Post-traumatic headache (PTH) is a highly disabling secondary headache disorder and one of the most common sequelae of mild traumatic brain injury, also known as concussion. Considerable overlap ...exists between PTH and common primary headache disorders. The most common PTH phenotypes are migraine-like headache and tension-type-like headache. A better understanding of the pathophysiological similarities and differences between primary headache disorders and PTH could uncover unique treatment targets for PTH. Although possible underlying mechanisms of PTH have been elucidated, a substantial void remains in our understanding, and further research is needed. In this Review, we describe the evidence from animal and human studies that indicates involvement of several potential mechanisms in the development and persistence of PTH. These mechanisms include impaired descending modulation, neurometabolic changes, neuroinflammation and activation of the trigeminal sensory system. Furthermore, we outline future research directions to establish biomarkers involved in progression from acute to persistent PTH, and we identify potential drug targets to prevent and treat persistent PTH.
The origin of migraine pain is unknown, but may involve the dura mater. In unilateral migraine without aura, Khan et al. report that the middle meningeal artery is the only artery with greater ...circumference increase on the pain side versus non-pain side, suggesting a meningeal contribution to migraine headache.
Abstract
The origin of migraine pain is unknown but possibly implicates the dura mater, which is pain sensitive in proximity to the meningeal arteries. Therefore, subtle changes in vessel calibre on the head pain side could reflect activation of dural perivascular nociceptors that leads to migraine headache. To test this hypothesis, we measured circumference changes of cranial arteries in patients with cilostazol-induced unilateral migraine without aura using 3 T high resolution magnetic resonance angiography. The middle meningeal artery was of key interest, as it is the main supply of the dura mater. We also measured the superficial temporal and external carotid arteries as additional extracranial segments, and the middle cerebral, the cerebral and cavernous parts of the internal carotid (ICAcerebral and ICAcavernous), and the basilar arteries as intracranial arterial segments. Magnetic resonance angiography scans were performed at baseline, migraine onset, after sumatriptan, and ≥27 h after migraine onset. Thirty patients underwent magnetic resonance angiography scans, of which 26 patients developed unilateral attacks of migraine without aura and were included in the final analysis. Eleven patients treated their migraine with sumatriptan while the remaining 15 patients did not treat their attacks with analgesics or triptans. At migraine onset, only the middle meningeal artery exhibited greater circumference increase on the pain side (0.24 ± 0.37 mm) compared to the non-pain side (0.06 ± 0.38 mm) (P = 0.002). None of the remaining arteries revealed any pain-side specific changes in circumference (P > 0.05), but exhibited bilateral dilation. Sumatriptan constricted all extracerebral arteries (P < 0.05). In the late phase of migraine, we found sustained bilateral dilation of the middle meningeal artery. In conclusion, onset of migraine is associated with increase in middle meningeal artery circumference specific to the head pain side. Our findings suggest that vasodilation of the middle meningeal artery may be a surrogate marker for activation of dural perivascular nociceptors, indicating a meningeal site of migraine headache.
10.1093/brain/awy300_video1
awy300media1
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Here, we review the role of pituitary adenylate cyclase-activating peptide-38 (PACAP38) in migraine pathophysiology and data implicating PAC
1
receptor as a future drug target in migraine. Much ...remains to be fully elucidated about migraine pathophysiology, but recent attention has focused on signaling molecule PACAP38, a vasodilator able to induce migraine attacks in patients who experience migraine without aura. PACAP38, with marked and sustained effect, dilates extracerebral arteries but not the middle cerebral artery. The selective affinity of PACAP38 to the PAC
1
receptor makes this receptor a highly interesting and potential novel target for migraine treatment. Efficacy of antagonism of this receptor should be investigated in randomized clinical trials.
Background
A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since ...then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments.
Methods
The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided.
Results
We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts’ opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives.
Conclusion
Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.
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.
Conclusion
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.
