Characteristics of post-traumatic headaches in children following mild traumatic brain injury and their response to treatment: a prospective cohort

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1 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE Characteristics of post-traumatic headaches in children following mild traumatic brain injury and their response to treatment: a prospective cohort ANDREA KUCZYNSKI 1 SUSAN CRAWFORD 2 LISA BODELL 2 DEBORAH DEWEY 1,2 KAREN M BARLOW 1,2 1 University of Calgary, Calgary, AB; 2 Alberta Children s Hospital Research Institute, Calgary, AB, Canada. Correspondence to Dr Karen Maria Barlow, Alberta Children s Hospital, C Shaganappi Trail NW, Calgary, Alberta, CA T3B 6A8, Canada. karen.barlow@albertahealthservices.ca This article is commented on by Mack on pages of this issue. PUBLICATION DATA Accepted for publication 24th January Published online 5th April ABBREVIATIONS mtbi Mild traumatic brain injury PCS Post-concussion syndrome PCSI Post Concussive Symptom Inventory PTH Post-traumatic headache AIM Post-traumatic headaches (PTHs) following mild traumatic brain injury (mtbi) are common; however, few studies have examined the characteristics of PTHs or their response to treatment. The aims of this study were (1) to describe the clinical characteristics of PTH in a prospective cohort of children presenting to a paediatric emergency department with mtbi, and (2) to evaluate the response of PTH to treatment. METHOD The emergency department cohort was obtained from a prospective longitudinal cohort study of symptoms following mtbi (n=670; 385 males, 285 females) and a comparison group of children with extracranial injury (n=120; 61 males, 59 females). A retrospective chart review of a separate cohort of children from a brain injury clinic (the treatment cohort) treated for PTH was performed (n=44; 29 females, 15 males; mean age 14y 1mo, SD 3y 1mo). The median time since injury was 6.9 months (range 1 29mo). The mean follow-up interval after treatment started was 5.5 weeks (SD 4.3wks). RESULTS Among the emergency department cohort (n=39; 20 males, 19 females; mean age 11y 1mo, SD 4y 3mo) 11% of children were symptomatic with PTHs at a mean of 15.8 days (SD 11.6d) post injury. Three months post injury, 7.8% of children complained of headaches; of those, 56% had pre-existing headaches and 18% had experienced migraine before the injury. Although headache type varied, 55% met the criteria for migraine. A family or past medical history of migraine was present in 82% of cases. Among the treatment cohort, medications included amitriptyline, flunarizine, topiramate, and melatonin, with an overall response rate of 64%. CONCLUSION This is the first prospective cohort study to describe the clinical characteristics of PTHs following mtbi in children. Migraine was the most common headache type seen; other headaches included tension-type, cervicogenic, and occipital neuralgias, and 64% responded to treatment. Referral to a headache specialist should be considered, especially when the features are not typical of one of the primary headache disorders. Mild traumatic brain injury (mtbi) accounts for 70 to 90% of all traumatic brain injuries, and many children who experience an mtbi continue to have symptoms for over 3 months. 1,2 As many as one in five children will experience an mtbi by the age of 10 years, and this incidence may be increasing. 3 Until recently, mtbi was thought to have no long-term consequences; however, in the past few years we have seen a dramatic increase in the medical literature and wider media on the potential medical and psychosocial problems associated with mtbi. Our previous research demonstrated that 11% of children who present to an emergency department with mtbi experience post-concussion symptoms for 3 months or longer, and 2% of children have symptoms that persist for over a year. 2 Common postconcussion symptoms include somatic complaints (e.g. headaches, dizziness, nausea, fatigue, sleep disturbances, photo/phonophobia), cognitive deficits (e.g. poor concentration, memory problems, slowed thinking), and emotional symptoms (e.g. depression, irritability). Although routine neurological investigations are often normal, the child and his or her family are often significantly debilitated. 4 Post-traumatic headaches (PTHs) are one of the most common symptoms following mtbi, and perhaps the most disabling. The International Headache Society criteria (2nd edition; IHCD-II) define PTHs as headaches, with no typical characteristics known, which occur within 7 days of a traumatic brain injury and are either acute, where the headache resolves within 3 months of the trauma, or chronic where the headache persists for more than 3 months. 5 PTH accounts for 4% of headache disorders seen in tertiary 636 DOI: /dmcn The Authors. Developmental Medicine & Child Neurology 2013 Mac Keith Press

