OnabotulinumtoxinA Injections for Patients with Chronic Migraine During the COVID-19 Pandemic

This is an open access journal distributed under the terms of the Creative Commons Attribution 4.0 License in which authors agree to make articles, including data, graphics, and supplements, legally available for reuse, without permission or fees, for virtually any purpose. Any individual or institution is free to copy, distribute, reproduce, or reuse these publications, as long as the author and original source are properly cited and credited. OnabotulinumtoxinA Injections for Patients with Chronic Migraine During the COVID-19 Pandemic

Headaches are among the top prevalent conditions that physicians encounter in their daily practice. Migraine headaches affect nearly15% of the United States population (approximately 45 million). 1,2 Over 50% of all patients with migraine report significant or severe impairment and disability.2 Migraine is the leading cause of years lived with disability among patients between ages 15 and 49 years old -the most productive years. 3 According to the World Health Organization headache report, up to 4% of the world's population experience chronic migraine (headaches occurring on at least 15 days per month with at least 8 of these headaches meeting migraine criteria). 4 Approximately, 65% of patients with episodic migraine and 75% of patients with chronic migraine have missed family events and activities in the past month due to migraine-related impairment. 5 Migraine also significantly impacts work-related activities. It has been estimated that 11% of patients with chronic migraine have been missing at least 1 day of work per week in the past 2 weeks. 6 Based on migraine attack frequency and related disability, headache experts suggest offering prophylactic treatment options to patients with four migraine attacks per month or more. 7 Nevertheless, it has been estimated that only 26-29% of patients continue to adhere to their prophylactic treatment regimen at 6 months and only 17-20% continue to use their oral preventive medications at 12 months. 8,9 OnabotulinumtoxinA injection is an established FDA-approved therapy for chronic migraine prevention.

The COVID Pandemic and OnabotulinumtoxinA Injection
Novel Coronavirus-2019 (COVID-19) infection can cause severe acute respiratory syndrome (SARS-CoV-2). Older patients, as well as patients with significant comorbidities (e.g. immunosuppression, cardiovascular disease, chronic respiratory disease, diabetes, cancer) are at risk to develop serious illness. On March 11, 2020, the WHO declared it a pandemic. 10 Currently, as of April 2020, there have been over 2,300,000 confirmed cases around the globe, including over 150,000 deaths. 11 This is an open access journal distributed under the terms of the Creative Commons Attribution 4.0 License in which authors agree to make articles, including data, graphics, and supplements, legally available for reuse, without permission or fees, for virtually any purpose. Any individual or institution is free to copy, distribute, reproduce, or reuse these publications, as long as the author and original source are properly cited and credited.
The virus is highly contagious as the reproductive number (R0), which represents the number of secondary infections resulting from an infected individual, is reported to be 2.6. 12 Globally, healthcare systems across the world have been faced with unique challenges for controlling the spread of infection. To limit the spread of infection and to preserve limited health care resources, elective surgeries have been canceled or postponed, including pain procedures. 13 This has negatively impacted the care of headache patients with complex needs and lead to the interruption of injection of onabotulinumtoxinA for chronic migraine prevention.
Lack of adequate prophylactic therapy may result in frequent ER visits and hospitalizations. Therefore, stable and effective therapy is warranted to improve patients' quality of life and minimize the utilization of healthcare resources. Although most of the routine visits could be performed using various telemedicine platforms or over the phone, the injections of onabotulinumtoxinA requires in-person procedure visit. OnabotulinumtoxinA injection is an established standard of care prophylactic treatment modality that requires injections to be repeated every 90 days and ideally should not be interrupted. 14,15 There are special considerations for using onabotulinumtoxinA during COVID-19 pandemic. SARS-CoV-2 presentation varies dramatically, but usually, patients present with fever and cough. There are asymptomatic and there are severe cases. Several cases of new-onset Guillain-Barré syndrome have also been described in patients recently diagnosed with SARS-CoV. 16,17,18 Guillain-Barré syndrome is a contraindication for onabotulinumtoxinA injection, and therefore, risks and benefits, and alternative treatment options should be carefully weighed and discussed with the patient. 19,20,21

