Ultramicronized Palmitoylethanolamide and Luteolin: Drug Candidates in Post-COVID-19 Critical Illness Neuropathy and Positioning-Related Peripheral Nerve Injury of the Upper Extremity

Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium and patients with serious infection can stay in intensive care unit (ICU) for weeks in a clinical scenario of systemic inflammatory response syndrome, likely related to the subsequent development of critical illness polyneuropathy (CIP). It is in fact now accepted that COVID-19 ICU surviving patients can develop CIP;moreover, prone positioning-related stretch may favor the onset of positioning-related peripheral nerve injuries (PNI). Therefore, the urgent need to test drug candidates for the treatment of these debilitating sequelae is emerged even more. For the first time in medical literature, we have successfully treated after informed consent a 71-year-old Italian man suffering from post-COVID-19 CIP burdened with positioning-related PNI of the left upper extremity by means of ultramicronized palmitoylethanolamide 400 mg plus ultramicronized luteolin 40 mg (Gl & igrave;alia), two tablets a day 12 hours apart for 6 months. In the wake of our pilot study, a larger clinical trial to definitively ascertain the advantages of this neuroprotective, neurotrophic, and anti-inflammatory therapy is advocated.

The distribution of acquired peripheral nerve injuries associated with severe COVID-19 implicate a mechanism of entrapment neuropathy: a multicenter case series and clinical feasibility study of a wearable, wireless pressure sensor.

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.

MACROGLOSSIA IN THE SETTING OF COVID-19

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Macroglossia is a rare but life-threatening symptom that disrupts a person's ability to talk, swallow, and can also compromise their airway. Although not very well studied, there are several case reports describing a possible association between COVID-19 infection and macroglossia in people with African ancestry. We present an African American man who developed significant macroglossia several days after testing positive for COVID-19. CASE PRESENTATION: A 59 y/o African American male with a history of chronic bronchitis and tobacco use presented with 4 days of dyspnea. Sars-Cov-2 PCR was positive. Chest x-ray revealed bilateral, diffuse lung infiltrates. He had an elevated CRP of 295 and a d-dimer of 265. He became lethargic and hypercapnic requiring intubation which was nontraumatic. He was sedated, paralyzed, and proned. He received steroid therapy, broad spectrum antibiotics and a dose of Sarilumab. About a week later, he developed macroglossia that worsened over the course of days. Side effect profiles of each of his medications did not reveal any increased likelihood of macroglossia. C1Q complement cascade was mildly elevated and C1 esterase inhibitor level was normal. Diagnosis and treatment was necessary at this point as concerns for tongue central necrosis were raised and baseline tongue size would be required for proper evaluation and surgical intervention if necessary. He was given 4 units of FFP for possible angioedema with no improvement. CT Neck W/ contrast revealed edema and protrusion of the tongue without a discrete mass. Workup for acromegaly, sarcoidosis, amyloidosis, and hypothyroidism were negative. A pressure ulcer developed on his tongue due to the endotracheal tube and so he underwent tracheostomy. His tongue was draped in Chlorhexidine soaked gauze as well as Vashe wound solution. As he recovered from COVID-19 pneumonia, his respiratory status improved as well as his macroglossia. His tracheostomy was decannulated and his tongue returned to its baseline size. DISCUSSION: Macroglossia can lead to complications including airway compromise, dysphagia, or speech difficulties. It has been heavily proposed in the literature that COVID-19 infection can lead to postinfectious inflammatory peripheral nerve injury secondary to immune driven mechanisms. It was also previously proposed in literature based on immune-histochemical analysis of a tongue tissue sample taken from a COVID-19 patient that tongue muscle atrophy occurs as well as macrophage infiltration similar to that of nerve injury repair which can eventually lead to macroglossia. CONCLUSIONS: As the effects of COVID-19 are becoming better studied overtime, macroglossia, especially in those with African ancestry, is increasingly coming under the radar. This case report seeks to educate clinicians on this possible sequela and encourage supportive treatment in hopes that the tongue will recover. Reference #1: McCrossan S, Martin S, Hill C. Tongue Reduction for Macroglossia. J Craniofac Surg. 2021;32(5):1856-1859. doi:10.1097/SCS.0000000000007276 Reference #2: Colombo D, Del Nonno F, Nardacci R, Falasca L. May macroglossia in COVID-19 be related not only to angioedema?. J Infect Public Health. 2022;15(1):112-115. doi:10.1016/j.jiph.2021.10.026 Reference #3: Fernandez CE, Franz CK, Ko JH, et al. Imaging Review of Peripheral Nerve Injuries in Patients with COVID-19. Radiology. 2020;298 (3). https://doi.org/10.1148/radiol.2020203116 DISCLOSURES: No relevant relationships by Megan Devine No relevant relationships by Devin Haney No relevant relationships by Es-Haq Hassanin No relevant relationships by Nadim Islam No relevant relationships by Alyssa Weyer

