Headache in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

A Narrative Review

Amir Soheil Tolebeyan, MD; Niushen Zhang, MD; Vanessa Cooper, MD; Deena E. Kuruvilla, MD


Headache. 2020;60(10):2131-2138. 

In This Article

Abstract and Introduction


Objective: To summarize available literature regarding headache as a manifestation of coronaviruses and to describe potential underlying mechanisms.

Review Methods: References for this review were identified by searches within PubMed without any date restrictions. The search terms used were coronavirus disease 2019 (COVID-19) clinical manifestation, COVID-19 epidemiology, neurologic findings in COVID-19, headache in COVID-19, neurologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and headache in SARS-CoV-2.

Results: Headache is one of the most common neurologic complaints in patients with SARS-CoV-2. While the pathophysiological connection between headache and SARS-CoV-2 is unclear, inflammatory mechanisms may play a key role. One of the mechanisms cited in the literature of migraine and other headache disorders is the activation of nociceptive sensory neurons by cytokines and chemokines. A similar mechanism has been reported in SARS-CoV-2 with the release of cytokines and chemokines by macrophages throughout the course of infection. Other mechanisms for headache in SARS-CoV-2 include (1) viral neuroinvasion as seen with viral encephalitis; (2) hypoxemia due to the well-described pulmonary manifestations of the disease; and (3) thrombosis secondary to COVID-19 induced hypercoagulable states.

Conclusion: According to the Centers for Disease Control, common symptoms of human coronavirus include fever, cough, runny nose, sore throat, and headache. In the case of SARS-CoV-2, there are limited reports about headaches, one of the most common clinical manifestations. There are currently no studies that focus specifically on headache among patients with SARS-CoV-2 infection.


Coronaviruses are positive-sense ribonucleic acid (RNA) viruses that have been shown to invade the respiratory system, gastrointestinal (GI) system, and the central nervous system (CNS). At the end of 2019, scientists identified a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the city of Wuhan, China.[1] In February of 2020, the World Health Organization named the infection, "COVID-19" and characterized it as a pandemic on March 11, 2020.[1,2]

Coronaviruses are 100 nm on average with a crown-like shape due to their membrane glycoproteins spikes.[3] Previously identified viruses in the same family of betacoronaviruses, (but with different clades), include the Middle East respiratory syndrome virus and severe acute respiratory syndrome (SARS-CoV-1) virus.[4–6] Both SARS-CoV-2 and SARS-CoV-1 attach to the angiotensin-converting enzyme 2 (ACE2) for cell entry.[4,5] ACE2 is expressed in neurons, astrocytes, oligodendrocytes, substantia nigra, ventricles, middle temporal gyrus, posterior cingulate cortex, and olfactory bulb.[7] In China, a phylogenetic analysis of 103 strains identified 2 types of SARS-CoV-2 virus (L type [70%] and S type [30%]). There was no significant difference reported in clinical manifestations of these 2 subtypes.[6] According to several reports, the incubation period is predominantly between 2 days and 2 weeks after exposure. Most patients develop symptoms of SARS-CoV-2 infection within the first 4–5 days after exposure.[8,9]

The aim of the present narrative review was to qualitatively summarize data from published literature on headache as a manifestation of SARS-CoV-2 and to discuss the potential underlying mechanisms of headache in adults affected by SARS-CoV-2.