Received: 9 May 2021 | Accepted: 23 June 2021 DOI: 10.1111/head.14197 B R I E F C O M M U N I C AT I O N S Toward a better understanding of persistent headache after mild COVID-­19: Three migraine-­like yet distinct scenarios Edoardo Caronna MD1,2 | Alicia Alpuente MD1,2 | Marta Torres-­Ferrus MD, PhD1,2 | Patricia Pozo-­Rosich MD, PhD1,2 1 Headache Unit, Neurology Department, Hospital Universitari Vall d’Hebron, Abstract Barcelona, Spain One year after the outbreak of coronavirus disease 2019 (COVID-­19), referrals for 2 Headache and Neurological Pain Research Group, Vall d’Hebron Research persistent headache, often defined as “post-­COVID headache,” have become increas- Institute, Department of Medicine, ingly common in outpatient headache clinics. However, it is important to take into Universitat Autònoma de Barcelona, Barcelona, Spain consideration that this term may include a spectrum of clinically different headache types. We describe three cases of migraine-­like headaches in individuals with a his- Correspondence Patricia Pozo-­Rosich, Headache Unit tory of mild COVID-­19 infection to demonstrate some of the different phenotypes of Neurology Department, Hospital persistent headaches seen. These cases highlight the importance of a careful evalua- Universitari Vall d’Hebron, Ps. Vall d’Hebron 119-­129, Barcelona 08035, tion when assessing the complexities of “post-­COVID headache” as well as the need Spain. to further investigate the different, underlying, pathophysiological mechanisms. Email: ppozo@vhebron.net KEYWORDS headache, migraine, post-­COVID-­19, SARS-­CoV-­2 I NTRO D U C TI O N practice appears to indicate the presence of many different headache types. This would imply that the term “post-­COVID headache” may Severe acute respiratory syndrome coronavirus 2 (SARS-­ CoV-­ 2) be too broad to describe the complex spectrum seen. Different types is a novel coronavirus, responsible for coronavirus disease 2019 of headaches may be a result of different pathophysiological mech- (COVID-­19),1 that emerged in China at the end of 2019 causing the cur- anisms, even if they display similar characteristics, such as migraine-­ rent global pandemic.2 During the acute phase of infection,3 COVID-­19 like features. Consequently, they may have different prognoses and can trigger a headache that is phenotypically similar to migraine or responses to treatment. tension-­type headache,3,4 among other neurological symptoms.5 Here, we describe the cases of three different patients, evalu- Some patients do not fully recover after the acute phase and ated in our headache clinic, with “post-­COVID headache.” We focus experience persistent symptoms and/or delayed or long-­ term on patients with a history of mild COVID-­19 infection and migraine-­ complications of COVID-­19, generally referred to as “post-­COVID like features to stress the existence of a complex scenario even syndrome.”6 These symptoms may include memory impairment, within a group of patients with similar characteristics. We discuss insomnia, fatigue, dizziness, etc.7,8 Headache is also a post-­COVID our main findings and their implications below. symptom9 in some patients and consultations for persistent head- ache attributed to COVID-­19, often referred to as “post-­COVID headache,” are presumably being seen more often in clinical PATI E NT 1: M I G R A I N E C H RO N I FI C ATI O N practice. Although data on persistent headache attributed to COVID-­19 A 56-­year-­old woman with a history of low-­frequency episodic mi- are still lacking, clinical observation by neurologists during their daily graine (<1 day/month) and the absence of other comorbidities, who Abbreviations: BTX, onabotulinumtoxinA; COVID-­19, coronavirus disease 2019; RT-­P CR, real-­time reverse transcriptase polymerase-­chain reaction; SARS-­CoV-­2 , severe acute respiratory syndrome coronavirus 2. Headache. 2021;61:1277–1280. wileyonlinelibrary.com/journal/head© 2021 American Headache Society | 1277 1278 | HEADACHE TA B L E 1 Main features of the three patients presented Patient 1 Patient 2 Patient 3 Demographics Age, years 56 55 44 Menopause Yes Yes N/A Sex Female Female Male Family migraine history Yes No No Personal migraine history Yes No No COVID-­19 and headache characteristics COVID-­19 severity Mild Mild Mild Headache in the acute phase Yes Yes No Anosmia/ageusia Yes Yes No Migraine-­like features Yes Yes Yes Concomitant “post-­COVID” symptoms Fatigue, insomnia Hyposmia, fatigue, insomnia Fatigue, insomnia, mood disorder, loss of memory, dizziness Treatment response Response to triptans Yes Yes No Response to preventive medications Yes Yes No (AMT+BTX) Abbreviations: AMT, amitryptiline; BTX, onabotulinumtoxinA; N/A, not applicable. had menopause at the age of 49, had a mild COVID-­19 infection. then added BTX to her treatment and after 3 months, the patient ex- The patient exhibited symptoms of headache, anosmia/ageusia, perienced a reduction in headache frequency to around 