Among primary headache syndromes, NDPH is one of the most treatment-refractory and difficult-to-diagnose cephalic syndromes. NDPH is a long-term headache with a distinct and clearly-remembered onset and with pain becoming continuous and unremitting within 24 hours [16]. Although duration > 3 months is listed among the diagnostic criteria, daily persistence from onset and unremitting headache within 24 hours is considered one of the most distinctive features of NDPH. It is mostly bilateral, from moderate to severe intensity [23], and may exhibit features of migraine (unilateral pain, pulsating quality, worsening with physical activity, photophobia, phonophobia, nausea, and vomiting), tension-type headache, or both [7, 14, 24, 25]. The prevalence in the general population is low [26, 27]. However, in patients with chronic daily headache followed at tertiary headache centers, the prevalence ranges from 21–28% in pediatric and 2–11% in adult populations [8, 9, 12, 28–30].
Studies of NDPH published before the COVID-19 pandemic reported systemic infections (primarily flu-like syndrome or Epstein-Barr virus infection) as one of the main triggering factors (from 14–43% of cases) [24, 25, 31–33]. After the emergence of COVID-19, Trigo López et al. [34] fully characterized 106 patients with acute headache attributed to SARS-CoV-2 in whom 94% met the ICHD-3 criteria for systemic viral infection-related headache. However, these were not classified as NDPH. The first COVID-19-triggered NDPH case was reported by Sampaio Rocha-Filho and Voss in 2020 [12]. Then, more studies of probable NDPH cases in adults along with SARS-CoV-2 infection [12, 15] and in children and adolescents [18] have followed. The most recent study being a comprehensive multicenter case series from Italy [35].
In this context, we conducted the first study in Latin America exploring the clinical-epidemiological features in a representative cohort of individuals with persistent headache after SARS-CoV-2 infection and the risk factors associated with NDPH. This study showed that at least a quarter of the participants who had persistent headache after COVID-19 met the criteria for NDPH according to ICHD-3 [16]. Compared to NDPH pre-COVID-19 studies, the mean age and female predominance of participants with NDPH were similar to those reported in India [36], Italy [37], and the USA [23–25, 38]. Conversely, race was determined according to the participant’s self-perception, showing a predominance of mixed and white race, in contrast to other studies showing a predominance of only white race [23–25, 34, 38]. To date, the only large study assessing specifically NDPH and COVID-19 is a case series from Italy [35]. Out of a series of 11 patients with persistent headaches, only eight patients met the inclusion criteria for NDPH (36.4%) or probable NDPH (36.4%). The remaining three patients with persistent headache were classified as probable migraine (9.1%), and migraine-like headache secondary to COVID-19 (18.2%). All NDPH patients were female, with a median age of 37 years, a median VAS intensity score of 8, and mostly bilateral (90.9%). On follow-up, only three patients (27.3%) remained as NDPH and one patient (9.1%) as probable NDPH. The remaining patients were reclassified [35]. Among NDPH patients, tension-type like was the most common pattern while a migraine-like pattern was the most common among probable NDPH patients.
Despite the cross-sectional nature of the study, we were able to identify 106 patients meeting the NDPH/probable NDPH diagnostic criteria. To ensure accuracy in accordance with the NDPH diagnostic criteria, the survey was evaluated by neurologists, infectious disease specialists, and epidemiologists. Participants who did not have a distinct and clearly-remembered onset of headache or did not experience daily headaches were excluded from the study. Additionally, individuals with a history of headaches who did not report any change in headache symptoms after infection with SARS-CoV-2 were not included in the study.
