The Role of Advanced Technologies against COVID-19: Prevention, Detection, and Treatments.

Concurrent with the global outbreak of COVID-19, the race began among scientists to generate effective therapeutics for the treatment of COVID-19. In this regard, advanced technology such as nanotechnology, cell-based therapies, tissue engineering and regenerative medicine, nerve stimulation and artificial intelligence (AI) are attractive because they can offer new solutions for the prevention, diagnosis and treatment of COVID-19. Nanotechnology can design rapid and specific tests with high sensitivity for detecting infection and synthases new drugs and vaccines based on nanomaterials to directly deliver the intended antiviral agent to the desired site in the body and also provide new surfaces that do not allow virus adhesion. Mesenchymal stem cells and exosomes secreted from them apply in regenerative medicine and regulate inflammatory responses. Cell therapy and tissue engineering are combined to repair or substitute damaged tissues or cells. Tissue engineering using biomaterials, cells, and signaling molecules can develop new therapeutic and diagnostic platforms and help scientists fight viral diseases. Nerve stimulation technology can augment body's natural ability to modulate the inflammatory response and inhibit pro-inflammatory cytokines and consequently suppress cytokine storm. People can access free online health counseling services through AI and it helps very fast for screening and diagnosis of COVID-19 patients. This study is aimed first to give brief information about COVID-19 and the epidemiology of the disease. After that, we highlight important developments in the field of advanced technologies relevant to the prevention, detection, and treatment of the current pandemic.

First in-neonate use of non-invasive transcutaneous auricular vagus nerve stimulation: 18-month neurodevelopmental and sensory follow-up

Objective: Non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) paired with oral feeding is a novel intervention for infants with feeding delays that may improve feeding and help avoid a gastrostomy tube (Gtube). However, the long-term impact of this neurostimulation on infant's development remains unknown. We investigated the neurodevelopmental and sensory outcomes of infants who received taVNS paired with bottle feeding. Method(s): Twenty-one of 35 toddlers who participated in the open label trial of taVNS paired with one or two feeds a day for 2-3 weeks, underwent comprehensive developmental assessments at 18 months of age using Cognitive Adaptive Test, Clinical Linguistics and Auditory Milestone, and Peabody gross motor scores. Twelve of those assessed achieved full oral feeds ('responders') and 9 had G-tube placed for feeds ('non-responders'). Before COVID, 12 toddlers (5 responders, 7 non-responders) were also assessed in the home using the Bayley-III and Sensory Profile (SP-2) assessments. Area deprivation index (ADI) was used to measure resource poor environments and relate to test scores. We used Fishers exact test and Pearson correlation coefficients to compare neurodevelopmental and sensory performance in responders versus non-responders. Result(s): taVNS responders showed significantly better general sensory processing in SP-2 than did non-responders (p =0.04). There were no significant differences in Bayley-III or CAT/CLAMS/ASQ scores in areas of cognition, receptive language, fine motor, and gross motor skills in this small sample size, but are similar to published scores for preterm infants who received G-tubes. ADI was not significantly associated with neurodevelopmental scores. Conclusion(s): These results suggest that taVNS paired with feeding may have a potential long-term positive neurodevelopmental effect on sensory processing in neonates with poor feeding. The current open-label results need testing in randomized controlled trials of taVNS paired with oral feeding in developmentally delayed infants failing oral feeds. Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Neurodevelopment, taVNS, feeding, developmental delaysCopyright © 2023

Po251 / #854 Noninvasive Closed Loop Diaphragm Stimulation for Ventilated Icu Patients: E-Poster Viewing