Plain Language Summary
New daily persistent headache (NDPH) is a chronic headache for which the cause remains unknown and with no established evidence‐based treatments. In our retrospective study from the Danish Headache Center, we explored potential medication solutions for NDPH in 51 patients. Candesartan and mirtazapine showed some benefit for patients with NDPH in 26% and 15% of our patients, respectively, highlighting a need for further investigations into the potential benefits of these drugs.
Summary Background Extracranial arterial dilatation has been hypothesised to be the cause of pain in patients who have migraine without aura. To test that hypothesis, we aimed to measure extracranial ...and intracranial arteries during attacks of migraine without aura. Methods In this cross-sectional study, we recruited patients aged 18–60 years from the Danish Headache Centre and via announcements on a Danish website. We did magnetic resonance angiography during spontaneous unilateral migraine attacks. Primary endpoints were difference in circumference of extracranial and intracranial arterial segments comparing attack and attack-free days and the pain and the non-pain side. The extracranial arterial segments measured were the external carotid (ECA), the superficial temporal (STA), the middle meningeal (MMA), and the cervical part of the internal carotid (ICAcervical ) arteries. The intracranial arterial segments were the cavernous (ICAcavernous ) and cerebral (ICAcerebral ) parts of the internal carotid, the middle cerebral (MCA), and the basilar (BA) arteries. This study is registered at Clinicaltrials.gov , number NCT01471314. Findings Between Oct 12, 2010, and Feb 8, 2012, we recruited 78 patients, of whom 19 women had a scan during migraine and were included in the final analysis. On migraine compared with non-migraine days, we detected no statistically significant dilatation of the extracranial arteries on the pain side (ECA, mean difference 1·2% 95% CI −5·7 to 8·2 p=0·985, STA 3·6% –3·7 to 11·0 p=0·532, MMA 1·7% –1·7 to 5·2 p=0·341, and ICAcervical 2·3% –0·3 to 4·9 p=0·093); the intracranial arteries were more dilated during attacks (MCA, 13·0% 6·4 to 19·6 p=0·001, ICAcerebral 11·5% 5·6 to 17·3 p=0·0004, and ICAcavernous 11·4% 5·3 to 17·5 p=0·001), except for the BA (1·6% –2·7 to 5·9 p=0·621). Compared with the non-pain side, during attacks we detected dilatation on the pain side of the intracranial arteries (MCA, mean difference 10·5% 0·7–20·3 p=0·044, ICAcerebral (14·4% 4·6–24·1 p=0·013), and ICAcavernous (9·1% 3·9–14·4 p=0·003) but not of the extracranial arteries (ECA, 2·1% –3·8 to 9·2 p=0·238, STA, 3·6% –3·7 to 10·8 p=0·525, MMA, 2·7% –1·3 to 5·6 p=0·531, and ICAcervical , 5·0% –0·5 to 10·4 p=0·119). Interpretation Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation. Funding University of Copenhagen, the Lundbeck Foundation, the Research Foundation of the Capital Region of Denmark, Danish Council for Independent Research-Medical Sciences, and the Novo Nordisk Foundation.
Migraine is a prevalent and debilitating neurologic disorder. Advancements in understanding the underlying pathophysiological mechanisms are spearheading the effort to introduce disease-specific ...treatment options. In recent years this effort has largely focused on alteration of endogenous neuropeptide signaling, namely the peptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Human studies into the pathophysiological underpinnings of CGRP and PACAP in migraine are manifold and here we review the works investigating these neuropeptides in patients suffering from migraine in order to elucidate the background for developing new treatment options for this vastly disabling disorder.
Discharge against medical advice (DAMA) is an unexpected event for patients and healthcare personnel. The study aimed to assess the prevalence of DAMA in neonates along with characteristics of ...neonates who got DAMA and, causes and predictors of DAMA.
