New Daily Persistent Headache Research Articles

Challenges in the management of new daily persistent headache at a tertiary headache center-A retrospective real-world evidence study.

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). 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. 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 Table2). 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. 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.

Altered functional connectivity of brainstem nuclei in new daily persistent headache: Evidence from resting-state functional magnetic resonance imaging.

The new daily persistent headache (NDPH) is a rare primary headache disorder. However, the underlying mechanisms of NDPH remain incompletely understood. This study aims to apply seed-based analysis to explore the functional connectivity (FC) of brainstem nuclei in patients with NDPH using resting-state functional magnetic resonance imaging (MRI). The FC analysis from the region of interest (ROI) to whole brain voxels was used to investigate 29 patients with NDPH and 37 well-matched healthy controls (HCs) with 3.0 Tesla MRI. The 76 nuclei in the brainstem atlas were defined as ROIs. Furthermore, we explored the correlations between FC and patients' clinical characteristics and neuropsychological evaluations. Patients with NDPH exhibited reduced FC in multiple brainstem nuclei compared to HCs (including right inferior medullary reticular formation, right mesencephalic reticular formation, bilateral locus coeruleus, bilateral laterodorsal tegmental nucleus-central gray of the rhombencephalon, median raphe, left medial parabrachial nucleus, periaqueductal gray, and bilateral ventral tegmental area-parabrachial pigmented nucleus complex) and increased FC in periaqueductal gray. No significant correlations were found between the FC of these brain regions and clinical characteristics or neuropsychological evaluations after Bonferroni correction (p > 0.00016). Our results demonstrated that patients with NDPH have abnormal FC of brainstem nuclei involved in the perception and regulation of pain and emotions.

New daily persistent headache after SARS-CoV-2 infection in Latin America: a cross-sectional study

BackgroundPersistent 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.MethodsWe 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.ResultsFour 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.ConclusionThis 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.

Mapping brain functional networks topological characteristics in new daily persistent headache: a magnetoencephalography study

BackgroundThe 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.MethodsResting-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.ResultsIn 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.ConclusionThe 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.

New Daily Persistent Headache (NDPH): Unraveling the Complexities of Diagnosis, Pathophysiology, and Treatment.

The current article aims to provide an overview of new daily persistent headache (NDPH), with a particular emphasis on its pathophysiology, evaluation, and current treatment options. NDPH is an uncommon and heterogeneous condition associated with various comorbidities and is of great significance due to its prolonged duration and high severity. Variable causes and clinical aspects of NDPH may reflect differences in its underlying pathophysiological mechanisms, including genetics, environmental triggers, neuroinflammation, and brain changes. When assessing a patient with NDPH, potential triggers, past medical history, and differential diagnosis should be carefully considered. Non-pharmacological interventions aimed to improve diet, sleep patterns, and reduce consumption of caffeine and alcohol are recommended for all patients. Nerve blockade and nerve stimulation seem to be more efficacious in children than adults. Antiviral medications and neuroinflammation-targeting treatments may be helpful, particularly, when an infectious disease or severe inflammation is suspected. NDPH patients with concurrent affective disorders may benefit from treatment with serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or benzodiazepines. Cerebrospinal-fluid-lowering medications may be useful for headaches started with a thunderclap or a Valsalva maneuver. Possible treatments for refractory NDPH include intravenous ketamine or lidocaine, onabotulinumtoxinA, and calcitonin gene-related peptide antibodies. Considering the variety of NDPH, it is critical to properly screen patients for correct diagnosis. Proper identification of potential mimics may enable precise therapy opportunities, yet there is no gold standard treatment for NDPH. Further well-designed studies are needed to elucidate the underlying mechanisms and develop effective treatment strategies for NDPH.