Introduction: Many COVID-19 patients need prolonged artificial ventilation. Skeletal muscle wastes rapidly when deprived of neural activation, and in ventilated patients the diaphragm muscle begins to atrophy within 24 hours (ventilator induced diaphragmatic dysfunction, VIDD). This profoundly weakens the diaphragm, complicating the weaning of the patient off the ventilator, and increasing the risk of complications such as bacterial pneumonia. 40% of the total duration of mechanical ventilation in ITU patients is accounted for by the weaning period, after the initial illness has resolved. Prevention of VIDD would therefore both improve individual outcomes, and also release ITU capacity. We aim to prevent VIDD by exercising the diaphragm with electrical stimulation of the nerves that control it. Evidence suggests that muscle wasting can be prevented by quite low levels of exercise (e.g. 200 contractions per day). Materials / Methods: The diaphragm is activated by the phrenic nerves, formed from branches of the C3-C5 nerve roots in the neck. These nerves may be electrically stimulated in the lower neck. An electrode array is positioned on each side of the neck using surface landmarks. The system automatically determines the best electrode to use in each array. Sensors built into the ventilatory circuit are monitored both to match stimulation to the respiratory cycle and to determine the effects of stimulation. Result(s): We have designed and built a prototype system for unsupervised noninvasive phrenic nerve stimulation. The system delivers one contraction every 7 minutes, synchronised to early inspiration so as not to disrupt ventilation. Electrode impedances are measured before each stimulus, and the closed loop system continuously monitors the effects of stimulation on airflow and adjusts stimulation parameters to compensate for changes in coupling, for example due to head movement. Discussion(s): This stimulator system overcomes several limitations of existing solutions, namely the resource implications and risk profile of invasive electrodes, and the requirement for supervised operation. While invasive systems are applied selectively for these reasons, routine use of our system can be envisaged. This system was inspired by COVID-19 patients but is not limited to them, and has broad applicability to ventilated intensive care patients in general, for example patients with traumatic brain injury. Conclusion(s): Non-invasive stimulation of the phrenic nerves using pressure-free skin surface electrodes is feasible and safe. It offers the potential for prevention of VIDD and thereby faster ventilator weaning and shorter stay on ITU. Clinical trials are planned in 2022. Learning Objectives: After this presentation delegates should be aware of: 1. Ventilation induced diaphragm dysfunction (VIDD) and its importance in patients having lengthy periods of ventilation, as in many cases of COVID-19. 2. The fact that low levels of activity can maintain the condition of skeletal muscles including the diaphragm muscle 3. The potential for noninvasive stimulation of the phrenic nerves to provide 'diaphragm exercise' and prevent VIDD. Keywords: phrenic nerve stimulation, diaphragm, ventilation, COVID-19Copyright © 2022

Clinical applications of transcutaneous auricular neurostimulation for opioid use disorder and pain

Symposium title: Addressing chronic pain and the opioid epidemic using auricular neuromodulation Symposium description: Our proposed symposium integrates a diverse group of scientist and clinician experts (Drs. Cunningham, Wilkes, Khodaparast, Badran) who have committed to exploring the anti-nociceptive and opioid sparing effects of auricular neuromodulation to progress toward non-opioid interventions for chronic pain and opioid use disorders. The demand for chronic pain therapies has increased at an unprecedented rate over the last several decades, contributing in part to a surge in prescription and illicit opioid demand. Countless patients were escalated to prolonged, high-dose opioid regimens over years of treatment. By 2014, 5.4% of U.S. adults were estimated to use prescription opioids on a long-term basis. As the harms of opioid proliferation became increasingly clear, a dramatic paradigm shift occurred in which these drugs are now perceived as more dangerous than beneficial for chronic pain. New clinical guidelines highlight the risks of high-dose regimens as well as the limited benefits, particularly insufficient analgesia and hyperalgesia, associated with long-term use. According to this new perspective, the preferred therapeutic modality for many patients is to safely taper, or even completely stop, using opioids. Transcutaneous auricular neurostimulation (tAN) is a novel therapeutic paradigm that includes stimulation of both the auricular branch of the vagus nerve and auriculotemporal nerve (branch of trigeminal). tAN therapy results in clinically significant reductions in opioid withdrawal symptoms associated with opioid detoxification and tapering. Either adjunctive vagal or trigeminal stimulation modulates pain transmission suggesting overlapping common effector pathways, possibly targeting the endogenous opioid system, which could lead to a synergistic therapeutic benefit for pain. This symposium will explore the scientific basis for this hypothesis across targeted and interconnected topics, including fundamental neuropharmacological mechanisms underlying pain and opioids, clinical challenges of tapering opioids, managing opioid withdrawal symptoms with tAN, and the prospects for tAN to deliver a safe alternative treatment option for pain disorders. The United States is experiencing an epidemic for prescription and non-prescription opioids, which have continued to rise since the 1990s. During 2015, approximately 2.1 million people were severely dependent on prescription opioids, and 513,000 on heroin. In 2020, the Centers for Disease Control reported 93,331 substance use overdose deaths. The continuing increase in opioid-related deaths from 2015 (18%) to 2020 (60%) is partly attributed to the mental health crisis during the Covid-19 pandemic. Aside from pain mitigation, individuals with opioid use disorder (OUD) may be motivated to continue drug-seeking by both the positive reinforcement of the euphoric effects of opioids and the negative reinforcement of opioid withdrawal symptoms due to cessation. Alternative approaches for OUD are a major priority for government agencies given the substantial impact on health, social, and economic welfare. Transcutaneous auricular neurostimulation (tAN) is a non-invasive form of vagus and trigeminal neuromodulation that was recently proven to be an efficacious non-pharmacologic based treatment for reducing opioid withdrawal symptoms. In 2021, tAN therapy received FDA clearance as an adjunctive treatment for opioid withdrawal symptoms in adults. tAN therapy was also proven safe and effective in reducing symptoms of neonatal opioid withdrawal syndrome (NOWS) in neonates. tAN as an adjuvant was safe, well-tolerated, while facilitating the successful rapid weaning of oral morphine and decreasing length of stay in the neonatal ICU. Based on these preliminary findings, tAN therapy is currently in two NIH-funded pivotal clinical trials to: 1) evaluate the long-term effects of tAN on opioid use relapse prevention and cravings in adults with OUD, and 2) determine f tAN therapy can reduce withdrawal symptoms and reduce morphine length of treatment for neonates with NOWS. Lastly, we will explore how tAN could be utilized as neuromodulatory approach for opioid sparing, and ultimately pain mitigation. Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Vagus Nerve Stimulation, Opioid Use Disorder, Pain, NeurostimulationCopyright © 2023