8–­10 days/ and malaise at the end of May 2020. The presence of COVID-­19 month and a return in character to her usual migraine. The patient's was confirmed using a positive real-­ time reverse transcriptase allodynia also disappeared. Her symptoms remained stable through- polymerase-­chain reaction (RT-­PCR) assay test. Headache was the out the second cycle of BTX. first symptom of infection, starting a couple of days prior to the other symptoms. The patient's headache was characterized as being: frontally located, throbbing in quality, with a moderate–­severe pain PATIENT 2: LONG-­L ASTING COVID HEADACHE intensity, and associated with nausea, photophobia, and phonopho- bia. She reported that it differed from her usual migraine in that the A 55-­year-­old woman, with no personal or family history of a pri- pain since onset was constant. This constant pain was most likely mary headache disorder and no other comorbidities, who underwent the reason why the patient started overusing acute medication (par- menopause at age 51, had a mild COVID-­19 infection. She exhib- acetamol and nonsteroidal anti-­inflammatory drugs) during the first ited symptoms of headache, anosmia/ageusia, cough, shortness of 2 months, although later the lack of pain relief made her reduce her breath, malaise, and diarrhea at the end of March 2020. The pres- analgesic intake. The patient also started noticing allodynia while ence of COVID-­19 was confirmed by a positive RT-­PCR. Pneumonia combing her hair. was ruled out with a chest X-­ray. The patient's headache started a The patient first visited our headache clinic at the end of October few days after the appearance of her other symptoms. Headache 2020 to discuss persistent headache. She also reported fatigue and characteristics included holocranial location, moderate severity, insomnia. Results from a CT scan with contrast, lab work, and a neu- and tightness/pressure in terms of type of pain although the patient rological examination were within the norm and did not suggest the also reported moments of more severe, throbbing pain. Headache presence of secondary causes. The patient did not have hypertension was accompanied by photophobia, phonophobia, and nausea. The or any new onset comorbidity. The patient was instructed on life- patient was unable to engage in her usual physical exercise due to style changes and, given the disabling nature of her headaches and worsening of pain with movement. She had constant pain following other symptomology, was offered combined preventive treatment headache onset and was taking paracetamol daily. with amitriptyline 25 mg QD, also beneficial in treating her insomnia, The patient first visited our headache clinic at the beginning and onabotulinumtoxinA (BTX) 195U based on her chronic migraine-­ of July 2020 because of the presence of persistent headache. like phenotype. Because of the patient's initial reluctance toward Furthermore, she was still experiencing hyposmia, fatigue, and BTX, we began with amitriptyline only. After 4 weeks, the patient's insomnia. An MRI of the brain with MR angiography, blood tests, sleep quality had improved; however, she continued to experience as well as a neurological examination were performed but did not headache almost daily, although with a reduction in intensity. We yield any secondary causes. We discussed lifestyle changes with the HEADACHE | 1279 patient and, based on the same rationale as in Patient 1, a combined DISCUSSION preventive treatment plan of amitriptyline 25 mg QD coupled with BTX 195U were initiated immediately. Three months later, the pa- Although we are aware of a potentially wide spectrum of persis- tient's sleep quality had improved alongside an important reduction tent post-­COVID headaches, we report these three cases as they in both headache frequency (1–­2 headache days/week) and sever- (1) demonstrate the existence of phenotypically similar (i.e., all of ity (50%–­75% reduction). On headache days with migraine features, these cases had migraine-­like features and were found in patients the patient displayed a good response to almotriptan 12.5 mg. The having undergone a mild COVID-­19 infection) but considerably dif- patient remained clinically stable with two subsequent BTX adminis- ferent headache subtypes and (2) represent some of the patients trations, although she did report the effects of the treatment “wear- we have observed in clinical practice (Table 1). Moreover, in light ing off” prior to each injection. of the emerging complications post-­COVID-­19, they raise several questions of scientific and clinical interest in headache, based on the following aspects: PATI E NT 3 : D E L AY E D -­O N S E T-­COV I D First, Patient 1 seems to suggest SARS-­CoV-­2 as a risk factor H E A DAC H E for the sudden worsening of a previous headache disorder, such as migraine, potentially leading to its chronification. Worsening of A 44-­year-­old man with asthma and no personal or family