Phenotype of new daily persistent headache: subtypes and comparison to transformed chronic daily headache

BackgroundIt is unknown whether new daily persistent headache (NDPH) is a single disorder or heterogenous group of disorders, and whether it is a unique disorder from chronic migraine and chronic tension-type headache. We describe a large group of patients with primary NDPH, compare its phenotype to transformed chronic daily headache (T-CDH), and use cluster analysis to reveal potential sub-phenotypes in the NDPH group.MethodsWe performed a case–control study using prospectively collected clinical data in patients with primary NDPH and T-CDH (encompassing chronic migraine and chronic tension-type headache). We used logistic regression with propensity score matching to compare demographics, phenotype, comorbidities, and treatment responses between NDPH and T-CDH. We used K-means cluster analysis with Gower distance to identify sub-clusters in the NDPH group based on a combination of demographics, phenotype, and comorbidities.ResultsWe identified 366 patients with NDPH and 696 with T-CDH who met inclusion criteria. Patients with NDPH were less likely to be female (62.6% vs. 73.3%, p < 0.001). Nausea, vomiting, photophobia, phonophobia, motion sensitivity, vertigo, and cranial autonomic symptoms were all significantly less frequent in NDPH than T-CDH (p value for all < 0.001). Acute treatments appeared less effective in NDPH than T-CDH, and medication overuse was less common (16% vs. 42%, p < 0.001). Response to most classes of oral preventive treatments was poor in both groups. The most effective treatment in NDPH was doselupin in 45.7% patients (95% CI 34.8–56.5%). Cluster analysis identified three subgroups of NDPH. Cluster 1 was older, had a high proportion of male patients, and less severe headaches. Cluster 2 was predominantly female, had severe headaches, and few associated symptoms. Cluster 3 was predominantly female with a high prevalence of migrainous symptoms and headache triggers.ConclusionsWhilst there is overlap in the phenotype of NDPH and T-CDH, the differences in migrainous, cranial autonomic symptoms, and vulnerability to medication overuse suggest that they are not the same disorder. NDPH may be fractionated into three sub-phenotypes, which require further investigation.

Verification of a clinical decision support system for the diagnosis of headache disorders based on patient–computer interactions: a multi-center study

BackgroundAlthough headache disorders are common, the current diagnostic approach is unsatisfactory. Previously, we designed a guideline-based clinical decision support system (CDSS 1.0) for diagnosing headache disorders. However, the system requires doctors to enter electronic information, which may limit widespread use.MethodsIn this study, we developed the updated CDSS 2.0, which handles clinical information acquisition via human–computer conversations conducted on personal mobile devices in an outpatient setting. We tested CDSS 2.0 at headache clinics in 16 hospitals in 14 provinces of China.ResultsOf the 653 patients recruited, 18.68% (122/652) were suspected by specialists to have secondary headaches. According to “red-flag” responses, all these participants were warned of potential secondary risks by CDSS 2.0. For the remaining 531 patients, we compared the diagnostic accuracy of assessments made using only electronic data firstly. In Comparison A, the system correctly recognized 115/129 (89.15%) cases of migraine without aura (MO), 32/32 (100%) cases of migraine with aura (MA), 10/10 (100%) cases of chronic migraine (CM), 77/95 (81.05%) cases of probable migraine (PM), 11/11 (100%) cases of infrequent episodic tension-type headache (iETTH), 36/45 (80.00%) cases of frequent episodic tension-type headache (fETTH), 23/25 (92.00%) cases of chronic tension-type headache (CTTH), 53/60 (88.33%) cases of probable tension-type headache (PTTH), 8/9 (88.89%) cases of cluster headache (CH), 5/5 (100%) cases of new daily persistent headache (NDPH), and 28/29 (96.55%) cases of medication overuse headache (MOH). In Comparison B, after combining outpatient medical records, the correct recognition rates of MO (76.03%), MA (96.15%), CM (90%), PM (75.29%), iETTH (88.89%), fETTH (72.73%), CTTH (95.65%), PTTH (79.66%), CH (77.78%), NDPH (80%), and MOH (84.85%) were still satisfactory. A patient satisfaction survey indicated that the conversational questionnaire was very well accepted, with high levels of satisfaction reported by 852 patients.ConclusionsThe CDSS 2.0 achieved high diagnostic accuracy for most primary and some secondary headaches. Human–computer conversation data were well integrated into the diagnostic process, and the system was well accepted by patients. The follow-up process and doctor–client interactions will be future areas of research for the development of CDSS for headaches.