A new case of myasthenia gravis following COVID-19 Vaccination

Background: Myasthenia gravis (MG) is an autoimmune disease of unknown etiology. Infections are known as a major cause of MG exacerbations. A few studies have shown an association between new onset MG and SARS-CoV-2 infection. Case presentation: We have reported a case of new onset myasthenia gravis in a 68-year-old man presented with bulbar symptoms a few days after receiving COVID-19 vaccine (Sinopharm vaccine). The disease was confirmed by high titer of antibody against acetylcholine receptor and electrophysiological examinations. Conclusion(s): Among the adverse effects reported with the COVID-19 vaccine, new onset myasthenia gravis is very rare. The underlying mechanism is unknown but the immune response after vaccination and molecular mimicry theory has been proposed.Copyright © 2022

It Takes Two to Make a Thing Go Wrong

Seventy-three-year-old diabetic male was a high-risk transfer from Alaska for respiratory decompensation in the setting of progressive bulbar and proximal weakness. He was diagnosed with COVID-19 two months prior and viral mononucleosis 1 month prior to presentation. While the patient had a fall 3 months prior to presentation, and decreased mobility at home, there was abrupt onset of progressive upper/lower extremity weakness, dysphagia, and difficulties managing secretions 2 weeks prior to presentation. Initial exam was notable for MRC 3-4/5 proximal upper/lower extremity weakness, areflexia, and negative inspiratory force of 224 to 230 cm H20. A subtle periorbital heliotrope rash was documented. Lumbar puncture demonstrated albumino-cytologic dissociation (protein 142 mg/dL, 6 WBCs) and CK remained elevated (1930 U/L) despite intravenous hydration. Outside electrodiagnostic testing demonstrated a sensorimotor axonal neuropathy with questionable myopathic features on needle electromyography. Given concern for an inflammatory neuropathy and concomitant inflammatory myopathy, intravenous immunoglobulin 2G/kg and IV methylprednisolone 1G/day over 5 days was started. He was transferred for further diagnostic workup and supportive care 6 days after presentation and required intubation within 24 hours of admission. Exam showed progressive proximal and distal weakness of the extremities and general areflexia/hyporeflexia. Repeat electromyography confirmed a severe sensorimotor axonal polyneuropathy without acquired demyelinating features and normal repetitive nerve stimulation. While the patient could no longer activate muscles voluntarily, proximal muscles had increased spontaneous activity with predominant myotonia. Neuroaxis imaging was notable only for enhancement of the lumbar nerve roots. Combined vastus lateralis muscle biopsy and serologic testing confirmed a second pathologic process contributing to the patient's weakness. This case highlights the cooccurrence of 2 distinct neuropathological entities, with potential relation to a prior viral infection, and the importance of ancillary testing to guide treatment for acute causes of neuromuscular respiratory failure.

