Accepted Article

DR MATTHEW STUART ROBBINS (Orcid ID : 0000-0002-5426-5333)

Article type : Residents and Fellows: Opinions in Headache Education

Corresponding author mail id: [email protected]

TITLE PAGE
COVID19 and Headache: A Primer for Trainees

Authors:
Sarah M. Bobker, M.D.
Department of Neurology
New York Presbyterian Hospital/Weill Cornell Medicine
New York, NY, USA
Mailing address: 2466 Francisco Street, Unit #106, San Francisco, CA, 94123, USA

Matthew S. Robbins, M.D.

Department of Neurology
New York Presbyterian Hospital/Weill Cornell Medicine
New York, NY, USA

Conflict of Interest: Dr. Bobker is an assistant editor for Headache. Dr. Robbins serves on the
editorial board of Headache and the board of directors of the American Headache Society (non-
remunerative positions). He receives an editorial stipend from Springer (Current Pain and Headache
Reports) and book royalties from Wiley.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/head.13884
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Accepted Article
Key words: COVID19, headache, trainees, telemedicine

No sources of financial support used.

Abbreviations:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)
Severe acute respiratory syndrome coronavirus (SARS-CoV1)
Middle East respiratory syndrome coronavirus (MERS-CoV)
Human coronavirus (hCoV)
Central nervous system (CNS)
Acute disseminated encephalomyelitis (ADEM)
Cytokine release syndrome (CRS)
Chimeric antigen receptor (CAR)
Cerebral venous thrombosis (CVT)
Acute necrotizing encephalopathy (ANE)
Disseminated intravascular coagulation (DIC)
Venous thromboembolism (VTE)
Transient receptor potential (TRP)
Nonsteroidal anti-inflammatory drugs (NSAIDS)
Angiotensin II receptor blockers (ARBs)

Acknowledgements: None

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ABSTRACT
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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 feature neurological
symptoms, commonly headache. The virus is highly contagious and is, therefore, changing clinical
practice by forcing limitations of in-person visits and procedural treatments, more quickly shifting
towards 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 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.

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TEXT
Accepted Article
INTRODUCTION
COVID19 was identified as a global pandemic by the World Health Organization in early
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
injury2. 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 symptom1. 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 pandemic3. Targeting the trainee audience, we
undertook a narrative review searching PubMed indexed publications through May 12th, 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

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brief summary regarding COVID19 as it relates to headache as a symptom, headache as a disease, and
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headache medicine practice in areas with high COVID19 prevalence.

HEADACHE AS A SYMPTOM OF COVID19

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 study4. A more recent report
from 2016 on human coronavirus (hCoV) in hospitalized children noted headache to be the most
recurring neurological symptom6. 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 virus7.
Upon hCoV cellular viral infection, there is release of inflammatory cytokines with resultant neuronal
damage appearing similar to demyelination4. 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 cells9,10. 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

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suggest11,12 or even as acute disseminated encephalomyelitis (ADEM) which has not yet been
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reported in SARS-CoV2 but has in hCoV13.
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 cells14
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
plasma1. The presence of these cytokines is known to result in direct tissue injury2 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 weakness15,16. Cerebral edema has led to deaths in a small
number of patients with CAR T cell neurotoxicity16 and is, likewise, considered to be a potential
cause of death in COVID199. 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 demyelination18. Treatments aimed at CRS in COVD19
include convalescent plasma, immunoglobulin, thymosin, cytotoxic T cell and B cell epitopes, as well
as tocilizumab19, which is also an effective treatment for the important secondary headache disorder
giant cell arteritis20.
Secondary effects of the systemic inflammation of CRS in SARS-CoV2 includes an increase
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 patients21 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) channels23. 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

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thought to polarize the T cell response in some patients towards a more proinflammatory state,
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characterized by Th17 and IL-17, as has similarly been elucidated in MERS-CoV24. 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 COVID1925.
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
needed to capture the clinical characteristics and timing of headache in SARS-CoV2 infection.

IMPACT OF COVID19 ON PATIENTS WITH HEADACHE DISORDERS AND ON HEADACHE

PRACTICE
Clinicians across all fields of medicine are applying “physical distancing” in the care of
patients in order to limit the spread of infection. Practically, this means abstaining from all
nonessential healthcare visits in person, including procedural visits. Patients with headache disorders
often depend on therapies like onabotulinumtoxinA, trigger point, and nerve block injections, and
have therefore been especially vulnerable to the possibility of inadequate care during this uncertain
time. Though headache clinicians have delineated alternative treatment options that minimize patient-
physician contact while still maximizing headache health, we recognize such stringent restrictions in
care are not necessarily universal to all headache clinical practices at this time.
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-blockers26 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 identified28. 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,

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neuroleptics, triptans, and use of any available neuromodulation devices27. Oral corticosteroids may
Accepted Article
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 headache30, 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-CoV31.
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
consultation32. 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 visits33. 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 care34. 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.

CONCLUSION
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 treatments27. 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
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.

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Accepted Article
9.2.2 Headache attributed to systemic viral infection

Description:

Headache caused by and occurring in association with other symptoms and/or clinical

signs of a systemic viral infection, in the absence of meningitis or encephalitis.

Diagnostic criteria:

A. Headache of any duration fulfilling criterion C

B. Both of the following:

1. systemic viral infection has been diagnosed

2. no evidence of meningitic or encephalitic involvement

C. Evidence of causation demonstrated by at least two of the following:

1. headache has developed in temporal relation to onset of the systemic viral

infection

2. headache has significantly worsened in parallel with worsening of the

systemic viral infection

3. headache has significantly improved or resolved in parallel with

improvement in or resolution of the systemic viral infection

4. headache has either or both of the following characteristics:

 a) diffuse pain

 b) moderate or severe intensity

D. Not better accounted for by another ICHD-3 diagnosis.

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