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.
Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a ...strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0–2 h) and post-hospital (2–12 h) phases. Mean blood flow velocity in the middle cerebral artery (VMCA) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase mean time 6 h (range 2–11). Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in VMCA and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.
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.
Background
Cytokines are important endogenous substances that are involved in immune and inflammatory responses. Neurogenic inflammation has been proposed to play a role in migraine involving altered ...cytokine levels. Therefore, we aimed to provide a systematic review on the current knowledge on cytokine levels in migraine patients during and outside attacks.
Methods
Databases of PubMed and Embase were systematically searched for studies investigating cytokine levels in migraine patients during and outside attacks.
Results
Screening yielded identification of 45 articles investigating 18 cytokines in total. We found that the interictal level of the anti-inflammatory cytokine, interleukin 10, was decreased, while the level of transforming growth factor beta 1 was increased in migraine patients compared to controls. Levels of pro-inflammatory cytokines, tumor necrosis factor α and interleukin 6, were increased outside attacks compared to controls. Ictal levels of cytokines were unchanged or varying compared to the interictal state in migraine patients. Three studies reported dynamic cytokines levels during the course of an attack.
Conclusion
The findings of the current review underline a possible involvement of cytokines in the proposed inflammatory mechanisms of migraine. However, future studies are needed to expand our knowledge of the exact role of cytokines in the migraine pathophysiology with focus on cytokines TNF-α, IL-1ß, IL-6 and IL-10 while applying refined methodology.
Objective
We investigated whether telephone follow‐up consultations could lead to appropriate adjustment of treatments and a higher degree of patient satisfaction among patients with migraine and ...tension‐type headache (TTH).
Background
Migraine and TTH are disabling headache forms requiring optimized treatment.
Methods
In a prospective, non‐randomized, quality control study with controls comparing telephone‐interview intervention (TeII) with business‐as‐usual (BAU) treatment, we included newly referred patients with migraine and/or TTH. The TeII group was contacted by telephone by healthcare professionals at 8 and 16 weeks after the first visit addressing headache treatment. Electronic questionnaires were sent to all participants before the first visit and after 6 months. Predefined outcomes were number of patients with change in preventive and acute medication; change in headache frequency; migraine frequency; scores from the eight‐item Headache Under‐Response to Treatment (HURT‐8) questionnaire, Insomnia Severity Index (ISI), and Hospital Anxiety and Depression Scale (HADS); and patient satisfaction after 6 months.
Results
From May 2020 to April 2021, there were 230 patients enrolled in the TeII program, whereof 96 patients were included in the analysis. For the BAU group, 91 patients with similar sex and age distribution were identified via medical‐record reviews in the same period. More patients in the TeII group than in the BAU group had a change in acute medication (27/96 28% vs. five of 91 6%, p < 0.001) and preventive medication (28/96 29% vs. 12/91 13%, p = 0.006). Headache days per month decreased in the TeII group (−4.6, 95% confidence interval CI −6.5 to −2.7; p = 0.001) and the BAU group (−2.5, 95% CI −4.6 to −0.4; p = 0.018), without significant difference between the groups (p = 0.080). There was no difference in migraine frequency between the groups (TeII: 1.0 day, 95% CI, −1.3 to 1.0; BAU: 1.0 day, 95% CI, −2.5 to 0.5; p = 0.718) or HURT‐8 score (TeII: 10.5, 95% CI 9.5–11.5; BAU: 13.0, 95% CI 11.7–14.2; p = 0.053). There were no changes in the ISI score (TeII: 1.0, interquartile range IQR 6; p = 0.152; BAU: 0.5, IQR 4.5; p = 0.824), HADS‐Anxiety score (TeII: −5, IQR 5.3; p = 0.186; BAU: 1.0, IQR 4.0; p = 0.445), or HADS‐Depression score (TeII: 0.0, IQR 3.0; p = 0.163; BAU: 0.0, IQR 2.0; p = 0.303) in any of the groups. There was a higher degree of patient satisfaction in the TeII group compared with the BAU group in treatment (median IQR score 4 3–5 vs. 3 3–4, p < 0.001), headache improvement (median IQR 3 2–4 vs. 2 1–3, p = 0.002), the headache program (median IQR 4 3–5 vs. 3 3–4, p < 0.001), and information (median IQR 4 3–5 vs. 3 3–4, p = 0.005).
Conclusion
Patients with migraine and/or TTH benefit from a telephone follow‐up approach within the first 6 months of their treatment course in terms of more efficient treatment and higher patient satisfaction.
Background
A myofascial trigger point is defined as a hyperirritable spot in skeletal muscle that is associated with a hypersensitive palpable nodule in a taut band. It has been suggested that ...myofascial trigger points take part in chronic pain conditions including primary headache disorders. The aim of this narrative review is to present an overview of the current imaging modalities used for the detection of myofascial trigger points and to review studies of myofascial trigger points in migraine and tension-type headache.
Findings
Different modalities have been used to assess myofascial trigger points including ultrasound, microdialysis, electromyography, infrared thermography, and magnetic resonance imaging. Ultrasound is the most promising of these modalities and may be used to identify MTrPs if specific methods are used, but there is no precise description of a gold standard using these techniques, and they have yet to be evaluated in headache patients.