Normal glymphatic system function in patients with new daily persistent headache using diffusion tensor image analysis along the perivascular space.

To investigate the glymphatic function in patients with new daily persistent headache (NDPH) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. NDPH, a rare and treatment-refractory primary headache disorder, is poorly understood. There is limited evidence to suggest that headaches are associated with glymphatic dysfunction. Thus far, no studies have evaluated glymphatic function in patients with NDPH. In this cross-sectional study conducted in the Headache Center of Beijing Tiantan Hospital, patients with NDPH and healthy controls were enrolled. All participants underwent brain magnetic resonance imaging examinations. Clinical characteristics and neuropsychological evaluation were examined in patients with NDPH. ALPS indexes for both hemispheres were measured to determine the glymphatic system function in patients with NDPH and healthy controls. In total, 27 patients with NDPH (14 males, 13 females; age [mean ± standard deviation (SD)]: 36.6 ± 20.6) and 33 healthy controls (15 males, 18 females; age [mean ± SD]: 36.0 ± 10.8) were included in the analysis. No significant differences between groups were observed in the left ALPS index (1.583 ± 0.182 vs. 1.586 ± 0.175, mean difference = 0.003, 95% confidence interval [CI] of difference = -0.089 to 0.096, p = 0.942), or right ALPS index (1.578 ± 0.230 vs. 1.559 ± 0.206, mean difference = -0.027, 95% CI of difference = -0.132 to 0.094, p = 0.738). Additionally, ALPS indexes were not correlated with clinical characteristics or neuropsychiatric scores. No glymphatic dysfunction was detected in patients with NDPH by means of the ALPS method. Additional studies with larger samples are needed to confirm these preliminary findings and improve the understanding of glymphatic function in NDPH.

Mapping the aberrant brain functional connectivity in new daily persistent headache: a resting-state functional magnetic resonance imaging study

Background and purposeThe 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).MethodsBrain 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.ResultsCompared 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).ConclusionsPatients with NDPH showed aberrant FC in multiple brain regions involved in perception and regulation of emotion and pain.Trial registrationClinicalTrials.gov Identifier: NCT05334927.

Cytokines in primary headache disorders: a systematic review and meta-analysis

BackgroundThe role of inflammation and cytokines in the pathophysiology of primary headache disorders is uncertain. We performed a systematic review and meta-analysis to synthesise the results of studies comparing peripheral blood cytokine levels between patients with migraine, tension-type headache, cluster headache, or new daily persistent headache (NDPH), and healthy controls; and in migraine between the ictal and interictal stages.MethodsWe searched PubMed/Medline and Embase from inception until July 2022. We included original research studies which measured unstimulated levels of any cytokines in peripheral blood using enzyme-linked immunosorbent assay or similar assay. We assessed risk of bias using the Newcastle–Ottawa Quality Assessment Scale. We used random effects meta-analysis with inverse variance weighted average to calculate standardised mean difference (SMD), 95% confidence intervals, and heterogeneity for each comparison. This study is registered with PROSPERO (registration number CRD42023393363). No funding was received for this study.ResultsThirty-eight studies, including 1335 patients with migraine (32 studies), 302 with tension-type headache (nine studies), 42 with cluster headache (two studies), and 1225 healthy controls met inclusion criteria.Meta-analysis showed significantly higher interleukin (IL)-6 (SMD 1.07, 95% CI 0.40–1.73, p = 0.002), tumour necrosis factor (TNF)-α (SMD 0.61, 95% CI 0.14–1.09, p = 0.01), and IL-8 (SMD 1.56, 95% CI 0.03–3.09, p = 0.04), in patients with migraine compared to healthy controls, and significantly higher interleukin-1β (IL-1β) (SMD 0.34, 95% CI 0.06–0.62, p = 0.02) during the ictal phase of migraine compared to the interictal phase. Transforming growth factor (TGF)-β (SMD 0.52, 95% CI 0.18–0.86, p = 0.003) and TNF-α (SMD 0.64, 95% CI 0.33–0.96, p = 0.0001) were both higher in patients with tension-type headache than controls.ConclusionsThe higher levels of the proinflammatory cytokines IL-6, IL-8 and TNF-α in migraine compared to controls, and IL-1β during the ictal stage, suggest a role for inflammation in the pathophysiology of migraine, however prospective studies are required to confirm causality and investigate the mechanisms for the increase in cytokine levels identified. Cytokines may also have a role in tension-type headache. Due a lack of data, no conclusions can be made regarding cluster headache or NDPH.

