal vessel diameter of mini pigs (n=2) was followed over 3 h after an intravitreal injection of the formulation, as well as the release of BQ123 from the polymer system for approximately 7 days (n=6). RESULTS: In vitro, a constant release profile was obtained, releasing approximately 91% of BQ123 within 7 days. Histology on the porcine retinal tissues showed good ex vivo biocompatibility. In vivo, a vasodilative response was observed, with a retinal vessel diameter increase from 14% after 15 min, for approximately 39% after 3 h. At t=3 h, the BQ123 concentration in the vitreous humor was 0.7±0.2 µg/mL, followed by 1.5±1.0 and 1.1±0.8 µg/mL after 3 and 7 days, respectively. 39.9%±6.0% of BQ123 was still present in the polymer depot at t=7 days. CONCLUSIONS: The results show that an intravitreal injection of this drug delivery system leads to a prolonged vasodilative response and a BQ123 release over 7 days, suggesting its therapeutic potential in the management of retinal ischemic conditions.

Choroidoretinal granuloma in a young female patient.

A 16-year-old Brazilian female patient presented with blurring of vision in the right eye. Corrected visual acuity was OD 2/20, OS 20/20. Afferent pupillary defect was absent and anterior segment examination revealed anterior uveitis. Fundus examination showed light vitritis and a raised grey-white granuloma located at posterior pole with focal serous retinal detachment on optical coherence. Indocyacnine green angiography disclosed a complete mask effect in granuloma's area. Differential diagnoses were infectious (bacterial, viral, fungal and parasites) diseases, systemic inflammatory diseases, tumours. Blood serologies (HIV, toxoplasma, Borrelia, cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), rubeola) showed positive results for IgM and IgG for toxoplasma, and anterior chamber tap (PCR for toxoplasma, CMV, HSV, VZV) revealed toxoplasma DNA. Anti-toxoplasma therapy, pyrimethamine, sulfadiazine and calcium folinate, was administered immediately. On follow-up granuloma regression was observed, with complete visual restoration. This case demonstrates a clinically challenging posterior pole granuloma.

Long-term results of the effect of intravitreal ranibizumab on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration.

PURPOSE: To study the effect of intravitreal (IVT) ranibizumab on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration (AMD). METHODS: Ten eyes of 10 patients with previously untreated neovascular AMD were included. All eyes had three monthly IVT injections of ranibizumab and then were retreated as needed, based on visual acuity and optical coherence tomography (OCT) criteria. The diameter of the retinal arterioles was measured in vivo with a retinal vessel analyser (RVA) before the first IVT injection, 7 and 30 days after the first, the second and the third injection, and at month 12 of follow-up. RESULTS: A significant vasoconstriction of the retinal arterioles was observed following each one of the first three IVT injections of ranibizumab. Thirty days following the first, second and third injection, there was a mean decrease of 8.4 ± 3.2%, 11.9 ± 4.5% and 18.5 ± 7.2%, respectively, of the retinal arteriolar diameter compared with baseline (p < 0.01). At month 12, the vasoconstriction was still present with a mean decrease of 19.1 ± 8.3% of the retinal arteriolar diameter compared with baseline (p < 0.01). Median number of ranibizumab injections was 4 (range 3-10). There was no correlation between the number of injections and percentage diameter decrease at month 12 (r = -0.54, p > 0.1). There was no significant change in mean arterial pressure (MAP) during the period of follow-up (p > 0.05). CONCLUSIONS: These results suggest that IVT ranibizumab induces sustained retinal arteriolar vasoconstriction in eyes with neovascular AMD.

Experimental application of tissue adhesives in corneal traumas.

OBJECTIVE: To evaluate intraoperative difficulties of the use of glues for corneal trauma.
 METHODS: Partial or full-thickness perpendicular corneal incisions (3-4 mm straight cuts) near the limbus (perpendicular or parallel to it) were made in 8 albino rabbits and were then sealed with fibrin or cyanoacrylate glue. Follow-up examinations were performed under the surgical microscope. Tissue specimens were also taken for light microscopic evaluation. 
 RESULTS: The cyanoacrylate glue polymerized almost immediately after application on the tissue, limiting the ability of the surgeon to oppose the corneal incisions appropriately. The fibrin glue polymerized more gradually, giving enough time for manipulations to reconstruct the wound properly and for removal of excessive glue, especially when the 2 components were applied separately. Excessive glue and crust formation on the eye surface induced irritation.
 CONCLUSIONS: Fibrin glue for the reconstruction of corneal wounds was easier to use than cyanoacrylate glue and caused less glue crust formation on the corneal surface. The speed of polymerization is an important factor. Excessive glue on the cornea was irritating.