his- headache following acute SARS-­CoV-­2 infection has been reported tory of a primary headache disorder had a mild COVID-­19 infec- by several patients with migraine.10 Thus, the lingering headache tion. He exhibited symptoms including cough, shortness of breath, observed, despite COVID-­ 19 resolution, may reflect persistent and malaise at the end of March 2020. The presence of COVID-­19 changes in migraine characteristics as a result of COVID-­19, rather was confirmed by a positive RT-­P CR. Pneumonia was ruled out by than a new type of headache. Considering the high frequency of mi- a chest X-­ray. The patient did not experience loss of smell/taste graine in the general population, Patient 1 is a potential representa- or headache in the acute phase of infection. In May 2020, when tion of one of the most common displays of post-­COVID headache. his respiratory symptoms began to improve, he started to report Second, migraine-­like features are present in patients without a the presence of headaches with holocranial localization, throbbing personal migraine history, as shown in Patients 2 and 3, pointing to pain, photophobia, phonophobia, nausea, and worsening of pain an acquired activation of the trigeminovascular system by the SARS-­ with movement. Over the course of the following weeks, his head- CoV-­2 infection.3 In support of this hypothesis, a recent study has aches increased to a constant, daily frequency although he could found SARS-­CoV-­2 proteins in trigeminal branches and the trigeminal still distinguish severe migraine-­like days from milder ones. He was ganglion.11 The detection of these migraine characteristics may guide not overusing acute medication given he did not experience any acute and preventive therapeutic strategies, although the response kind of pain relief from analgesic use. An MRI of the brain with to specific migraine treatments may not be always effective (i.e., MR angiography, blood tests, and neurological examinations were Patient 3) as a result of other concomitant factors or mechanisms. performed in that period and were not suggestive of secondary Third, persistent headache attributed to COVID-­19 may emerge causes. despite not having experienced headache in the acute infection The patient first visited our headache clinic in mid-­July 2020 phase, as observed in Patient 3. Therefore, headache as a long-­ because of the presence of persistent headache. He complained of lasting symptom following the acute phase of COVID-­19 infection fatigue and insomnia and was found to be newly hypertensive at may be pathophysiologically different from headache appearing as 140/90 mm Hg. First, we attempted to address other possible fac- a delayed symptom when the infection is about to resolve. For ex- tors related to headache through the use of a combined preventive ample, factors such as altered levels of glutamate and hypoxic injury treatment plan of amitriptyline 25 mg QD for insomnia and cande- are believed to play a more prominent role in the post-­COVID-­19 sartan 16 mg QD for hypertension. The patient was also instructed phase.12 This suggests that new daily persistent headache (Patients to undertake changes in lifestyle. Five weeks later, hypertension 2 and 3) may, in reality, harbor different subtypes with different clin- was controlled, sleep quality had partially improved, but the pa- ical courses. tient did not report any significant clinical changes in his persistent Fourth, headache can be associated with many other symptoms headaches. BTX 195U was added to the patient's treatment plan but (insomnia, memory loss, dizziness, fatigue, etc.) that identify “post-­ was discontinued after two cycles due to a lack of improvement. COVID-­19 syndrome,” as seen in Patient 3. The presence of these Rizatriptan 10 mg was ineffective in treating migraine-­like days. comorbid conditions could (1) point to the involvement of different During the follow-­up, the patient started reporting other symptoms pathophysiological pathways (e.g., brainstem in insomnia,13 neu- such as cognitive impairment, memory loss, heart palpitations, and rotransmitter depletion in neuropsychiatric symptoms12) all leading dizziness, for which he had scheduled a visit at a memory unit and to headache and (2) directly affect headache prognosis.14,15 a cardiology clinic, respectively. On the patient's last visit in April Thus, future research studies should focus on studying how 2021, escitalopram 10 mg QD was started due to changes in mood. these aspects (i.e., migraine history, migraine-­like features, head- He was still experiencing disabling, daily, and constant headache and ache in the acute phase, headache onset post-­COVID, presence had not returned to work or his usual activities. of associated symptoms) interact in determining specific clinical 1280 | HEADACHE 2. World Health Organization. Coronavirus Disease 2019 (COVID-­19). phenotypes, to better understand their mechanisms and define the Situation report—­ 51. 