A double-blind placebo-controlled pilot study of immunoglobulin for small fiber neuropathy associated with TS-HDS and FGFR-3 autoantibodies.

INTRODUCTION/AIMS: Small fiber neuropathies (SFN) have been associated with two autoantibodies, trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3), and intravenous immune globulin (IVIG) has been suggested as a potential therapy. The study objective is to determine the efficacy of IVIG on nerve density, pain and neurologic examinations in patients with SFN associated with TS-HDS and FGFR-3 autoantibodies. METHODS: This was a double-blind placebo-controlled pilot study. Subjects with SFN confirmed by history, examination, and skin biopsy with elevated autoantibodies to TS-HDS and/or FGFR-3 received IVIG (or blinded placebo) 2 grams/kg followed by 1 gram/kg every 3 wk for a total of 6 treatments. All subjects had Utah Early Neuropathy Scores (UENS), questionnaires and skin biopsies with quantitation of intra-epidermal nerve fiber density (IENFD) taken from adjacent sites at the distal leg at baseline and 6 mo later. The primary outcome was the change in IENFD over 6 mo. RESULTS: Twenty subjects were enrolled; 17 completed treatment (8 IVIG, 9 placebo). Three did not have final data due to coronavirus disease 2019 (COVID-19). Skin biopsy IENFD improved by 0.5 ± 0.8 fibers/mm in the placebo group and improved by 0.6 ± 0.6 fibers/mm in the IVIG-treated group (p = NS).Over 24 wk the change in pain scores (11 point pain scale) was -1.9 ± 2.6 in the placebo group, and - 1.7 ± 0.9 in the IVIG group (p = NS), the UENS improved by 3.0 ± 5.8 in the placebo group and improved by 1.8 ± 3.9 in the IVIG group (p = NS). DISCUSSION: This pilot study did not detect a benefit of treatment with IVIG in patients with SFN and autoantibodies to TS-HDS and FGFR-3.

Treatment and prevention of the post-COVID syndrome

In December 2019, one of the most severe pandemics in modern history, COVID-19 infection, originated in China, which led to the devastating consequences in the global healthcare system. In 2020, about one in five COVID-19 patients required hospitalization and 5% remained in the intensive care units that strongly contributed to the healthcare crisis all over the world. The main principle of successful therapy for post-COVID syndrome is a holistic, multidisciplinary approach involving a large team of medical specialists. The main issue here may be a development of the complicated pathological processes, involving damage to small nerve fibers and the development of micro-, microcirculatory, and respiratory disorders in combination with autoimmune dysfunction, the development of hypercoagulability, and immunological inflammation contributes to the progression of multiple organ dysfunctions in these patients. Therefore, treatment options include corrections of all of the abovementioned conditions that require further extensive research. © 2023 Elsevier Inc. All rights reserved.

Small Fiber Neuropathy Following COVID-19 Infection

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection has been associated with the development and persistence of various neurological symptoms in some patients. There have been few prior case reports of small fiber neuropathy (SFN) associated with this infection. However, literature is limited, and the etiology of these symptoms is unclear. Some reports suggested neuroinflammation. Objective(s): To present case series of 3 patients who developed small fiber neuropathy after SARS-COV2 infection. Method(s): We identified patients with SFN after SARSCOV2 infection from our neuromuscular database. We performed chart review and obtained clinical, demographic and, outcomes information of these patients. Result(s): The age of patients was 46, 56 and 71 years. Two female and one male. Time to neuropathy symptom evaluation in clinic from positive COVID19 test was 4 months, 6 months, and 10 months, respectively. None of the patients were hospitalized or given additional medications for COVID treatment. Patients 1& 3 had mild respiratory symptoms. Patient 2 had no symptoms, just a routine pre-op test was positive. All patients had numbness, tingling and painful paresthesias as the main symptoms. The second patient reported autonomic symptoms of heart racing and temperature dysregulation. Nerve conduction studies did not show large fiber peripheral neuropathy in any of the patients. Skin biopsy was performed at 7 months, 8 months and 13 months respectively post COVID infection and was positive in all 3 patients. There was no other etiology identified for the neuropathy Treatment included gabapentin for the first patient, the second patient received narcotic medication for a surgery and continued this for her neuropathic symptomsand the third patient is not on any medications for SFN. Conclusion(s): SFN can be associated with prior SARSCOV infection. There is need for further research to determine possible underlying neuropathological mechanisms and find effective treatments in COVID-related SFN.