New strategy to study corneal endothelial cell transplantation: the chick cornea model.

PURPOSE: To set up a culture assay of chick corneal endothelial cells (CECs) for transplantation into host corneas. METHODS: Histology sections were performed at 6, 9, 12, 15, and 18 embryonic days of development of the chick embryo. Visualization of the gross morphology of CECs and of epithelium, stroma, and Descemet membrane was performed. Transplantation of CECs at 18 embryonic days of development into explanted, denuded from endothelial cell, host corneas of the same stage was attempted. RESULTS: The results from the histological sections clearly indicate that after embryonic day 12, the endothelial cells are well differentiated and the proliferation is complete. Transplanted CECs were able to migrate and integrate into the denuded host corneas. CONCLUSIONS: This study demonstrated its feasibility using an easy accessible model of chick cornea. With this technique, sufficient CECs may be obtained for biochemical and functional investigations using only nonhatched chickens that are easily accessible and easy to manipulate.

Vasomotor effect of intravitreal juxta-arteriolar injection of L-lactate on the retinal arterioles after acute branch retinal vein occlusion in minipigs.

PURPOSE: To investigate the effect of L-lactate on retinal arteriolar diameter after acute branch retinal vein occlusion (BRVO) in minipigs. METHODS: Thirteen eyes of 13 minipigs were evaluated, with the animals under general anesthesia. BRVO was induced by a standard method of argon laser endophotocoagulation. Two hours after BRVO, an intravitreal, juxta-arteriolar microinjection of 50 µL L-lactate 0.5 M (pH 7.4) was performed in nine eyes. Four eyes received a microinjection of 50 µL of the solvent (pH 7.4) that was used to prepare the solution of L-lactate and served as controls. Retinal arteriolar diameter changes were measured using a retinal vessel analyzer. RESULTS: Overall (n = 13), 2 hours after BRVO, there was a 9.0% ± 1.4% decrease in the retinal arteriolar diameter in the affected ares compared to baseline (P < 0.001). An increase of 26.2% ± 8.2% (P = 0.004) of the arteriolar diameter was evidenced 5 minutes after L-lactate juxta-arteriolar microinjection (n = 9) compared with the diameter before L-lactate microinjection. Thereafter, the vasodilatory effect of L-lactate persisted and remained significant until the end of the study period (27.7% ± 7.8% at 30 minutes) compared with the diameter before L-lactate microinjection (P = 0.002). Microinjection of the solvent alone (n = 4) did not produce any significant effect on the retinal arterioles, which remained constricted at all time-points (P > 0.1). CONCLUSIONS: These findings demonstrate a significant arteriolar vasodilation after intravitreal juxta-arteriolar L-lactate microinjection in eyes with experimental BRVO in the affected areas. L-lactate microinjection can reverse the arteriolar vasoconstriction that occurs in acute experimental BRVO.

WITHDRAWN: One Year Results of the Effect of Intravitreal Ranibizumab on the Retinal Arteriolar Diameter in Patients with Neovascular Age-Related Macular Degeneration.

Withdrawn at the request of the author.

Retinal vessel analyzer measurements of the effect of panretinal photocoagulation on the retinal arteriolar diameter in diabetic retinopathy.

PURPOSE: The purpose of this study was to investigate the effect of panretinal photocoagulation (PRP) on the retinal arteriolar diameter in patients with diabetic retinopathy using a retinal vessel analyzer. METHODS: Ten eyes of 6 consecutive patients with type II diabetes and severe nonproliferative or proliferative diabetic retinopathy were studied prospectively. Measurements of the retinal arteriolar diameter were performed before the first photocoagulation session and after the end of the PRP treatment. RESULTS: Retinal arteriolar diameter before PRP was 131 +/- 15 arbitrary units and decreased to 112 +/- 14 arbitrary units after PRP (P = 0.012). There was a significant vasoconstriction of 13.8% +/- 8.3% following PRP. Mean visual acuity before and after PRP was 0.31 +/- 0.36 logarithm of the minimal angle of resolution and 0.28 +/- 0.30 logarithm of the minimal angle of resolution, respectively (P = 0.68). There was no significant change in mean arterial pressure before and after PRP (P = 0.89). There was no correlation between the visual acuity change or the number of laser burns and the percentage change in the retinal arteriolar diameter (P > 0.1). CONCLUSION: Panretinal photocoagulation has a vasoconstrictive effect on retinal arterioles in patients with severe nonproliferative or proliferative diabetic retinopathy. These results are consistent with an autoregulatory response of the retinal circulation to increased inner retinal oxygen tension after PRP. The retinal vessel analyzer is a fast, accurate, noninvasive, online measuring system for the study of the retinal vascular response to PRP in patients with diabetic retinopathy.

Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration.

OBJECTIVE: To study the effect of intravitreal (IVT) ranibizumab (Lucentis; Genentech, Inc, San Francisco, CA) on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration (AMD). DESIGN: Prospective consecutive interventional case series. PARTICIPANTS: Eleven eyes of eleven patients with previously untreated neovascular AMD. METHODS: All eyes had 3 monthly IVT injections of ranibizumab. The diameter of the retinal arterioles was measured in vivo with a retinal vessel analyzer (RVA) before the first IVT injection and then 7 and 30 days after the first, second, and third injections. MAIN OUTCOME MEASURES: Primary end points were changes in retinal arteriolar diameter and mean arterial pressure (MAP) after IVT ranibizumab. Secondary end points were changes in best-corrected visual acuity (BCVA), central retinal thickness, and intraocular pressure after IVT ranibizumab, and appearance of adverse events during the follow-up period. RESULTS: A significant decrease of the retinal arteriolar diameter was observed after each IVT injection of ranibizumab. Thirty days after the first, second, and third injections, there was a mean decrease of 8.1+/-3.2%, 11.5+/-4.4%, and 17.6+/-7.4%, respectively, of the retinal arteriolar diameter compared with baseline values (P<0.01). There was no significant change in MAP during the period of follow-up (P>0.05). Thirty days after the third IVT injection of ranibizumab, mean BCVA improved by 6.5+/-4.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central retinal thickness decreased by 91+/-122 microm (P = 0.03). CONCLUSIONS: These results suggest that IVT ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular AMD after IVT ranibizumab. Further studies evaluating larger sample sizes are needed to confirm these results and potential adverse effects on the retinal circulation in patients with AMD and retinal vascular diseases. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Lactate-induced retinal arteriolar vasodilation implicates neuronal nitric oxide synthesis in minipigs.

PURPOSE: To investigate the role of neuronal nitric oxide (NO) synthesis in the retinal vasodilatory response to lactate in minipigs. METHODS: Thirteen eyes of 13 minipigs were evaluated. Ten eyes received an intravenous infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME). After 1 hour, the same eyes received an intravitreous juxta-arteriolar microinjection of 30 microL of L-lactate 0.5 M (pH 7.4) through a micropipette. Ten minutes later, 9 of 10 eyes received an intravitreous juxta-arteriolar microinjection of 30 microL of L-NAME 0.01 M (pH 7.4), and 1 received physiologic saline solution (PSS). The remaining three eyes received a microinjection of 30 microL of L-lactate 0.5 M (pH 7.4), without intravenous or intravitreous L-NAME. RESULTS: The three eyes that received juxta-arteriolar injection of L-lactate only showed a reproducible increase in retinal arteriolar diameter that persisted during the entire study period (maximum effect at 20 minutes, 40.9% +/- 3.2%). Retinal arteriolar diameter decreased by 4.1% 1 hour after intravenous L-NAME when compared with baseline but the difference did not reach significance. The juxta-arteriolar injection of L-lactate induced a significant increase in retinal arteriolar diameter (22.7% and 28.7% at 5 and 10 minutes, respectively; P < 0.01), followed by a significant decrease (8.6%; P < 0.01) 10 minutes after juxta-arteriolar injection of L-NAME. Injection of PSS had no effect on retinal arteriolar diameter. CONCLUSIONS: Juxta-arteriolar administration of L-lactate induced vasodilation, which was also observed with continuous intravenous infusion of L-NAME. Moreover, juxta-arteriolar L-NAME microinjection significantly suppressed the vasodilatory effect of L-lactate. These data suggest that neuronal-derived NO is an important mediator of lactate-induced vasodilation in minipigs.