The Challenges in Identifying the Patient's COVID-19 Status
Experts advocate for screening all surgical patients to determine their COVID-19 status (e.g. COVID-19 positive, suspected positive (under investigation). 22 However, testing capabilities are not widely available yet. If the community spread of COVID-19 infection is significant and in the absence of universal testing, all asymptomatic patients should be presumed to be COVID-19 positive. 23 On the other hand, if the community spread is low and a patient is asymptomatic or if tested COVID-19 negative, then the procedure may be performed following usual established guidelines. However; based on recent evidence, The CDC updated their interim guidance on April 12, 2020 This Interim Guidance was updated and archived on April 12, 2020 to reflect new recommendations for community-related exposure to COVID-19, which changed the period of exposure risk from "onset of symptoms" to "48 hours before symptom onset". 24 Approximately 80% of infected individuals present with no or mild symptoms. 25 Accordingly, clinical screening to identify infected patients is not reliable. This emphasizes the need for universal testing. To complicate the challenging clinical situation even further, there is significant variability in the accuracy of different available diagnostic testing modalities with high false-negative rates. 26 Hight index of suspension should be exercised and maintain safety precautions. The infection attack rate is estimated to be 50-80% of the population, so all patients should be presumed to have COVID-19 positive. 27

Personal Protective Equipment (PPE)
Personal protective equipment is usually classified into three categories: contact precautions, droplet precautions and airborne precautions. 28 Generally, appropriate level of PPE is determined by the medical procedure and the proximity of healthcare provider to the patient.
Botox procedures are not considered aerosolgenerating procedure (AGP), and therefore droplets precautions are recommended as a minimum. 29 However, airborne precautions are preferable as the physician is in remarkable proximity to the patient's face (unexpected coughing or sneezing). The patient should wear surgical facemask to restrict droplet spread and prevent transmission of  This is an open access journal distributed under the terms of the Creative Commons Attribution 4.0 License in which authors agree to make articles, including data, graphics, and supplements, legally available for reuse, without permission or fees, for virtually any purpose. Any individual or institution is free to copy, distribute, reproduce, or reuse these publications, as long as the author and original source are properly cited and credited.

Disclosures
Dr. Samer Narouze is the current EIC for Annals of Headache Medicine. Dr Dmitri Souza was the acting EIC handling this manuscript.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Procedural Recommendations for OnabotulinumtoxinA Injection During COVID-19
Risk stratification • The risks of exacerbations of migraine headaches and possible ER/hospital admissions should be carefully weighed against continuing onabotulinumtoxinA injections. • Switching to other preventive therapies, including calcitonin gene-related peptide (CGRP) modulating drugs, may be discussed with the patient.

Guillain-Barré Syndrome
• All patients with recent febrile symptoms and who have recovered completely (regardless of known COVID-19 status) should be screened for any evidence for Guillain-Barré syndrome or neuromuscular disorders, and, if positive or suspicious, referred to an appropriate specialist, and the procedure should be avoided. Determining the patient's COVID-19 status • Universal testing should be considered.
• However, due to the current significant testing limitations, all asymptomatic patients should be presumed to be COVID-19 positive. Procedure room • The procedure should be performed in a procedure room.
• The use of common office areas should be avoided to reduce the risk of cross-infection. Modifying the environment • Educating and training the staff to limit unnecessary staff exposure to the patient.
• The number of personnel present during the procedure should be kept to the minimum. Appropriate personal protective equipment (PPE) • Droplet precautions are recommended as a minimum. Gloves, face shield or goggles, fluid resistant surgical face mask and gown. • Airborne precautions are preferable (close contact with the patient face). Gloves, face shield or goggles, respirator mask (e.g. N95 mask) and gown. • The patient should wear surgical facemask.