Reducing harm from Covid-ICU proning related peripheral neuropathies - Comparing patient outcomes for 2020 and 2021 surges and recommendations for future care

Introduction: Prone positioning is commonly used when treating ventilated Covid-19 patients. Whilst there have been some reports of ICU proning-related injuries to the brachial plexus well before the pandemic (Goettler et al. 2002), it is usually a very uncommon complication. Despite guidance from the Faculty of Intensive Care Medicine on the care of the proned patient, cases of peripheral neuropathies following ICU admission have significantly increased during the Covid-19 pandemic at our centre (Miller et al. 2021). Nerve injury is associated with reduced quality of life, impaired activity participation and persistent pain (Bailey et al. 2009). Objectives: The aim of this quality improvement project was to identify the effect that new guideline development and related healthcare professional education had on the number and severity of peripheral neuropathies identified following Covid-19 ICU admission. Methods: Between March 2020 and May 2021, we collected clinical data from patients who sustained peripheral neuropathies during their inpatient stay for Covid-19. Data were collected via face-to-face patient assessments within acute nerve clinics or post-ICU rehabilitation wards. A grading system was used to categorise the peripheral nerve injuries into severe, intermediate and mild (Power et al. 2020). Electronic ICU clinical noting was examined to identify the frequency and duration of each proning episode for each patient who presented with nerve injury. Following the first surge in 2020 updated proning guidelines were developed with ICU team leaders and disseminated. This involved face-to-face education of frontline staff. Results: At our centre 93 patients survived Covid ICU between March -June 2020 (surge 1) and 21 of those sustained nerve injury (22.58%). 309 patients survived Covid ICU between September 2020 -May 2021 (surge 2) and 12 of those sustained nerve injury (3.88%). For patients who sustained nerve injury, the average number of prones changed between surges from 6 to 13. The average duration of each episode of proning changed from 17.8hrs to 18.6hrs. Despite the increase in prone frequency, nerve injury occurrence reduced (proportionate to the number of patients who survived Covid ICU) by 82%. 14/21 (66%) injuries acquired in the first surge were of high grade and 4/ 12 (33%) were of high grade during the second surge. Conclusion: Optimising positioning of the proned ventilated patient may reduce the incidence of nerve injury. However, we must also acknowledge that changes in medical management between surges (i.e. use of dexamethasone, remdesivir) may have contributed to this. Individuals still developed severe injury despite this change in practice. Further research looking into risk factors and further methods of optimising the prone positioning on ICU is warranted to reduce the occurrence of this potentially life-changing injury.

Autoimmunity, cancer and COVID-19 abnormally activate wound healing pathways: critical role of inflammation.

Recent evidence indicates that targeting IL-6 provides broad therapeutic approaches to several diseases. In patients with cancer, autoimmune diseases, severe respiratory infections [e.g. coronavirus disease 2019 (COVID-19)] and wound healing, IL-6 plays a critical role in modulating the systemic and local microenvironment. Elevated serum levels of IL-6 interfere with the systemic immune response and are associated with disease progression and prognosis. As already noted, monoclonal antibodies blocking either IL-6 or binding of IL-6 to receptors have been used/tested successfully in the treatment of rheumatoid arthritis, many cancer types, and COVID-19. Therefore, in the present review, we compare the impact of IL-6 and anti-IL-6 therapy to demonstrate common (pathological) features of the studied diseases such as formation of granulation tissue with the presence of myofibroblasts and deposition of new extracellular matrix. We also discuss abnormal activation of other wound-healing-related pathways that have been implicated in autoimmune disorders, cancer or COVID-19.

