ID: 215433 The History of Spinal Cord Stimulation to Treat Painful Diabetic Peripheral Neuropathy

Introduction: Diabetic peripheral neuropathy (DPN) is the most common neuropathic syndrome seen in patients with diabetes. Roughly 30% of the diabetes patient population1 experience painful DPN symptoms including bilateral stabbing or burning pain in addition to numbness in the feet and lower legs. Traditionally painful DPN symptoms have been treated with conventional medical management (CMM) including glycemic control, general risk factor management, as well as pharmaceutical agents. These treatment approaches are often unsuccessful in the long-term1. Spinal cord stimulation (SCS) has been demonstrated as an effective treatment for painful DPN of the lower extremities with multiple publications dating back to 1996 showing benefits of SCS for pain relief and improved Quality of Life (QoL) in DPN patients (Figure 1)2-18. Method(s): A systematic literature review of the robust body of evidence for SCS in the treatment of painful DPN was conducted. Publications were selected for inclusion by two independent reviewers using defined selection criteria. Additional relevant publications from outside the search dates were included. Result(s): SCS was first documented as an effective treatment for DPN in three single-arm studies published between 1996 and 20122,4,5, one of which was followed-up to thirty-six months18, and another to seven-years3. These studies paved the way for two RCTs published in 20146,7, one of which was followed-up to five-years in two publications8,10, and another7 was followed-up with analyses on QoL9 and an evaluation of the effects of burst SCS17. Two meta-analyses were published in 2020 and 202111,12. A post-hoc analysis of a multi-center single-arm study on high frequency (10kHz) SCS to treat DPN was published in 202013 and followed by an RCT published in 202114 with additional 1-year follow-up15,16. Collectively these studies demonstrate that SCS is an effective therapy for patients with painful DPN by reducing pain and increasing QoL for DPN patients (Figure 1). Conclusion(s): This review of a large body of evidence shows a decades-long history of the effectiveness of SCS for symptom relief in patients suffering from painful DPN. Future research on the effectiveness of new waveforms and novel methods of energy delivery to the spinal cord are needed. The study of outcomes in addition to pain relief is also needed, which may better illustrate the breadth of effects of SCS therapy on the underlying disease factors. Increasing awareness of the current evidence is essential to increasing therapy adoption by expanding payer support and influencing referring health care provider behavior. Disclosure: Eric Grigsby, MD: AE Mann Foundation: Consulting Fee: Self, Bioness Inc.: Consulting Fee: Self, Medallion Therapeutics: Consulting Fee: Self, Medtronic: Consulting Fee: Self, SPR Therapeutics: Consultant: Self, Tenex Health: Consultant: Self, Voyager Therapeutics: Consultant: Self, Xalud: Consulting Fee: Self, AE Mann Foundation: Consulting Fee: Self, Medallion Therapeutics: Consulting Fee: Self, Bioness Inc.: N/A: Self, Medallion Therapeutics: N/A: Self, SPR Therapeutics: N/A: Self, Abbott / St. Jude Medical: N/A: Self, Tenex: N/A: Self, Vertos: N/A: Self, Xalud: N/A: Self, AE Mann Foundation: Consulting Fee: Self, Bioness Inc.: Consulting Fee: Self, Medtronic, Inc.: N/A: Self, Collegium Pharmaceutical, Inc.: Trustee: Self, Flowonix Medical: Served on speakers' bureau: Self, Jazz Pharmaceuticals: Served on speakers' bureau: Self, Jazz Pharmaceuticals: Trustee: Self, Spinal Restoration, Inc.: Trustee: Self, Jazz Pharmaceuticals: N/A: Self, Alfred Mann Foundation: N/A: Self, Boston Scientific: N/A: Self, CNS Therapeutics: N/A: Self, Collegium Pharmaceutical, Inc.: N/A: Self, Flowonix Medical: N/A: Self, Jazz Pharmaceuticals: N/A: Self, Medtronic, Inc.: N/A: Self, Myoscience: N/A: Self, NeurAxon Inc.: N/A: Self, Spinal Restoration, Inc.: N/A: Self, St. Jude Medical, Inc.: N/A: Self, Abbott Laboratories: Consultant: Self, Alfred Mann Foundation: Consulting Fee: Self, Cervel Neurotech, Inc.: Consultant: Self, CNS Therapeutics: Consultant: Self, Covidien: Consultant: Self, Cumberland Pharmaceuticals, Inc.: Consultant: Self, Flowonix Medical: Consultant: Self, Jazz Pharmaceuticals: Consultant: Self, Mainstay Medical: Consultant: Self, Medtronic, Inc.: Consultant: Self, Myoscience: Consultant: Self, NeuroPhage Pharmaceuticals: Consultant: Self, Nevro Corp: Consultant: Self, Palyon: Consultant: Self, Spinal Modulation: Consultant: Self, SPR Therapeutics: Consultant: Self, St. Jude Medical, Inc.: Consultant: Self, Tenex Health, Inc.: Consultant: Self, VertiFlex Inc.: Consultant: Self, Vertos Medical, Inc.: Consultant: Self, Xalud Therapeutics, Inc.: Contracted Research: Self, Medtronic, Inc.: Served on speakers' bureau: Self, Flowonix Medical: Served on advisory board: Self, Medtronic, Inc.: N/A: Self, Jazz Pharmaceuticals: N/A: Self, Medtronic, Inc.: Ownership Interest: Own Stock, Stock Options, Future Stock Options: Self, Nevro Corp: Ownership Interest: Own Stock, Stock Options, Future Stock Options: Self, Rachel Slangen, PhD: None, Lisa Johanek, PhD: Medtronic: Salary/Employee: Self, Maddie LaRue, PHD: Medtronic: Employee:, Cecile de Vos, PhD: None, Melissa Murphy: Medtronic: Consulting Fee:, Relievant: Consulting Fee:Copyright © 2023

Pole-to-pole involvement of varicella zoster virus reactivation following COVID-19 vaccination.