Update in the understanding of new daily persistent headache

Background Accumulating evidence suggests various specific triggers may lead to new daily persistent headache (NDPH)-like presentations, suggesting that new daily persistent headache is a heterogenous syndrome, and challenging the concept that new daily persistent headache is a primary headache disorder.Method We searched the PubMed database up to August 2022 for keywords including persistent daily headache with both primary and secondary etiologies. We summarized the literature and provided a narrative review of the clinical presentation, diagnostic work-ups, possible pathophysiology, treatment response, and clinical outcomes.Results and conclusion New daily persistent headache is a controversial but clinically important topic. New daily persistent headache is likely not a single entity but a syndrome with different etiologies. The issue with past studies of new daily persistent headache is that patients with different etiologies/subtypes were pooled together. Different studies may investigate distinct subsets of patients, which renders the inter-study comparison, both positive and negative results, difficult. The identification (and removal) of a specific trigger might provide the opportunity for clinical improvement in certain patients, even when the disease has lasted for months or years. Nonetheless, if there is a specific trigger, it remains unknown or unidentified for a great proportion of the patients. We need to continue to study this unique headache population to better understand underlying pathogenesis and, most importantly, to establish effective treatment strategies that hopefully resolve the continuous cycle of pain.

Case report: Monoclonal antibodies as an alternative treatment for new daily persistent headache

Background: New Daily Persistent Headache (NDPH) is a disabling daily headache that causes huge frustration for patients and headache specialists. Elevated TNF-alpha levels, that elevate CGRP levels, on the CSF of NDPH patients has been described as a possible cause of this disease. TNF-alpha inhibitors like doxycycline, venlafaxine, montelukast and lithium have been used in the past to treat NDPH patients, with relatively good success as described from case reports. Conclusion: We report three NDPH patients that improved with the administration of Anti CGRP monoclonal antibodies (mAbs), after trying multiple treatments. We propose this class of drugs, as a therapeutic option for NDPH.

Refractory Headaches.

Medication overuse headache (MOH), new daily persistent headache (NDPH), and persistent refractory headache attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection represent a significant burden in terms of disability and quality of life, and a challenge in terms of definition, pathophysiology, and treatment. Regarding MOH, prevention without withdrawal is not inferior to prevention with withdrawal. Preventive medications like topiramate, onabotulinumtoxinA, and calcitonin gene-related peptide (CGRP) monoclonal antibodies improve chronic migraine with MOH regardless of withdrawal. The differential diagnosis of NDPH is broad and should be carefully examined. There are no guidelines for the treatment of NDPH, but options include a short course of steroids, nerve blocks, topiramate, nortriptyline, gabapentin, CGRP monoclonal antibodies, and onabotulinumtoxinA. The persistence of headache 3 months after SARS-CoV2 infection is a predictor of poor prognosis.

Alterations in the structure and function of the brain in adolescents with new daily persistent headache: A pilot MRI study.