A Case of Autoimmune Small Fiber Neuropathy as Possible Post COVID Sequelae.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is reported to induce and augment autoimmune processes. Moreover, postinfectious effects of coronavirus disease 2019 (COVID-19) are still poorly understood and often resemble symptoms of the acute infection phase. A patient with swollen extremities was presented to the Department of Angiology at the Medical University of Vienna with complaints of muscle and joint pain, paresthesia, and arterial hypertension with intense headache. Prior to these complaints, she had been suffering from various symptoms since November 2020, following a SARS-CoV-2 infection in the same month. These included recurrent sore throat, heartburn, dizziness, and headache. Paresthesia and muscle and joint pain started in temporal relation to a human papillomavirus (HPV) vaccination. Since the patient was suffering from severe pain, intensive pain management was performed. Skin and nerve biopsies revealed autoimmune small fiber neuropathy. The patient's condition could be related to COVID-19, as her first symptoms began in temporal relation to the SARS-CoV-2 infection. Furthermore, in the disease course, antinuclear (ANA) and anti-Ro antibodies, as well as anti-cyclic citrullinated peptide (anti-CCP) antibodies, could be detected. Together with the symptoms of xerophthalmia and pharyngeal dryness, primary Sjögren's syndrome was diagnosed. In conclusion, though biopsy results could not distinguish a cause of the disease, SARS-CoV-2 infection can be discussed as a likely trigger for the patient's autoimmune reactions.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in 2023.

In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants; Shoenfeld's syndrome) was first described. ASIA aimed to organize under a single umbrella, the existing evidence regarding certain environmental factors which possess immune stimulatory properties, in order to shed light on a common pathway of autoimmune pathogenesis. Such environmental immune stimulators, or adjuvants, include among others: aluminum salts as in vaccines, various medical implants, as well as various infectious agents. After the launch of the ASIA syndrome, the expansion and recognition of this syndrome by different researchers from different countries began. During the past decades, evidence had been accumulating that (auto)immune symptoms can be triggered by exposure to environmental immune stimulatory factors that act as an adjuvant in genetically susceptible individuals. A panoply of unexplained subjective and autonomic-related symptoms has been reported in patients with ASIA syndrome. The current review summarizes and updates accumulated knowledge from the past decades, describing new adjuvants- (e.g. polypropylene meshes) and vaccine- (e.g. HPV and COVID vaccines) induced ASIA. Furthermore, a direct association between inflammatory/autoimmune diseases with ASIA syndrome, will be discussed. Recent cases will strengthen some of the criteria depicted in ASIA syndrome such as clear improvement of symptoms by the removal of adjuvants (e.g. silicone breast implants) from the body of patients. Finally, we will introduce additional factors to be included in the criteria for ASIA syndrome such as: (1) dysregulated non-classical autoantibodies directed against G-protein coupled receptors (GPCRs) of the autonomic nervous system and (2)) small fiber neuropathy (SFN), both of which might explain, at least in part, the development of 'dysautonomia' reported in many ASIA patients.

Small Fiber Neuropathy Triggered by COVID-19 Vaccination: Association with FGFR3 Autoantibodies and Improvement during Intravenous Immunoglobulin Treatment.

