key: cord-0738220-k3vgy3or authors: Bobker, Sarah M.; Robbins, Matthew S. title: COVID19 and Headache: A Primer for Trainees date: 2020-06-10 journal: Headache DOI: 10.1111/head.13884 sha: 4e0b65d9b9c488c493e211c00ba7ca1bc07cb005 doc_id: 738220 cord_uid: k3vgy3or OBJECTIVE: To summarize for the trainee audience the possible mechanisms of headache in patients with COVID19 as well as to outline the impact of the pandemic on patients with headache disorders and headache medicine in clinical practice. BACKGROUND: COVID19 is a global pandemic caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2, of which a large subset of patients features neurological symptoms, commonly headache. The virus is highly contagious and is, therefore, changing clinical practice by forcing the limitations of in‐person visits and procedural treatments, more quickly shifting toward the widespread adaptation of telemedicine services. DESIGN/RESULTS: We review what is currently known about the pathophysiology of COVID19 and how it relates to possible mechanisms of headache, including indirect, potential direct, and secondary causes. Alternative options for the treatment of patients with headache disorders and the use of telemedicine are also explored. CONCLUSIONS: Limited information exists regarding the mechanisms and timing of headache in patients with COVID19, though causes relate to plausible direct viral invasion of the nervous system as well as the cytokine release syndrome. Though headache care in the COVID19 era requires alterations, the improved preventive treatment options now available and evidence for feasibility and safety of telemedicine well positions clinicians to take care of such patients, especially in the COVID19 epicenter of New York City. March 2020. COVID19 is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), a single-stranded RNA virus that is now one of seven coronaviruses known to infect humans. Though most human coronaviruses cause mild respiratory diseases, other fatal coronavirus infections have emerged in the past two decades, namely the severe acute respiratory syndrome coronavirus (SARS-CoV1) and the Middle East respiratory syndrome coronavirus (MERS-CoV) 1 . The novel SARS-CoV2 has already proven itself to be deadly, primarily acting on the lungs but with effects on several other organ systems, notably the renal, hematologic, and nervous systems. A sizeable subset of patients with SARS-CoV2 feature neurological symptoms, often including headache. As the literature continues to grow, we are largely seeing the neurologic manifestations of SARS-CoV2 occur in three categories: central nervous system (dizziness, headache, cerebrovascular disease, seizure, altered consciousness), peripheral nervous system (anosmia, ageusia, visual impairment, neuropathic pain, Guillain-Barre Syndrome and variants), and skeletal muscular injury 2 . In one observational study from Wuhan, of the 36.4% of COVID19 patients who showed neurologic manifestations, the most common symptom was dizziness (16.8%) followed closely by headache (13.1%) 2 . In another prospective analysis out of Wuhan, headache was present in 8% of all patients, overall the most common neurological symptom 1 . Neither of these studies collected data on milder nervous system symptoms and, therefore, likely failed to capture those with anosmia and aguesia to offer direct quantitative comparison to those with headache. Additionally, the care of patients with preexisting headache disorders has been drastically impacted by the COVID19 pandemic. Where we practice in New York City, the COVID19 epicenter, trainees in headache and neurology have been subject to redeployment to directly manage patients with COVID19, evaluate neurological complications in such patients, and contend with managing existing patients with headache disorders during this pandemic 3 . Targeting the trainee audience, we undertook a narrative review searching PubMed indexed publications through May 12 th , 2020 for headache and neurologic complications associated with SARS-CoV2. Articles shared on social media relevant to this topic were also collected and considered for this review. Here, we aim to provide a This article is protected by copyright. All rights reserved brief summary regarding COVID19 as it relates to headache as a symptom, headache as a disease, and headache medicine practice in areas with high COVID19 prevalence. Respiratory viruses in general can cause neurologic symptoms with headache being among the most common (alongside encephalopathy, seizure, and encephalitis) 4 . In fact, headache is an accepted symptom of a systemic viral infection according to the International Classification of Headache Disorders ( Table 1) 5 . The exact mechanisms of headache attributed to systemic infection are not yet fully investigated, though with possible causes attributed to fever and exogenous or endogenous pyrogens, direct effects of the microorganisms themselves, and activation of several immunoinflammatory mediators (cytokines, glutamate, cyclooxygenase-2/prostaglandin E2 system, nitric oxide system, and reactive oxygen species) 5 . In 2009, the most frequent neurological sign reported of the H1N1 pandemic was headache (35%) in one retrospective study 4 . A more recent report from 2016 on human coronavirus (hCoV) in hospitalized children noted headache to be the most recurring neurological symptom 6 . Without robust pathological data, the exact