Evaluation of intravitreal injections as a risk factor for capsular rupture during cataract surgery.

OBJECTIVE: To determine whether previous intravitreal injections are an independent risk factor for posterior capsular rupture (PCR) during cataract surgery after adjusting for known risk factors. DESIGN: Single-centre medical records analysis of a population-based cohort at a university-based referral centre. A retrospective cohort study has been conducted with inclusion of cataract surgeries done from January 1, 2005 to December 31, 2020 at the Department of Ophthalmology, Medical University of Graz, Austria. PARTICIPANTS: All consecutive cataract surgeries done in patients of at least 18 years of age from January 1, 2005 to December 31, 2020 have been included. METHODS: Association between previous intravitreal injections and PCR rates has been analysed through univariable and multivariable generalized estimating equations (GEE). Other investigated risk factors were age, combined surgery, pseudoexfoliation, surgeon's experience, and type of cataract surgery. RESULTS: A statistically significant higher rate of posterior capsular rupture during cataract surgery has been found in patients with previous intravitreal therapy compared with patients with no history of intravitreal therapy (OR 1.27, 95% CI 1.10-1.46, p = 0.008). However, after adjusting for confounding risk factors, no statistically significant effect was seen (OR 1.04, 95% CI 0.89-1.21, p = 0.664). CONCLUSION: We found no association between history of intravitreal injections and PCR during cataract surgery after adjusting for known risk factors. Further studies upon interactions between history of intravitreal injections and known risk factors for PCR, especially pseudoexfoliation, are needed.

Metformin in Glaucoma Treatment.

PRCIS: Rigorous trials are essential to develop comprehensive treatment strategies that fully exploit the therapeutic potential of metformin in the treatment of glaucoma. OBJECTIVE: The objective of this study was to evaluate the potentially beneficial effect of metformin on glaucoma risk factors and to investigate the underlying mechanisms. The aim is to contribute to the development of new treatment strategies for glaucoma. METHODS: We searched for studies that assessed the effects of metformin on glaucoma risk factors and the associated underlying mechanisms. Our search included electronic databases such as PUBMED, EMBASE, and clinicaltrials.gov. RESULTS: Unfortunately, we did not find any clinical trials that specifically investigated the impact of metformin on glaucoma. However, data from experimental studies demonstrated the capability of metformin to modulate various pathways that could contribute to neuroprotection in glaucoma. CONCLUSION: In order to develop comprehensive treatment strategies that fully exploit the therapeutic potential of metformin in the treatment of glaucoma, rigorous trials are essential. These studies are necessary to demonstrate both the safety and efficacy of metformin in the context of glaucoma treatment.

Protective Effect of Amblyopia on Age-Related Macular Degeneration.

PURPOSE: Our aim was to evaluate whether patients with age-related macular degeneration (AMD) and cooccurrent amblyopia are more likely to have diseases diagnosed on both the ipsilateral and the contralateral side in a large Austrian database. DESIGN: Retrospective cross-sectional study. METHODS: Setting: Institutional practice. PATIENT POPULATION: Medical records of all patients who visited the Department of Ophthalmology of the Medical University of Graz between December 1996 and June 2021 were searched for the co-occurrence of AMD and amblyopia. MAIN OUTCOME MEASURES: Data from patients with AMD diagnosed on 1 eye side were used for further analysis. Spectral-domain optical coherence tomography images were analyzed to confirm the lateral asymmetry of AMD. RESULTS: A total of 327,443 patients were screened for the co-occurrence of AMD and amblyopia. Of them, 8742 patients had AMD diagnosed on 1 eye side and 5051 patients had unilateral amblyopia. In total, 163 patients were found to have AMD diagnosed on 1 side and unilateral amblyopia in combination. Of these, 126 patients had AMD and amblyopia on contralateral sides and 37 had AMD and amblyopia on the ipsilateral side (P < .001). CONCLUSIONS: Less amblyopic patients had AMD diagnosed on the amblyopic eye compared with the nonamblyopic eye. In cases of lateral asymmetry, the nonamblyopic eye is more likely to have the more advanced form of AMD.

Postoperative Pain after Different Transscleral Laser Cyclophotocoagulation Procedures.