Multiple case series have demonstrated the emergence of small fiber neuropathy following acute coronavirus disease 2019 (COVID-19) infections. Further, one large case supports that the COVID-19 vaccine has been reported to result in small fiber neuropathy. We report a case of a patient with confirmed small fiber neuropathy post-COVID-19 vaccination with positive FGFR3 antibodies. The effect of intravenous immunoglobulin (IVIG) has been recently explored for treatment of presumed autoimmune small fiber neuropathy. To our knowledge, this is the first published case report of COVID vaccination-induced FGFR3-associated small fiber neuropathy improving in the context of IVIG administration as demonstrated by normalization of small fiber density measured by skin biopsy accompanied by marked improvement in the patient's symptoms.

Demonstrating new-onset or worsened sudomotor function post-COVID-19 on comparative analysis of autonomic function pre-and post-SARS-CoV-2 infection.

Background: Autonomic dysfunction including sudomotor abnormalities have been reported in association with SARS-CoV-2 infection. Objective: There are no previous studies that have compared autonomic function objectively in patients pre- and post- SARS-CoV-2 infection.We aimed to identify if SARS-CoV-2 virus is triggering and/or worsening dysautonomia by comparing autonomic function tests in a group of patients pre-and post-SARS-CoV-2 infection. Design/methods: Six participants were enrolled and divided into two groups. The first group of 4 participants reported worsened autonomic symptoms post-SARS-CoV-2 infection. These individuals had their first autonomic test prior to COVID-19 pandemic outbreak (July 2019-December 2019). Autonomic function testing was repeated in these participants, 6 months to 1-year post-SARS-CoV-2 infection (June 2021).The second group of 2 participants reported new-onset autonomic symptoms post-COVID-19 infection and were also tested within 6 months post-SARS-CoV-2 infection.All participants had mild COVID-19 infection per WHO criteria. They had no evidence of large fiber neuropathy as demonstrated by normal neurophysiological studies (EMG/NCS). They were all screened for known causes of autonomic dysfunction and without risk factors of hypertension/hyperlipidemia, thyroid dysfunction, diabetes/prediabetes, vitamin deficiencies, history of HIV, hepatitis, or syphilis, prior radiation or chemical exposure or evidence of monoclonal gammopathy, or autoimmune condition. Results: Participants were female (age: 21-37y) and all endorsed orthostatic intolerance (6/6). Gastrointestinal symptoms (⅚), new-onset paresthesias, (3/6), and sexual dysfunction (2/6) were reported. Parasympathetic autonomic function remained stable 6-months to 1-year post-COVID-19 infection and no parasympathetic dysfunction was demonstrated in participants with new-onset dysautonomia symptoms. Postural orthostatic tachycardia was noted in half of the patients, being observed in one patient pre- SARS-CoV-2 infection and persisting post-SARS-CoV-2 infection; while new-onset postural tachycardia was observed in 1/3rd of patients. Sympathetic cholinergic (sudomotor) dysfunction was demonstrated in ALL participants. Worsened, or new-onset, sudomotor dysfunction was demonstrated in those with mild or normal sudomotor function on pre-COVID-19 autonomic testing. Conclusions: Sympathetic adrenergic and cholinergic dysautonomia probably account for some of the symptoms of Long COVID-19. Sudomotor dysfunction was demonstrated as consistently worsened or new-sequelae to COVID-19 infection. COVID-19 may be responsible for triggering new-onset or worsened small-fiber neuropathy in this sample, supporting previously reported studies with similar findings. However, the findings in our study are preliminary, and studies with larger sample size are needed to confirm these observations.

Impaired VEGF-A-Mediated Neurovascular Crosstalk Induced by SARS-CoV-2 Spike Protein: A Potential Hypothesis Explaining Long COVID-19 Symptoms and COVID-19 Vaccine Side Effects?

Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease. Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines. Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization. The S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the vascular endothelial growth factor (VEGF)-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors. SARS-CoV-2-infected individuals may exhibit increased plasma levels of VEGF-A during both acute illness and convalescence, which could be responsible for diffuse microvascular and neurological damage. A few studies suggest that serum VEGF-A may also be a potential biomarker for long COVID-19, whereas evidence for COVID-19 vaccines is lacking and merits further investigation.

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.