The aim of this study is to report the clinical features, imaging findings including confocal imaging, corneal nerve fiber analysis, and management outcomes in a series of three cases of varicella zoster virus (VZV) reactivation following one dose of coronavirus disease 2019 (COVID-19) vaccination. This was a retrospective and observational study. All the patients who developed uveitis post-vaccination were pooled together. Patients who had VZV reactivation were included. Two cases had polymerase chain reaction positive for VZV from aqueous humor. At the time of presentation, IgG and IgM spike protein antibodies for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were tested. Out of this pool, three patients with classical features to describe pole-to-pole manifestations were chosen. A 36-year-old lady with post-vaccination sclerokeratouveitis associated with reactivation of herpes zoster ophthalmicus, a 56-year-old lady with post-vaccination acute anterior uveitis associated with herpes zoster ophthalmicus, and a 43-year-old gentleman with post-vaccination acute retinal necrosis were included. We present a possible link between anti-SARS-CoV-2 virus vaccination and varicella zoster reactivation in these patients and also describe the clinical features, imaging findings including confocal imaging, corneal nerve fiber analysis, and management with detailed discussion.

Evaluation of acute effects of pulmonary involvement and hypoxia on retina and choroid in coronavirus disease 2019: An optic coherence tomography study.

PURPOSE: We investigated the acute subclinical choroidal and retinal changes caused by Coronavirus Disease 2019 (COVID-19) in patients with and without pulmonary involvement, using spectral domain optic coherence tomography. METHODS: This prospective case-control study included COVID-19 patients: 50 with pulmonary involvement and 118 with non-pulmonary involvement. All patients were examined 1 month after recovering from COVID-19. The changes were followed using optic coherence tomography parameters such as choroidal and macular thickness and retinal nerve fibre layer and ganglion cell complex measurements. RESULTS: All choroidal thicknesses in the pulmonary involvement group were lower than in the non-pulmonary involvement group and the subfoveal choroidal thickness differed significantly (p=0.036). Although there were no significant differences between the central and average macular thicknesses in the two groups, they were slightly thicker in the pulmonary involvement group (p=0.152 and p=0.180, respectively). A significant decrease was detected in the pulmonary involvement group in all ganglion cell complex segments, except for the outer nasal inferior segment (p<0.05). In addition, a thinning tendency was observed in all retinal nerve fibre layer quadrants in the pulmonary involvement group compared to the non-pulmonary involvement group. CONCLUSION: In COVID-19 patients with pulmonary involvement, subclinical choroidal and retinal changes may occur due to hypoxia and ischemia in the acute period. These patients may be predisposed to ischemic retinal and optic nerve diseases in the future. Therefore, COVID-19 patients with pulmonary involvement should be followed for ophthalmological diseases.

Neurofilament light-chain and CSF parameters do not change after SARS-COV-2 vaccination in patients with MS

Introduction: Coronavirus disease 2019 (COVID-19) ranges from paucisymptomatic course to severe pneumonia and lifethreatening conditions. Although the efficacy and safety of that vaccines in counteract COVID-19 have been established yet, patients with Multiple Sclerosis (MS) are still concerned about vaccination believing that vaccines may worsen their underlying disease. Objective(s): To assess the effect of the new COVID-19 vaccines in a cohort of patients with MS, Dementia, Parkinson disease and atypical parkinsonismson neurofilament light chain (NfL) and other cerebrospinal fluid (CSF) parameters. Aim(s): to determine possibile variation of CSF parameters indicating blood brain barrier disruption and to calculate NfL levels comparing different time points since vaccination against SARS-CoV-2. Method(s):We enrolled patients admitted to the Neurologic Unit of University Hospital Paolo Giaccone who underwent lumbar puncture (LP) between February 2021 and December 2021. CSF parameters and NfL were compared between unvaccinated and vaccinated patients at three different intervals from vaccination (<4 weeks, 4-8 weeks, 8 weeks). Also, these parameters were evaluated between patients with MS and patients with Dementias, Parkinson disease and atypical parkinsonisms. Result(s): A total of 116 patients underwent LP (median age 59 years, [37-51];50% females);n=14 (<4 weeks), n=10 (4-8 weeks), n=25 (>8 weeks) and n=25 (unvaccinated) respectively were included in the final analysis. No significative differences emerged between vaccinated and unvaccinated patients for TPc (p=0.2), CSF glucose (p=0.5), CSF/SGluratio (p=0.3), number of cells per mm3(p=0.7) and CSF-NfL (p=0.6). When comparing vaccinated and unvaccinated patients according to underlying neurological diagnosis, no further differences emerged evaluating CSF parameters between groups (overall p>0.5). CSF-TPc and NfL positively correlated with participants' age (p=0.03) while number of cells per mm3was inversely correlated (p<0.0001). Conclusion(s): NfL and CSF parameters did not differ between vaccinated and unvaccinated patients. COVID-19 vaccines are not associated with neuroinflammation and neuro-axonal degeneration in people with MS and other neurological diseases.