BACKGROUND: As the number of surgical options in glaucoma treatment is continuously rising, evidence regarding distinctive features of these surgeries is becoming more and more important for clinicians to choose the right surgical treatment for each individual patient. METHODS: For this retrospective data analysis, we included glaucoma patients treated with either continuous wave (CW-TSCPC) or micropulse transscleral cyclophotocoagulation (MP-TSCPC) in an inpatient setting. Pain intensity was assessed using a numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst imaginable pain) during hospitalization. CW-TSCPC was performed using OcuLight® Six (IRIDEX Corporation, Mountain View, CA, USA) and MP-TSCPC was performed using the IRIDEX® Cyclo-G6 System (IRIDEX Corporation, Mountain View, CA, USA). RESULTS: A total of 243 consecutive cases of TSCPC were included. Of these, 144 (59.26%) were treated with CW-TSCPC and 99 (40.74%) with MP-TSCPC. Using the univariable model, the risk for postoperative pain was observed to be lower in MP-TSCPC compared with CW-TSCPC (unadjusted: OR 0.46, 95% CI 0.24-0.84, p = 0.017), but this did not hold using the multivariable model (adjusted: OR 0.52, 95% CI 0.27-1.02, p = 0.056). Simultaneously conducted anterior retinal cryotherapy was associated with a higher risk for postoperative pain (OR 4.41, 95% CI 2.01-9.69, p < 0.001). CONCLUSIONS: We found that the occurrence of postoperative pain was not different in CW-TSCPC compared with MP-TSCPC in a multivariable model. In cases of simultaneous anterior retinal cryotherapy, the risk for postoperative pain was significantly higher.

Neurofilament light chain: a new marker for neuronal decay in the anterior chamber fluid of patients with glaucoma.

BACKGROUND/AIMS: Neurofilament light chain (NfL) levels in cerebrospinal fluid and serum are reliable indicators for neuroaxonal damage in a broad spectrum of neurodegenerative diseases. Herein, we investigate NfL levels in serum and anterior chamber fluid of patients with glaucoma. METHODS: Patients scheduled for routine glaucoma or cataract surgery were recruited for this study. Retinal nerve fibre layer thickness was measured by optical coherence tomography (OCT, Heidelberg Spectralis). NfL levels in serum and in anterior chamber fluid were analysed with Simoa SR-X Analyzer (Quanterix; NFLIGHT, Lexington, Massachusetts, USA). T-test was used for parametric data and Mann-Whitney-U test for nonparametric data. Spearman's rank-order correlation was used to investigate correlations. P values<0.05 were considered as statistically significant. RESULTS: Sixty patients with glaucoma and 58 controls were enrolled. Serum NfL concentration of patients with glaucoma was similar to serum NfL concentration in controls (median (IQR); 22.7 (18.9) pg/mL vs 22.5 (24.0) pg/mL; p=0.763). A positive correlation of serum NfL with age was observed in both patients with glaucoma (r=0.77; p<0.001) and in the control group (r=0.82, p<0.001). In the anterior chamber fluid, the NfL concentration was substantially increased in patients with glaucoma compared with controls (20.7 (101.3) pg/mL vs 3.1 (2.9) pg/mL; p<0.001). Furthermore, we found a positive correlation of anterior chamber fluid NfL with preoperative intraocular pressure (r=0.39, p=0.003) and with retinal nerve fibre layer thickness (r=0.58, p<0.001). CONCLUSION: NfL levels in anterior chamber fluid are elevated in patients with glaucoma and correlate with intraocular pressure and retinal nerve fibre layer thickness. The presented data strongly support anterior chamber fluid NfL as a new marker for glaucoma.

α-Synuclein modulates fibronectin expression in the trabecular meshwork independent of TGFß2.