Neuropathies Amidst the Pandemic: Remote Phenotype Validation and Assessment of Patient Needs

The past two years have been significantly overshadowed by the respiratory virus Covid-19. This has shown a relevant impact on health care systems, so that at a specialized neuromuscular center, we experienced a shortness of personnel and time, and in parallel, we were facing many unanswered questions addressed to us by patients with rare diseases. In this study, we developed a new questionnaire to assess patient needs, concerns, and symptoms confronting the global pandemic. We included individuals with hereditary neuropathies (n=15), autoimmune-inflammatory neuropathies (n=26), or idiopathic small fiber neuropathies (n=45). For validation, we used previous clinical examination reports. Forty-six percent of the included patients were female, 52% male, and one patient diverse. The mean age at examination was 52.67±13.37 years (range: 19-79 years). Most of the patients (59%) reported mild to moderate limitations in their daily life activities due to Covid-19. Severe impairment was reported in 28%. Due to the pandemic, 54% of the patients reported to be concerned about their own and 76% about their relatives' health. Patients with a positive family history were 2.4x more likely to be seriously worried about other family members. We observed that patients with more wide-spread sensory loss reported higher impairment levels than those with distal sensory loss only. Overall, 37% of the patients said that contracting Covid-19 was their main concern, including the presumed risk of a severe course. Further 34% were worried that their neuropathy might worsen if they ever contracted Covid-19. Thirtythree percent of the patients experienced limitations in their treatment options, e.g. by not being able to continue their physical therapy. Seven percent were concerned about social distancing, as daily care required direct interactions with others. Whereas 65% of the included individuals confirmed that they felt appropriately informed by their treating physicians, 21% wished to receive more information. Sixteen percent, however, said that they did not dare to ask their questions in order to not disturb the health care personnel amidst the crisis. Patients with hereditary, autoimmune, or small fiber neuropathies did not show any differences in their Covid-related dailylife impairment. Previous clinical results correlated with patient-reported sensory levels;and gait unsteadiness was reported significantly more often in patients with afferent ataxia. We conclude that Covid-19 imposes a relevant daily-life burden on neuropathy patients. Patient-reported outcome measures are a valid remote strategy if in-person visits are not possible.

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.

Small Fiber Neuropathy Associated With the Moderna SARS-CoV-2 Vaccine.

Efforts of controlling viral transmission began soon after the first cases of coronavirus disease 2019 (COVID-19) infections were identified. Initial efforts were related to contact precautions, hand hygiene, and mask-wearing; however, it was soon evident that a robust global immunization drive was the most effective way to curb disease transmission. In the United States, the first doses of COVID-19 vaccines were rolled out soon after the FDA granted emergency use authorization for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. What this also meant was that many of the routine phases that any new drug or vaccine goes through before being released publicly were bypassed. Over the past two years, various side effects and reactions have been seen after COVID-19 vaccine administration, the most common being local injection site events (e.g., pain, redness, swelling) and systemic effects (e.g., fatigue, headaches, myalgias). We report the case of a 64-year-old female who developed bilateral lower extremity numbness and tingling within weeks of receiving the third dose of Moderna SARS-CoV-2 vaccine. The patient underwent extensive testing to ascertain the diagnosis. She had negative autonomic testing and normal nerve conduction study/electromyography (EMG), which did not reveal large fiber neuropathy. Eventually, the patient underwent a skin biopsy, which revealed small fiber neuropathy. This case report highlights the importance of keeping a broad differential for rare side effects, such as small fiber neuropathy, that are currently being seen and reported in the literature.