Deep Learning Artificial Intelligence in Vision-Threatening Disease in Clinical and Community Screenings

Purpose : Age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma are vision-threatening diseases (VTDs) affecting 36 million people in the USA. With 5.7 ophthalmologists per 100,000 Americans, over 50% of VTDs go undetected. We assessed deep learning Artificial Intelligence (DLAI) in VTD detection in community and clinical settings. Methods : 223 subjects (mean age 54.6, 58% male) from community screenings (A) and clinic (B) underwent 45-degree retinal imaging. In A (non-dilated), an onsite telemedicine reader (R1) and remote ophthalmologist (R2) graded image quality (gamma and alignment, 1-5 scale) and referable VTD using the international grading scales for AMD and DR, and cup-to-disc ratio and nerve fiber layer for glaucoma. In B (dilated), gradings were collected from R1 and the clinical diagnosis (d). A senior ophthalmologist (R3) adjudicated disputed findings. In A, DLAI VTD referral was compared to R1/R2/R3 consensus (S);in B, overall referral was compared to R1/d/R3 consensus (C). Images were uploaded to a cloud-based DLAI (SELENA+, EyRIS Pte Ltd) (Fig 1). Cohen's kappa assessed intergrader agreement. Results : R1 and R2 found 4.7% eyes ungradable. DLAI marked 55.6% ungradable;74.6% of them were for AMD. Of the DLAI ungradable eyes, image quality was ≤ 3, and 56.2% had ≥ 1+ cataract (R1). Compared to in A, in B DLAI had higher sensitivity (97.1% vs. 63.2%) and positive predictive value (69.4% vs. 32%). In A, DLAI had higher specificity (94.5% vs.16.7%) and negative predictive value (98.4% vs. 75.0%) (Table 1). In A, Cohen's kappa was 0.946 between R1 and R2, with a 13% disagreement rate. In 56% of the disagreements, R3 agreed with R1. In B, Cohen's kappa was 0.874 for R1 and d;R1 referred more than d. In A and B, DLAI referred more than R1, R2, and H/C. DLAI referred all eyes with > 1 VTD (1%) for further examination. Grading times for DLAI, R1, and R2 were 30, 129, and 68 seconds. Conclusions : DLAI performed best in DR and glaucoma detection;a potential solution for the high ungradable rate can be for DLAI to re-center uploaded images. DLAI can increase efficiency and accessibility of screenings for multiple VTDs, in both underserved populations and clinic. The ability to minimize direct contact confers an advantage during COVID-19. Further studies will investigate DLAI use in VTD progression.

Automated Puff Tonometry in Comprehensive Community Based Screening for Vision Threatening Diseases during SARS-CoV-2

Purpose : Over 50% of individuals with vision-threatening disease (VTD) (e.g., diabetic retinopathy, glaucoma, macular degeneration) are unaware of their condition, and once diagnosed, 80% will not follow up for clinical care, especially since the onset of SARS-CoV-2 in 2020. Remote teleophthalmology with real-time robotic teleconsultation was implemented to include automated puff-tonometry (APT) as pre-triage to identify patients who require more detailed clinical assessment and treatment. Methods : 224 subjects (58% male) of average age 55 years were screened over 8 events. Following COVID-19 protocols screenings took place in New Jersey churches and health fairs featuring a high prevalence of African American and Hispanic subjects. Masked and self-reported vaccinated subjects underwent medical history, blood pressure, visual acuity (with pinhole), automated puff-tonometry (APT) for intraocular pressures (IOP), automated refraction, non-mydriatic retinal imaging, optical coherence tomography (OCT), and wearable visual field device (WVFD) testing. Face masks were fitted with surgical tape on the nose bridge to limit instrument fogging. To minimize equipment contact, all subjects were screened in the standing position, including APT and retinal imaging (Fig.1). Chi-square and t-tests were performed to assess factors associated with glaucoma referral. Subjects without IOP readings were excluded;significance was set at p<0.05. Results : 10.29% of measured eyes had an IOP>18 and underwent additional testing including OCT-B of the optic nerve head, nerve fiber layer, and ganglion cell complex. 31.43% of eyes with IOP>18 underwent teleconsultation with a glaucoma specialist, vs. 8.85% of eyes with IOP≤18 ((p<0.001), Table 1). The difference in mean age in subjects with glaucoma referral vs. without (57.42 vs. 51.61 years) was significant (p=0.008). Conclusions : APT was useful in supporting on-site OCT-B imaging and WVFD referral (37.67%, 8.52% of total subjects) that yielded 17.94% referral to on-site teleconsultation through a real-time telerobot. Future investigation will include larger and more diverse community-based populations.

Community Based Eye Screenings Using Retinal and OCT-B Combination Imaging in Glaucoma During COVID-19

