Impact of Failed Intracranial Epilepsy Surgery on the Effectiveness of Subsequent Vagus Nerve Stimulation

Abstract BACKGROUND Using the Cyberonics registry, Amar and colleagues reported poorer efficacy of vagus nerve stimulation (VNS) in patients who failed intracranial epilepsy surgery (IES). OBJECTIVE To study the impact of failed IES and other surrogate marker of severe epilepsy on VNS effectiveness in a large cohort with treatment-resistant epilepsy (TRE). METHODS We retrospectively reviewed 376 patients (188 female patients; 265 adults; mean age, 29.4 years at implantation) with TRE who underwent VNS implantation between 1997 and 2008 and had at least 1 year of follow-up. One hundred ten patients (29.3%) had failed ≥1 prior craniotomies for TRE, and 266 (70.7%) had no history of IES. RESULTS The mean duration of VNS therapy was 5.1 years. Patients with prior IES were more commonly male and adult, had a greater number of seizure types, and more commonly had focal or multifocal vs generalized seizures (P > .05). There was no significant difference in the mean percentage seizure reduction between patients with and without a history of IES (59.1% vs 56.5%; P = .42). There was no correlation between type of failed IES (callosotomy vs resection) and seizure reduction with VNS therapy. CONCLUSION Failed IES did not affect the response to VNS therapy. Unlike prior reports, patients with callosotomy did not respond better than those who had resective surgery. Nearly 50% of patients experienced at least 50% reduction in seizure frequency. For patients with TRE, including patients who failed cranial epilepsy surgeries, VNS should be considered a palliative treatment option.

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Vagus Nerve Stimulation Therapy for the Treatment of Seizures in Refractory Postencephalitic Epilepsy: A Retrospective Study

Frontiers in Neuroscience ◽

10.3389/fnins.2021.685685 ◽

2021 ◽

Vol 15 ◽

Author(s):

Yulin Sun ◽

Jian Chen ◽

Tie Fang ◽

Lin Wan ◽

Xiuyu Shi ◽

...

Keyword(s):

Retrospective Study ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Intraoperative Complications ◽

Effective Rate ◽

Seizure Reduction ◽

Grand Total ◽

The Mean

BackgroundVagus nerve stimulation (VNS) has been demonstrated to be safe and effective for patients with refractory epilepsy, but there are few reports on the use of VNS for postencephalitic epilepsy (PEE). This retrospective study aimed to evaluate the efficacy of VNS for refractory PEE.MethodsWe retrospectively studied 20 patients with refractory PEE who underwent VNS between August 2017 and October 2019 in Chinese PLA General Hospital and Beijing Children’s Hospital. VNS efficacy was evaluated based on seizure reduction, effective rate (percentage of cases with seizure reduction ≥ 50%), McHugh classification, modified Early Childhood Epilepsy Severity Scale (E-Chess) score, and Grand Total EEG (GTE) score. The follow-up time points were 3, 6, and 12 months after VNS. Pre- and postoperative data were compared and analyzed.ResultsThe median [interquartile range (IQR)] seizure reduction rates at 3, 6, and 12 months after VNS were 23.72% (0, 55%), 46.61% (0, 79.04%), and 67.99% (0, 93.78%), respectively. The effective rates were 30% at 3 months, 45% at 6 months, and 70% at 12 months. E-chess scores before the operation and at 3, 6, and 12 months after the operation were 10 (10, 10.75), 9 (9, 10), 9 (9, 9.75), and 9 (8.25, 9) (P < 0.05), respectively. GTE scores before surgery and at 12 months after the operation were 11 (9, 13) and 9 (7, 11) (P < 0.05), respectively. The mean intensity of VNS current was 1.76 ± 0.39 (range: 1.0–2.5) mA. No intraoperative complications or severe post-operative adverse effects were reported.ConclusionsOur study shows that VNS can reduce the frequency and severity of seizure in patients with refractory PEE. VNS has a good application prospect in patients with refractory PEE.

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Abstract TP146: Vagus Nerve Stimulation Paired With Rehabilitation To Improve Upper Limb Function

Stroke ◽

10.1161/str.48.suppl_1.tp146 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Jesse Dawson ◽

Theresa J Kimberley ◽

Gerard E Francisco ◽

Patricia Smith ◽

Steven C Cramer ◽

...