The purpose of this study was to explore brain morphological and functional connectivity alterations in adolescents with new daily persistent headache (NDPH) compared to pain-free, healthy controls. NDPH is one of the most disabling and least understood primary headache conditions. To date, no studies have considered the role of brain function and structure in pediatric patients with NDPH. In this cross-sectional study, resting-state functional and structural images were acquired for 13 patients with NDPH (M age=15.9, standard deviation [SD] ± 1.4) and 13 age- and sex-matched controls (M age=16.2, SD ± 1.8) using magnetic resonance imaging. Participants were recruited from the Pediatric Headache Program at Boston Children's Hospital and from the Greater Boston area. In patients, clinical features of NDPH, including disease duration, pain intensity ratings, pain sensitivity, and functional disability were also assessed, and their associations with functional and structural brain alterations were explored. Compared to controls, patients with NDPH demonstrated reduced cortical thickness in the bilateral superior temporal gyrus, left superior, and middle frontal gyrus areas (p < 0.05, Monte Carlo corrected for multiple comparisons). Furthermore, reduced cortical thickness of the left superior frontal gyrus was related to elevated pain sensitivity in NDPH (r=-0.79, p=0.006). Patients showed altered functional connectivity between regions involved in emotional and cognitive networks of pain, including the amygdala, insula, frontal regions, and cerebellar subregions. The present study provides the first preliminary evidence of functional and structural brain differences in pediatric patients with NDPH compared to controls. Identifying alterations in cortical thickness and resting-state connectivity between specific brain regions could provide characteristics of NDPH and probable mechanisms that may guide personalized therapeutic interventions.

Neurological and Psychiatric Symptoms of COVID-19: A Narrative Review

Recently dubbed Long COVID or Long-Haul COVID, those recovering from the initial COVID-19 infection may maintain clinical signs for longer than two or more weeks following the initial onset of the infection. The virus can gain entry into the CNS through axonal transport mediated through the olfactory nerve or hematogenous spread and can also cross the blood–brain barrier to access the temporal lobe and the brainstem. The neurologic and neuropsychiatric symptoms associated with COVID-19 patients are becoming a highly studied area due to the increased frequency of reported cases. Multiple hospital case series and observational studies have found a headache to be a common symptom among patients who are symptomatic with the SARS-CoV-2 virus. The headache described by many of these patients is similar to new daily persistent headache (NDPH). NDPH potentially develops in response to pro-inflammatory cytokines during a persistent systemic or CNS inflammation, mostly due to the initial infection. The treatments investigated were high-dose steroids, tetracycline derivatives, onabotulinum toxin type A, and long-term multidrug regimens. Among the identified symptoms of post-COVID-19 viral illness, fatigue appears to be the most ubiquitous. High-dose vitamin C is currently a suggested therapy proposed for its antioxidant, anti-inflammatory, and immunomodulatory properties. The mental health consequences of this diagnosis are being identified among large portions of COVID-19 survivors. Among these consequences, cases of major depressive disorder (MDD) and anxiety are being reported and closely examined. The aim of this narrative review is to highlight the neurological and psychiatric symptoms that have been associated with Long-Haul COVID and their possible treatments.

Structural Brain Changes Are Associated with Pain Sensitivity in New Daily Persistent Headache

New daily persistent headache (NDPH) is a rare form of chronic daily headache with poorly understood pathophysiology. The aim of this study was to investigate for the first time the presence of possible brain changes in pediatric NDPH and their associations with pain-related measures. Structural images were acquired for 13 patients with NDPH and 13 pain-free, healthy controls using magnetic resonance imaging (20 females, 12-18 years old, mean age=16.1, SD=1.6). In patients, brain changes were correlated with disease duration, pain intensity ratings, pain sensitivity, and functional disability. Deceased cortical thickness was found in the bilateral superior temporal gyrus, left superior frontal gyrus, and left middle frontal gyrus areas in patients with NDPH compared to controls (cluster-wise threshold of p<0.05, Monte Carlo corrected). In addition, decreased cortical thickness in the left superior frontal gyrus was associated with elevated pain sensitivity in NDPH. Our results might represent abnormal pain modulation in NDPH including increased pain sensitivity through cognitive control processes in the developing brain. The detected brain changes could help understand the underlying mechanisms of NDPH that could guide future investigations and personalized therapeutic interventions. This study was primarily supported by Migraine Research Foundation (NCT03447782).