2020. https://www.who.int/docs/defau​ lt-­ best therapeutic strategies. sourc​e/coron​aviru​se/situa​tion-­repor ​t s/20200​311-­sitre​p-­51-­covid​ -­19.pdf?sfvrs​n=1ba62​e57_10 3. Caronna E, Ballvé A, Llauradó A, et al. Headache: a striking pro- AC K N OW L E D G M E N T dromal and persistent symptom, predictive of COVID-­ 19 clini- We acknowledge the collaboration of Angela Marti-­Marca. cal evolution. Cephalalgia. 2020;40(13):1410-­ 1421. https://doi. org/10.1177/03331​02420​965157 C O N FL I C T O F I N T E R E S T 4. Trigo López J, García-­A zorín D, Planchuelo-­Gómez Á, García-­Iglesias Dr. Caronna has received honoraria from Lundbeck, Novartis, and C, Dueñas-­Gutiérrez C, Guerrero ÁL. Phenotypic characterization of acute headache attributed to SARS-­CoV-­2: an ICHD-­3 validation Chiesi. Dr. Alpuente has received honoraria from Allergan plc, Novartis, study on 106 hospitalized patients. Cephalalgia. 2020;40(13):1432-­ and Chiesi. Dr. Torres-­Ferrus has received honoraria from Allergan plc, 1442. https://doi.org/10.1177/03331​02420​965146 Novartis, and Chiesi. Dr. Pozo-­Rosich has received honoraria as a con- 5. Pezzini A, Padovani A. Lifting the mask on neurological manifesta- sultant and speaker for: Allergan-­AbbVie, Almirall, Biohaven, Chiesi, Eli tions of COVID-­19. Nat Rev Neurol. 2020;16(11):636-­6 44. https:// doi.org/10.1038/s4158​2-­020-­0398-­3 Lilly, Medscape, Neurodiem, Novartis, and Teva. Her research group 6. Silva Andrade B, Siqueira S, de Assis Soares WR, et al. Long-­COVID has received research grants from Novartis and funding for clinical tri- and post-­ COVID health complications: an up-­ to-­ date review als from Alder, Amgen, Electrocore, Eli Lilly, Novartis, and Teva. She is on clinical conditions and their possible molecular mechanisms. an Elected Trustee of the board for the International Headache Society Viruses. 2021;13(4):700. https://doi.org/10.3390/v1304​0700 7. Nalbandian A, Sehgal K, Gupta A, et al. Post-­acute COVID-­19 syn- and a member of the Council for the European Headache Federation. drome. Nat Med. 2021;27(4):601-­ 615. https://doi.org/10.1038/ She is a member of the editorial board for Revista de Neurologia. She s4159​1-­021-­01283​-­z is an editor for Cephalalgia, Headache, Neurologia, Frontiers of Neurology 8. Huang C, Huang L, Wang Y, et al. 6-­ month consequences of and an advisor for The Journal of Headache and Pain. She is a member of COVID-­19 in patients discharged from hospital: a cohort study. Lancet. 2021;397(10270):220-­232. https://doi.org/10.1016/S0140​ the Clinical Trials Standing Committee for the International Headache -­6736(20)32656​-­8 Society. She has edited the Guidelines for the Diagnosis and Treatment 9. Sampaio Rocha-­Filho PA, Voss L. Persistent headache and persistent of Headache for the Spanish Society of Neurology. She is the founder anosmia associated with COVID-­19. Headache. 2020;60(8):1797-­ of www.midol​ordec​abeza.org. P.P.-­R. does not own stocks from any 1799. https://doi.org/10.1111/head.13941 10. Al-­Hashel JY, Ismail II. Impact of coronavirus disease 2019 pharmaceutical company. There are no conflicts of interest with re- (COVID-­ 19) pandemic on patients with migraine: a web-­ based gard to this manuscript. survey study. J Headache Pain. 2020;21(1):115. https://doi. org/10.1186/s1019​4-­020-­01183​-­6 AU T H O R C O N T R I B U T I O N S 11. Meinhardt J, Radke J, Dittmayer C, et al. Olfactory transmucosal Study concept and design: Edoardo Caronna, Patricia Pozo-­ Rosich. SARS-­CoV-­2 invasion as a port of central nervous system entry in individuals with COVID-­19. Nat Neurosci. 2021;24(2):168-­175. Acquisition of data: Edoardo Caronna. Analysis and interpretation of data: https://doi.org/10.1038/s4159​3-­020-­0 0758​-­5 Edoardo Caronna, Patricia Pozo-­Rosich. Drafting of the manuscript: 12. Boldrini M, Canoll PD, Klein RS. How COVID-­19 affects the brain. Edoardo Caronna, Patricia Pozo-­Rosich. Revising it for intellectual con- JAMA Psychiatry. 2021;78(6):682-­ 683. https://doi.org/10.1001/ tent: Edoardo Caronna, Alicia Alpuente, Marta Torres-­Ferrus, Patricia jamap​sychi​atry.2021.0500 13. Vgontzas A, Pavlović JM. Sleep disorders and migraine: review of Pozo-­Rosich. Final approval of the completed manuscript: Edoardo literature and potential pathophysiology mechanisms. Headache. Caronna, Alicia Alpuente, Marta Torres-­Ferrus, Patricia Pozo-­Rosich. 2018;58(7):1030-­1039. https://doi.org/10.1111/head.13358 14. Negro A, Seidel JL, Houben T, et al. Acute sleep deprivation en- PAT I E N T C O N S E N T hances susceptibility to the migraine substrate cortical spread- ing depolarization. J Headache Pain. 2020;21(1):86. https://doi. All patients provided fully informed, voluntary and written consent org/10.1186/s1019​4-­020-­01155​-­w to publish. 15. Minen MT, Begasse De Dhaem O, Kroon Van Diest A, et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 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