Purpose : Retinal imaging is the gold standard in tele-ophthalmology. Limitations in twodimensional imaging can lead to poor triage or unnecessary clinical referrals, especially during COVID-19. Combined retinal imaging with Optical Coherence Tomography-B scan (OCT-B) in detecting vision threatening diseases (VTDs) such as glaucoma in communitybased screenings adds a third dimension to subject data. Methods : A non-mydriatic Topcon 3D Maestro1 imaging system was deployed in this pilot study to screen 120 subjects (43.3% male, mean age 55.1) in community-based screenings. Measurements of vertical cup-to-disc ratio (VCDR), nerve fiber layer (NFL) thickness and macular and ganglion cell layer (GCL) thickness were collected along with color retinal images by the Maestro1. Visual acuity and intraocular pressures (IOP) were obtained as part of the screening protocol. Four types of OCTs were acquired: 78.33% 3D Wide, 13.33% 3D Macula, 5.83% 3D Disc, and 2.51% 5-Line Cross. An on-site certified reader (CR) interpreted results and provided consultation follow-up to a remote ophthalmic subspecialist. Results : Of 222 eyes, OCT-B confirmed follow-up in 86.94%. 88.3% of subjects had referable eye pathology: 23.33% to general or specialty eye clinic and 65% to telemedicine. CR glaucoma referral based on OCT-B scan, VCDR and NFL defects was compared to OCT-B referral based on VCDR ≥0.65. Cohen's kappa was 0.546 with 30% disagreement. Compared to CR, OCT-B generated VCDR had a 91.1% specificity and 42.3% sensitivity in detecting glaucoma. VCDR, IOP, NFL, and GCL measurements were significantly correlated with CR glaucoma referral (p<0.05). Only VCDR, NFL, and GCL were significantly correlated with Maestro 1 glaucoma referral (p<0.05). Conclusions : OCT-B images provide valuable added diagnostic information about referrals in glaucoma. Its ability to capture greater depth of information about the eye, such as NFL and GCL measurements, compared to traditional two-dimensional retinal photography, warrants consideration for OCT-B as a replacement for non-mydriatic retinal photography as the gold standard in ophthalmic diagnostics. Further studies can investigate the utility trend analysis of OCT-B in predicting VTD's progression over time.

Telemedicine Assisted Postoperative Care Following Microincision Vitrectomy Surgery

Purpose : Microincision vitrectomy surgery (MIVS) studies have shown low complication rates. In the setting of the COVID-19 pandemic and rural satellite clinics, we investigated the role of telemedicine as an alternative to postoperative visit (POV) regimens after uncomplicated MIVS. Methods : This IRB approved, prospective single-site, and single-surgeon study included patients without any history of glaucoma, ocular trauma, or severe systemic or ocular disease who underwent uncomplicated MIVS for any indication between January-August 2021. Prophylactic topical pressure-lowering drops were prescribed if POV intraocular pressure (IOP) was ≥22 mmHg. POVs included the same day after surgery, week(s) 1, 2, 8, and 12. Patients were randomly assigned (1:1) into two arms: telemedicine (TM) or In-person (IP). Weeks 1 and 8 POV utilized protocol-based and questionnaire guided undilated exams performed by an ophthalmology fellow that were conducted either TM or IP, according to arm assignment. Any patients with concerning symptoms identified at these visits were scheduled for dilated exams with the surgeon. All patients underwent dilated exams performed by the surgeon on the same day after surgery, weeks 2 and 12. Primary endpoint was mean best corrected visual acuity (BCVA). Secondary endpoints included changes in intraocular pressure (IOP), retinal nerve fiber layer thickness, and number of additional visits. Statistical analysis included Mann Whitney U and chi-square tests. Results : Fifty-two eyes from 50 patients (33 female, 17 male;p-value=0.02) with mean ages of 68.4±6.8 years underwent 55 total surgeries with 25 or 27G MIVS platforms. Forty-seven patients have completed all POVs. Mean preop BCVA logMAR was 0.53±0.55 and 0.40±0.45, and at 12 weeks, they were 0.39±0.45 and 0.26±0.33 for the TM and IP groups, respectively. No significant between-group differences were found for primary or secondary outcomes. All cases of abnormal IOP resolved by the following POV with pressure lowering drops. Concerning symptoms were identified in five patients requiring additional visits, revealing two cases of worsening macular edema (1 TM and 1 IP) and one case each of cataract progression (TM), vitreous hemorrhage (IP), and macular hole recurrence (TM). No complications presented at the TM or IP visits. Conclusions : Telemedicine-assisted POV regimens may be a safe and convenient alternative for patients undergoing uncomplicated MIVS.

COVID-19 Associated Optic Neuritis

Purpose : While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well known for its respiratory complications, ocular manifestations are emerging. This case report describes a patient with bilateral optic neuritis associated with coronavirus disease 2019 (COVID-19). Methods : A 46-year-old male presented with two weeks of pain with eye movement immediately after testing positive for COVID-19 and four days of bilateral blurry vision. Data including history, ocular examination, Humphrey visual field testing (HVF), magnetic resonance imaging (MRI), and serological testing was collected. Results : Visual acuity (VA) was 20/100 in the right eye (OD) and 20/70 in the left eye (OS) with pinhole VA of 20/40 in each eye. Pupil exam, intraocular pressures, and confrontational visual fields were normal. Ocular motility was full, however the patient endorsed pain with eye movement in all directions. The right optic nerve had blurred disc margins while the left optic nerve was unremarkable on exam. Color vision was decreased to 13/15 by Ishihara testing in each eye. MRI of the brain and orbits revealed bilateral thickening and T2 hyperintensity and hyperenhancement of the intercanalicular and intraorbital optic nerves with sparing of the nerve sheath and no demyelinating lesions (Figure 1). Bilateral central scotomas were seen on HVF (Figure 2). At this point, the patient's clinical picture was concerning for optic neuritis associated with COVID-19. A complete blood count, comprehensive metabolic panel, myelin-oligodendrocyte glycoprotein antibody, and aquaporin 4 antibody were unremarkable. Testing for tuberculosis, sarcoidosis, syphilis, thyroid disease, and rheumatologic and autoimmune disorders was normal. The patient was treated with corticosteroids. Within three to six weeks, the patient's symptoms and abnormal exam findings resolved. Conclusions : Infectious pathogens and their subsequent inflammation can cause optic neuritis. It is postulated that T cells release inflammatory mediators and cytokines that cross the blood brain barrier and lead to destruction of myelin, neuronal cell death, axonal degeneration, and vision loss. SARS-CoV-2 could cause a similar inflammatory response leading to optic neuritis and is important to consider in cases without a clear etiology.