The Enigma of New Daily Persistent Headache: What Solutions for Pediatric Age?

To analyze systematically the evidence currently available from the literature regarding the diagnosis, clinical characteristics, treatment and outcome of new daily persistent headache (NDPH). NDPH is a primary headache characterized by an abrupt onset with continuous daily pain that can persist for many months. Although self-limiting forms have been described, NDPH is frequently associated with high disability even in children and adolescents. For this reason, it is very important to recognize it from a diagnostic point of view and to treat it. We found little specific data on NDPH in developmental age. Most of the therapy studies have been conducted on adults with conflicting data. Currently, pediatric NDPH therapy is based on experiences in adult patients and in individuals with other forms of primary chronic headache, hence the need for more pediatric studies to fill this information gap.

Update of New Daily Persistent Headache.

Purpose of ReviewThe diagnostic criteria of new daily persistent headache (NDPH) have been revised since 2013. The current review focused on the progress of NDPH research over the last few years.Recent FindingsVarious new triggers and different NDPH mimics have been reported. The association with both cephalic and extracephalic pathologies suggests that NDPH is rather a syndrome with more than one disease mechanism. Recent clinical studies confirmed that migrainous headache remained the most prominent phenotype of NDPH, echoing the change of the diagnostic criteria in 2013. Diagnostic workup, including imaging studies, was unremarkable, except serving to exclude secondary etiologies. Studies on treatment options have yet shown promising targets, and randomized clinical trials are still lacking.SummaryMultiple mechanisms, both cranial and systemic, may be involved synergically in the generation of NDPH-like headaches. The search for effective treatment options should base on better understanding of disease mechanisms.

New Daily Persistent Headache in Children

Source: Strong E, Pierce EL, Langdon R, et al. New daily persistent headache in a pediatric population. J Child Neurol. 2021; 36(10):888–893; doi:10.1177/08830738211004514Investigators from Children’s National Hospital, Washington, DC, conducted a retrospective study to describe the characteristics of new daily persistent headache (NDPH) in pediatric patients. Study participants were patients seen at the Children’s National Hospital Headache Clinic between 2016 and 2018 who were included in a clinic patient registry and were identified as having NDPH using ICD-10 codes. All enrolled youths were evaluated by headache specialists; a standardized history intake form was used to record clinical characteristics. Data abstracted from the medical record of study participants included demographics, site of headache and quality of pain, presence of migrainous features (photophobia, phonophobia, reduced activity), medications and non-pharmacologic treatments, head imaging results, comorbidities, and family history of headaches. Patients additionally were diagnosed with medication overuse headaches based on International Classification of Headache Disorders, 3rd Edition criteria.Among a total of 3,620 visits to the headache clinic during the 2-year study period, 245 patients were diagnosed with NDPH. The average age of the NDPH patients was 14.7 years, with a range of 12.7 to 16.8 years. Among these youths with NDPH, 79% were female, and 73% were white. The most common site of headache was frontal in 66% of patients, followed by occipital (26%), and temporal (22%). The quality of the pain was described as pulsatile and throbbing in 38% of study participants, and the median pain level on the Wong-Baker FACES scale was 6 out of 10. Migrainous features were common, with 85% of patients reporting photophobia, 85% phonophobia, and 88% reduced activity level. Comorbidities in the NDPH patients included anxiety (reported in 19%) and depression (10%); there was a history of head trauma in 23%. Overall, 54% of participants had undergone neuroimaging, including MRI in 43% and CT in 11%. No findings to explain headaches were seen. There was a family history of headache in 70% of patients. Abortive medications had been tried in nearly 80% of study participants, with ibuprofen (51%) and acetaminophen (29%) most commonly used. A diagnosis of medication overuse headache was made in 36% of patients. Preventive medications were used by 35%. Non-pharmacologic treatment had been tried in 16%, including pain-focused cognitive behavioral therapy, acupuncture, and physical therapy desensitization.The authors conclude that NDPH is a common cause of chronic headache in pediatric patients.Dr Alissa has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Headache in children is a concerning complaint for both parents and physicians. Although generally benign, the fear of a tumor or a serious underlying condition is real.1 In 2019, the American Academy of Pediatrics’ Healthy Children publication released instructions to parents about when to call their pediatrician if their child suffers a headache. The instructions stated that although most headaches are harmless, recurrent headaches can cause school problems, behavioral problems, and/or depression.2 The same instructions warned parents to be careful using over-the-counter medication because more than 3 doses per week can cause medication overuse headache.2 In a recent study, Neiswand et al were not able to find any reliable effects of preventive medications to treat children with headache when compared to adults.3NDPH may have features of both migraine and tension-type headache. The same preventive medications indicated for chronic migraine or chronic tension-type headache, including tricyclic antidepressants amitriptyline and topiramate, commonly are used in NDPH despite the lack of standardized guidelines.4 Integrating conventional medicine with mind-body-spirit methods such as acupuncture, stimulation, and physical therapy has been useful in managing headache in adolescents.5The current investigators diagnosed 14% of their total headache population with NDPH. Migrainous features were noted in nearly 90% of their adolescent patients compared to 50% of adults,6 which suggests that pediatric NDPH is more likely to present with characteristics consistent with migraine than adults. Abortive medications had been used in 79% of participants, most commonly ibuprofen and acetaminophen, and more than half had failed at least 1 medication. On the other hand, 35% of participants were treated with preventive medication, most commonly amitriptyline and topiramate, with the same failure proportion.This study’s limitations included lack of reporting the morbidity of headaches, such as missing school for the patients and/or work for their parents. The authors failed to provide guidance regarding appropriate interventions or preventive measures to consider when facing patients with NDPH.NDPH is a relatively common diagnosis in children with chronic headache. It is debilitating and highly refractory to treatment.For the uninitiated, NDPH is a relatively newly described subtype of chronic headache.7 It is severe, unremitting, and persists for at least 3 months. Perhaps the authors failed to report effective preventive and abortive pharmacotherapies as they have yet to be identified.