Keyword(s):

Vagus Nerve ◽

Upper Extremity ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Human Study ◽

Controlled Study ◽

Eligibility Criteria ◽

Double Blind ◽

Upper Limb Function ◽

Significant Difference

Introduction: Vagus Nerve Stimulation (VNS) paired with rehabilitation induces movement specific plasticity in rat motor cortex and improves forepaw function in a rat ischemic model compared to rehabilitation alone. A 20 subject first-in-human study in the UK indicated acceptable safety and feasibility of this approach in patients with arm weakness after stroke and showed a significant difference in favour of VNS paired with rehabilitation in the per-protocol analysis (Upper Extremity Fugl Meyer difference of 9.6 points for VNS vs. 3.0 Control; p = 0.038). We conducted a new, double-blind sham controlled study to further assess this technique. Methods: Subjects with chronic moderate to severe upper extremity hemiparesis secondary to ischemic stroke (Upper Extremity Fugl Meyer (UEFM) 20-50) were enrolled at four sites (3 US, 1 UK). After baseline assessments subjects were implanted with a vagus nerve stimulation device if all eligibility criteria were met. Following implantation, randomization was made to either paired VNS (1/2 second, 30 Hz., 0.8 mA, 100 uS stimulation with task-specific movement) or sham control (stimulation only on first 5 movements). All received the same intensive and task-specific rehabilitation and had 18 treatment sessions (2-hourly, 3 times a week for 6-weeks, approximately 50 repetitions per task and 300 to 400 repetition movements per session). Outcomes were assessed on the first and 30 th day following completion of the 6-week therapy course. Results: Sixteen patients (8 female) were implanted (8 VNS, 8 Control). Mean age (SD) was 63.2(6.9), with an average (SD) of 21.7 months (12.9) post stroke. One study related serious adverse event was reported (a wound infection that resolved with IV antibiotics). Blinded results (change in UEFM, WMFT, and UEFM responders for both groups) will be available and presented. Conclusions: A pivotal study of VNS paired with rehabilitation movements will be justified if preliminary results are confirmed.

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Genetic variations of adenosine kinase as predictable biomarkers of efficacy of vagus nerve stimulation in patients with pharmacoresistant epilepsy

Journal of Neurosurgery ◽

10.3171/2021.3.jns21141 ◽

2021 ◽

pp. 1-10

Author(s):

Yifan Zhang ◽

Xiongfei Wang ◽

Chongyang Tang ◽

Yuguang Guan ◽

Fan Chen ◽

...

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Refractory Epilepsy ◽

Genetic Variations ◽

Adenosine Kinase ◽

Minor Allele ◽

Seizure Freedom ◽

Seizure Reduction ◽

Genes Encoding

OBJECTIVE Vagus nerve stimulation (VNS) is an alternative treatment option for individuals with refractory epilepsy, with nearly 40% of patients showing no benefit after VNS and only 6%–8% achieving seizure freedom. It is presently unclear why some patients respond to treatment and others do not. Therefore, identification of biomarkers to predict efficacy of VNS is of utmost importance. The objective of this study was to explore whether genetic variations in genes involved in adenosine kinase (ADK), ecto-5′-nucleotidase (NT5E), and adenosine A1 receptor (A1R) are linked to outcome of VNS in patients with refractory epilepsy. METHODS Thirty single-nucleotide polymorphisms (SNPs), including 9 in genes encoding ADK, 3 in genes encoding NT5E, and 18 in genes encoding A1R, were genotyped in 194 refractory epilepsy patients who underwent VNS. The chi-square test and binary logistic regression were used to determine associations between genetic differences and VNS efficacy. RESULTS A significant association between ADK SNPs rs11001109, rs7899674, and rs946185 and seizure reduction with VNS was found. Regardless of sex, age, seizure frequency and type, antiseizure drug use, etiology, and prior surgical history, all patients (10/10 patients [100%]) with minor allele homozygosity at rs11001109 (genotype AA) or rs946185 (AA) achieved > 50% seizure reduction and 4 patients (4/10 [40%]) achieved seizure freedom. VNS therapy demonstrated higher efficacy among carriers of minor allele rs7899674 (CG + GG) (68.3% vs 48.8% for patients with major allele homozygosity). CONCLUSIONS Homozygous ADK SNPs rs11001109 (AA) and rs946185 (AA), as well as minor allele rs7899674 (CG + GG), may serve as useful biomarkers for prediction of VNS therapy outcome.

