Persistent Headache and Cephalic Allodynia Attributed to Head Trauma in Children and Adolescents

Markus, Tal Eidlitz; Zeharia, Avraham; Cohen, Y.; Konen, Osnat

doi:10.1177/0883073816650036

Cited by 19 publications

(18 citation statements)

References 29 publications

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“…In particular, allodynia, pain in response to non-painful stimuli, is often measured in animal models. CA is common during a migraine attack (40–42) and is also reported in over 50% of patients with post-traumatic headache (43,44). When sensory thresholds were tested in human subjects, 53% of patients with PTH displayed cephalic allodynia compared to only 20% of TBI patients who did not have PTH and 0% of control subjects (44).…”

Section: Discussionmentioning

confidence: 99%

CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice

et al. 2019

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Background Acute and persistent post-traumatic headache are often debilitating consequences of traumatic brain injury. Underlying physiological mechanisms of post-traumatic headache and its persistence remain unknown, and there are currently no approved therapies for these conditions. Post-traumatic headache often presents with a migraine-like phenotype. As calcitonin-gene related peptide promotes migraine headache, we explored the efficacy and timing of intervention with an anti- calcitonin-gene related peptide monoclonal antibody in novel preclinical models of acute post-traumatic headache and persistent post-traumatic headache following a mild traumatic brain injury event in mice. Methods Male, C57Bl/6 J mice received a sham procedure or mild traumatic brain injury resulting from a weight drop that allowed free head rotation while under minimal anesthesia. Periorbital and hindpaw tactile stimulation were used to assess mild traumatic brain injury-induced cutaneous allodynia. Two weeks after the injury, mice were challenged with stress, a common aggravator of migraine and post-traumatic headache, by exposure to bright lights (i.e. bright light stress) and cutaneous allodynia was measured hourly for 5 hours. A murine anti- calcitonin-gene related peptide monoclonal antibody was administered after mild traumatic brain injury at different time points to allow evaluation of the consequences of either early and sustained calcitonin-gene related peptide sequestration or late administration only prior to bright light stress. Results Mice with mild traumatic brain injury, but not a sham procedure, exhibited both periorbital and hindpaw cutaneous allodynia that resolved by post-injury day 13. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-instated periorbital and hindpaw cutaneous allodynia in injured, but not sham mice. Repeated administration of anti-calcitonin-gene related peptide monoclonal antibody at 2 hours, 7 and 14 days post mild traumatic brain injury significantly attenuated the expression of cutaneous allodynia when evaluated over the 14-day post injury time course and also prevented bright light stress-induced cutaneous allodynia in injured mice. Administration of anti-calcitonin-gene related peptide monoclonal antibody only at 2 hours and 7 days after mild traumatic brain injury blocked injury-induced cutaneous allodynia and partially prevented bright light stress-induced cutaneous allodynia. A single administration of anti-calcitonin-gene related peptide monoclonal antibody after the resolution of the peak injury-induced cutaneous allodynia, but prior to bright light stress challenge, did not prevent bright light stress-induced cutaneous allodynia. Conclusions We used a clinically relevant mild traumatic brain injury event in mice along with a provocative stimulus as novel models of acute post-traumatic headache and persistent post-traumatic headache. Following mild traumatic brain injury, mice demonstrated transient periorbital and hindpaw cutaneous allodynia suggestive of post-traumatic headache-related pain and establishment of central sensitization. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-established cutaneous allodynia, suggestive of persistent post-traumatic headache-related pain. Continuous early sequestration of calcitonin-gene related peptide prevented both acute post-traumatic headache and persistent post-traumatic headache. In contrast, delayed anti-calcitonin-gene related peptide monoclonal antibody treatment following establishment of central sensitization was ineffective in preventing persistent post-traumatic headache. These observations suggest that mechanisms involving calcitonin-gene related peptide underlie the expression of acute post-traumatic headache, and drive the development of central sensitization, increasing vulnerability to headache triggers and promoting persistent post-traumatic headache. Early and continuous calcitonin-gene related peptide blockade following mild traumatic brain injury may represent a viable treatment option for post-traumatic headache and for the prevention of post-traumatic headache persistence. Abbreviations CA Cutaneous allodynia CGRP Calcitonin gene-related peptide mTBI Mild traumatic brain injury PTH Post-traumatic headache APTH Acute post-traumatic headache PPTH Persistent post-traumatic headache

