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 Table of Contents  
Year : 2021  |  Volume : 38  |  Issue : 4  |  Page : 201-208

COVID 19-Associated headache: Critical review after a scientific webinar

1 Department of Neurology, Health Sciences University, Istanbul Education and Research Hospital, Istanbul, Turkey
2 Dr. Selahattin Cizrelioglu State Hospital, Şırnak, Turkey
3 Department of Neurology, Mersin University School of Medicine, Mersin, Turkey

Date of Submission09-Aug-2021
Date of Decision25-Sep-2021
Date of Acceptance26-Sep-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Arife Cimen Atalar
Department of Neurology, Health Sciences University, Istanbul Education and Research Hospital, Istanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/nsn.nsn_148_21

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Coronavirus disease 2019 (COVID-19)-related headache is the fifth most frequent symptom and the most common neurologic manifestation of the disease with a prevalence of 6.5%–27.9%. Headache related to COVID-19 shows diverse features and can clinically manifest with different phenotypes. The most common clinical presentation is bilateral (mostly frontal or frontotemporal location), long-lasting, pressing/pulsating quality, and partially or completely resistant to analgesic treatment. The activation of the trigeminovascular system by either direct invasion of the virus or indirect mechanisms induced by cytokine storm, excess neuroinflammation, vasculopathy, and ischemia are the possible underlying pathophysiologic mechanisms. Patients with preexisting primary headaches is another important issue that needs to be enlightened to determine whether these patients are more susceptible to COVID-19-related headache. Headache is also an important symptom in patients with long COVID syndrome, which has a serious negative impact on the individuals' quality of life in the long term. Populations such as children, pregnant women, and the elderly are more vulnerable to COVID-19, and it is obvious that COVID-19 affects these populations differently. The headache characteristics and course of headache in these special populations is an important research topic that needs more focused studies. In this review, we attempted to update physicians with the new developments about COVID-19-related headaches and discuss the subject with different aspects in light of the recent “COVID-19-associated headache webinar” organized by the Global Migraine and Pain society (GMPS) in collaboration with the global COVID-19 Neuro Research Coalition and the European Academy of Neurology (EAN).

Keywords: COVID-19, COVID-19–related headache, headache, long COVID

How to cite this article:
Atalar AC, Alpaslan Türk BG, Özge A. COVID 19-Associated headache: Critical review after a scientific webinar. Neurol Sci Neurophysiol 2021;38:201-8

How to cite this URL:
Atalar AC, Alpaslan Türk BG, Özge A. COVID 19-Associated headache: Critical review after a scientific webinar. Neurol Sci Neurophysiol [serial online] 2021 [cited 2022 May 19];38:201-8. Available from: http://www.nsnjournal.org/text.asp?2021/38/4/201/334051

  Introduction Top

Since the emergence of the coronavirus disease 2019 (COVID-19) outbreak in December 2019, numerous studies have reported headache as the fifth most frequent symptom and the most common neurologic manifestation of the disease.[1],[2],[3],[4],[5] Due to the differences between inclusion criteria and study designs, the prevalence of headache in COVID-19 shows highly variable rates across studies and is mostly estimated as 6.5%–14%, but even higher rates up to 27.9% have been reported.[3],[6],[7],[8] It is also reported as the most detected symptom among all neurologic symptoms in hospitalized patients with COVID-19.[9] Headache can occur early in the course of the infection (mostly in the first 72 h) either as an isolated symptom or the initial symptom of COVID-19 before the emergence of cough or fever.[10],[11] Although headache entitled “acute headache attributed to systemic viral infection (code” is not a new entity and has already been described in the International Classification of Headache Disorders (ICHD-3) classification, the prevalence of headache in patients with COVID-19 is probably higher (up to 2.2 fold) than headache related to other common cold viruses, and it has some distinctive features.[4],[12] The most common clinical presentation of COVID-19-associated headache is described as bilateral (mostly frontal or frontotemporal location), long-lasting, a pressing/pulsating quality, and partially or completely resistant to analgesic treatment.[4],[11],[13],[14] In patients with preexisting primary headache such as migraine or tension-type headache, the pain might be more intense and/or a new-onset headache might emerge, different from their usual type of crisis.[3],[4],[6]

Several mechanisms have been suggested such as the activation of the trigeminovascular system by either direct invasion of the virus or indirect mechanisms induced by cytokine storm, vasculopathy, or ischemia, but there is no consensus yet, and more extensive studies are needed to clarify the pathogenesis.[12],[15]

Recently, a new entity named “long COVID headache” has been recognized as a part of a set of symptoms several months after COVID-19. It was identified as “a persistent headache for at least 6 months, which is either a new-onset headache with cognitive blunting (brain fog), or the worsening of a preexisting headache, particularly migraine.[7],[15] The prevalence of headache as a long COVID-19 symptom is estimated as 15%–44% according to different studies, and the burden of headache significantly decreases the quality of life in survivors of COVID-19 among other post-COVID symptoms.[16],[17],[18] After the introduction of COVID-19 vaccinations, the possible adverse effects of vaccines including vaccine-related headache have begun to draw the attention of the researchers and have become a new area of investigation.