While it is known that viral infections may trigger NDPH, the acute infection headache could have been classified as “Headache attributed to infection” or even to the subclassification “Headache attributed to systemic viral infection”. However, this secondary headache should have improved upon resolution of the acute phase infection. Therefore, these diagnoses do not adequately describe the patients classified as NDPH, who persisted with headache for weeks and months after the infection onset. Conversely, the clear line between NDPH, “Chronic headache attributed to systemic viral infection”, and long COVID syndrome may be a challenging draw as primary and secondary headache diagnoses may overlap. The ICDH-3 provides guidance on how to choose the most-likely diagnosis. Headache is one of the most common neurologic symptoms reported in long COVID [39, 40]. The World Health Organization defines the post-COVID-19 condition or long COVID as new symptoms or the presence of symptoms for over two months, within three months following initial SARS-CoV-2 infection that cannot be explained by any other reason [41]. Long COVID headache and NDPH share a similar clinical picture and its temporal relationship with acute COVID-19, but long COVID headaches may behave as a chronic intermittent headache since they may not be present every day, may respond to analgesics, and may be affected by the severity of the disease [8]. A persistent pattern and sudden onset may point better to NDPH diagnosis [42]. Fernández-de-Las-Peñas et al. [43] presented a diagnostic model that outlines the distinctive features of NDPH and delayed-onset post-COVID-19 headache in patients with prolonged COVID-19 symptoms. While symptoms such as fatigue, sleep disorders, and anxiety were commonly observed in these patients, the clinical characteristics of persistent headache align more closely with those of NDPH.
While mechanisms of NDPH remain largely unknown, several putative mechanisms have been proposed to explain the presence of headache in the spectrum of long COVID. Although clinically different from NDPH, long COVID headache’s potential mechanisms could help guide research into the mechanisms of COVID-19-triggered NDPH (Fig. 4). It is hypothesized that COVID-19 may provoke an exaggerated inflammatory response that overstimulates the trigeminovascular system leading to headaches [10] as occurs in patients with cluster headache, where some assumptions focus on altered neurotransmitter release in this system triggering their attacks [44].
Neuro-invasion has been confirmed in post-mortem brain tissue studies due to the presence of angiotensin-converting enzyme 2 (ACE2) receptors and type 2 transmembrane serine proteases in neural cells [49, 50]. The brainstem is where most ACE2 receptors have been found and this may explain autonomic dysregulation in long COVID patients [51]. In clinical observational studies, patients with neurological symptoms who recovered from COVID-19 had brain structural and metabolic abnormalities [45, 46, 52]. The mechanism on how SARS-CoV-2 enters the central nervous system remains unclear [39, 47]. However, studies documenting the presence of virus in neural and capillary endothelial cells suggest endothelial transcytosis as a possible route of access to the central nervous system [48]. Other mechanisms include immunological over activation leading to persistent neuroinflammation [39, 47]. The ongoing inflammatory response after acute COVID-19 remission keep the expression of proinflammatory cytokines such as IFN-β, IFN-λ1, IFN-γ, IL-2, IL-6, IL-17, CXCL8, CXCL9, and CXC10 upregulated, the activation of non-classical and intermediate monocytes, fibroblasts, and myeloid cells [39]. Monocyte expansion due to chronic antigen stimulation may lead to blood brain barrier disruption and neuroinflammation. T-cell dysfunction presents as exhausted CD4+ and CD8+ and low CD4+ central memory leading to a decreased effector function [39]. Additionally, glial cells become over activated due to high cytokine activity and brain injury. High levels of CCL11 have been found in patients with neurological symptoms of long COVID, inducing microglial migration, leading to hippocampal neurogenesis and ultimately to cognitive dysfunction (mental fog) [39].
Factors predisposing NDPH remain poorly understood. Consistent with previous studies, COVID-19 clinical severity and the presence of comorbidities were not associated with the development of persistent headache [7, 8]. However, in these studies, persistent headache is not a synonym of NDPH.
While prior history of migraine has been widely associated with persistent headache after SARS-CoV-2 infection [8, 10]. In this study, neither personal history nor family history of migraine were associated with NDPH after COVID-19. Smoking has been identified as a common trigger and intensifier for headaches [53], which is in line with a higher pack-year index found in smokers with NDPH. This makes sense since there is an increased exposure to smoking. Nevertheless, the heterogeneity of NDPH renders comparison between studies challenging and inconclusive when specific subgroups are not studied separately [54].