This case-control study was carried out in Special Care Newborn Unit (SCANU) at Chittagong Medical College Hospital from July 2017 to December 2017. Clinical and demographic characteristics of neonates with DAMA were compared with that of discharged neonates. The causes of DAMA were identified by a semi-structured questionnaire. Predictors of DAMA were determined using a logistic regression model with a 95% confidence interval. A total of 6167 neonates were admitted and 1588 got DAMA. Most of the DAMA neonates were male (61.3%), term (74.7%), outborn (69.8%), delivered vaginally (65.7%), and had standard weight at admission (54.3%). A significant relationship (p < 0.001) was found between the variables of residence, place of delivery, mode of delivery, gestational age, weight at admission, and day and time of outcome with the type of discharge. False perceptions of wellbeing (28.7%), inadequate facilities for mothers (14.5%), and financial problems (14.1%) were the prevalent causes behind DAMA. Predictors of DAMA were preterm gestation (AOR 1.3, 95% CI 1.07-1.7, p = 0.013), vaginal delivery (AOR 1.56, 95% CI 1.31-1.86, p < 0.001), timing of outcome after office hours (AOR 477.15, 95% CI 236-964.6, p < 0.001), and weekends (AOR 2.55, 95% CI 2.06-3.17, p < 0.001). Neonates suffering from sepsis (AOR 1.4, 95% CI 1.1-1.7, p< 0.001), Respiratory Distress Syndrome (AOR 3.1, 95% CI 1.9-5.2, p< 0.001), prematurity without other complications (AOR 2.1, 95% CI 1.45-3.1, p < 0.001) or who were referred from north-western districts (AOR 1.48, 95% CI 1.13-1.95, p = 0.004) had higher odds for DAMA.
Identification of predictors and reasons behind DAMA may provide opportunities to improve the hospital environment and service related issues so that such vulnerable neonates can complete their treatment. We should ensure better communication with parents, provide provision for mothers' corner, especially for outborn neonates, maintain a standard ratio of neonates and healthcare providers, and adopt specific DAMA policy by the hospital authority.
The aim is to provide an overview of recent studies of structural brain abnormalities in migraine and to discuss the potential clinical significance of their findings.
Brain structure continues to be ...a topic of extensive research in migraine. Despite advances in neuroimaging techniques, it is not yet clear if migraine is associated with grey matter changes. Recent large population-based studies sustain the notion of increased prevalence of white matter abnormalities in migraine, and possibly of silent infarct-like lesions. The clinical relevance of this association is not clear. Structural changes are not related to cognitive decline, but a link to an increased risk of stroke, especially in patients with aura, cannot be ruled out.
Migraine may be a risk factor for structural changes in the brain. It is not yet clear how factors such as migraine sub-type, attack frequency, and sex affects this association. Additional longitudinal studies are needed to address these issues. Brain structure changes in migraine could potentially serve as disease biomarkers or as a mean of identifying sub-groups of patients with specific therapeutic needs and prognoses.
Background
Pituitary adenylate cyclase-activating polypeptide (PACAP) is widely distributed in the nervous system and is involved in migraine pathophysiology. Understanding the function of the ...blood-brain barrier (BBB) in relation to PACAP is important to the understand the mechanisms behind PACAP-induced migraine attacks, but also to develop antimigraine drugs targeting the PACAP receptors Here, we aim to review the transport ability of PACAP across the BBB.
Methods
We performed a systematic literature search on PubMed to identify studies reporting original data on PACAP and BBB. The search was finalized in July 2017.
Results
The literature search identified 96 papers of which 11 contained relevant data. In addition, two papers were known to be relevant and were included. A total of 13 papers studies were included in the final analysis. Preclinical studies (
n
= 10) suggest the existence of specific PACAP
transport
systems across the BBB, while human PACAP studies failed to show vasodilator effect of PACAP on the cerebral arteries from the lumen (
n
= 3).
Conclusion
PACAP38 is transported over the BBB actively, while PACAP27 cross the BBB by diffusion over the membrane, but after crossing the endothelial membrane both isoforms are either rapidly degraded or efflux back from brain to blood. Thus, a direct central action of the PACAPs is unlikely. This is supported by studies showing selective PACAP effect on extra-cerebral arteries.
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