BACKGROUND: New onset or worsening of a headache disorder substantially contributes to the disease burden of post-COVID-19. Its management poses a suitable means to enhance patients\' participation in professional, social, and personal activities. Unfortunately, the pathophysiology of post-COVID-19 headaches is poorly understood. This study aims to investigate the role of (neuro-) inflammatory mechanisms in order to guide the development of anti-inflammatory treatment strategies.
METHODS: We included patients from the interdisciplinary post-COVID-19 Rehabilitation Study (PoCoRe, n = 184 patients) run at a tertiary care university hospital, comprising patients with PCR-confirmed SARS-CoV-2 infection ≥ 6 weeks prior to their initial consultation. Patients reporting any headache since their infection were considered for this study (n = 93). These were interviewed and classified according to the International Classification of Headache Disorders, Third Edition (ICHD-3) by headache specialists. Patient sera were additionally analysed for levels of VILIP-1, MCP-1 (CCL2), sTREM-2, BDNF, TGF-ß1, VEGF, IL-6, sTREM-1, ß-NGF, IL-18, TNF-alpha, sRAGE, and CX3CL1 (Fractalkine). Markers of inflammation were compared between four groups of patients (none, unchanged, worsened, or new headache disorder).
RESULTS: Patients reported experiencing more severe headaches (n = 17), new onset headaches (n = 46), unchanged headaches (n = 18), and surprisingly, some patients denied having any headaches (n = 12) despite self-reports. Serum levels of CX3CL1 were increased in the worsened (2145 [811-4866] pg/ml) and new onset (1668 [0-7357] pg/ml) headache group as compared to patients with no (1129 [0-5379] pg/ml) or unchanged (1478 [346-4332] pg/ml) headaches. Other markers also differed between groups, but most significantly between patients with worsened (TGF-ß1: 60 [0-310] pg/ml, VEGF: 328 [86-842] pg/ml, ß-NGF: 6 [3-38] pg/ml) as compared to unchanged headaches (TGF-ß1: 29 [0-77] pg/ml, VEGF: 183 [72-380] pg/ml, ß-NGF: 3 [2-89] pg/ml). The results did not differ between headache phenotypes.
CONCLUSIONS: This study provides evidence that worsened or new headaches following COVID-19 are associated with pro-(neuro-)inflammatory profiles. This supports the use of anti-inflammatory treatment options in this population, especially in the subacute phase.

UNASSIGNED: Little is known about the frequency and impact of the persistent headache and about the incidence of chronic daily headache (CDH) after coronavirus disease 2019 (COVID-19). The aim of this prospective cohort study was to assess the incidence, risk factors, characteristics, and impact of CDH in patients with COVID-19.
UNASSIGNED: In the first stage, 288 patients were interviewed by telephone after the acute phase of COVID-19. Subsequently, 199 patients who presented headache were reinterviewed at least one year after COVID-19. Headaches that persisted beyond the acute phase of COVID-19 for three or more months and presented frequency ≥ 45 days over the first three months were considered to be CDH.
UNASSIGNED: One hundred and twenty-three patients were included, 56% were females; median age: 50 years (25th and 75th percentile: 41;58). The headache persisted beyond the acute phase of COVID-19 in 52%, and 20.3% had CDH (95% confidence interval: 13.6-28.2). Individuals who previously had headaches and who had headaches of greater intensity during the acute phase were at higher risk of developing CDH. The group with CDH included more females, greater impact of headache, more persistence of headache beyond the 120th day of COVID-19 and less throbbing headache than did the other individuals whose headache persisted.
UNASSIGNED: Patients who had COVID-19 had a high incidence of CDH. Previous headache and greater intensity of headache were associated with higher risk of CDH.