Demonstrating New-onset orWorsened Sudomotor Function post COVID-19

Objective: Identify if SARS-CoV-2 virus is triggering and/or worsening dysautonomia by reviewing the function of autonomic patients pre-COVID-19 and post-COVID-19 infection, as well as new onset autonomic patients post-COVID-19 infection. Background: Autonomic dysfunction may be part of acute and long COVID-19 infection. Design/Methods: Six participants were enrolled and divided into two groups. The first group of 4 volunteers reported worsened autonomic symptoms post-COVID-19 infection. These individuals had first autonomic test prior to COVID-19 pandemic outbreak (July 2019- December 2019). Autonomic function testing was repeated in these participants, 6 months to 1- year post-COVID-19 infection (June, 2021). The second group of 2 volunteers reported newonset autonomic symptoms post-COVID-19 infection and were tested March-May, 2021. All participants were screened for known causes of autonomic dysfunction and had normal neurophysiological studies (EMG/NCS), no hypertension/hyperlipidemia or thyroid dysfunction, no diabetes/prediabetes, no vitamin deficiencies, no history of HIV, hepatitis, or syphilis, no prior radiation or chemical exposure and no evidence of monoclonal gammopathy, or autoimmune condition. Participants were diagnosed with COVID-19 via PCR testing, and tested again via SARS-CoV-2 capsid-antibody test. Results: All volunteers were female (age: 21-37y) and endorsed orthostatic intolerance. Gastrointestinal symptoms (5/6), new-onset paresthesias, drier skin (3/6), and sexual dysfunction (2/6) were reported. Dysgeusia reported in 50%, but was not demonstrated on neurological examination. Parasympathetic autonomic function remained stable 6-months to 1- year post-COVID-19 infection and not demonstrated in participants with new-onset symptoms. Sympathetic-adrenergic dysfunction as new-onset orthostatic hypotension and abnormalities on blood-pressure response to Valsalva was found in 50% of participants. Sympathetic cholinergic (sudomotor) dysfunction was demonstrated in ALL participants. Worsened, or new-onset, sudomotor dysfunction was demonstrated in those with mild or normal sudomotor function on pre-COVID-19 autonomic testing Conclusions: Sudomotor dysfunction was demonstrated as worsened or new-sequelae to COVID-19 infection. COVID-19 may be responsible for new-onset or worsened small-fiber neuropathy in this sample.

Autonomic dysfunction following COVID-19 infection: an early experience

Objective: We present an early systematic analysis of autonomic dysfunction following COVID19 to provide initial insights into the spectrum of this condition. Background: Post-COVID-19 syndrome is a poorly understood aspect of the current pandemic, with clinical features that overlap with symptoms of autonomic/small fiber dysfunction. Design/Methods: We conducted a retrospective review of all patients with confirmed history of COVID-19 infection referred for autonomic testing for symptoms concerning for para-/postinfectious autonomic dysfunction at Mayo Clinic Rochester or Jacksonville between March 2020 and January 2021. Results: We identified 27 patients fulfilling the search criteria. Symptoms developed between 0 and 122 days following the acute infection and included lightheadedness (93%), orthostatic headache (22%), syncope (11%), hyperhidrosis (11%), and burning pain (11%). Sudomotor function was abnormal in 36%, cardiovagal function in 27%, and cardiovascular adrenergic function in 7%. The most common clinical scenario was orthostatic symptoms without tachycardia or hypotension (41%);22% of patients fulfilled the criteria for postural tachycardia syndrome (POTS), and 11% had borderline findings to support orthostatic intolerance. One patient each was diagnosed with autoimmune autonomic ganglionopathy, inappropriate sinus tachycardia, vasodepressor syncope, cough/vasovagal syncope, exacerbation of preexisting orthostatic hypotension, exacerbation of sensory and autonomic neuropathy, and exacerbation of small fiber neuropathy. Conclusions: Abnormalities on autonomic testing were seen in the majority of patients but were mild in most cases. The most common finding was orthostatic intolerance, often without objective hemodynamic abnormalities on testing. Unmasking/exacerbation of preexisting conditions was seen. The temporal association between infection and autonomic symptoms implies a causal relationship, which however cannot be proven by this study.

