Headache Horizons: Headache in Long COVID

The post-acute sequelae of SARS-CoV-2, otherwise known as “long COVID,” refers to the persistence of symptoms weeks to months after initial infection with SARS-CoV-2, the virus that causes COVID-19.¹ In those with long COVID, approximately 80% developed at least 1 long-term symptom 2 or more weeks after acute COVID-19, with headache among the most common of these symptoms.¹ Long-term symptoms can occur even in those who recovered from mild-to-moderate acute COVID-19 without hospitalization.² Understanding of the mechanism or clinical course of long COVID remains limited. Most studies to date list the various symptoms of long COVID (ie, headache, fatigue, neuropsychiatric symptoms, and cognitive difficulties) without detailing the characteristics of these symptoms.^1,2

Headache in COVID-19 and Long COVID

Most reports in the literature describe COVID-19–related headache in the context of acute COVID-19, which is typically severe, holocranial, and rapidly evolving with migraine-like qualities, including throbbing pain, aggravation by routine movements, and sensory disturbances.³ A large study surveyed individuals with headache and found that bilateral headache, duration longer than 72 hours, and analgesic resistance were significant variables differentiating headache in people with vs without COVID-19.⁴ Patients with a preexisting migraine or tension-type headache were found to have a significantly higher frequency of COVID-19–related headache.⁵

Persistent headache after recovery from acute COVID-19 is being increasingly recognized, but the specific attributes of these headaches are not well characterized. Acute and chronic headache attributed to systemic viral infection is described in the International Classification of Headache Disorders, 3rd edition (ICHD-3) but is supposed to directly coincide with viral illness and significantly improve as the viral illness resolves. In contrast, in long COVID-related headache, it has been postulated that the trigeminovascular system—which can be activated during the inflammatory state of an active infection—is somehow sensitized, leading to more frequent headaches that persist beyond acute COVID-19.⁶ In this article, we describe long COVID-related headache attributes in a cohort of 50 persons with persistent headaches after recovery from acute COVID-19.

Cohort Characteristics

The first 50 consecutive adults with headache, who were seen at least 6 weeks after their diagnosis with COVID-19 in a clinic specializing in neurologic complications of long COVID were evaluated by a single neurologist. Demographic data (Table 1) recorded included gender, age, race, and medical history. The evaluations occurred from February 5, 2021 through February 21, 2022.

Time from COVID-19 diagnosis to initial consultation, history of hospitalization for COVID-19, type of headache(s), number of headache days in a month, and the course and treatment of headaches after acute COVID-19 were recorded (Table 2). Brain MRI was ordered for 36 individuals who had significant new neurologic symptoms or a headache that was new or different from their headaches before COVID-19, and 33 of the ordered MRIs were obtained and evaluated.

Long COVID-Related Headache Characteristics

The average length of time from acute COVID-19 to neurology consultation was 32.6 weeks. Hospitalization for COVID-19 had occurred for 22%, and 88% had positive test results for COVID-19 verified by antigen, polymerase chain reaction (PCR), or antibody (for those diagnosed prior to vaccination availability) tests.

The characteristics of headache seen in this long COVID clinic are summarized in Table 2. Half of the cohort had a history of tension or migraine headache prior to acute COVID-19. The types of headaches varied. Chronic migraine, migraine without aura and tension-type headaches were the most common. Several patients had multiple types of headaches. Many had a new headache type that differed from the headaches they had prior to COVID-19. A period with no headaches after COVID-19 and before onset of current headache type was experienced by 30%.

The mean number of headache days per month was 16.7±11.3. Comorbid neuropsychiatric symptoms included cognitive difficulties, insomnia, and anxiety/depression.

Neuroimaging Findings

Among the 33 individuals who had brain MRIs, 60.6% had no significant findings, 36.3% had nonspecific microvascular white matter changes, and 3.0% (1 person) had mild communicating hydrocephalus. Among the 12 individuals with nonspecific microvascular white matter changes, 7 had risk factors for small vessel changes (eg, a history of hypertension, hyperlipidemia, diabetes, or migraine). No prior brain MRIs were available for comparison.

Response to Headache Treatment

At the initial consultation, 72.0% of the cohort had been prescribed a new preventive treatment and 28% were prescribed a new abortive treatment. Improvement in headache since onset occurred for 83.7% of the cohort. Several people had been prescribed preventives prior to initial evaluation but stopped them because of side effects or ineffectiveness.

Discussion

Although headache is a common symptom of acute COVID-19, it is less understood why headache can persist in some well after recovery from COVID-19. Considering the widespread impact of the COVID-19 pandemic and identification of long COVID in many with persistent symptoms, it is valuable to continue characterizing headache attributes in long COVID. Our case series offers a detailed analysis of the heterogenous presentation of headaches in long COVID based on a single center experience. The most common presentations were migraine with aura, chronic migraine, and tension-type headaches. Half of the participants had a history of tension or migraine headache before having COVID-19. Among those with long COVID-related headache and a prior history of headache disorders, the headache phenotypes were not always the same before and after COVID-19.

Headache during the acute phase of COVID-19 and the development of persistent headache and fatigue in long COVID appear to be associated. In a case-control study of persons who were hospitalized during the first wave of the COVID-19 pandemic in Spain, those who reported a headache at the onset of acute infection tended to have persistent post-COVID symptoms 7 months after hospital discharge, including headache, which was more likely to be tension-type, and fatigue.⁷ Multiple mechanisms have been proposed for headaches during and after COVID-19, most of which involve a role for damage triggered by inflammation or endothelial cell dysfunction. It is possible that the increased circulating proinflammatory mediators and cytokines during active COVID-19 may activate perivascular trigeminal nerve endings.⁸ Similarly, pain pathways within the brainstem may be injured from inflammatory processes, considering that a series of autopsies have shown activated astrocytes and microglia and cytotoxic T-cell infiltration in the brainstem.⁹ Increased serum levels of proinflammatory cytokines could contribute to altered neurotransmission, neurotoxicity, and hypoxic injury in the brain.¹⁰ The SARS-CoV-2 virus may also bind to endothelial cells containing angiotensin-converting enzyme 2 (ACE2) receptors, triggering microthrombi and further inflammation, which could cause further damage.¹⁰ Endothelial cell damage may explain the small vessel white matter changes seen on the brain MRIs of people with long COVID who have risk factors for microvascular disease.

Beyond direct or parainfectious effects of COVID-19, headaches may be further exacerbated by other conditions (eg, insomnia and mood disorders), which patients with long COVID often experience.¹¹ As this clinic continues, we hope to better understand the course of headaches in long COVID, including whether they eventually improve, evolve to become chronic, and respond to treatment. Our study is limited by the small sample size, single-site experience, and short-term follow-up. A larger study that includes multiple sites and longer-term longitudinal follow-up (eg, a registry study) would be useful to determine which therapies are directly helpful for headache in long COVID and whether treatment of other long-COVID symptoms also helps headache. For now, a beneficial treatment plan is one that is tailored to the individual patient, and this can often involve a multidisciplinary approach.