Three-Year Durability of Restorative Neurostimulation Effectiveness in Patients With Chronic Low Back Pain and Multifidus Muscle Dysfunction.

BACKGROUND: Restorative neurostimulation is a rehabilitative treatment for patients with refractory chronic low back pain (CLBP) associated with dysfunction of the lumbar multifidus muscle resulting in impaired neuromuscular control. The ReActiv8-B randomized, sham-controlled trial provided evidence of the effectiveness and safety of an implanted, restorative neurostimulator. The two-year analysis previously published in this journal demonstrated accrual of clinical benefits and long-term durability. OBJECTIVE: Evaluation of three-year effectiveness and safety in patients with refractory, disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. MATERIALS AND METHODS: Prospective, observational follow-up of the 204 implanted trial participants. Low back pain visual analog scale (VAS), Oswestry Disability Index (ODI), EuroQol quality of life survey, and opioid intake were assessed at baseline, six months, and one, two, and three years after activation. The mixed-effects model repeated measures approach was used to provide implicit imputations of missing data for continuous outcomes and multiple imputation for proportion estimates. RESULTS: Data were collected from 133 participants, and 16 patients missed their three-year follow-up because of coronavirus disease restrictions but remain available for future follow-up. A total of 62% of participants had a ≥ 70% VAS reduction, and 67% reported CLBP resolution (VAS ≤ 2.5cm); 63% had a reduction in ODI of ≥ 20 points; 83% had improvements of ≥ 50% in VAS and/or ≥ 20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 71% (36/51) participants on opioids at baseline had voluntarily discontinued (49%) or reduced (22%) opioid intake. The attenuation of effectiveness in the imputed (N = 204) analyses was relatively small and did not affect the statistical significance and clinical relevance of these results. The safety profile remains favorable, and no lead migrations have been observed to date. CONCLUSION: At three years, 83% of participants experienced clinically substantial improvements in pain, disability, or both. The results confirm the long-term effectiveness, durability, and safety of restorative neurostimulation in patients with disabling CLBP associated with multifidus muscle dysfunction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02577354.

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best.

A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.

Case Report: Auricular vagus nerve stimulation possibly alleviates COVID-19 disease on a high-risk patient.

Introduction: SARS-CoV-2 is a highly contagious virus that was identified as the cause of COVID-19 disease in early 2020. The infection is clinically similar to interstitial pneumonia and acute respiratory distress syndrome (ARDS) and often shows cardiovascular damage. Patients with cardiovascular risk factors are more prone to COVID-19 disease and their sequelae. Due to the anti-inflammatory effect and the improvement in pulmonary function, auricular vagus nerve stimulation (aVNS) therapy might alleviate a COVID-19 infection. Patient and Methods: A high-risk patient with cardiovascular diseases and Implantable Cardioverter Defibrillator (ICD), type 2 diabetes and peripheral arterial disease IV, according to Rutherford`s classification, became infected with COVID-19. The patient underwent wound surgery because of an infected necrosis with a methicillin-resistant Staphylococcus aureus (MRSA) of his small toe and was already on aVNS therapy to relieve his leg pain and improve microcirculation. AVNS was performed with the AuriStim device (Multisana GmbH, Austria), which stimulates vagally innervated regions of the auricle by administering electrical stimulation via percutaneous electrodes for 6 weeks. Results: The multimorbid high-risk patient, who was expected to go through a severe course of the COVID-19 disease, showed hardly any symptoms during ongoing aVNS therapy, while other family members, being much younger and healthy suffered from a more serious course with headache, pneumonia and general weakness. Conclusion: The auricular vagus nerve stimulation is a clinically tested and safe procedure and might represent an alternative and effective way of treating COVID-19 disease. Nevertheless, due to several limitations of this case report, randomized controlled studies are needed to evaluate the efficacy of aVNS therapy on COVID-19 disease.