In this report, we attempt to update physicians with the new developments about the COVID-19-related headache and discuss the subject with different aspects in light of the recent “COVID-19-associated headache webinar” organized by the Global Migraine and Pain society (GMPS) in collaboration with the global COVID-19 Neuro Research Coalition and the European Academy of Neurology (EAN).

  COVID-19–Related Headache Can Teach Us Mechanisms Underlying Infection-Related Headache Top

Respiratory viruses, coronaviruses, in particular, have neuroinvasive and neurotrophic abilities that might lead to neurologic involvement, and headache is among the most common neurologic symptoms.[19] Headache related to a systematical viral infection has a special code in the ICHD-3 and was accepted as a secondary headache type by headache specialists, but our knowledge about the exact pathophysiologic mechanisms underlying this headache is still very limited.[3],[4],[6],[20]

The novel coronavirus, namely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a single-stranded ribonucleic acid (RNA) virus with a neuroinvasive potential that affects the nervous system by binding to angiotensin-converting enzyme 2 (ACE2) receptors in the peripheral and central nervous system.[5] The pathophysiologic basis of SARS-CoV-2 infection-related headache is still not clarified and is currently a field of interest for researches, but there are various hypotheses including direct and indirect mechanisms, similar to the other respiratory system viruses.[9],[19]

A possible mechanism for headache related to COVID-19 might be the direct invasion of the trigeminal nerve endings in the nasal or oral cavity.[6],[14] Because ACE2 receptors serve as a host receptor for SARS-CoV-2, the virus competes with ACE-2 to bind to these receptors, resulting in the downregulation of ACE2, which is the key enzyme for Angiotensin II (Ag II) production. Ag II is responsible for pathologic changes such as vasoconstriction and oxidative stress and may have a role in the regulation of nociception.[6],[21] The presence of substance P and calcitonin gene-related peptide (CGRP) at the dorsal root ganglia and trigeminal ganglia in conjunction with Ag II production has been shown in animal and human models and might support this hypothesis.[6]

Another suggested mechanism for headache is that the virus in the bloodstream might infect the vascular endothelial cells where a great amount of ACE2 receptors are located and result in the activation of the trigeminovascular system (vascular theory).[6]

A third and strong explanation for headache in COVID-19 might be associated with the presence of “cytokine release syndrome (CRS).” The presence of pro-inflammatory cytokines such as interleukin (IL-6), interleukin (IL1B), and interferon (IFN)-ƴ in the plasma of patients with COVID-19 with CRS, may trigger direct tissue damage or a cascade of systemic inflammation.[11] The increase of circulatory inflammatory substances such as CGRP, IL-6, high mobility group box 1 protein (HMGB1), and NLR family pyrin domain containing 3 (NLRP3) might trigger the nociceptive trigeminovascular system, activate the trigeminal afferents in the dura mater, and as a consequence, lead to headache.[8],[11],[19],[22]

Some of the other indirect mechanisms of headache, which are not headache specific, can be summarized as hypoxia, inflammation, dehydration, and metabolic instability.[19]

  Headache Characteristics in COVID-19 and COVID-19–Related Headache Phenotypes Top

Headache related to COVID-19 should be considered as a separate entity other than just an infection-related headache with its differential characteristics. Data that have accumulated since the beginning of the pandemic era revealed that headaches related to COVID-19 showed diverse features and could clinically manifest with different phenotypes. [Figure 1] shows the etiologies and differential diagnostic tools of headaches in a time relationship with COVID-19 [Figure 1].
Figure 1: Etiologies and differential diagnostic tools of headaches in a time relationship with Coronavirus disease 2019