Active myofascial trigger points are prevalent in migraine patients. Manual palpation can trigger migraine attacks. All intervention studies aiming at trigger points are positive, but this needs to be further verified in placebo-controlled environments. These findings may imply a causal bottom-up association, but studies of migraine patients with comorbid fibromyalgia syndrome suggest otherwise. Whether myofascial trigger points contribute to an increased migraine burden in terms of frequency and intensity is unclear.
Active myofascial trigger points are prevalent in tension-type headache coherent with the hypothesis that peripheral mechanisms are involved in the pathophysiology of this headache disorder. Active myofascial trigger points in pericranial muscles in tension-type headache patients are correlated with generalized lower pain pressure thresholds indicating they may contribute to a central sensitization. However, the number of active myofascial trigger points is higher in adults compared with adolescents regardless of no significant association with headache parameters. This suggests myofascial trigger points are accumulated over time as a consequence of TTH rather than contributing to the pathophysiology.
Conclusions
Myofascial trigger points are prevalent in both migraine and tension-type headache, but the role they play in the pathophysiology of each disorder and to which degree is unclarified. In the future, ultrasound elastography may be an acceptable diagnostic test.
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.
Objective
To investigate clinical characteristics and treatment patterns in persistent post-traumatic headache attributed to mild traumatic brain injury.
Methods
A total of 100 individuals with ...persistent post-traumatic headache attributed to mild traumatic brain injury were enrolled between July 2018 and June 2019. Deep phenotyping was performed using a semi-structured interview while allodynia was assessed using the 12-item Allodynia Symptom Checklist.
Results
In 100 subjects with persistent post-traumatic headache, the mean headache frequency was 25.4 ± 7.1 days per month. The most common headache phenotype was chronic migraine-like headache (n = 61) followed by combined episodic migraine-like and tension-type-like headache (n = 29) while nine subjects reported “pure” chronic tension-type-like headache. The most frequent trigger factors were stress, lack of sleep, and bright lights. A history of preventive medication use was reported by 63 subjects, of which 79% reported failure of at least one preventive drug, while 19% reported failure of at least four preventive drugs. Cutaneous allodynia was absent in 54% of the subjects, mild in 23%, moderate in 17%, and severe in 6%.
Conclusions
The headache profile of individuals with persistent post-traumatic headache most often resembled a chronic migraine-like phenotype or a combined episodic migraine-like and tension-type-like headache phenotype. Migraine-specific preventive medications were largely reported to be ineffective. Therefore, there is a pressing need for pathophysiological insights and disease-specific therapies.
Following acute ischemic stroke (AIS) many patients experience cognitive impairment which interferes neurorehabilitation. Understanding and monitoring pathophysiologic processes behind cognitive ...symptoms requires accessible methods during testing and training. Functional near-infrared spectroscopy (fNIRS) can assess activational hemodynamic responses in the prefrontal cortex (PFC) and feasibly be used as a biomarker to support stroke rehabilitation.
Exploring the feasibility of fNIRS as a biomarker during the Stroop Color and Word Test (SCWT) assessing executive function in AIS patients.
Observational study of 21 patients with mild to moderate AIS and 22 healthy age- and sex-matched controls (HC) examined with fNIRS of PFC during the SCWT. Hemodynamic responses were analyzed with general linear modeling.
The SCWT was performed worse by AIS patients than HC. Neither patients nor HC showed PFC activation, but an inverse activational pattern primarily in superolateral and superomedial PFC significantly lower in AIS. Hemodynamic responses were incoherent to test difficulty and performance. No other group differences or lateralization were found.
AIS patients had impaired executive function assessed by the SCWT, while both groups showed an inverse hemodynamic response significantly larger in HC. Investigations assessing the physiology behind inverse hemodynamic responses are warranted before deeming clinical implementation reasonable.
Migraine with aura is prevalent in high-altitude populations suggesting an association between migraine aura and hypoxia. We investigated whether experimental hypoxia triggers migraine and aura ...attacks in patients suffering from migraine with aura. We also investigated the metabolic and vascular response to hypoxia. In a randomized double-blind crossover study design, 15 migraine with aura patients were exposed to 180 min of normobaric hypoxia (capillary oxygen saturation 70-75%) or sham on two separate days and 14 healthy controls were exposed to hypoxia. Glutamate and lactate concentrations in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three and possible aura in 4 of 15 patients. Hypoxia did not change glutamate concentration in the visual cortex compared to sham, but increased lactate concentration (P = 0.028) and circumference of the cranial arteries (P < 0.05). We found no difference in the metabolic or vascular responses to hypoxia between migraine patients and controls. In conclusion, hypoxia induced migraine-like attacks with and without aura and dilated the cranial arteries in patients with migraine with aura. Hypoxia-induced attacks were not associated with altered concentration of glutamate or other metabolites. The present study suggests that hypoxia may provoke migraine headache and aura symptoms in some patients. The mechanisms behind the migraine-inducing effect of hypoxia should be further investigated.
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