Assessment of Optical Coherence Tomography Findings Based on COVID-19 Status and Demographics

Purpose : The full scope of ophthalmic manifestations of coronavirus disease 2019 (COVID-19) has yet to be appreciated. We used optical coherence tomography (OCT) to compare subjects with a history of COVID-19 disease and those without evidence of past disease across qualitative and quantitative metrics. Methods : Subjects diagnosed by reverse-transcriptase polymerase chain reaction with COVID-19 or presence of SARS-CoV-2 antibodies (N=25) and those with no history or antibody evidence of disease (N=25) were prospectively assessed using a Zeiss Cirrus HD OCT Model 5000. Retinal nerve fiber layer (RNFL), macular ganglion cell complex (GCC), and foveal thickness were tabulated. Retinal structural findings were evaluated by a retina specialist. Results were stratified by age, race, ethnicity, gender, and presence of comorbidities (diabetes and hypertension). Student's t-test, linear and logistic regression, univariate analysis with COVID+ subjects, and multivariate analysis with all subjects were performed. Significance was set at p<0.05. Results : COVID+ subjects did not show significant differences compared to COVID- subjects across any parameters. There were significant differences across demographic groups. Univariate analysis showed that COVID+ Asians had thinner RNFL (p=0.014, right;p=0.018, left) and GCC (p=0.041, right;p=0.051, left) than COVID+ Blacks and Whites. COVID+ Hispanics had decreased foveal thickness compared to COVID+ non-Hispanics (p=0.019, right;p=0.004, left). Multivariate analysis confirmed that Blacks (p=0.015, left) and Whites (p=0.010, left) had thicker GCC than Asians and that Hispanics had decreased foveal thickness (p=0.041, left) compared to non-Hispanics. The middle age group had thinner GCC (p=0.022, right;p=0.024, left) than the youngest age group. While COVID+ Blacks were more likely to have retinal structural changes than COVID+ subjects of other races with a trend toward significance (OR=5.00, p=0.084), multivariate analysis did not confirm this disparity. Conclusions : Analysis of this cohort did not reveal significant differences between COVID+ and COVID- individuals. However, comparison of demographic parameters did show significant differences across age, race, and ethnicity. The reasons for these disparities are obscure. Further studies with a greater number of subjects may reveal differences based on COVID-19 status.

Optical coherence tomography angiography based assessment of macular vessel density, retinal layer metrics and subfoveal choroidal thickness in COVID-19 patients

Purpose : OCTA is a non-invasive imaging technique for assessment of retino-choroidal vasculature. It allows for the quantitative assessment of retinal microvasculature. This study evaluates macular vessel density (VD), foveal avascular zone (FAZ) area, subfoveal choroidal thickness (SFCT) and retinal layer metrics by optical coherence tomography angiography (OCTA) in COVID-19 recovered patients. Additionally we studied the correlation of OCTA parameters with severity and duration of COVID-19 disease, steroid administration, and vaccination status. Methods : It is a case-control study of 180 patients. OCTA parameters namely-superficial and deep VD in various sectors-total, superior, inferior, central, inner, superior-inner, inferior-inner, full;superficial and deep FAZ area;SFCT: central subfield thickness (CST) were measured. Additionally, retinal layer metrics, including nerve fiber layer, ganglion cell layer-inner plexiform complex, inner nuclear layer, outer plexiform layer, and outer nuclear layer were compared between cases and controls. A correlation analysis of OCTA parameters was done with severity and duration of disease. Results : FAZ area (superficial and deep);retinal layer metrics including ganglion cell layer and inner plexiform layer, outer plexiform layer and outer nuclear layer showed significant reduction while there was a significant increase in SFCT in COVID-19 patients. Corticosteroid treatment resulted in significant decrease in VD. A positive correlation was elicited between FAZ area and disease duration;while VD correlated negatively with the duration of disease. Multivariate analysis showed significant relationship between superficial FAZ area, deep FAZ area and SFCT. Conclusions : OCTA showed alteration in retinal microvasculature and metrics in COVID-19 patients. Choroid being a highly vascular structure was also affected. There was a resultant alteration in FAZ area and SFCT. Moreover, thrombotic phenomenon associated with COVID could alter retinal layer metrics. Additionally, corticosteroids also appear to alter retinal microvasculature. This study could help understand the wide-spread thrombotic phenomenon often associated with COVID infection and predisposition for the same among specific patients.

Corneal innervation changes after Sars-Cov-2 Infection. An In vivo Confocal Microscopy Study