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The most prominent phenotype observed is a bilateral headache with a pulsating or pressing quality, located in a frontal or temporoparietal area with moderate or severe intensity and mostly occurs in the early course of the disease.[6],[10],[23] The pain is partially/none responsive to common analgesics, might be long lasting, and can show itself mostly in a migraine-type headache form (migrainous symptoms such as nausea, photophobia, and phonophobia were the most frequently associated symptoms with headache).[11],[13],[14]

A retrospective study on 106 hospitalized patients suggested that COVID-19-related headaches could manifest as either migraine-type or tension-type headache features or a COVID-19-specific phenotype. The migraineous phenotype was linked to a more intense and disabiling headache symptoms as well as a more severe COVID-19, but the second phenotype showing tension-type headache features was linked to a less disabiling and less severe headache with a milder infection. COVID-19-specific phenotype was associated with lymphopenia, high levels of procalcitonin and C-reactive protein, and characterized by bilateral (diffuse) frontally localized, pressing intense pain, and hypersensitivity to stimuli.[23]

One of the largest studies performed on 3458 patients identified the headache characteristics in COVID-19 as bilateral with a duration longer than 72 h, more prominent in the male sex, analgesic resistant, and more frequently associated with anosmia/ageusia and gastrointestinal symptoms.[3] Another study by Karadaş et al. attempted to differentiate COVID-19-related headache as a new-onset headache with bilateral (dominant at frontal regions), severe, throbbing headache with a long duration accompanied by pulmonary involvement, and increased IL-6 levels. They also suggested two separate headache phenotypes depending on the intensity, duration, and frequency of headaches in addition to pulmonary involvement, IL-6 levels, and treatment response. The first headache type was characterized by severe, long-duration, frequent headache attacks, and unresponsive to paracetamol (85%). All patients had pulmonary infiltration and higher levels of IL-6. The second type was classified as paracetamol-responsive, moderate headaches (96%), and patients without pulmonary infiltration (40%).[11] In line with these studies, a survey study on 2194 patients by García-Azorín et al. supported the presence of anosmia as an independent factor associated with COVID-19-related headache, reporting that the presence of systemic symptoms and the high frequency of headache-related red flags might suggest a possible secondary headache cause.[7] In light of these studies, a set of preliminary criteria regarding COVID-19-related headache for the ICHD-3 was proposed by our study group recently[4] [Figure 2]. This proposal aimed to differentiate COVID-19-related headache from other headache disorders and guide physicians and researchers to standardize future investigations to conceive appropriately designed comparable translational studies.
Figure 2: Proposed International Classification of Headache Disorders-3 criteria for Coronavirus disease -related headache[4]
*Adapted from Baykan B et al. Urgent Need for ICHD Criteria for COVID-19-Related Headache: Scrutinized Classification Opens the Way for Research. Arch Neuropsychiatry. 2021 Mar 8;58(1):79-80.

Click here to view

Another important point to discuss is the headache characteristics in patients with preexisting primary headaches such as migraines. Whether these patients are more susceptible to COVID-19-related headache still needs to be enlightened with more extensive studies. A study on 112 health-care professionals reported that patients with preexisting migraines more frequently presented exacerbation with pulsating pain triggered by physical activity and accompanying symptoms such as nausea, vomiting, phonophobia, osmophobia, and photophobia.[14] Another observational study disclosed that prior history of headache was more prominent in female patients with more intense headaches during COVID-19.[7] It is important to note that patients with a prior primary headache such as migraine easily noticed COVID-19-related headache as a different entity from their usual attacks and identified the pain as a new-onset headache or a more refractory headache.[24] A study in patients with COVID-19 with prior primary headache disorders showed that the headache during COVID-19 had an unusual presentation in 42% of patients, as a recent-onset headache, 49% as a change in headache pattern, and 39% identified the pain as the worst headache they had ever experienced.[25] By contrast, there is a subgroup of patients with a migraine history that do not experience any worsening of their headaches during COVID-19 or even a decrease of their usual attack frequency.[3] The reasons for the improvement of headaches in these patients have not been explained and need clarification.