α-Synuclein (α-Syn) is implicated in Parkinson's disease (PD), a neuromotor disorder with prominent visual symptoms. The underlying cause of motor dysfunction has been studied extensively, and is attributed to the death of dopaminergic neurons mediated in part by intracellular aggregation of α-Syn. The cause of visual symptoms, however, is less clear. Neuroretinal degeneration due to the presence of aggregated α-Syn has been reported, but the evidence is controversial. Other symptoms including those arising from primary open angle glaucoma (POAG) are believed to be the side-effects of medications prescribed for PD. Here, we explored the alternative hypothesis that dysfunction of α-Syn in the anterior eye alters the interaction between the actin cytoskeleton of trabecular meshwork (TM) cells with the extracellular matrix (ECM), impairing their ability to respond to physiological changes in intraocular pressure (IOP). A similar dysfunction in neurons is responsible for impaired neuritogenesis, a characteristic feature of PD. Using cadaveric human and bovine TM tissue and primary human TM cells as models, we report two main observations: 1) α-Syn is expressed in human and bovine TM cells, and significant amounts of monomeric and oligomeric α-Syn are present in the AH, and 2) primary human TM cells and human and bovine TM tissue endocytose extracellular recombinant monomeric and oligomeric α-Syn via the prion protein (PrPC), and upregulate fibronectin (FN) and α-smooth muscle actin (α-SMA), fibrogenic proteins implicated in POAG. Transforming growth factor ß2 (TGFß2), a fibrogenic cytokine implicated in ∼50% cases of POAG, is also increased, and so is RhoA-associated coiled-coil-containing protein kinase 1 (ROCK-1). However, silencing of α-Syn in primary human TM cells reduces FN, α-SMA, and ROCK-1 in the absence or presence of over-expressed active TGFß2, suggesting modulation of FN and ROCK-1 independent of, or upstream of TGFß2. These observations suggest that extracellular α-Syn modulates ECM proteins in the TM independently or via PrPC by activating the RhoA-ROCK pathway. These observations reveal a novel function of α-Syn in the anterior eye, and offer new therapeutic options.

Determining the center of a keratoconus: Comparison of different tomographic parameters and impact of disease severity.

Purpose: There exists remarkable variation in definitions for the location of the center of a keratoconus. The objective of this study was to analyze deviations between locations obtained by different tomographic maps for that purpose. Furthermore, it was investigated whether these deviations are influenced by disease severity. Methods: In 162 eyes with keratoconus, corneal tomographic maps derived by Scheimpflug technology were retrospectively analyzed to determine the cone location with 5 different methods: maximum axial curvature of the front surface (Kmax), maximum tangential curvature of the front surface (tKmax), minimum pachymetry (Pachymin), maximum elevation of the front surface (ELEF), and maximum elevation of the back surface (ELEB). Distances between the locations were calculated and tested for a correlation with keratoconus severity and distance between cone and corneal vertex. Results: Cone locations derived from the curvature maps (Kmax, tKmax) showed the lowest agreement with the locations determined by pachymetry or elevation maps. The largest distances were found between Kmax and Pachymin [Median and Interquartile range: 1.19 mm (0.87, 1.60)], Kmax and ELEB [1.12 mm (0.79, 1.41)], and Kmax and ELEF [0.97 mm (0.64, 1.27)]. Low distances (<0.5 mm) were calculated between ELEB and ELEF, and ELEB and Pachymin. All of the calculated distances between the locations showed a significant negative correlation with keratoconus severity and most of them increased significantly with a more peripheral position of the cone (p < 0.05). Conclusions: There was low consistency between different methods for describing the location of a keratoconus. Curvature-based determinations of the cone center (Kmax, tKmax) showed the highest deviations and should not be used for that purpose. However, the discrepancies between different cone location methods diminished with increasing disease severity and more central position of the cone.

Glaucoma Medication and Quality of Life after Phacoemulsification Combined with a Xen Gel Stent.

Glaucoma has a significant impact on quality of life. Here, we aimed to evaluate the influence of a reduction in glaucoma medications on quality of life and patient satisfaction after phacoemulsification combined with the Xen gel stent. We carried out a cross-sectional survey of patients who underwent phacoemulsification with the Xen gel stent at the Medical University of Graz, Austria. Quality of life was assessed using the German version of the Glaucoma Symptoms Scale (GSS)-questionnaire. Patients were also asked whether the operation reduced glaucoma medications and to indicate their overall satisfaction from 1 (totally discontented) up to 10 (totally contented). Questionnaires of 80 patients were evaluated. A total of 36 patients (45.0%) reported a reduction in glaucoma medications. Three items of the GSS were significantly better in patients who needed fewer glaucoma medications after the operation ("hard to see in daylight", 75.0 ± 31.1 vs. 57.7 ± 39.1, p = 0.035; "hard to see in dark places", 81.1 ± 28.7 vs. 54.9 ± 41.2, p = 0.002; and "halos around lights", 88.3 ± 25.9 vs. 68.8 ± 38.6, p = 0.002). Patient satisfaction was significantly higher when the procedure led to a reduction in glaucoma medication (8.3 ± 2.0 vs. 6.8 ± 3.1; p = 0.034). The reported quality of life and patient satisfaction were significantly better when phacoemulsification with the Xen gel stent reduced the number of glaucoma medications needed.