Abstracts of the 12th Annual Meeting of the Italian Association for the study of the Peripheral Nervous System (ASNP)

The proceedings contain 69 papers. The topics discussed include: chemotherapy induced peripheral neurotoxicy: why should we care?;studying the caudal nerve anatomy and physiology to refine detection of peripheral nerve damage in rodent models;anxiety and depression in Charcot-Marie-tooth disease: data from the Italian CMT National Registry;fatigue in CMT: a web based survey from the Italian CMT National Registry;early molecular diagnosis of mutations on the transthyretin gene as a strategy to improve the prognosis of hereditary transthyretin-mediated amyloidosis - an update of the GENILAM project;THR124MET myelin protein zero mutation mimicking motor neuron disease;torsional neuropathy in parsonage turner syndrome following anti-COVID19 vaccination. how to detect and manage with it?;isolated musculocutaneous involvement in parsonage-turner syndrome associated with SARS-COV2 vaccination;neonatal FC receptor expression in patients with chronic dysimmune neuropathy. a feasibility study;and peripheral neuropathies after common organ transplantations. literature review and the use of electrophysiological tests and ultrasound.

COVID-19 Neuromuscular Involvement in Post-Acute Rehabilitation.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with muscle and nerve injuries as a consequence of prolonged critical illness or the infection itself. In this study, we evaluated neuromuscular involvement in patients who underwent post-acute intensive rehabilitation after COVID-19. METHODS: Clinical and neurophysiological evaluations, including nerve conduction studies and electromyography, were performed on 21 consecutive patients admitted for rehabilitation after COVID-19. RESULTS: Clinical signs suggesting muscle or nerve involvement (weakness, reduced deep tendon reflexes, impaired sensitivity, abnormal gait) were found in 19 patients. Neurophysiological examinations confirmed neuromuscular involvement in 17 patients: a likely association of critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) was found in 5 patients; CIM alone was found in 4 patients; axonal sensory-motor polyneuropathy was found in 4 patients (CIP in 2 patients, metabolic polyneuropathy in 2 patients); Guillain-Barré syndrome was found in 2 patients (classical demyelinating sensory-motor polyneuropathy and acute motor axonal neuropathy, respectively); peroneal nerve injury was found in 1 patient; and pre-existing L4 radiculopathy was found in 1 patient. CONCLUSIONS: Neuromuscular involvement is a very common finding among patients admitted for rehabilitation after COVID-19, and proper investigation should be conducted when muscle or nerve injury is suspected for adequate rehabilitative strategy planning.

Complex regional pain syndrome after severe COVID-19 - A case report.

Neurological complications are frequently reported in an intensive care unit (ICU), as a manifestation of a critical systemic illness or of its treatment. On the specific setting of COVID-19 patients, peripheral nerve lesions can have a multiplicity of causes, such as post-infectious neuropathy, positioning-related neuropathy or iatrogeny. An unusual but potentially disabling complication of any peripheral nerve lesion is Complex Regional Pain Syndrome (CRPS). Although there have been no mechanistic studies assessing how SARS-CoV-2 might directly impact nociception, it is hypothesized that the systemic hyperinflammation seen in severe COVID-19 may contribute to peripheral and central neuronal sensitization, possibly increasing the risk of developing CRPS. This case report highlights the potential hazards and consequences of peripheral nerve injuries on an ICU setting in COVID-19 patients, as well as the importance of a multidisciplinary approach for an early diagnosis and treatment, which are directly related to a better prognosis.

Intensive Care Unit-Acquired Weakness and Positioning-Related Peripheral Nerve Injuries in COVID-19: A Case Series of Three Patients and the Latest Literature Review.

A subgroup of COVID-19 patients requires intensive respiratory care. The prolonged immobilization and aggressive treatments predispose these patients to develop intensive care unit-acquired weakness (ICUAW). Furthermore, this condition could increase the chance of positioning-related peripheral nerve injuries. On the basis of the latest literature review, we describe a case series of three patients with COVID-19 who developed ICUAW complicated by positioning-related peripheral nerve injuries Every patient presented sensorimotor axonal polyneuropathy and concomitant myopathy in electrophysiological studies. Furthermore, muscle MRI helped the diagnosis of ICUAW, showing massive damage predominantly in the proximal muscles. Notably, nerve ultrasound detected positioning-related peripheral nerve injuries, even though the concomitant ICUAW substantially masked their clinical features. During the acute phase of severe COVID-19 infection, most medical attention tends to be assigned to critical care management, and neuromuscular complications such as ICUAW and positioning-related peripheral nerve injuries could be underestimated. Hence, when starting post-ICU care for COVID-19 cases, the combination of electrophysiological and imaging studies will aid appropriate evaluation on the patients with COVID-19-related ICUAW.