Finally, the wearing of personal protective equipment (PPE) such as N95 face masks might be a trigger factor for developing de novo PPE-associated headaches or worsening of preexisting primary headache disorders as shown in various studies.[6],[26]

  Long COVID-19 Headache Top

Long COVID-19 (also known as post-acute COVID-19 syndrome) is a newly introduced term, implying a set of symptoms that could last up to months, beyond the acute phase and the recovery of COVID-19.[18]

Headache is among the most common neurologic symptoms of long COVID, with a frequency up to 65% and could either manifest with a new-onset persistent headache for at least 6 months accompanied by cognitive blunting (brain fog) or with a worsening of the headache in a patient with a primary headache disorder (chronification).[15],[18],[27] In patients with acute COVID-19, headache is one of the five symptoms (other than fatigue, dyspnea, hoarse voice, and myalgia) experienced within the 1st week of the infection as a predictive marker of a possible long COVID syndrome.[28]

The pathophysiologic mechanisms of long COVID headache concomitant with other neurologic symptoms (cognitive problems, memory deficits, sleep disorders, and fatigue) need to be elucidated because it could worsen the quality of life of the patients by leading to the chronification of the headache.[15],[17] That inflammasomal activation and damaged innate immune signaling are common mechanisms in both migraine and COVID-related headache may give us clues to the hidden mechanisms underlying the condition.[15]

  COVID-19 in Special Groups (Children, Pregnant Women, The Elderly) Top


COVID-19 in children tends to be less frequent with a milder course when compared with the adult population.[29] In addition to common respiratory symptoms, gastrointestinal complications, a special and less frequent syndrome, namely, “multisystem inflammatory syndrome in children (MIS-C)” (Kawasaki syndrome-like hyper-inflammatory disorder with acute hypotension and cardiogenic shock) and neurologic symptoms such as headache, dizziness, anosmia, and ageusia may also be a part of the clinical spectrum.[30],[31] A recent study including 82 hospitalized children with COVID-19 revealed that headache was the most common neurologic symptom with a prevalence of 34%.[31] Pediatric patients can present headache either as an isolated symptom or a part of another neurologic disorder related to COVID-19, such as MIS-C, encephalopathy, stroke, and encephalitis. The headache in children with MIS-C was shown to be more frequent than others and tended to be more severe.[29] Some of the proposed mechanisms for explaining the neurologic involvement in children are direct viral injury to the cells, vascular endothelial injury, inflammatory/autoimmune injury mechanisms and indirect effects via cardiovascular complications, and cerebral hypoxia due to respiratory failure. Although which of these mechanisms is dominant in children remains unknown, it is clear that COVID-19 affects children and adults differently. A plausible explanation of the lower susceptibility of children to neurologic involvement may be the low expression of ACE2 receptors in the olfactory epithelium of children, but this hypothesis needs to be confirmed with further extensive studies with longer follow-up.[30],[31],[32]

Another issue is the course of previous headache disorders under lockdown conditions. A large cohort study from Italy reported that some usable lifestyle modifications represented the main factor impacting the course of primary headache disorders in children and adolescents. The authors specifically illustrated that the reduction in school-related stress during the lockdown period was the main factor explaining the general headache improvement in the population.[33]

Pregnant women

Pregnant women are a vulnerable group for respiratory infections, with an increased risk of acquiring pneumonia and susceptibility to severe complications due to the adaptive changes of the respiratory and immune systems.[34] Data on the impact of COVID-19 on pregnant women and their babies are very limited due to the lack of extensive studies; thus the management of COVID-19 in this special group might be challenging. Neurologic manifestations including anosmia, hypogeusia, and impaired consciousness have been described in pregnant women at similar rates as in the nonpregnant population.[35] According to different studies, headache was reported to be one of the most common symptoms of COVID-19 in pregnancy in both hospitalized and nonhospitalized women with a prevalence of 24.5%; however, it tended to be less severe compared with nonpregnant women.[36],[37] Currently, no specific characteristics of headache have been described, probably due to the lack of focused studies on this topic. It is of utmost importance to know whether the presence of headache along with other neurologic symptoms such as acute cerebrovascular disease and seizures may prompt an investigation for preeclampsia in the obstetric population and therefore could be a red flag for pregnant women. In addition, due to the increased risk of thrombosis in pregnant women, headache should be evaluated as an alarm sign for possible sinus venous thrombosis, and further diagnostic investigations should be planned accordingly.[38]

The elderly

Headache is one of the most frequent neurologic symptoms (6%–17%) in the elderly population besides fatigue, dizziness, confusion, delirium, and gait disturbance, especially in patients with previous known neurodegenerative disorders such as dementia.[39] The characteristics of headache in patients aged >50 years is similar to the younger population but less severe, usually with a duration of 2–5 days, holocranial, frontal or temporally located, and mostly responsive to analgesics.[40] Further studies focused on risk factors, characteristics, and the prognosis of headache in the elderly are needed to understand the relationship of COVID-19 infection with headache in this special group.