Association of periodontitis and diabetic macular edema in various stages of diabetic retinopathy.

OBJECTIVES: Periodontitis and diabetes are known to have a bidirectional relationship. Diabetic macular edema is a complication of diabetes that is strongly influenced by inflammatory pathways. However, it remains to be established whether inflammation at other locations, such as periodontitis, affects diabetic macular edema. Here, we investigated the prevalence of periodontitis in patients treated for diabetic macular edema. MATERIALS AND METHODS: Patients with diabetic macular edema were recruited for this cross-sectional study at the Medical University of Graz. Macular edema was documented by optical coherence tomography. Periodontal status was assessed by computerized periodontal probing and panoramic X-ray imaging. Bleeding on probing, clinical attachment level, probing pocket depth, and plaque index were compared between different stages of diabetic retinopathy. RESULTS: Eighty-three eyes of 45 patients with diabetic macular edema were enrolled. Forty-four eyes (53.0%) had early stages of diabetic retinopathy (mild and moderate), and 39 eyes (47.0%) had late stages (severe and proliferative). Patients with mild or moderate DR were more likely to have more severe periodontal conditions than patients with severe or proliferative DR. Fourteen patients with mild DR (82.4%), 7 patients with moderate DR (87.5%), 4 patients with severe DR (100.0%), and 15 patients with proliferative DR (93.8%) had some degree of PD. The periodontal inflamed surface areas and the percentages of tooth sites that bled on probing were significantly higher in patients with early stages of diabetic retinopathy than in those with late stages of the disease (p < 0.05). Patients with periodontal inflamed surface areas of more than 500 mm2 required significantly more intravitreal injections in the last year than those with milder forms of periodontitis (n = 6.9 ± 3.1 versus n = 5.0 ± 3.5, p = 0.03). CONCLUSION: In patients with diabetic macular edema, periodontitis is more prevalent in early stages of diabetic retinopathy. We suggest regular dental check-ups for diabetic patients, especially when diabetic macular edema is already present. CLINICAL RELEVANCE: Patients with diabetic macular edema should be screened for periodontitis and vice versa, particularly early in the course of diabetes.

ß-Cleavage of the prion protein in the human eye: Implications for the spread of infectious prions and human ocular disorders.

Recently, we reported ß-cleavage of the prion protein (PrPC) in human ocular tissues. Here, we explored whether this is unique to the human eye, and its functional implications. A comparison of the cleavage pattern of PrPC in human ocular tissues with common nocturnal and diurnal animals revealed mainly ß-cleavage in humans, and mostly full-length PrPC in animal retinas. Soluble FL PrPC and N-terminal fragment (N2) released from ß-cleavage was observed in the aqueous and vitreous humor (AH & VH). Expression of human PrPC in ARPE-19 cells, a human retinal pigmented epithelial cell line, also showed ß-cleaved PrPC. Surprisingly, ß-cleavage was not altered by a variety of insults, including oxidative stress, suggesting a unique role of this cleavage in the human eye. It is likely that ß-cleaved C- or N-terminal fragments of PrPC protect from various insults unique to the human eye. On the contrary, ß-cleaved C-terminus of PrPC is susceptible to conversion to the pathological PrP-scrapie form, and includes the binding sites for ß1-integrin and amyloid-ß, molecules implicated in several ocular disorders. Considering the species and tissue-specific cleavage of PrPC, our data suggest re-evaluation of prion infectivity and other ocular disorders of the human eye conducted in mouse models.

Vitrectomy for diabetic macular edema and the relevance of external limiting membrane.