Case Series: Post-COVID Small Fiber Neuropathy

Objective: To report a case series documenting biopsy-proven small fiber neuropathy (SFN) after COVID-19. Background: Patients recovering from COVID-19 who present with sensory as well as autonomic symptoms, including positional orthostatic tachycardia syndrome (POTS), frequently have negative electrodiagnostic testing. Skin biopsy may be required to reveal SFN. Design/Methods: This is a retrospective case series of patients seen in the Yale Neurology COVID-19 Clinic with positive SARS-CoV-2 PCR or antibody or a clinically consistent illness. After laboratory testing and a negative nerve conduction study, all patients underwent skin biopsy to test for intraepidermal SFN. Case 1: A 40F with pre-diabetes (HbA1c 6.2%) developed burning, numbness, and tingling in the hands and legs and POTS 6 weeks after acute COVID-19. Skin biopsy demonstrated non-length dependent SFN. Complete remission of neuropathy symptoms occurred within days of intravenous immunoglobulin (IVIG) therapy, which has been continued longitudinally. Case 2: A 65F with non-insulin dependent diabetes (HbA1c 8.0%) developed excruciating burning pain in her feet and orthostasis within weeks of acute COVID-19. Skin biopsy demonstrated non-length dependent SFN. She experienced partial relief of symptoms after IVIG and gabapentin. Case 3: A 43F with pre-diabetes (HbA1c 6.0%) developed orthostasis, numbness, paresthesias, and a “sunburned” feeling in her face, back, hands, and feet 2 weeks after acute COVID-19. Skin biopsy demonstrated length-dependent SFN. Symptoms improved over several months of pregabalin treatment, but have not resolved. The patient deferred immunotherapy. Case 4: A 40M developed POTS, numbness, and paresthesias in his face and left leg up to the knee within weeks of a clinical COVID-19 illness. Skin biopsy demonstrated non-length dependent SFN. IVIG therapy has resulted in significant improvement in symptoms. Conclusions: Sensory symptoms and POTS occur post-COVID, and SFN should be considered in the differential. Given the time of onset and response to immunotherapy, post-COVID SFN may have an underlying autoimmune etiology.

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.

COVID-Long Haulers Can Develop POTS (Postural Orthostatic Tachycardia Syndrome) with Small Fiber Neuropathy and Abnormal Autonomic Testing

Objective: A substantial number of COVID long-haulers have developed POTS, which warrants further investigation. This study is intended as a first look at a new and growing patient population that is bringing greater attention to the prevalent autonomic disease of POTS. Background: POTS (Postural Orthostatic Tachycardia Syndrome) is a disorder of autonomic dysregulation involving overactive compensation for postural blood pressure changes. This debilitating syndrome can be associated with small fiber neuropathy and a broad spectrum of autonomic symptoms including palpitations, changes in sweating, and gastrointestinal problems like constipation. Respiratory and gastrointestinal viruses have been known to cause onset of POTS pathophysiology. In approximately 10% of COVID cases, patients experience long-term health effects after the conclusion of their COVID infection. These patients are called COVID “long-haulers.” Design/Methods: We conducted a chart review of 25 Cleveland Clinic post-COVID POTS patients who are mostly female (84%) to learn about this patient population's distribution of top symptoms, comorbidities, autonomic testing, and autonomic questionnaire scores. Top three symptoms were determined based on the physician's note from the patients' initial visit to the Cleveland Clinic Neurology Department. Results: Our chart review revealed a high occurrence of excitatory comorbidities such as chronic migraine (44%) and irritable bowel syndrome (24%). In addition, when assessing patients' top three POTS symptoms, we found that palpitations, fatigue, and dyspnea were affecting patients most. As with POTS in general, autonomic testing outside of tilt table testing (85.7%) shows variable results with QSART (50%), skin punch biopsy (37.5%), deep breathing (14.3%), and Valsalva testing (0%) all showing positivity rates of 50% or less for our patient sample. Conclusions: Post-COVID POTS could be an excitatory process with hyperadrenergic signaling based on the symptoms and comorbidities. We hope that this chart review will be the launching point for future studies aimed at achieving greater understanding of the post-COVID POTS phenomenon.