Characterization of Headache in COVID-19: a Retrospective Multicenter Study

DOI: https://doi.org/10.1007/s12035- 021- 02430- w

Abstract-Summary Headache is the most common neurological symptom in COVID-19, reported in 6.5–34% of patients.

Few studies have analyzed its characteristics, and some of them included cases

without laboratory confirmation or reported only critical patients.

We aimed to analyze the clinical characteristics of COVID-19 associated head-

ache in laboratory-confirmed cases.

We conducted a retrospective evaluation of patients with COVID-19 and neuro-

logical symptoms.

Patients who reported headache answered an interview about its clinical

characteristics.

Twenty-four patients with COVID-19 associated headache completed the

interview.

We have not found any characteristic that could differentiate COVID-19 associ- ated headache from other causes of headache, possibly because of its multifactorial mechanism.

Extended: Headache is the most common neurological symptom in COVID-19,

reaching a prevalence between 6.5 and 34% [276–278].

We have not found any particular characteristic that could help differentiate COVID-19–associated headache from headache secondary to other viral infections or non-infectious diseases, as was the case with some authors before us [257, 279].

Introduction The virus was identified as a new type of coronavirus (CoV), dubbed SARS-CoV-2, and its associated disease received the name of COVID-19 [280].

COVID-19 was primarily characterized as a respiratory disease; however, with the increase in the number of cases, reports emerged stating that the disease affected other organs and systems, with some studies reporting a prevalence above 35% of patients with neurological symptoms [213].

Headache is the most common neurological symptom in COVID-19, reaching a

prevalence between 6.5 and 34% [276–278].

Many studies about COVID-19 associated headache were conducted on seri- ously ill patients, were reported in single cases or small case series, included a majority of patients with an unconfirmed clinical diagnosis, or had headache as a secondary outcome measured [213, 252, 258].

We aimed to evaluate all consecutive patients with a laboratory-confirmed diag- nosis of COVID-19 with neurological symptoms for the prevalence of headache and describe its characteristics.

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Material and Methods Patients over 18 years of age diagnosed with COVID-19 who had neurological symptoms were evaluated for the presence of headache and its characteristics.

Clinical charts of patients with a recent diagnosis of COVID-19, confirmed by PCR or serology, were evaluated by the researchers for the presence of neurological symptoms, such as altered level of consciousness, focal neurological deficits, anos- mia, ageusia, epileptic seizures, or persistent headache.

Demographic characteristics, comorbidities, severity of clinical presentation,

laboratory test results, and headache characteristics were described.

Every patient that complained about headache during the course of the disease

was included.

Characteristics of headache associated with COVID-19 were described, includ- ing time of onset; severity; location; pain quality; duration; response to analgesics; associated symptoms (e.g., nausea, vomiting); and factors of worsening, such as physical activity or cough.

Comparative analyses between patients with and without headache were done

using Chi-square test for categorical variables.

Results Twenty-four patients accurately responded all headache related questions.

Patients with headache were more likely to have fever than those without (19 of

24 vs. 24 of 56, p = 0.0028).

Fever in any moment during the disease period was documented in 19 of the 24 patients (79.1%), which occurred mainly in a different moment from the headache. Fever concomitant with headache was identified in only two patients (8.3%). Among patients who presented headaches during COVID-19 infection, most of

them (50%) occurred in the first day of symptoms.

Headache persisted after other symptoms of viral infection had subsided in 3

patients (12.5%).

The vast majority of patients (75%) had no previous history of headache, and only 6 (25%) already had a previous history of headache, of these 4 (66.7%) reported having a change in headache pattern.

Discussion Headache can be associated with acute fever, although in most cases of COVID19 in our series (89.4%) fever and headache were not concomitant, and some patients also had headache that lasted longer than fever and all other symptoms of acute viral ill- ness, including cough, suggesting that headache was not a direct consequence of acute fever, as might be the case in other acute febrile diseases, but might be related to systemic infection, among other factors.

A so-called cytokine storm can occur in COVID-19 patients involving the mas- sive release of inflammatory mediators including cytokines, glutamate, PGE2, NO, and reactive oxygen species which affect the hypothalamus triggering fever, along with activation of microglia, macrophages, astrocytes, and endothelial cells, dis- rupting the blood brain barrier [281].

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COVID-19 and SARS-COV2 Vaccines

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In one retrospective cohort study including 79 hospitalized patients, COVID-19 encephalopathy did not cause great changes in CSF in terms of cell count and protein amount, but an increase in neuronal injury biomarker neuron-specific enolase (NSE) [282], suggesting a minor, if any, role for viral meningitis in neurologic symptoms.

Conclusion Headache is a highly prevalent symptom in COVID-19.

Characterization of headache is a challenge due to the fact that it is probably

caused by multifactorial etiology and changes with the course of the disease.

We have not found any characteristic that could differentiate COVID-19–associ- ated headache from other causes of headache, possibly because of its multifactorial mechanism.

Further studies with larger samples, of a prospective nature with multiple points of clinical data collection and analysis of systemic and CSF inflammatory markers, could help clarify the mechanisms of headache in COVID-19 patients and its asso- ciation with other neurological symptoms and severity of systemic disease.

Acknowledgement A machine generated summary based on the work of dos Anjos de Paula, Rafael César; de Maria Frota Vasconcelos, Thaís; da Costa, Francisco Bruno Santana; de Brito, Lara Albuquerque; Torres, Danielle Mesquita; Moura, Alissa Elen Formiga; Oliveira, Danilo Nunes; de Lima Henn, Guilherme Alves; Rodrigues, Pedro Gustavo Barros; de Sousa Pereira, Isabelle; Braga, Ianna Lacerda Sampaio; Rocha, Felipe Araújo; Frota, Norberto Anízio Ferreira; Carvalho, Fernanda Martins Maia; Pitombeira, Milena Sales; Tavares-Junior, José Wagner Leonel; Montenegro, Raquel Carvalho; Braga-Neto, Pedro; Nóbrega, Paulo Ribeiro; Sobreira-Neto, Manoel Alves 2021 in Molecular Neurobiology.

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