way in which the SARS-CoV2 virus affects the nervous system is not yet fully realized, though many possible causal or contributory mechanisms are under investigation. More generic indirect mechanisms for headache causality in SARS-CoV2 may exist that are not disease specific, including hypoxia, dehydration, systemic inflammation, and metabolic disturbances. Further, SARS-CoV2 could directly invade the central nervous system (CNS) via the olfactory bulb, akin to a similar mechanism already described in mice for the familial hCoV virus 7 . Upon hCoV cellular viral infection, there is release of inflammatory cytokines with resultant neuronal damage appearing similar to demyelination 4 . Although there is not confirmation of such a mechanism of SARS-CoV2, the frequent presence of anosmia (51%) in conjunction with cough and fever and even as an isolated symptom (17%) 8 suggests a possibility of olfactory nerve invasion, though specific neuronal or glial mechanisms do remain unclear. SARS-CoV2 binds to angiotensin converting enzyme 2 (ACE2) receptors to gain entry inside cells and such receptors are also expressed on neurons and glial cells 9, 10 . Herein results the potential for direct viral infection as the cause of headache, perhaps even in the severe forms of infectious meningoencephalitis as case reports This article is protected by copyright. All rights reserved suggest 11, 12 or even as acute disseminated encephalomyelitis (ADEM) which has not yet been reported in SARS-CoV2 but has in hCoV 13 . Another important consideration for the mechanism of headache in SARS-CoV2 is related to cytokine release syndrome (CRS). CRS is a supraphysiological response that typically occurs following use of immunotherapy that activates or engages T-cells and/or other immune effector cells 14 and is often associated with neurotoxicity. In patients with severe SARS-CoV2, higher concentrations of pro-inflammatory cytokines (such as IL-6, IL1B, and IFNγ) have similarly been measured in plasma 1 . The presence of these cytokines is known to result in direct tissue injury 2 and a further inflammatory cascade. In immunotherapy, neurotoxic symptoms seen with chimeric antigen receptor (CAR) T cells include headache (in as high as 42% of patients) 15 , encephalopathy, somnolence or obtundation, tremors, seizures, and focal weakness 15, 16 . Cerebral edema has led to deaths in a small number of patients with CAR T cell neurotoxicity 16 and is, likewise, considered to be a potential cause of death in COVID19 9 . Further, SARS-CoV2 has shown association with acute necrotizing encephalopathy (ANE) 17 , a rare complication of influenza and other viral infections with suggested mechanism related to intracranial cytokine storms that result in blood-brain barrier breakdown but without direct viral invasion or parainfectious demyelination 18 . Treatments aimed at CRS in COVD19 include convalescent plasma, immunoglobulin, thymosin, cytotoxic T cell and B cell epitopes, as well as tocilizumab 19 , which is also an effective treatment for the important secondary headache disorder giant cell arteritis 20 . in other inflammatory markers, such as D-dimer and calcitonin gene related peptide (CGRP), which play a role in headache. First, D-dimer elevation in COVID19 is common and has even shown to be a predictor of mortality in hospitalized patients 21 tied to its role in disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE) 22 . Neurological complications of elevations in D-dimer therefore include stroke and cerebral venous thrombosis (CVT), both of which lead to headache. Second, CGRP is a neuropeptide that has now been highly implicated in migraine pathophysiology with a suspected link to transient receptor potential (TRP) channels 23 . In the case of SARS-CoV2 there is presumptive viral activation of TRP channels that are involved in cough, anosmia, and gastrointestinal disturbances. This activation results in CGRP release which is then This article is protected by copyright. All rights reserved thought to polarize the T cell response in some patients towards a more proinflammatory state, characterized by Th17 and IL-17, as has similarly been elucidated in MERS-CoV 24 . In fact, a new agent for the acute treatment of migraine, intranasal vazegepant (a CGRP receptor antagonist), is currently in a phase 2 trial for treatment of the lung inflammation in COVID19 25 . Anecdotally in our practice in the United States epicenter of COVID19, we have observed many patients who have headache earlier in their course, often correlating with fever, myalgias, and cough, akin to other systemic viral illnesses. However, some patients seem to develop headache later, after initial COVID19 symptom onset, which may be more related to CRS. Prospective studies are In migraine prevention, onabotulinumtoxinA injections should be avoided when possible and supplemented with other preventive therapies like self-injectable CGRP monoclonal antibodies and oral agents such as beta-blockers 26 and angiotensin II receptor blockers (ARBs) 27 , among the many other common preventive drug classes. In regards to nonsteroidal anti-inflammatory drugs (NSAIDS) and angiotensin-converting enzyme inhibitors/ARBs in particular, though initial speculation suggested use of them might be associated with a worse COVID19 clinical course, no such evidence has been identified 28 . In the acute treatment of migraine, status migrainosus, and cluster