Clinical features of new daily persistent headache: A retrospective chart review of 328 cases.

To describe the clinical features of new daily persistent headache (NDPH) at an outpatient neurology clinic with a subspecialty interest in headache in Houston, Texas. A retrospective chart review was performed by a neurologist subspecialty certified in headache medicine of all patients seen from September 1, 2011 through February 28, 2020 (8.5years) with a provisional diagnosis of NDPH and abstracted charts meeting criteria for primary NDPH. A total of 328 patients met the International Classification of Headache Disorders, 3rd edition criteria including 215 (65.5%) female patients. The mean age of onset was 40.3years (range 12-87years) with a mean age at first consultation in the study clinic of 42.6years (range 12-87years). The median [25th, 75th] duration of NDPH at initial consultation was 0.7 [0.3, 2.0] years, and at last visit, it was 1.9 [0.7, 4.8] years. The headaches were side-locked unilateral in 28/328 (8.5%). 12/328 cases (3.6%) with a thunderclap onset are reported. There was no obvious seasonal or other cyclical variation. The pain was usually moderate to severe and more often severe for the migraine phenotype (MP; 260/328 [79.3%] of cases) than for the tension-type phenotype (TTP). Precipitating factors were the following: stressful life events, 67/328 (20.4%); upper respiratory infection or flu-like illness, 33/328 (10.1%); and extracranial surgery, 5/328 (1.5%). Exacerbating or aggravating factors similar to migraine triggers were more often reported with the MP than with the TTP in this sample. For the MP, vertigo or dizziness was reported by 19/260 (7.3%) and a visual aura by 21/260 (8.1%) with descriptions provided. The prognostic types were the following for all patients: persisting (refractory), 305/328 (93.0%); relapsing-remitting, 9/328 (2.7%); and remitting (self-limited), 14/328 (4.3%). NDPH is typically of moderate to severe intensity often with migraine features without obvious seasonal or other cyclical variation. Most cases are refractory. 3.6% have a thunderclap onset often with a good response to treatment.