During the acute phase of COVID-19, patients with persistent headache reported neuropsychological spectrum symptoms more frequently, such as fatigue, sleep problems, anxiety, and mental fog. These symptoms are within the long COVID syndrome, but also are in patients with persistent headache who tended to develop these symptoms more frequently at disease onset [10, 11]. Conversely, participants with NDPH experienced face or forehead sweating more frequently, upper eyelid drooping and/or pupillary constriction, and palpebral edema during the acute phase of COVID-19, symptoms that would relate this type of headache more to a cluster headache [16]. In this study, palpebral edema was the only concomitant symptom during the acute COVID-19 phase associated with NDPH.
Persistent headache after SARS-CoV-2 infection is a clinically heterogeneous entity. The findings of this study align with previous reports highlighting its oppressive quality and frontal-bilateral topography [11, 55]. Although headache may locate anywhere in the head, in this study, occipital pain was the most common location and was significantly associated with NDPH. Furthermore, the burning character was also associated with NDPH. While the proportion of patients presenting with a burning character was low and an oppressive-type headache character is more common [6, 18, 19, 25, 56], a burning character may point towards more specifically to NDPH. Patients who fulfilled the diagnostic criteria for NDPH were also more likely to develop headache of severe/unbearable intensity compared to the non-NDPH group; however, disease-associated burden and disability remain high in patients with NDPH [32] and are indistinguishable from those with chronic migraine [57]. In contrast, factors identified that point away from NPDH were afternoon onset periodicity despite that NDPH may present at any time of the day, and the presence of factors that attenuate the pain. The latter is obvious since NDPH pain usually is refractory to treatment.
Finally, concomitant symptoms in patients with NDPH include sleep disturbances, light-headedness, blurred vision, neck stiffness, concentration problems, sensory disturbances such as numbness or tingling, vertigo, lethargy, and other non-specific syndromes [38]. Mood disorders are considerably more prevalent in patients with NDPH compared to healthy subjects. Moreover, severe anxiety and depressive symptoms were reported in 66% and 40%, respectively, of patients with NDPH [56], findings similar to those of this study, in which a high prevalence of anxious symptoms, sleep problems, and mental fog was observed in patients with NDPH.
This study has several limitations. First, despite the responses included from 11 Latin American countries, the sample was not representative in some of these countries due to the low number of participants. Furthermore, only Spanish-speaking countries were included, thus excluding Brazil and Haiti, and more than 60% of the responses included were from Venezuelan participants, which may pose a sampling bias. Second, despite the effort to group participants with a diagnosis of NDPH, it was not possible to confirm this diagnosis due to the cross-sectional nature of the study and the absence of neuroimaging to exclude other secondary causes of headache, including meningitis (aseptic or chronic), idiopathic intracranial hypertension, intracranial hypotension, mass lesion, sphenoid sinusitis, hydrocephalus, and cerebral vein thrombosis. However, in most of these clinical instances, imaging studies would also be unrevealing [54]. Third, responding to a self-completed online survey carries the risk of participant recall bias, especially if there was a prolonged time between the COVID-19 episode and the time of survey completion. Fourth, the dissemination of the online survey through instant messaging, emails, and social networks could cause selection bias, including only participants with access to smart devices and/or the Internet. Therefore, the findings should be interpreted with caution. Finally, since this is a cross-sectional study, there is no follow-up data available. As a result, some participants’ clinical conditions may have changed over time, which may require their diagnosis to be reclassified in the future. Nevertheless, the study’s strengths are the relatively diverse study population included, a high variety of vaccine types reported by the participants, and a systematic way of data collection that prevented missing data or participants not meeting the inclusion criteria from being included. We believe the findings may provide useful information that could serve as the background for future research as an aid to diagnosis of this complex cephalic syndrome.