Effect of Peripheral Neuromodulation on Headache in Post Covid-19 Survivors

Objective: The purpose of present study was to evaluate the impact of peripheral neuromodulation through vagus nerve stimulation on headache in Post COVID-19 survivors. Method(s): Thirty Post COVID-19 survivors from both genders (17 females and 13 males) aged from 20 to 40 years who suffered from Post COVID-19 headache were recruited and randomized into two groups of equal number. Subjects in group A (study group) received transcutaneous vagus nerve stimulation as well as the designed physiotherapy program whereas subjects in group B (control group) underwent placebo transcutaneous vagus nerve stimulation on vagus nerve in addition to the same designed physical therapy program. The treatment was carried-out for 5 sessions each week for four weeks. Visual analogue scale (VAS) was used to measure the intensity of headache pain whereas the headache disability index (HDI) was used to measure the disability resulted from headache. Result(s): The findings showed significant decline in VAS and HDI post treatment in study group (A) and control group (B) in comparison with that pretreatment (p<0.001). Between-group analysis showed no significant difference between the two groups pretreatment (p>0.05), whereas there was significant decline in VAS and HDI in study group in comparison with that of the control group posttreatment (p<0.05). Conclusion(s): peripheral neuromodulation is more effective in managing headache in post COVID-19 survivors. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19. METHODS: A randomized blinded pilot study was carried out with 21 individuals hospitalized with COVID-19 who received 14 sessions of active (a-taVNS) or sham taVNS (s-taVNS). The level of interleukin-6 (IL-6), interleukin-10 (IL-10), cortisol, and C-reactive protein (CRP) in plasma and clinical evolution pre- and post-intervention were evaluated. The memory and attention levels were evaluated 14 days after the end of the treatment. RESULTS: After treatment, significant intragroup differences were found in the CRP (p = 0.01), IL-6 (p = 0.01), and cortisol (p = 0.01) levels; however, in the comparison between the groups, only the CRP level was statistically lower for the a-taVNS (p = 0.04). The impression of improvement in memory and attention was greater in the a-taVNS than in the s-taVNS (p = 0.01, p = 0.04, respectively). There was no difference between the other clinical outcomes. CONCLUSIONS: taVNS is a viable and safe intervention in the acute care of patients with COVID-19, which can modulate their inflammatory profile and improve cognitive symptoms. However, improvements in overall clinical outcomes were not detected. Larger sample sizes and longer follow-ups are needed to confirm the anti-inflammatory and clinical effects of taVNS in patients with COVID-19. TRIALS REGISTRY: The Brazilian Registry of Clinical Trials (RBR-399t4g5).

Neuromodulation Virtual Care Technology Provides Safe and Effective Drg/Scs Remote Programming: E-Poster Viewing

Introduction: About 20.4% of US adults suffer from chronic pain and need consistent management plans which were disrupted in 2020 with the COVID-19 pandemic.1,2,3 Patients who use programmable neuromodulation devices to treat chronic pain typically require follow-up visits to address changes in symptoms. An FDA-approved teleprogramming platform enables real-time remote programming via mobile devices for movement disorder and chronic pain patients who use neuromodulation devices. The platform eases the burden travel imposed on many patients, allowing physicians to quickly resolve patient symptoms. The Remote Optimization, Adjustment, and Measurement for Chronic Pain Therapy (ROAM-CPT) study is a post-market, prospective, non-randomized, multi-center investigation to determine that the telehealth system meets patients' therapeutic needs safely and effectively. Materials / Methods: 62 consented subjects across 4 sites, with an implanted neuromodulation device, participating in the REALITY study (NCT03876054) were enrolled in ROAM-CPT and were provided access to the telehealth software. A questionnaire designed for both patient and physician was available after each remote session. The primary success rate was determined by the ability to establish an audio-video connection, complete remote programming or device check, and provide patient clinical care similar to an in-patient session. Additionally, the physicians' and patients' preferences, satisfaction, and reduction in the burden of care compared to in-person sessions were determined. Result(s): 15 patients initiated and completed an audio-video session. All physicians' confirmed services are akin to in-person sessions. During the study, 53.3% of the sessions were complex programming (change in three or more parameters), 26.7% simple programming (change in 1-2 parameter), and 20.0% device interrogation. Overall, all surveyed providers preferred remote care and 93.3% (14/15) of subjects did not require additional clinical care services. Of the 15 subjects across 4 sites, all but 1 reported rapid resolution (reduction in pain), preferred remote care to in-patient, and would recommend a remote session. Patients also reported getting faster appointment time as well as saving travel time and resources typically spent towards an in-person session. Discussion(s): The remote neuromodulation technology provides secure audio-video chat connectivity, programming changes such as amplitude, systems check, and session reports. Physicians easily provide patients care using this platform while patients' therapeutic needs were quickly resolved from the comfort of their homes using their mobile devices. Conclusion(s): Teleprogramming provides real-time programming capabilities and optimizes therapy for patients with neurostimulation devices. Learning Objectives: 1. Teleprogramming provides real-time, safe programming that equals an in-person session. No safety concerns were recorded for all 15 session 2. Virtual clinic affords clinicians the ability to provide quick patient care, does not increase the need for additional follow-up. All 15 participating patients reported resolved therapy needs. 14/15 did not require additional follow-up. 3. Physicians and patients both prefer Virtual clinic 4/4 surveyed physicians and 14/15 surveyed patients preferred virtual clinic. Keywords: Teleprogramming, Neuromodulation, Neurosphere, Virtual clinic, Remote programming, Telehealth Copyright © 2022