PURPOSE: To evaluate the relevance of external limiting membrane (ELM) on the visual and morphological results in eyes with diabetic macular edema (DME) that underwent pars plana vitrectomy (PPV) with epiretinal membrane (ERM) and internal limiting membrane (ILM) peeling. METHODS: Medical records of patients with DME who underwent PPV at our unit between January 2017 and December 2019 were reviewed. We assessed preoperative and postoperative best-corrected visual acuity (BCVA), central macular thickness (CMT) using spectral domain OCT (optical coherence tomography). Exclusion criteria were previous PPV; incomplete data; concomitant diseases including retinal vein occlusion, age-related macular degeneration, uveitis; and a follow-up of less than 12 months. The surgeries were performed using 23- or 27-gauge vitrectomy. The ELM was graded depending on its configuration (grade 0 = intact, grade 1 to 3: disruption of varying extent). RESULTS: Ninety-nine eyes were enrolled. The postoperative follow up averaged 23.7 months. The preoperative and final BCVA averaged 0.71 ± 0.28 and 0.52 ± 0.3 logMAR, respectively (p = 0.002). The CMT averaged 515.2 ± 209.1 µm preoperatively and 327 ± 66.1 µm postoperatively (p = 0.001). Eyes with intact ELM (n = 8) had a significantly better BCVA compared to those with ELM disruption (0.28 ± 0.14 vs. 0.7 ± 0.25 logMAR, p = 0.01). The final CMT was similar among the groups (intact ELM: 317 ± 54.6 µm; ELM disruption: 334 ± 75.2, p = 0.31). CONCLUSIONS: PPV with ERM and ILM peeling is an effective treatment of DME. Eyes with intact ELM preoperatively had a significantly better final visual outcome. To maximize the benefit for patients with DME we recommend early PPV as long as ELM is intact.

Release of Iron-Loaded Ferritin in Sodium Iodate-Induced Model of Age Related Macular Degeneration: An In-Vitro and In-Vivo Study.

To evaluate the role of iron in sodium iodate (NaIO3)-induced model of age-related macular degeneration (AMD) in ARPE-19 cells in-vitro and in mouse models in-vivo. ARPE-19 cells, a human retinal pigment epithelial cell line, was exposed to 10 mM NaIO3 for 24 h, and the expression and localization of major iron modulating proteins was evaluated by Western blotting (WB) and immunostaining. Synthesis and maturation of cathepsin-D (cat-D), a lysosomal enzyme, was evaluated by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) and WB, respectively. For in-vivo studies, C57BL/6 mice were injected with 40 mg/kg mouse body weight of NaIO3 intraperitoneally, and their retina was evaluated after 3 weeks as above. NaIO3 induced a 10-fold increase in ferritin in ARPE-19 cells, which co-localized with LC3II, an autophagosomal marker, and LAMP-1, a lysosomal marker. A similar increase in ferritin was noted in retinal lysates and retinal sections of NaIO3-injected mice by WB and immunostaining. Impaired synthesis and maturation of cat-D was also noted. Accumulated ferritin was loaded with iron, and released from retinal pigmented epithelial (RPE) cells in Perls' and LAMP-1 positive vesicles. NaIO3 impairs lysosomal degradation of ferritin by decreasing the transcription and maturation of cat-D in RPE cells. Iron-loaded ferritin accumulates in lysosomes and is released in lysosomal membrane-enclosed vesicles to the extracellular milieu. Accumulation of ferritin in RPE cells and fusion of ferritin-containing vesicles with adjacent photoreceptor cells is likely to create an iron overload, compromising their viability. Moreover, reduced activity of cat-D is likely to promote accumulation of other cellular debris in lysosomal vesicles, contributing to AMD-like pathology.

The Impact of Tape Sealing Face Masks on Visual Field Scores in the Era of COVID-19: A Randomized Cross-over Study.