OBJECTIVE: In this retrospective cross-sectional real-world evidence study from the Danish Headache Center (DHC), a national tertiary headache center in Denmark, we sought to identify potential pharmacological agents for the treatment of new daily persistent headache (NDPH).
BACKGROUND: NDPH is an enigmatic headache disorder with abrupt onset and chronic duration for which evidence-based treatments are lacking. NDPH is a diagnosis of exclusion, for which secondary headaches must be ruled out and the etiology remains idiopathic. The sparse investigations of this disorder have not yielded a pathophysiological basis and no effective treatment for NDPH has been found.
METHODS: All patients with an NDPH diagnosis at the DHC were enrolled (n = 64). First, we reviewed the records of all patients with an NDPH diagnosis to evaluate whether they fulfilled the diagnostic criteria. Next, we extracted all the trialled acute and prophylactic pharmacological interventions for the included patients. Then, pharmacological interventions that had been tried in ≥ 20 patients were analyzed post hoc with efficacy as the outcome, which was stratified in five effect categories (\"no effect,\" \"partial effect,\" \"full effect,\" \"partial effect and cessation due to adverse events,\" and \"full effect and cessation due to adverse events\"). Descriptive statistical analysis was performed, and the results were schematically presented (see Table 2).
RESULTS: Fifty-one patients out of 64 were found to fulfill NDPH criteria and were included in the study. The drugs tried by ≥ 20 patients were amitriptyline (n = 34), candesartan (n = 27), and mirtazapine (n = 20). No patients experienced a complete effect with these drugs while 9% (3/34), 26% (7/27), and 15% (3/20) experienced a partial effect with no adverse events that led to treatment discontinuation, respectively. The remaining patients experienced either no effect or a partial effect with adverse events leading to treatment discontinuation.
CONCLUSIONS: In this study we add real-world evidence to suggest that prophylactic drugs conventionally used for treating chronic migraine and chronic tension-type headache have limited utility for treating NDPH; however, a partial response in 26% of patients using candesartan and 15% of patients using mirtazapine warrants further investigation in randomized double-blinded placebo-controlled trials.

Other primary headache disorders (OPHD) are under-investigated compared to frequent primary headache types like migraine, tension-type headache, and trigeminal autonomic cephalalgias. Knowledge of the distribution and characteristics of OPHD subtypes is crucial for their recognition. We aimed to determine the prevalence at the hospital and headache clinics and clinical characteristics of OPHDs in patients from 13 countries.
We analyzed a large dataset from the cross-sectional study Head-MENA-A (Middle East, North Africa, Asia). Consecutive patients over 10 years of age presenting with headaches were included from outpatient, inpatient, and emergency settings. A structured questionnaire addressing demographics, headache characteristics, accompanying symptoms, and triggers was administered. Headache subtypes were diagnosed according to the ICHD-3 criteria.
Among patients complaining of headaches (n = 3722), 106 (2.9%) were diagnosed with OPHD. Fifty-two patients (1.4% of all headache patients) had only OPHD, while 54 (1.5%) had both OPHD and a co-existing primary headache (mostly migraine). All OPHDs were more common in females. The most frequent subtypes were new daily persistent headache and primary stabbing headache (0.2% each among all admitted patients). Photophobia and phonophobia were the most frequent accompanying symptoms, while physical activity (28.8%), stress (15.4%), and the Valsalva maneuver (15.4%) were the most common triggering factors. The majority of triggering factors were more pronounced in patients with both migraine and OPHD.
Other primary headaches are rare and heterogeneous. Their high co-existence with migraine suggests shared predisposing factors, hinting at a \"headache continuum\" concept for primary headaches.

BACKGROUND: Persistent headache is a frequent symptom after coronavirus disease 2019 (COVID-19) and there is currently limited knowledge about its clinical spectrum and predisposing factors. A subset of patients may be experiencing new daily persistent headache (NDPH) after COVID-19, which is among the most treatment-refractory primary headache syndromes.
METHODS: We conducted a cross-sectional study in Latin America to characterize individuals with persistent headache after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to identify factors associated with NDPH. Participants over 18 years old who tested positive for SARS-CoV-2 infection and reported persistent headache among their symptoms completed an online survey that included demographics, past medical history, persistent headache clinical characteristics, and COVID-19 vaccination status. Based on participants\' responses, NDPH diagnostic criteria were used to group participants into NDPH and non-NDPH groups. Participant data was summarized by descriptive statistics. Student\'s t and Mann-Whitney U tests were used according to the distribution of quantitative variables. For categorical variables, Pearson\'s chi-square and Fisher\'s exact tests were used according to the size of expected frequencies. Binomial logistic regression using the backward stepwise selection method was performed to identify factors associated with NDPH.
RESULTS: Four hundred and twenty-one participants from 11 Latin American countries met the inclusion criteria. One in four participants met the NDPH diagnostic criteria. The mean age was 40 years, with most participants being female (82%). Over 90% of the participants reported having had mild/moderate COVID-19. Most participants had a history of headache before developing COVID-19 (58%), mainly migraine type (32%). The most predominant clinical characteristics in the NDPH group were occipital location, severe/unbearable intensity, burning character, and radiating pain (p < 0.05). A higher proportion of anxiety symptoms, sleep problems, myalgia, mental fog, paresthesia, nausea, sweating of the face or forehead, and ageusia or hypogeusia as concomitant symptoms were reported in participants with NDPH (p < 0.05). Palpebral edema as a concomitant symptom during the acute phase of COVID-19, occipital location, and burning character of the headache were risk factors associated with NDPH.
CONCLUSIONS: This is the first study in Latin America that explored the clinical spectrum of NDPH after SARS-CoV-2 infection and its associated factors. Clinical evaluation of COVID-19 patients presenting with persistent headache should take into consideration NDPH.