WE-159. Critical Illness Neuropathy in Severe COVID-19: a case series

Introduction: Neurological complications of SARS-CoV-2 disease have received growing attention, but only few studies have described to date clinical and neurophysiological findings in COVID patients during their stay in intensive care units (ICUs). Here, we assessed the presence of either critical illness neuropathy (CIP) or myopathy (CIM) in ICU patients. Method(s): Patients underwent a neurophysiological assessment, including bilateral examination of the median, ulnar, deep peroneal and tibial motor nerves and of the median, ulnar, radial, and sural sensory nerves. Needle electromyography (EMG) was performed for both distal and proximal muscles of the lower and upper limbs. The technique of Direct Muscle Stimulation (DMS) was applied either to the deltoid or tibialis anterior muscles. Peak to peak amplitudes and onset latencies of the responses evoked by DMS (DMSamp, DMSlat) or by motor nerve stimulation (MNSamp, MNSlat) were compared. The ratio MNSamp to DMSamp (NMR) and the MNSlat to DMSlat difference (NMD: MNSlat-DMSlat) were also evaluated. Result(s): Nerve conduction studies showed a sensory-motor polyneuropathy with axonal neurogenic pattern, as confirmed by needle EMG. Both MNSamp and NMR were significantly reduced when compared to controls (p < 0.0001), whereas MNSlat and NMD were markedly increased (p = 0.0049). Conclusion(s): We have described COVID patients in the ICU with critical illness neuropathy (CIP). The predominance of CIP as compared to critical illness myopathy (CIM) has implications for the functional recovery and rehabilitation strategies in severe COVID-19. Copyright © 2022

Efficacy of transcutaneous posterior tibial nerve stimulation in functional constipation.

Most children with functional constipation (FC) improve with conventional treatments. However, a proportion of children have poor treatment outcomes. Management of intractable FC may include botulinum toxin injections, transanal irrigation, antegrade enemas, colonic resections, and in some cases sacral nerve stimulation (SNS). SNS is surgically placed, not readily available and expensive. Posterior tibial nerve stimulation (PTNS) allows transmission of electronic impulses and retrograde stimulation to the sacral nerve plexus in a portable, simple and non-invasive fashion. To assess the efficacy and safety of transcutaneous PTNS for the treatment of FC in children. Single-center, prospective interventional study. Children 4-14 years with Rome IV diagnosis of FC received ten daily PTNS (30 min/day) sessions. Electrodes placed over skin of ankle. Strength of stimulus was below pain threshold. Outcomes were assessed during treatment and 7 days after. Twenty-three subjects enrolled. Two children excluded (acute gastroenteritis, COVID-19 contact). Twenty completed the study (4-14 years), (8.4 ± 3.2 years, 71.4% female). We found significant improvement in the consistency of bowel movements (BM) (p = 0.005), fecal incontinence (FI) (p = 0.005), abdominal pain presence (p = < 0.001) and intensity (p = 0.005), and a significant for improvement in blood in stools (p = 0.037). There was 86.3% improvement in abdominal pain. 96.7% reported treatment satisfaction. Only one child required rescue therapy. CONCLUSION: We found significant improvement in stool consistency, FI, abdominal pain, and hematochezia. This suggests that transcutaneous PTNS could be a promising noninvasive treatment for FC in children. Large studies are needed. WHAT IS KNOWN: • Functional constipation is one of the most common disorders in children. • Current management of functional constipation consists of an integrative approach that includes medications, diet and behavioral strategies. WHAT IS NEW: • Posterior tibial nerve stimulation is a novel noninvasive and easy to use therapy that can improve stool consistency, fecal incontinence and blood in stools.