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Vagus Nerve Stimulation (VNS) in Super Refractory New Onset Refractory Status Epilepticus (NORSE)

Case Reports in Neurological Medicine ◽

10.1155/2019/7852017 ◽

2019 ◽

Vol 2019 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Mohankumar Kurukumbi ◽

James Leiphart ◽

Anam Asif ◽

Jing Wang

Keyword(s):

Status Epilepticus ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Refractory Epilepsy ◽

Refractory Status Epilepticus ◽

Refractory Status ◽

History Of ◽

Electrographic Seizures ◽

New Onset

The treatment protocol of status epilepticus has many associated toxicities so there is interest in alternate nonmedicinal therapies for managing New Onset Refractory Status Epilepticus (NORSE) patients. Vagus nerve stimulation (VNS) is an FDA-approved therapy for refractory epilepsy that has been shown to decrease the frequency and severity of seizures. We present the case of a patient with new-onset refractory status epilepticus (NORSE) whose seizures were successfully treated with vagus nerve stimulation. A 25-year-old male with no history of epilepsy or other neurological disorders presented with altered mental status and generalized tonic-clonic seizures following a two-week history of an upper respiratory tract infection. Lumbar puncture showed neutrophilic pleocytosis, and he was treated for bacterial and viral meningoencephalitis. In spite of treatment, his seizures began increasing in frequency. On day three, the patient entered status epilepticus (SE) refractory to intensive pharmacotherapy with maximal doses of valproate, levetiracetam, and propofol. On day four, SE remained refractory, so pentobarbital was introduced with targeted burst suppression pattern on electroencephalography (EEG). Patient continued to be refractory to these measures, so a vagus nerve stimulator (VNS) was implanted (day eight). Following VNS implantation, EEG demonstrated significant reduction of seizure activity and subsequent magnet swiping continued aborting electrographic seizures. No SE or electrographic seizures were reported for seventy-two hours, but few occasional discharges were reported. Seizures eventually recurred on day fourteen and the patient succumbed to his multiple comorbidities on day seventeen. Due to the efficacy of VNS in refractory epilepsy, there was interest in using it in refractory status epilepticus. Multiple case reports have described a benefit from implantation of VNS in the treatment of SE. The successful use of VNS to acutely terminate status epilepticus for seventy-two hours in this critically ill patient adds to current evidence that there is utility in using VNS for refractory status epilepticus.

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The Impact of Auricular Vagus Nerve Stimulation on Pain and Life Quality in Patients with Fibromyalgia Syndrome

BioMed Research International ◽

10.1155/2020/8656218 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Nazlı Kutlu ◽

Ali Veysel Özden ◽

Hasan Kerem Alptekin ◽

Jülide Öncü Alptekin

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Fibromyalgia Syndrome ◽

Life Quality ◽

Exercise Program ◽

Functional Evaluation ◽

Home Based ◽

Sf 36 ◽

The Impact

The purpose of this study is to evaluate the impact of auricular vagus nerve stimulation, applied in conjunction with an exercise treatment program, on pain and life quality in patients with fibromyalgia syndrome (FMS). To achieve the study objectives, 60 female patients between the ages 18 and 50, with diagnosed FMS according to the American College of Rheumatology (ACR) 2010 diagnostic criteria, were randomly divided into 2 groups of 30. The first group was assigned 20 sessions of a home-based exercise program, while the second group was assigned 20 sessions of auricular vagus nerve stimulation and 20 sessions of a home-based exercise program. Patients were assessed before and after the treatments using the Visual Analog Scale (VAS) for pain, Beck Depression Scale for depression, Beck Anxiety Scale for anxiety, Fibromyalgia Impact Questionnaire (FIQ) for functional evaluation, and Short Form-36 (SF-36) for life quality. In this randomized controlled trial, comparisons within the groups revealed that both groups had statistically significant improvements in pain, depression, anxiety, functionality, and life quality scores (p<0.05), while comparisons across the groups revealed that the group experiencing the vagus nerve stimulation had no statistically significant differences between the baseline scores, except for those of SF-36’s subparameters of physical function, social functionality, and pain. In fact, comparisons across the groups after the interventions revealed that the group experiencing the vagus nerve stimulation had better scores but not statistically significant. From analysis of this data, we observed that vagus nerve stimulation in FMS treatment did not give additional benefit together with exercise, except for three subparameters of SF-36. It was identified that further studies which separately investigate the effects of vagus nerve stimulation and exercise on FMS with longer follow-up periods and an increased number of patients are needed.

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Older Age and Longer Epilepsy Duration Do Not Predict Worse Seizure Reduction Outcome after Vagus Nerve Stimulation

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0037-1607396 ◽

2017 ◽

Vol 79 (02) ◽

pp. 152-158 ◽

Cited By ~ 6

Author(s):

Jitka Kocvarova ◽

Zdenek Novak ◽

Irena Dolezalova ◽

Michal Svoboda ◽

Milan Brazdil ◽

...