BACKGROUND: The brain functional network topology in new daily persistent headache (NDPH) is not well understood. In this study, we aim to assess the cortical functional network topological characteristics of NDPH using non-invasive neural signal recordings.
METHODS: Resting-state magnetoencephalography (MEG) was used to measure power fluctuations in neuronal oscillations from distributed cortical parcels in 35 patients with NDPH and 40 healthy controls (HCs). Their structural data were collected by 3T MRI. Functional connectivity (FC) of neural networks from 1 to 80 Hz frequency ranges was analyzed with topographic patterns and calculated network topological parameters with graph theory.
RESULTS: In the delta (1-4 Hz) and beta (13-30 Hz) bands, the lateral occipital cortex and superior frontal gyrus FC were increased in NDPH groups compared to HCs. Graph theory analysis revealed that the NDPH had significantly increased global efficiency in the delta band and decreased nodal clustering coefficient (left medial orbitofrontal cortex) in the theta (4-8 Hz) band. The clinical characteristics had a significant correlation with network topological parameters. Age at onset of patients showed a positive correlation with global efficiency in the delta band. The degree of depression of patients showed a negative correlation with the nodal clustering coefficient (left medial orbitofrontal cortex) in the theta band.
CONCLUSIONS: The FC and topology of NDPH in brain networks may be altered, potentially leading to cortical hyperexcitability. Moreover, medial orbitofrontal cortex is involved in the pathophysiological mechanism of depression in patients with NDPH. Increased FC observed in the lateral occipital cortex and superior frontal gyrus during resting-state MEG could serve as one of the imaging characteristics associated with NDPH.

BACKGROUND: New daily persistent headache (NDPH) is a rare primary headache disorder characterized by daily and persistent sudden onset headaches. The pathogenesis of NDPH remains unclear, and there are few white matter imaging studies related to NDPH. The purpose of this study was to investigate the micro-structural abnormalities of white matter in NDPH and provided insights into the pathogenesis of this disease based on tract-based spatial statistics (TBSS).
METHODS: Twenty-one patients with NDPH and 25 healthy controls (HCs) were included in this study. T1 structural and diffusion magnetic resonance imaging (MRI) were acquired from all participants. Differences in the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) between patients with NDPH and HCs were investigated using TBSS analysis.
RESULTS: Significantly decreased FA, increased MD and RD were found in patients with NDPH compared to HCs. White matter regions overlaid with decreased FA, increased MD and RD were found in 16 white matter tracts from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas and Johns Hopkins University White-Matter Tractography Atlas. Specifically, these white matter regions included the right anterior thalamic radiation (ATR), body of the corpus callosum (BCC), bilateral cingulum, left hippocampal cingulum (CGH), left corticospinal tract (CST), forceps major, fornix, left inferior fronto-occipital fasciculus (IFOF), bilateral inferior longitudinal fasciculus (ILF), left posterior limb of the internal capsule (PLIC), right retrolenticular part of the internal capsule (RPIC), splenium of the corpus callosum (SCC), right superior longitudinal fasciculus (SLF) and left uncinate fasciculus (UF). After Bonferroni correction, there were no correlations between the FA, MD, AD and RD values and the clinical characteristics of patients with NDPH (p > 0.05/96).
CONCLUSIONS: The results of our research indicated that patients with NDPH might have widespread abnormalities in the white matter of the brain.