Neuromodulation Strategies to Reduce Inflammation and Improve Lung Complications in COVID-19 Patients.

Since the outbreak of the COVID-19 pandemic, races across academia and industry have been initiated to identify and develop disease modifying or preventative therapeutic strategies has been initiated. The primary focus has been on pharmacological treatment of the immune and respiratory system and the development of a vaccine. The hyperinflammatory state ("cytokine storm") observed in many cases of COVID-19 indicates a prognostically negative disease progression that may lead to respiratory distress, multiple organ failure, shock, and death. Many critically ill patients continue to be at risk for significant, long-lasting morbidity or mortality. The human immune and respiratory systems are heavily regulated by the central nervous system, and intervention in the signaling of these neural pathways may permit targeted therapeutic control of excessive inflammation and pulmonary bronchoconstriction. Several technologies, both invasive and non-invasive, are available and approved for clinical use, but have not been extensively studied in treatment of the cytokine storm in COVID-19 patients. This manuscript provides an overview of the role of the nervous system in inflammation and respiration, the current understanding of neuromodulatory techniques from preclinical and clinical studies and provides a rationale for testing non-invasive neuromodulation to modulate acute systemic inflammation and respiratory dysfunction caused by SARS-CoV-2 and potentially other pathogens. The authors of this manuscript have co-founded the International Consortium on Neuromodulation for COVID-19 to advocate for and support studies of these technologies in the current coronavirus pandemic.

Transcutaneous electrical nerve stimulation for at-home treatment of nocturnal enuresis in children: Determining optimal pad placement

Introduction: Nocturnal enuresis (NE) is a common problem encountered in children that can be recalcitrant to currently available treatment options. Neuromodulation techniques are used to treat various urologic disorders but can be limited by convenience and compliance. Transcutaneous electrical nerve stimulation (TENS) is a neuromodulator that can be used at home to treat various conditions. The aim of this study was to determine if TENS can be offered as an effective at-home option that shows durability for NE in children, and to determine which pad placement is the most efficacious. Materials & Methods: A randomized clinical trial including 90 patients aged 5-18 years presenting with monosymptomatic NE was performed. After one month of behavioral therapy, they were treated with TENS therapy after randomization to three groups based on pad placement: suprapubic (SP), parasacral (PS), and ankle/posterior tibial (PT). TENS therapy was performed nightly for one month. Voiding diaries recording the number of wet nights, wet scale severity score (0-3), TENS compliance, quality of life (QOL) questionnaires, and any adverse reactions were collected monthly at baseline, during TENS therapy, and after TENS for durability assessment, and statistically analyzed after study completion. Results: No patient was cured of NE, and our study failed to show a statistical difference between the study arms in enuresis frequency during TENS. The only statistically significant improvement was QOL during TENS therapy (2.95 improvement for the PT group versus 1.2 and 1.5 regression for SP and PS groups, respectively, p=0.003). PT TENS therapy also showed improvements for enuresis frequency with 2.7 less episodes/month (versus 4.1 and 8.2 more episodes/month in the SP and PS groups, respectively, p=0.06) and the severity of wetness each night with a 0.17 improvement (versus 0.06 and 0.13 regression in the SP and PS groups, respectively, p=0.06) after TENS therapy was completed, however these did not meet statistical significance. Patients were compliant with using TENS therapy (90% or more in all groups) and there were no adverse events. Discussion: This study found that patients who used the PT pad placement for TENS showed significant improvements in QOL during therapy, however we were unable to show a significant difference in enuresis frequency during TENS between groups. The major limitation of our study was the high number of patients lost to follow-up during the COVID-19 pandemic. Conclusion: TENS therapy when combined with behavioral techniques can be an easy and safe tool that can be used at home to help treat NE, however, further studies are needed to optimize this type of therapy to show a clinically significant benefit.

Transcutaneous Auricular Vagus Nerve Stimulation Improves Inflammation but Does Not Interfere with Cardiac Modulation and Clinical Symptoms of Individuals with COVID-19: A Randomized Clinical Trial.