  Headache Related to COVID Vaccine Top

After the introduction of various types of vaccines, vaccine-related adverse effects have begun to draw attention because headache is one of the most common. An analysis from the Italian Medicines Agency database reporting adverse effects after receiving one dose of the three COVID-19 vaccines (messenger RNA [mRNA]-based Biontech, Pfizer, mRNA Moderna, and DNA adenovirus-based Vaxzevria, AstraZeneca), showed that the rate of headache/migraine episodes of recipients of COVID-19 vaccines up to May 9, 2021, was 129, 103, and 21/100,000 patients, respectively.[41] Another study including 1840 patients found that 30.6% of patients reported COVID-19 vaccine-related headache after vaccine administration, 25.9% of which lasted more than 2 days. The headache was mostly bilaterally located, less severe, and shorter-lasting than COVID-19-related headache and showed a female predominance. Patients with preexisting migraine, comorbid thyroid disease, COVID-related headache during infection, or headache related to the influenza vaccine were more susceptible to COVID-19 vaccine-related headache.[42] COVID vaccine-related headache may also be an important symptom of a possible cerebral venous thrombosis (CVT) related to vaccination. New-onset headache, a nonspecific but most common feature of CVT, can be seen in up to 67% of individuals during the initial few days after any COVID-19 vaccination. Therefore further diagnostic investigations such as neuroimaging may be considered in a young patient with new unusual headaches, clinical symptoms related to CVT, and thrombocytopenia within 4–28 days after adenovirus SARS-CoV-2 vaccination.[43]

  Management of COVID-19-Related Headache Top

Currently, there is no specific treatment for COVID-19-related headache, and headache attacks are usually treated based on the phenotype of the headache (e.g., migraine-like, tension type-like). In patients with migraine-type headaches, physicians can safely use treatments such as paracetamol and triptans for acute migraine attacks during COVID-19.[44] For patients unresponsive to paracetamol, greater occipital nerve blocks may be a good alternative to relieve headache attacks.[11] There is no contradictory evidence about the use of nonsteroidal anti-inflammatory drugs during COVID-19.[45] Antiemetic drugs and neuroleptics are among the other treatment choices for prolonged headache attacks.[44] In addition, a recent study reported indomethacin as another therapeutic option in patients with COVID-19-related headache that is unresponsive to common analgesics, anti-inflammatory drugs, and/or triptans.[46] For preventative treatment, treatment options such as beta-blocker agents, CGRP antagonists, Ag II receptor blockers, and external trigeminal nerve stimulation devices can be safely chosen. It is usually recommended to avoid invasive treatments including botulinum toxin, acupuncture, implantable neurostimulators during the pandemic due to the safety measures related to close contact.[44] Antiseizure drugs (e.g., valproate, topiramate, gabapentin, pregabalin) and tricyclic drugs that are commonly used in routine clinical practice should be used with caution during acute COVID-19 due to their common adverse effects such as fatigue, sedation, and fluid imbalance.[47],[48]

  Conclusions Top

COVID-19-related headache disorders represent an important topic that deserves a multi-/interdisciplinary approach and objective evaluation because of the specific features, which are different from a headache disorder attributed to a systemic viral infection. COVID-19-associated headaches show specific pathophysiology, mainly based on a complex relationship between an overactive inflammatory trigeminovascular system and vascular mechanism, which need to be investigated further. Specific groups such as children, the elderly, and pregnant women must be evaluated within a wide perspective in terms of phenotypic presentation and management issues. Secondary causes of headache disorders still have to be considered in the differential diagnosis of patients with preexisting headache disorders and patients with headache as the initial symptom of COVID-19. Long COVID is an important issue owing to the ensuing neurological syndrome that may include headache disorders and for its potential association with vaccination beyond the known picture. We need more comprehensive multi-/interdisciplinary studies working together with basic sciences, clinical sciences, and public health authorities to cope with this storm affecting the entire planet and humanity.


The authors thank the Global Migraine and Pain Society for hosting the webinar. We also are also grateful for creative collaboration with the global COVID-19 Neuro Research Coalition, for the valuable lecturers of the webinar and the technical team beyond the scenes (https://migraine-pain.org/covid-19associatedheadachewebinar).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

Criteria for inclusion in the authors/contributors list

Design, analysis, interpretation, literature review, writing, editing: AÇA, BGA, AÖ, BB.

All authors helped supervise the project and discussed the results and contributed to the final manuscript.

This review is written after “COVID-19 associated headache” webinar that was broadcasted online at 4/08/2021 (https://migraine-pain.org/covid-19associatedheadachewebinar).

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