Keyword(s):

Intellectual Disability ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Older Patients ◽

Age Groups ◽

Seizure Reduction ◽

Follow Up Care ◽

Patients With Epilepsy

Introduction We analyzed the results of vagus nerve stimulation (VNS) on older patients and patients with long-lasting epilepsy and included severely intellectually disabled patients. Patients and Methods A total of 103 adults with VNS implanted from 2005 to 2014 were studied. The responder rates, that is, the percentage of VNS patients who responded to VNS, classified as seizure reduction ≥ 50% (50R) and seizure reduction ≥ 90% (90R), were compared in defined age groups (< 40 and ≥ 40 years, and < 50 and ≥ 50 years) and epilepsy duration groups (< 20 and ≥ 20 years, < 30 and ≥ 30 years, and < 40 and ≥ 40 years) at the 1-year follow-up visit and the last follow-up visit (at least 2 years after surgery). The age distributions and responder rates were also studied in patients with an intellectual disability. Results The analysis did not confirm a significantly lower 50R or 90R rate in patients ≥ 40, ≥ 50, or ≥ 60 years when compared with their younger counterparts, but the 50R rate increase during follow-up care was the lowest in patients ≥ 50 and ≥ 60 years. The highest percentage of patients with an intellectual disability in the group < 40 years of age did not adversely affect the 50R rate. Longer epilepsy duration was not confirmed as a negative predictor of VNS outcome. There was a significantly higher 50R rate in patients with epilepsy duration ≥ 20 years (at the last follow-up visit) and a higher 90R rate in patients with epilepsy duration ≥ 30 years (at the 1-year follow-up visit). The increase in the 50R rate during follow-up care was lower in patients with epilepsy durations ≥ 30 and ≥ 40 years. Conclusions The study did not find worse VNS outcomes, as defined by the 50R or 90R rate, in older adult patients or in patients with a longer epilepsy duration. The increasing stimulation effect over time is less marked in older patients and in patients with longer epilepsy duration.

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Vagus nerve stimulation for depression: efficacy and safety in a European study

Psychological Medicine ◽

10.1017/s0033291707001924 ◽

2008 ◽

Vol 38 (5) ◽

pp. 651-661 ◽

Cited By ~ 104

Author(s):

T. E. Schlaepfer ◽

C. Frick ◽

A. Zobel ◽

W. Maier ◽

I. Heuser ◽

...

Keyword(s):

Side Effects ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Rating Scale ◽

Response Rates ◽

European Study ◽

Multi Centre Study ◽

Significant Difference ◽

Remission Rates

BackgroundVagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression.MethodAn open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically.ResultsThe baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (⩾50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%).ConclusionsVNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.

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A.6 Vagus Nerve Stimulation in patients with therapy resistant generalized epilepsy

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2021.268 ◽

2021 ◽

Vol 48 (s3) ◽

pp. S15-S15

Author(s):

AS Suller Marti ◽

SM Mirsattari ◽

KW MacDougall ◽

D Steven ◽

A Parrent ◽

...

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Hospital Admissions ◽

Focal Epilepsy ◽

Limited Information ◽

Best Response ◽

History Of ◽

Generalized Epilepsy

Background: For patients with generalized epilepsy who do not respond to anti-seizure medications, the therapeutic options are limited. Vagus nerve stimulation (VNS) is a treatment mainly approved for therapy resistant focal epilepsy. There is limited information on the use of VNS on generalized epilepsies, including Lennox Gastaut Syndrome(LGS) and genetic generalized epilepsy(GGE). Methods: We identified patients with a diagnosis of Lennox-Gastaut Syndrome or Genetic Generalized Epilepsy, who underwent VNS implantation, between1997 and July 2018. Results: A total of 46 patients were included in this study with a history of therapy resistant generalized epilepsy. The mean age at implantation was 24 years(IQR= 17.8-31 years) and 50%(n=23) were female. The most common etiologies were GGE in 37%(n=17) and LGS in 63%(n=29). Median follow-up since VNS implantation was 63 months(IQR:31-112.8months). 41.7%(n=12) of the LGS group became responders, and 64.7%(n=11) in the GGE group. The best response in seizure reduction was seen in generalized tonic-clonic seizures. There was a reduction of seizure-related hospital admissions from 89.7%(N=26) pre-implantation, to 41.4%(N=12) post-implantation (p<0.0001). The frequency of side effects due to the stimulation was similar in both groups(62.1% in LGS and 61.1% in GGE). Conclusions: VNS is an effective treatment in patients with therapy resistant generalized epilepsy, especially GGE.