Purpose : To measure the innervation of the corneal subbasal nerve plexus of Covid-19 patients and compare the results with values of healthy patients. Methods : A prospective, observational study was conducted analyzing 39 eyes of patients who had overcome Covid -19 and 46 eyes of healthy volunteers included as a control group (verified by antibody analysis and negative qPCR result) which underwent in vivo confocal microscopy with Rodstock Cornea Module© attached to Heildelberg HRT3© . Ocular surgery procedures, previous ocular infections or systemic diseases that could cause alteration in corneal innervation were exclusion criteria. At least 5 non overlapping images of each eye were selected and only one eye of each patient was included in the study. Following sub basal nervous plexus parameters were measured with ACC Metrics © software: Corneal Nerve Fiber Density (CNFD), Corneal Nerve Branch Density (CNBD), Corneal Nerve Fiber Length (CNFL), Corneal Total Branch Density (CTBD), Corneal Nerve Fiber Area (CNFA), Corneal Nerve Fractal Dimension (CNFrD). Data analysis was performed with SPSS® software for Windows 22.0 (SPSS® Inc, Chicago, IL.). The differences of age and sex between groups were checked with T-test and chi-square tests. The normality of the sample was checked with the Shapiro-Wilk test and the results were compared with the T test or the Man-Whitney U test based on the distribution of the data. The differences were considered statistically significant for p<0.05. Results : There was no difference in the sex distribution between the groups (p= 0.248). The average age (± standard error) was 46.61±17.55 years for Covid-19 patients and 43.11±16.95 years for healthy control group (p=0.353) The mean of the analyzed variables (± standard error) from Covid-19 patients versus control group were CNFD: 16.09±6.92 and 23.03±8.31 fibers/mm2 (p=0,00008), CNBD: 21.93±15.37 and 28.93±17.84 branches/mm2 (p=0.064), CNFL: 11.61±3.61 and 14.05±3.71 mm/mm2 (p=0.002), CTBD: 38.48±20.02 and 43.29 ± 23.94 (p=0.41), CNFA: 0.0057±0.0017 and 0.006±0.0023 mm2 /mm2 (p=0.853), CNFrD: 1.46±0.041 and 1.47±0.037 (p=0.007). Conclusions : According to the data obtained, corneal subbasal nerve plexus is decreased in Covid-19 patients compared to the healthy control group, statistically significant for density, length, and fractal dimension. The results show the presence of possible small fiber neuropathy induced by Covid-19 disease.

Virtual Reality Visual Field Exam in Community Screenings During COVID-19

Purpose : 57.5 million people worldwide are affected by glaucoma. However, 50% of those with glaucoma are unaware, and 80% of those identified for follow-up in community screenings (CS) fail to do so. Current standards of visual field testing are usually limited to the clinic. As such, a wearable perimetry headset was used to perform Virtual Reality Visual Field Acuity (VRVFA) examination for suspected visual field loss in the community minimizing exposure to COVID-19 and the need for follow-up. Methods : 31 subjects from 4 CS were screened by an onsite certified telemedicine reader (CR) who considered family history, visual acuity, intraocular pressures, cup-to-disc ratio, nerve fiber layer defects, and ganglion cell complex captured by non-mydriatic photography and ocular coherence tomography (OCT-B). Cataracts were also graded. Supervised VRVFA testing with a multilingual Palmscan VF2000 Analyzer (Fig.1) was performed in 6 minutes on average. Eyes with fixation losses >20% or false positive/negative ratios >0.375 were excluded. Visual field index (VFI), mean deviation (MD), pattern standard deviation (PSD), and mean sensitivity (MS) from VRVFA were compared to CR glaucoma referral and cataract grading. Descriptive statistics, independent samples t-tests, and Mood's median tests were performed. Subjects with positive findings underwent same-day robotic glaucoma specialist telepresence evaluation. Results : 37 eyes from 31 subjects met inclusion criteria (mean age 51.42 ± 14.57 years, 56.76% male, 94.59% Hispanic). 7 (18.92%) eyes were referred for glaucoma evaluation. Glaucoma referrals had significantly different VFI (66.86% vs 86.40%, p=0.027), MD (-9.60 vs -4.04, p=0.031), and MS (19.94 vs 26.01, p=0.027) (Fig. 2). 30 (81.08%) eyes were 0-1+ in cataract grading, 5 (13.51%) were 2-3+, and 2 (5.41%) were intra-ocular lenses (IOL);respectively, these subgroups were not significantly different in VFI (84.20% vs 92.80% vs 35.00%, p=0.147), MD (-4.70 vs -2.11 vs -18.41, p=0.147), PSD (3.52 vs 2.25 vs 9.69, p=0.053), or MS (25.38 vs 27.75 vs 9.91, p=0.147) (Fig. 2). Conclusions : VRVFA testing yielded valuable information on the extent of vision loss as a supportive screening tool for glaucoma congruent with referrals. Expanded testing is needed. Future studies may evaluate VRVFA utility in evaluating other peripheral vision threatening diseases.

2022 EAN/PNS GBS Guideline

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy. This is the first systematic clinical guideline, developed by an international task force using formal GRADE methodology. The diagnostic criteria remain primarily clinical, based on history and examination findings of acute progressive limb weakness and areflexia. Variants of GBS may include motor GBS, Miller Fisher Syndrome, and regional variants with weakness predominantly in lower limbs, face, or pharynx/neck/ arms. The differential diagnosis is wide. When uncertain, diagnosis may be assisted by nerve conduction tests, raised cerebrospinal fluid protein, and less often by MRI spine with contrast, or serum antibodies to gangliosides (especially for variants) or nodalparanodal antibodies (especially if not improving). Axonal versus demyelinating subtyping does not affect clinical management. A history of recent gastrointestinal or respiratory infection or of surgery may support the diagnosis. The risk of GBS is only very slightly increased after Covid-19 infection and after the adenovirus-vector vaccines to SARS-CoV2 (AstraZeneca or Johnson & Johnson) but not mRNA vaccines. Immune treatment is recommended with intravenous immunoglobulin or plasma exchange, for most patients except those mildly affected or after four weeks from onset. A repeat course is reasonable after a treatment-related fluctuation. Corticosteroids are not recommended. There is no evidence of benefi t from any other disease-modifying treatment. Respiratory function should be monitored by forced vital capacity and single breath count to assess the risk of needing mechanical ventilation, guided by the mEGRIS scale. Pain is very common. It may be musculoskeletal or neuropathic, and treated with gabapentin, tricyclic antidepressants or carbamazepine. Patients who fail to improve should be reassessed for the correct diagnosis and for axonal degeneration. Around 5% of patients with GBS may later develop CIDP but no test can reliably indicate this within the first eight weeks. Nodal-paranodal antibodies should be tested if CIDP is suspected or if the patient is not recovering well. The long-term outcome is less good in patients of older age, with preceding diarrhoea, or more severe weakness, as quantified by the mEGOS scale, and also in patients with smaller motor potential amplitudes or raised serum neurofilament light chain level.