headache, procedural visits for nerve blocks and patient visits to the emergency department for parenteral medications should also be avoided when possible. Alternative therapies include oral NSAIDS, This article is protected by copyright. All rights reserved neuroleptics, triptans, and use of any available neuromodulation devices 27 . Oral corticosteroids may be superior to nerve blocks for remission of status migrainosus within 24 hours (31% of patients compared to 24% 29 respectively) as well as a transitional treatment for cluster headache 30 , however, should be used cautiously given the Center for Disease Control's warning that corticosteroids may prolong viral replication in SARS-CoV2, as was observed in MERS-CoV 31 . One positive and likely long-lasting change coming out of the COVID19 crisis is headache medicine's swift adoption of telemedicine services. Several pre-COVID19 era studies have already shown the benefits of telemedicine in headache practice. In 2017, one randomized trial found telemedicine consultations for nonacute headache to be as efficient and safe as traditional consultation 32 . A pediatric headache clinic's prospective analysis from 2018 similarly showed telemedicine to be convenient, cost-effective, and patient-centered, thereby providing high patient and family satisfaction for routine follow up visits 33 . Further, in one randomized cohort of patients with severe migraine-related disability, telemedicine proved a feasible and effective mode of treatment when compared to in-office visits for migraine follow up care 34 . COVID19 has forced faster changes in practice than would have otherwise occurred, though fortunately with long-term improvements in both patient and clinician satisfaction, in efficiency, and in healthcare costs likely to result. The COVID19 pandemic has been notable for high transmissibility, morbidity, and mortality, requiring rapid adaptations of care. Neurological complications are proving common, with headache certainly included. Treatments under investigation have also been studied for secondary and primary headache disorders. Headache medicine clinicians in New York City in particular have had to prioritize minimizing emergency department visits and hospitalizations as well as face-to-face visits and procedural treatments 27 . We know that headache, particularly migraine, may worsen or begin after a major stressful life event, and an expected rise in post-traumatic stress disorder may accompany migraine worsening or onset in many patients. Consideration of the characteristics of patients with COVID19 who also develop headache is one area in need of future study, along with the geographical differences on COVID19-related headache prevalence. Further investigations are also Accepted Article needed to understand both the acute and long-term effects of SARS-CoV2 on the nervous system, on patients with pre-existing headache disorders, and on the current generation of headache providers. Clinical features of patients infected with 2019 novel coronavirus in Wuhan Neurologic manifestations of hospitalized patients with coronavirus disease Resident physician exposure to novel coronavirus (2019-nCoV, SARS-CoV-2) within New York City during exponential phase of COVID-19 pandemic: Report of the New York City Residency Program Directors COVID-19 Research Group Neurologic alterations due to respiratory virus infections Headache Classification Committee of the International Headache Society (IHS) Coronavirus infections in the central nervous system and respiratory tract show distinct features in hospitalized children Human respiratory coronavirus OC43: genetic stability and neuroinvasion Presentation of new onset anosmia during the COVID-19 pandemic Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms Neurology in the Time of COVID-19 Accepted Article This article is protected by copyright. All rights reserved Meningoencephalitis without Respiratory Failure in a Young Female Patient with COVID-19 Infection in Downtown Los Angeles A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2. International Journal of Infectious Diseases Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis Cytokine release syndrome Neurological toxicities associated with chimeric antigen receptor T-cell therapy Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features Imaging of acute disseminated encephalomyelitis The possible of immunotherapy for COVID-19: A systematic review Trial of tocilizumab in giant-cell arteritis Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy TRP channels and migraine: recent developments and new therapeutic opportunities MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile Biohaven Pharmaceuticals, Inc. Safety and Efficacy Trial of Vazegepant Intranasal for Hospitalized Patients With COVID-19 Requiring Supplemental Oxygen Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society Migraine Care in the Era of COVID-19: Clinical Pearls and Plea to Insurers. Headache: The Journal of Head and Face Pain Headache medication and the COVID-19 pandemic Unrecognized challenges of treating status migrainosus: An observational study Greater occipital nerve injection versus oral steroids for short term prophylaxis of cluster headache: A retrospective comparative study Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19 A randomized trial of telemedicine efficacy and This article is protected by copyright. All rights reserved