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P.022 The effect of vagus nerve stimulation on the quality of sleep in medically refractory epileptic patients

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2021.304 ◽

2021 ◽

Vol 48 (s3) ◽

pp. S26-S26

Author(s):

J Seth ◽

A Suller-Marti

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Limited Data ◽

Quality Of Sleep ◽

Obstructive Sleep ◽

Clinical Trails ◽

Patients With Epilepsy ◽

The Impact

Background: The quality of sleep is frequently impacted in patients with epilepsy. Vagus Nerve Stimulation is a relatively common treatment used in patients with medically resistant epilepsy. Some studies show an improvement in quality of life, however, there is limited data on the impact on sleep quality. Methods: A database analysis was conducted on Medline, Embase, and Cochrane to find studies that examined the VNS’s effect on quality of sleep in medically resistant epilepsy. These studies included randomized clinical trails, case studies or reports, cohort studies, and systematic reviews. Results: 75 papers were reviewed and 16 studies from eight countries were included in the analysis. A total of 93 patients with ages ranged from 10 – 49 were included. Analyzing the change in the quality of sleep after VNS was evaluated using Multiple Sleep Latency Test. The literature showed that at low stimulus intensities, VNS treatment improves daytime sleepiness in patients. However, VNS setting titration has a dose-dependent effect on obstructive sleep apnea where higher VNS frequencies are related to higher apnea events. Conclusions: Limited data is available on the impact of VNS on the quality of sleep. Further studies are required to evaluate the improvement of sleep in patients with VNS.

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Auricular Neuromodulation for Mass Vagus Nerve Stimulation: Insights From SOS COVID-19 a Multicentric, Randomized, Controlled, Double-Blind French Pilot Study

Frontiers in Physiology ◽

10.3389/fphys.2021.704599 ◽

2021 ◽

Vol 12 ◽

Author(s):

Claire-Marie Rangon ◽

Régine Barruet ◽

Abdelmadjid Mazouni ◽

Chloé Le Cossec ◽

Sophie Thevenin ◽

...

Keyword(s):

Clinical Trial ◽

Vagus Nerve ◽

Clinical Outcomes ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Treated Patient ◽

Double Blind ◽

Clinical Trial Registration ◽

Non Invasive ◽

The Impact

Importance: An exacerbated inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is believed to be one of the major causes of the morbidity and mortality of the coronavirus disease 2019 (COVID-19). Neuromodulation therapy, based on vagus nerve stimulation, was recently hypothesized to control both the SARS-CoV-2 replication and the ensuing inflammation likely through the inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway and could improve the clinical outcomes as an adjunct treatment. We proposed to test it by the stimulation of the auricular branch of the vagus nerve, i.e., auricular neuromodulation (AN), a non-invasive procedure through the insertion of semipermanent needles on the ears.Objective: The aim of this study was to assess the effect of AN on the clinical outcomes in patients affected by COVID-19.Design, Setting, and Participants: A multicenter, randomized, placebo-controlled, double-blind clinical trial included 31 patients with respiratory failure due to COVID-19 requiring hospitalization. Within 72 h after admission, patients received either AN (n = 14) or sham neuromodulation (SN, n = 15) in addition to the conventional treatments.Main Outcome and Measures: The primary endpoint of the study was the rate of a clinical benefit conferred by AN at Day 14 (D14) as assessed by a 7-point Clinical Progression Scale. The secondary endpoint of the study was the impact of AN on the rate of transfer to the intensive care unit (ICU) and on the survival rate at D14.Results: The AN procedure was well-tolerated without any reported side effects but with no significant improvement for the measures of both primary (p > 0.3) and secondary (p > 0.05) endpoints at the interim analysis. None of the AN-treated patients died but one in the SN group did (81 years). Two AN-treated patients (73 and 79 years, respectively) and one SN-treated patient (59 years) were transferred to ICU. Remarkably, AN-treated patients were older with more representation by males than in the SN arm (i.e., the median age of 75 vs. 65 years, 79% male vs. 47%).Conclusion: The AN procedure, which was used within 72 h after the admission of patients with COVID-19, was safe and could be successfully implemented during the first two waves of COVID-19 in France. Nevertheless, AN did not significantly improve the outcome of the patients in our small preliminary study. It is pertinent to explore further to validate AN as the non-invasive mass vagal stimulation solution for the forthcoming pandemics.Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [NCT04341415].

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