A RARE CASE of ACUTE INFLAMMATORY DEMYELINATING POLYRADICULOPATHY FOLLOWING the SECOND DOSE of PFIZER COVID-19 VACCINE

Background: We present a case of a 36 year-old female who developed Acute Immune-mediated Demyelinating Polyneuropathy (AIDP) after receiving the second dose of Pfzer COVID-19 vaccine. Objectives: To report a rare auto-immune complication of COIVD-19 vaccination. To educate and inform physicians about the approach to diagnosing AIDP and narrowing down its etiology. Methods: Case report and literature review Results: A 36 year-old female with no signifcant past medical history presented to the hospital with progressive bilateral paresthesia. She started to experience numbness and tingling sensation in her extremities 1 week after receiving the second dose of Pfzer COVID-19 vaccine. Following 5 days of symptoms onset, she was no longer able to hold onto objects and experienced difficulty ambulating without assistance. Physical exam was notable for decreased distal sensation to touch and pain in all 4 limbs, otherwise, the rest of her neurological and musculoskeletal evaluation was normal. MRI-head showed small scattered foci of increased FLAIR signal in the white matter, suggesting an underlying infammatory process. Electromyography (EMG) was performed and showed evidence of acute diffuse sensorimotor neuropathy with mixed axonal and demyelinating features. These results along with the clinical features allowed us to diagnose our patient with Acute Immune-mediated Demyelinating Polyneuropathy (AIDP). Extensive autoimmune workup, including anti-GM1, GD1b, Gq1b, ANA, DS-DNA, RF, CCP, and C/P ANCA, were unremarkable. She had positive anti-Ro atb but did not have any clinical or physical features that would suggest Sjogren's Syndrome. Vitamin levels (B12, folate, thiamine) were found to be normal. Infectious workup of serum and CSF which included hepatitis serologies, Campylobacter jejuni serology, Lyme atb, CMV atb, EBV atb were all negative. The possible etiology of her disease was attributed to Pfzer COVID-19 vaccine given the temporal correlation. She was subsequently treated with 6 cycles of IVIG which resulted in moderate symptomatic improvement. Conclusion: AIDP is an autoimmune-guided infammatory neuropathy which result in axonal degeneration of myelinated nerves [1]. In some extremely rare cases, molecular mimicry following vaccination may lead to this disease [1]. There have been reports of AIDP linked to Johnson & Johnson and AstraZeneca COVID-19 vaccines [2]. Recently, a few cases have also been observed with Pfzer COVID-19 vaccine [2-3]. Interestingly, the majority of these cases occurred after the frst dose of the vaccine, making our case even more peculiar [2]. We report this case as physicians should be made aware that AIDP is a potential complication of COVID-19 vaccination. Given the extreme rarity of these cases, it is also important to note that more common infectious and autoimmune etiology of AIDP should be investigated before attributing any potential causal relationship to COVID-19 vaccines.

Small fiber neuropathy following SARSCOV- 19 vaccination. A case series

Background and aims: Small fiber neuropathy (SFN) is a polymorphous disease affecting thin nervous fibers conducting temperature and pain sensations and involved in autonomic transmission. Etiology is diverse and remains elusive in 70% of cases. Methods: We describe a case series of 6 patients who developed symptoms of SFN following SARS-COV-19 vaccination. Neurologic examination was normal whilst paraclinical results were consistent with SFN. Confirmation by skin biopsy was obtained in 4 cases. Results: Six patients, 5 female and 1 male, ages 31, 34, 39, 42, 44 and 62 years, consulted our department with intense pain and numbness involving the arms and legs 2 to 15 days following SARS-COV-19 vaccination. Neurologic examination was normal. A preliminary diagnostic protocol comprising autoimmune, metabolic, infectious and inflammatory panel, cerebral and spinal cord magnetic resonance imaging and electromyography was normal. Functional neurophysiologic testing showed reduced activation of fibers involved in sweat gland control indicating SFN. Skin biopsy of distal calf and thigh in 4 patients, three female and one male, showed rarefaction of thin intraepidermic nerve fibers in a non length dependent manner, allowing for a diagnosis of SFN. Conclusion: Whereas autoimmune, infectious, metabolic, toxic and genetic causes are well described in SFN, evidence of possible association with vaccination is confounding. Given their small caliber and richness of surface antigens, small nervous fibers are vulnerable to a wide spectrum of disease. Immunologic factors intervening on a predisposing substrate could be a hypothesis for the mechanism involved in development of SFN following SARS-COV-19 and possibly other vaccination.