BACKGROUND: Youth with continuous (always present) headache are vastly understudied; much remains to be understood regarding treatment response in this population.
OBJECTIVE: To describe and explore biopsychosocial factors related to initial clinical outcomes among treatment-seeking youth with continuous headache.
METHODS: This retrospective cohort study extracted data of 782 pediatric patients (i.e., aged <18 years) with continuous headache from a large clinical repository. Youth in this study had experienced continuous headache for ≥1 month before presenting to a multidisciplinary headache specialty clinic appointment. Extracted data from this appointment included patients\' headache history, clinical diagnoses, and headache-related disability, as well as information about biopsychosocial factors implicated in headache management and/or maintenance (e.g., healthy lifestyle habits, history of feeling anxious or depressed). Additional data regarding patient headache characteristics, disability, and lifestyle habits were extracted from a subset of 529 youth who returned to clinic 4-16 weeks after their initial follow-up visit. After characterizing initial treatment response, exploratory analyses compared youth with the best and worst treatment outcomes on several potentially influential factors.
RESULTS: Approximately half of youth (280/526; 53.2%) continued to have continuous headache at follow-up, ~20% of youth (51/526) reported a significant (≥50%) reduction in headache frequency. Improvements in average headache severity (e.g., percentage with severe headaches at initial visit: 45.3% [354/771]; percentage with severe headaches at follow-up visit: 29.8% [156/524]) and headache-related disability were also observed (e.g., percentage severe disability at initial visit: 62.9% [490/779]; percentage severe disability at initial follow-up visit: 34.2% [181/529]). Individuals with the worst headache frequency and disability had a longer history of continuous headache (mean difference estimate = 5.76, p = 0.013) and worse initial disability than the best responders (χ2 [3, 264] = 23.49, p < 0.001). They were also more likely to have new daily persistent headache (χ2 [2, 264] = 12.61, p = 0.002), and were more likely to endorse feeling depressed (χ2 [1, 260] = 11.46, p < 0.001).
CONCLUSIONS: A notable percentage of youth with continuous headache show initial improvements in headache status. Prospective, longitudinal research is needed to rigorously examine factors associated with continuous headache treatment response.

OBJECTIVE: The pathogenesis of new daily persistent headache (NDPH) is not fully understood. We aim to map aberrant functional connectivity (FC) in patients with NDPH using resting-state functional magnetic resonance imaging (MRI).
METHODS: Brain structural and functional MRI data were acquired from 29 patients with NDPH and 37 well-matched healthy controls (HCs) in this cross-sectional study. Region of interest (ROI) based analysis was used to compare FC between patients and HCs, with 116 brain regions in the automated anatomical labeling (AAL) atlas were defined as seeds. The correlations between aberrant FC and patients\' clinical characteristics, and neuropsychological evaluation were also investigated.
RESULTS: Compared with HCs, patients with NDPH showed increased FC in the left inferior occipital gyrus, right thalamus and decreased FC in right lingual gyrus, left superior occipital gyrus, right middle occipital gyrus, left inferior occipital gyrus, right inferior occipital gyrus, right fusiform gyrus, left postcentral gyrus, right postcentral gyrus, right thalamus and right superior temporal gyrus. There were no correlation between FC of these brain regions and clinical characteristics, neuropsychological evaluation after Bonferroni correction (p > 0.05/266).
CONCLUSIONS: Patients with NDPH showed aberrant FC in multiple brain regions involved in perception and regulation of emotion and pain.
BACKGROUND: ClinicalTrials.gov Identifier: NCT05334927.

BACKGROUND: New daily persistent headache (NPDH) is a rare primary headache that is highly disabling. The pathophysiology of NDPH is still unclear, and we aimed to reveal the underlying mechanism of NDPH through functional magnetic resonance imaging (fMRI) analysis.
METHODS: In this cross-sectional study, thirty patients with NDPH and 30 healthy controls (HCs) were recruited. The blood oxygen level-dependent (BOLD) sequences of all participants were obtained using the GE 3.0 T system. We performed ReHo, ALFF (conventional band: 0.01-0.08 Hz, slow-5: 0.01-0.027 Hz, slow-4: 0.027-0.073 Hz) and seed-based to the whole brain functional connectivity (FC) analysis in the NDPH and HC groups. The sex difference analysis of ReHo, ALFF, and FC values was conducted in the NDPH group. We also conducted Pearson\'s correlation analysis between ReHo, ALFF, FC values and clinical characteristics (pain intensity, disease duration, HIT-6, GAD-7, PHQ-9, and PSQI scores).
RESULTS: Both increased ReHo (PFWE-corr = 0.012) and ALFF values (0.01-0.08 Hz, PFWE-corr = 0.009; 0.027-0.073 Hz, PFWE-corr =0.044) of the left middle occipital gyrus (MOG_L) were found in the NDPH group compared to the HC group. There was no significant difference in FC maps between the two groups. Compared to the HC group, no difference was found in ReHo (p = 0.284), ALFF (p = 0.246), and FC (p = 0.118) z scores of the MOG_L in the NDPH group. There was also no sex difference in ReHo (p = 0.288), ALFF (p = 0.859), or FC z score (p = 0.118) of the MOG_L in patients with NDPH. There was no correlation between ReHo, ALFF, FC z scores and clinical characteristics after Bonferroni correction (p < 0.05/18).
CONCLUSIONS: Patients with NDPH may have abnormal activation of the visual system. Abnormal visual activation may occur mainly in higher frequency band of the classical band. No sex differences in brain activity were found in patients with NDPH.