Transcranial auricular vagus nerve stimulation (taVNS) has shown effectiveness in reducing inflammation and depression. Thus, this study evaluated its effect on inflammation, cardiac autonomic modulation, and clinical symptoms in individuals affected by COVID-19. Methods: There were 52 randomized participants hospitalized with COVID-19 diagnosis who were to receive active (a-taVNS) or sham taVNS (s-taVNS) for 90 min twice a day for seven consecutive days. Interleukin 6 (IL-6), 10 (IL-10), cortisol, C-reactive protein (CRP), heart rate variability (HRV), and clinical symptoms were assessed before and after seven days of treatment. There were also seven- and fourteen-day follow-ups for clinical symptoms, including anxiety and depression levels, as well as a six-month follow-up for memory and attention levels. Results: There was significant reduction in CRP -23.9%, (95% CI -46.3 to -1.4) and IL-6 -37.7%, (95% CI -57.6 to -17.7) for the a-taVNS group. There were no changes in IL-10, cortisol levels, or in HRV results (p > 0.05) in both groups. There were no changes regarding clinical symptoms, except for a significant decrease in depression level (-2.85, 95% CI -5.44 to -0.27) in the a-taVNS group. Conclusion: taVNS showed effects on CRP, IL-6, and depression levels; however, it did not affect other clinical symptoms.

Durability of Symptom Relief with Restorative Neurostimulation for Mechanical Chronic Low Back Pain: Three-Year Follow-up Results of the Pivotal Trial: Track 3: Neurostimulation for Back and Leg Pain

Introduction: Mechanical chronic low back pain (CLBP) can be caused by impaired neuromuscular control and degeneration of the multifidus muscles, the most important stabilizers of the lumbar spine. An implantable Restorative Neurostimulation system bilaterally stimulates the medial branches of the L2 dorsal rami to override underlying multifidus inhibition to facilitate motor control restoration. A randomized sham-controlled pivotal trial provided evidence of safety, effectiveness and durability of this therapy (clinicaltrials.gov/show/NCT02577354).[1,2] Here we will report the three-year durability results. Materials / Methods: Eligible patients had activity limiting mechanical CLBP (VAS >=6cm;Oswestry Disability Index (ODI) >=21 points) despite medical management, which included at least pain medications and physical therapy. They had evidence of impaired multifidus motor control (positive prone instability test) and no indication for spine surgery. All patients were implanted with a Restorative Neurostimulation system (ReActiv8, Mainstay Medical, Dublin, Ireland). During the long-term follow-up phase, all participants delivered stimulation for up to 30 minutes twice daily eliciting repetitive, tonic multifidus contractions. Result(s): At baseline (N=204), participants were 47+/-9 years of age, had history of backpain for 14+/-11 years, had an average low back pain VAS of 7.3+/-0.7 cm, ODI of 39+/-10, EQ-5D of 0.585+/-0.174 points and had pain on 97+/-8% of days in the year prior to enrollment. Three-year data are available for 124 participants*. Average VAS improved by 5.0+/-2.4 cm, ODI by 23+/-15 points and EQ-5D by 0.223+/-0.199 (All P<0.0001);78% of participants had a >=50% VAS improvement;69% reported LBP-Resolution (VAS<=2.5 cm);65% had a >=20-point ODI improvement and 86% of participants were "definitely satisfied" with the treatment. Pain intensity and disability are interdependent symptoms and treatment success is determined by composite improvements in ODI and VAS: 84% had a substantial improvement of >=50% in VAS and/or >=20points in ODI, and 59% had these improvements in both VAS and ODI. Of participants using opioids at baseline, 72% had voluntarily discontinued or decreased consumption. Overall safety compares favorably to other neurostimulation systems, and no lead migrations were observed. During the third year of follow-up, 6 participants requested device removal citing resolution of pain. Discussion(s): See conclusions. Conclusion(s): Restorative-Neurostimulation is an effective, durable, and safe treatment for patients with refractory, activity-limiting CLBP secondary to impaired multifidus neuromuscular control. Consistent with the restorative mechanism, improvements accrue progressively over time. *Twenty-five follow-ups pending (Covid-19 restrictions) Learning Objectives: 1. Understand the long term pain outcomes (three year outcomes) of restorative neurostimulation for refractory chronic low back pain. 2. Understand the long term function outcomes (three year outcomes) of restorative neurostimulation for refractory chronic low back pain. 3. Understand the long term safety outcomes (three year outcomes) of restorative neurostimulation for refractory chronic low back pain. Keywords: nociceptive low back pain, multifidus, motor control, Restorative neurostimulation, chronic low back pain Copyright © 2022