Post-acute sequelae of SARS-CoV-2 infection (PASC): peripheral, autonomic, and central nervoussystem featuresin a child

Objective: To describe treatment with intravenous immune globulin (IVIG) of severe central, peripheral and autonomic (CNS, PNS, ANS) post-acute sequelae of SARS-CoV-2 infection (PASC) in a child. Background: PASC is defined as failure to recover from acute COVID-19 in those persistently symptomatic for>30 days from onset of infection with any pattern of tissue injury that remains evolving including the nervous system. Design/Methods: A child underwent extensive evaluation of the CNS, PNS and ANS according to the authors protocol for COVID-19 neurologic illness. Results: A 12-year-old girl was initially well until March 2020 until exposure to other family members testing positive for COVID-19 infection she contracted an upper respiratory infection illness with loss of taste, and excessive fatigue followed in July 2020 by burning, weakness, slurred speech and impaired cognition leading to a bedbound state and a concern she was suffering from conversion disorder. Examination in September 2020 showed mild delirium, tetraparesis, stocking sensory loss and areflexia. Electrodiagnosis showed mixed chronic distal demyelinating and axonal changes. Epidermal nerve fiber studies showed reduced calf and thigh densities. Autonomic studies showed symptomatic hypotension with tilting and reflex tachycardia. Brain FDG PET/MRI showed hypometabolism of bilateral anterior and mesial temporal, superior parietal, and lateral occipital lobes, anterior cingulate cortices, and the cerebellar hemispheres with hippocampus volumes <5% of age-matched controls. Lumbar puncture showed a total protein of 136 mg/dL. EEG and Mayo Clinic ENS2 panel did not show evidence of autoimmune encephalitis. From October 2020 to February 2021, she received monthly 2 g/kg/month of intravenous immune globulin (IVIg) with overall clinical improvement. Conclusions: The underlying basis of PASC, especially in the CNS, has not yet been fully appreciated awaiting controlled clinical and autopsy studies. IVIg is effective initial therapy of PASC to modulate neurologic post-infectious immunity. COVID Long Hauler and Long COVID are inappropriate terms for PASC.

A double-blind, placebo controlled trial of Gamunex-C in Patient with Small Fiber Neuropathy Associated with Autoantibodies to TS-HDS and FGFR3

Objective: To determine the efficacy of IVIG on nerve fiber density, pain and examination scores in a double blind placebo controlled pilot study of patients with SFN associated with TS-HDS and FGFR3. Background: Small fiber neuropathies (SFN) have many potential causes but >50% remain idiopathic. Two autoantibodies, TS-HDS and FGFR-3, are associated with ∼20% of idiopathic SFN cases with reports touting IVIG for treatment of presumed autoimmune SFN. Design/Methods: Twenty subjects with SFN confirmed by history, examination and skin biopsy with elevated autoantibodies to TS-HDS and/or FGFR3 received either IVIG (or blinded placebo) dosed at 2 grams/kg followed by 1 gram/kg every 3 weeks for a total of 6 treatments. All subjects had detailed small fiber examinations (UENS), questionnaires and skin biopsies taken from adjacent sites at the distal leg. Skin biopsies were stained for PGP9.5 and intra-epidermal nerve fiber density (IENFD) reported. Final follow up occurred 3 weeks after the final treatment (24 weeks). Results: Twenty subjects were enrolled;18 completed treatment (9 IVIG, 9 placebo completers -2 did not have final data due to COVID-19). Over 24 weeks the change in pain scores (11 point VAS scale) was -0.88±0.99 in the placebo group, and -0.56±2.8 in the IVIG group (P=NS), the UENS neuropathy score improved by 3.8±8.8 in the placebo group and improved by 3.7±4.1 in the IVIG group (P=NS). Skin biopsy IENFD improved by 1.24±1.79 fibers/mm in the placebo group and improved by 0.81±1.67 fibers/mm in the IVIG treated group (P=NS). Conclusions: This small double blind placebo controlled trial showed no difference between IVIG and placebo in any measurable outcome and does not support the use of IVIG for SFN associated with autoantibodies to TS-HDS and/or FGFR3.

Small Fiber Neuropathy Associated with SARCoV-2 Infection

Objective: The development and persistence of neurological symptoms following SARS-CoV-2 infection is referred to as “long-haul” syndrome. Here, we aim to study the role of small fiber neuropathy (SFN) underlying neuropathic symptoms associated with COVID-19 infection. Background: Post COVID-19 “long-haul” syndrome include chronic fatigue, brain fog, sleep disturbance and paraesthesias. These symptoms can overlap with those seen in SFN, which have not been investigated given the recent wave of pandemic and patients who developed new onset of symptoms following infection. Design/Methods: Using retrospective study between May 2020 - May 2021, we screened the skin biopsy database of patients who were referred from the Center of Post-COVID Care at the Mount Sinai Hospital. Thirteen patients were identified and undergone routine nerve conduction studies and electromyography which ruled out evidence of a large fiber neuropathy. Patients were then clinically evaluated and consented for skin punch biopsy. All specimens were processed using PGP9.5 immunostaining for evaluating intraepidermal nerve fiber density (IENFD) to confirm SFN. Results: We identified 13 patients, 8 women and 5 men (age 38-67 years) with follow-up duration between 8-12 months. All had negative neuropathy blood profile including HbA1c, ANA, B12, TSH, free T4, and serum immunofixation. Three patients had pre-existing but controlled neuropathy risk factors. None had neurological symptoms prior to the SARS-CoV-2 infection. All patients developed new-onset paresthesias within 2 months following infection, with an acute onset in 7 and co-existing autonomic symptoms in 7. Six patients had biopsyconfirmed SFN, all of whom showed both neuropathy symptoms and signs, with 2 showing autonomic dysfunction. Of the remaining 7 patients with negative skin biopsies, 6 showed no clinical neuropathy signs, and 1 exhibited signs with abnormal autonomic function testing. Conclusions: Our findings support that symptoms of SFN may develop during or shortly after COVID-19 illness. SFN may underlie the paresthesias associated with long-haul post-COVID-19 symptoms.