PRECIS: Tape sealing of the face mask can prevent fogging artifacts of visual field testing. Here, we demonstrate that tape sealing can improve visual field scores even when fogging artifacts are not obvious. PURPOSE: The purpose of this study was to demonstrate that visual field scores improve when the face masks are taped to prevent fogging artifacts. METHODS: A Single-center, randomized 2×2 cross-over study. Twenty-six visual fields of 13 patients of the glaucoma outpatient clinic were included. Patients were randomized in either sequence 1 (Octopus visual field examination without tape sealing, followed by examination with tape sealing) or sequence 2 (examination with, followed by without tape sealing). RESULTS: The results for mean defect and square root of loss variance differ significantly in the examination with and without tape sealing [mean difference (without-with) 0.39 dB, 95% confidence interval: 0.07-0.70 dB, P=0.018 and 0.49 dB, 95% confidence interval: 0.19-0.79 dB, P=0.003, respectively]. There was no sequence effect (P=0.967) for mean defect nor the square root of loss variance (P=0.779). A significant effect for period (P=0.023) for mean defect was yielded. CONCLUSION: Tape sealing of face masks during visual field testing prevented fogging artifacts and improved visual field scores even when fogging artifacts were not obvious and should be considered in clinical practice.

Prion Protein on Human Leukocytes Is Reduced in Iron Deficiency - Possible Implications for Age-related Macular Degeneration?

MATERIALS AND METHODS: Patients presenting to the department of ophthalmology of the Medical University of Graz for reasons unrelated to prion diseases were enrolled. Parameters of iron metabolism, including ferritin and soluble transferrin receptor were measured by routine laboratory tests. Serum prion protein was determined by enzyme-linked immunosorbent assay. Surface prion protein on CD14+ monocytes and CD4+ T cells was analyzed by fluorescence activated cell sorting. RESULTS: 95 patients were enrolled. Soluble transferrin receptor correlated significantly with prion protein levels on CD14+POM1+ monocytes (P = .001, r = -0.7) and on CD4+POM1+ T cells (P = .01, r = -0.62). CONCLUSION: Our findings suggest a connection between the physiological function of the prion protein and iron metabolism in humans.

Prions and prion diseases: Insights from the eye.

Prion diseases are invariably fatal neurodegenerative disorders that have gained much publicity due to their transmissible nature. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common human prion disorder, with an incidence of 1 in a million. Inherited prion disorders are relatively rare, and associated with mutations in the prion protein gene. More than 50 different point mutations, deletions, and insertions have been identified so far. Most are autosomal dominant and fully penetrant. Prion disorders also occur in animals, and are of major concern because of the potential for spreading to humans. The principal pathogenic event underlying all prion disorders is a change in the conformation of prion protein (PrPC) from a mainly α-helical to a ß-sheet rich isoform, PrP-scrapie (PrPSc). Accumulation of PrPSc in the brain parenchyma is the major cause of neuronal degeneration. The mechanism by which PrPSc is transmitted, propagates, and causes neurodegenerative changes has been investigated over the years, and several clues have emerged. Efforts are also ongoing for identifying specific and sensitive diagnostic tests for sCJD and animal prion disorders, but success has been limited. The eye is suitable for these evaluations because it shares several anatomical and physiological features with the brain, and can be observed in vivo during disease progression. The retina, considered an extension of the central nervous system, is involved extensively in prion disorders. Accordingly, Optical Coherence Tomography and electroretinogram have shown some promise as pre-mortem diagnostic tests for human and animal prion disorders. However, a complete understanding of the physiology of PrPC and pathobiology of PrPSc in the eye is essential for developing specific and sensitive tests. Below, we summarize recent progress in ocular physiology and pathology in prion disorders, and the eye as an anatomically accessible site to diagnose, monitor disease progression, and test therapeutic options.

Autoantibodies against the prion protein in individuals with PRNP mutations.

OBJECTIVE: To determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease. METHODS: In this case-control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human immunoglobulin G1-4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between (1) PRNP mutation carriers vs controls and (2) asymptomatic vs symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts. RESULTS: We found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status or clinical manifestation of prion disease. Post hoc analyses showed anti-PrPC autoantibody titers to be independent of personal history of autoimmune disease and other immunologic disorders, as well as PRNP codon 129 polymorphism. CONCLUSIONS: Pathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrPC immunity. Anti-PrPC immunoglobulin G autoantibodies are not associated with the onset of prion disease. The presence of anti-PrPC autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well-tolerated. CLINICALTRIALSGOV IDENTIFIER: NCT02837705.