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Section: Discussionmentioning

confidence: 99%

CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice

et al. 2019

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“…Trauma causing muscle strain, vertebral misalignment, or ligamentous injuries may compress, irritate, or activate the occipital or trigeminal nerves, resulting in neuralgic pain in the distribution of the nerve and/or activation of central pain systems involved in headache 17 . In a study of children with PTH, a high rate of cutaneous allodynia was observed in those with PTH (53.8%), leading to the hypothesis that central sensitization might be a shared pathophysiological mechanism with migraine 18 . A recent review has nicely summarized different theories regarding the emergence and persistence of post‐traumatic headache 19 …”

Section: Pathophysiology Of Concussion and Post‐traumatic Headachementioning

confidence: 99%

“…These include symptom expectation, adjustment disorder, poor coping mechanisms, post‐traumatic stress disorders, anxiety, depression, sleep disorders, and other psychosocial stressors 9,20 . Medication overuse headache (MOH) may also alter the pathophysiology of PPTH and complicate recovery 18 …”

Section: Pathophysiology Of Concussion and Post‐traumatic Headachementioning

confidence: 99%

Pediatric Post‐Traumatic Headache and Implications for Return to Sport: A Narrative Review

2020

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Background.-Headache attributed to mild traumatic injury of the head (aka: mild traumatic brain injury, mTBI), frequently abbreviated to Post-Traumatic Headache (PTH), is one of the most common and disabling symptoms after a head injury. PTH often phenotypes to migraine. Evidence for treating PTH in the pediatric population is limited. Widely accepted guidelines do not exist to aid the clinician and there are currently no placebo-controlled trials for the pharmacologic management of PTH in this age group. Recommendations for when to return a child or adolescent to sport if they develop and/or are being treated for persistent PTH (PPTH) are lacking. The objective of this narrative review is to review the implications of returning an adolescent with PPTH to sport.Methods.-Pediatric neurologists with special qualification in headache collaborated on this narrative review. Literature was searched up until Oct 2019 for articles pertaining to PTH, concussion, mTBI, and the return of a pediatric athlete to sport after mTBI. Article inclusion was at the discretion of the authors. There was author consensus regarding all recommendations made.Conclusion.-The authors recommend that strict adherence to the guidelines that return to sport cannot occur until a child is symptom free at rest, off any medication, may be unreasonable in certain situations. Symptom stability is the proposed new concept for return to sport.Abbreviations: CDC Center for Disease Control, mTBI mild traumatic brain injury, PPTH persistent post-traumatic headache, PTH post-traumatic headache, RTP return to play

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“…As animals cannot verbally indicate pain, in vivo models have focused on pain-related behavioural phenotypes considered indicative of headache. Cranial hypersensitivity, measured by Von Frey filaments, is one of the read-outs used to study cephalic cutaneous allodynia, which is present in both migraine [46] and post-traumatic headache [47] and reflects sensitization of the trigeminal system [48]. Using the same methodology, also peripheral (hind paw) hypersensitivity, which represents a marker of extra-cephalic allodynia, reflecting central sensitization at a level higher than the trigeminal system, may be assessed.…”

Section: Basic Science Preclinical Modelsmentioning

confidence: 99%

Position Paper on Post-Traumatic Headache: The Relationship Between Head Trauma, Stress Disorder, and Migraine

Lambru¹,

Benemei

Andreou

et al. 2020

Pain Ther

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Traumatic brain injury (mTBI) is a major public health concern, with mild TBI (mTBI) constituting the vast majority of the injuries. Posttraumatic headache (PTH) is one of the most frequent symptoms that follow a mTBI, occurring in isolation with a tension-type or migraine phenotype, or more often as part of a complex neurobehavioural array of symptoms. The existence of PTH as a separate entity from the primary headaches is still a matter of debate. Classification issues and a lack of methodologically robust epidemiological and clinical studies have made it difficult to elucidate the mechanisms underlying acute and even more assessing the efficacy of this class of treatments are underway. The broad overlap between PTH, migraine, and PTSD suggests that research in this field should start with a re-appraisal of the diagnostic criteria, followed by methodologically sound epidemiological and clinical studies. Preclinical research should strive to create more reliable PTH models to support human neuroimaging, neurochemical, and neurogenetic studies, aiming to underpin new pathophysiological hypotheses that may expand treatment targets and improve the management of PTH patients.

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Persistent Headache and Cephalic Allodynia Attributed to Head Trauma in Children and Adolescents

Cited by 19 publications

References 29 publications

CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice

CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice

Pediatric Post‐Traumatic Headache and Implications for Return to Sport: A Narrative Review

Position Paper on Post-Traumatic Headache: The Relationship Between Head Trauma, Stress Disorder, and Migraine

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