key: cord-0709874-c1lwcnf6 authors: Abrams, Rory M. C.; Simpson, David M.; Navis, Allison; Jette, Nathalie; Zhou, Lan; Shin, Susan C. title: Small fiber neuropathy associated with SARS‐CoV‐2 infection date: 2021-11-22 journal: Muscle Nerve DOI: 10.1002/mus.27458 sha: a7e6f7bc9f452ad4871cfef651f7fea5f0794412 doc_id: 709874 cord_uid: c1lwcnf6 INTRODUCTION/AIMS: The development and persistence of neurological symptoms following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is referred to as “long‐haul” syndrome. We aimed to determine whether small fiber neuropathy (SFN) was associated with SARS‐CoV‐2 infection. METHODS: We retrospectively studied the clinical features and outcomes of patients who were referred to us between May 2020 and May 2021 for painful paresthesia and numbness that developed during or after SARS‐CoV‐2 infection and who had nerve conduction studies showing no evidence of a large fiber polyneuropathy. RESULTS: We identified 13 patients, Eight women and five men with age ranging from 38–67 y. Follow‐up duration ranged from 8 to 12 mo. All patients developed new‐onset paresthesias within 2 mo following SARS‐CoV‐2 infection, with an acute onset in seven and co‐existing autonomic symptoms in seven. Three patients had pre‐existing but controlled neuropathy risk factors. Skin biopsy confirmed SFN in six, all of whom showed both neuropathy symptoms and signs, and two also showed autonomic dysfunction by autonomic function testing (AFT). Of the remaining seven patients who had normal skin biopsies, six showed no clinical neuropathy signs and one exhibited signs and had abnormal AFT. Two patients with markedly reduced intraepidermal nerve fiber densities and one with normal skin biopsy had severe and moderate coronavirus disease 2019 (COVID‐19); the remainder experienced mild COVID‐19 symptoms. Nine patients received symptomatic neuropathy treatment with paresthesias controlled in seven (77.8%). DISCUSSION: Our findings suggest that symptoms of SFN may develop during or shortly after COVID‐19. SFN may underlie the paresthesias associated with long‐haul post‐COVID‐19 symptoms. associated with COVID-19 has not been well studied. COVID-19 can exacerbate SFN symptoms, but to date, de novo SFN associated with COVID-19 appears to be very rare. 3 Autonomic dysfunction has been described in association with COVID-19, which can occur during or several months after the infection. [3] [4] [5] Herein, we retrospectively studied the demographics, clinical features, test findings, and outcomes of 13 patients with new-onset paresthesias suggestive of SFN that developed during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We searched our skin biopsy database and identified 13 patients with confirmed SARS-CoV-2 infection, who were referred to our neuromuscular clinic by the Center for Post-COVID Care at The Mount Sinai Hospital between May 2020 and May 2021 for evaluation of paresthesia. All these patients received routine nerve conduction studies (NCS) and electromyography, which showed no evidence of a large fiber polyneuropathy. They also underwent clinical evaluation and skin biopsy to confirm SFN by one of the authors. Threemillimeter punch skin biopsies were performed at the distal leg and proximal thigh of each patient after appropriate consent was obtained. Biopsy specimens were processed and immunostained using PGP9.5 antibody for intraepidermal nerve fiber density (IENFD) evaluation by either Boston University Medical Center or Johns Hopkins University Cutaneous Nerve Laboratory. These two laboratories use the same methodology and follow the same published guidelines. 6 Four patients also underwent standardized autonomic function testing (AFT) with quantitative sudomotor axon reflex testing (QSART), heart rate responses to deep breathing, Valsalva maneuver, assessment of blood pressure changes in response to passive head-up tilt. Patient demographics, clinical features, test findings, therapy, and outcomes are detailed in Table 1 for those with abnormal skin biopsy and in Table 2 for those with normal biopsy results. Eight patients (61.5%) were females, and five were males (38.5%). Ages ranged from 38 to 67 y, with a median of 50 y. Ten patients had confirmed SARS-CoV-2 infection by nasopharyngeal polymerase chain reaction (PCR), and three patients were confirmed by antibody tests. COVID-19 was severe in one, moderate in two, mild in nine, and asymptomatic in one (Supporting Information Appendix S1, which is available online). Time Symptoms of SFN can occur regardless of COVID-19 severity. All but three of our patients had mild or asymptomatic COVID-19 symptoms. It is intriguing that in six biopsy-proven SFN cases, the reduction of IENFD was length-dependent with the distal leg being solely or more affected than the proximal thigh, despite that the SFN symptoms were diffuse and appeared non-length-dependent in three of six. The sensory deficits on examination were also length-dependent in these patients. Although non-length-dependent SFN is more likely to be associated with an immune-mediated process than length-dependent SFN, an immune-mediated process can also cause length-dependent SFN. 7, 8 None of these patients received immunotherapy specifically for their SFN symptoms, and nine received symptomatic treatment with mixed results. While most of our patients responded to symptomatic treatment for neuropathic pain, the symptoms were not well controlled in two who had IENFD severely reduced at the distal leg and moderately reduced at the proximal thigh (Patient 1 and Patient 2). Further studies are required to determine if there is any role for immunotherapy in this setting. Such clinical studies to test these treatments will assess efficacy and ultimately may help post-COVID survivors with lingering chronic painful paresthesias. This study has several limitations. It is retrospective and the cohort is small. Given that most patients in this study developed COVID-19 during the initial New York City peak of the pandemic in March-April 2020, it is possible that patients with milder neuropathy symptoms may have recovered and were never assessed with a skin biopsy at the peak of their post-infectious symptoms. Increased and earlier recognition of SFN is crucial to address what is clearly an under-recognized source of morbidity. None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm this report is consistent with those guidelines. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Post-acute COVID-19 syndrome Long-Haul COVID Autonomic dysfunction following COVID-19 infection: an early experience Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report European Federation of Neurological Societies/peripheral nerve society guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy Non-length dependent small fibre neuropathy/ganglionopathy Characterization of non-length-dependent small-fiber sensory neuropathy Clinical Spectrum of SARS-CoV-2 Infection Additional supporting information may be found in the online version of the article at the publisher's website.