2 headache clinics, 6 but there are few reports on the prevalence and clinical characteristics in children The medical literature on PTH in children includes only 818 children with mtbi surprisingly few considering that one in five children experiences an mtbi by the age of 10 years. 7,11,15 18 The prevalence of PTH in children with mtbi in these studies varied between 9% and 72% depending on the clinical cohort, research methods, and follow-up period. Our study aimed to add significantly to the current body of literature regarding PTH in children by investigating the prevalence and clinical characteristics of the disorder in a prospective cohort of children with mtbi who presented at a paediatric emergency department. There are no controlled trials or reports of how children with PTH respond to the varying pharmacological treatment strategies. Furthermore, there are no placebo-controlled pharmacological intervention studies for the treatment of PTH in adults. 19 To our knowledge, only three studies have examined the response to such preventative therapies. Erickson 14 reported that treatment with topiramate was associated with a significant decline in PTH burden (49% response rate) compared with treatment with low-dose tricyclic antidepressant (28% response rate). Packard 20 analysed the response to divalproex sodium in 100 patients and found a mild to moderate response in 60%; and Saran 21 evaluated amitriptyline in 12 patients with depression and PTH in comparison with 12 patients with primary depression, and found no reduction in headache burden. The aims of this study were twofold: first, to describe the prevalence and clinical characteristics of PTH in a prospective cohort of children with mtbi; second, to evaluate the response of paediatric PTH to treatment in a cohort of children seen in a brain injury clinic. METHOD Cohort of emergency department attendees The cohort of emergency department attendees was obtained from a prospective cohort study of symptom survival following mtbi without extracranial injury in children between July 2005 and June Any child (aged 0 18y) who presented to the emergency department having experienced an mtbi without extracranial injury was included in the study. mtbi was defined as a Glasgow Coma Scale score of 13 to 15, loss of consciousness or altered mental state lasting less than 20 minutes, absence of focal neurological deficits, and post-traumatic amnesia lasting for less than 24 hours. 12 We identified 1264 children, and 670 (53%) consented to participate in the study. A comparison group of children with extracranial injuries was identified in the emergency department (n=120; 61 males, 59 females). We have reported the details of the methods and the comparison group in a previous study. 2 All participants were interviewed by telephone 7 to 10 days after injury and follow-up continued monthly until symptoms resolved (n=670; 385 males, 285 females). The percentage of children lost to follow-up was 13% in the mtbi group and 10% in the comparison group of children with extracranial injuries. What this paper adds 7.8% of children reported headaches 3 months after mtbi. A family or past medical history of migraine was present in 82%. Migraine was most frequent (54%), but other headache types were also common. 64% of children responded to conventional treatments for headache disorders. Referral to headache specialist is appropriate where symptoms persist. Headache was evaluated using the Post Concussive Symptom Inventory (PCSI), where symptoms are rated as 0, never a problem ; 1, rarely a problem ; 2, sometimes a problem ; 3, often a problem ; and 4, always a problem. Pre-injury symptoms, including headache, were also evaluated at 7 to 10 days post injury using the PCSI (pre-injury) questionnaire. If symptoms persisted at 2 months post injury, an appointment with a neurologist was offered (n=52). Thirty-nine of 52 children (75%) with chronic PTH were seen and a standard questionnaire and examination, including headache characterization, was performed (Table I). Treatment cohort To examine the treatment response, a separate cohort of children with mtbi attending a paediatric brain injury clinic was identified. A standardized questionnaire eliciting acute injury details, post-concussive symptoms, headache characteristics, and family history was completed for all children with mtbi referred to this clinic. Ninety-two children with Table I: Demographic and injury details of children with persistent headaches following mtbi from a prospective emergency department cohort and children receiving prophylactic treatment for post-traumatic headache seen in a paediatric brain injury clinic Patient characteristics Prospective emergency department cohort with persistent PTH (n=39) Clinic treatment cohort (n=44) Age (y) Mean 11.1 Mean 14.1 <0.01 (SD 4.3) (SD 3.1) Female/Males 19/20 29/ Time since injury (mo) Median 2 Median 6.9 <0.01 (range ) (range 1 29) Loss of consciousness Neuroimaging 5 24 Abnormal neuroimaging 1 9 Mechanism of injury Sport-related Fall 11 5 Motor vehicle accident 3 9 Abusive 0 5 Struck by object 3 0 Pre-existing headache disorder Migraine 12 6 Non-specific headache 6 10 Family history of migraine Pre-existing headache and/or family history of migraine p Post-traumatic Headaches in Children Andrea Kuczynski et al. 637

3 persistent post-concussion syndrome (PCS) were seen between 2007 and June Children who received prophylactic treatment for headaches which met the ICHD-II criteria for PTH were identified (n=44). The clinical characteristics and response to treatment of PTH were recorded. PTHs were subclassified using the ICHD-II modified for children by a neurologist with expertise in headache disorders. 22 The clinical characteristics are presented in Table II. Monthly follow-up was carried out (mean 5.5wks; SD 4.3wks; median 4wks; interquartile range [IQR] 3wks) until symptoms resolved. Migrainous headaches lacking one diagnostic criterion were classified as Table II: Clinical characteristics of post-traumatic headache persisting for longer than 3 months in children following mild traumatic brain injury in a prospective emergency department cohort and a treatment cohort Emergency department prospective cohort (n=39) n Treatment cohort (n=44) n Location Frontal Temporal 7 6 Holocephalic 5 9 Retro-orbital 3 4 Occipital 2 7 Associated neck pain 2 7 Type of pain Pulsatile 11 8 Pressure 3 5 Squeezing 2 2 Sharp/stabbing 5 9 Unable to describe 17 Associated features Nausea Vomiting 4 11 Photophobia Phonophobia Visual aura 3 14 Vertigo 2 7 Exacerbated by exercise 2 17 Other features Orthostatic hypotensive 6 3 symptoms Depression 2 7 Other mood changes Cognitive problems Length of headache Minutes h h 13 1 >4h 7 18 Frequency of headaches Daily Three or more/week 5 8 Headache classification Migraine (with or without aura) Tension-type 2 4 Occipital neuralgia 1 1 Vestibular disorder 2 1 Cervicogenic 1 2 Headache associated with 2 6 mood disorder Primary exertion headache 2 Mixed headaches 4 Medication overuse 2 2 Unclassifiable 8 17 probable migraine, 22 and those lacking two diagnostic criteria were denoted as unclassified. A reduction in headache frequency of 50% or greater, together with a functional improvement, was considered significant. An unknown response was documented when patients discontinued medication early or where there was a loss to follow-up. This study was approved by the University of Calgary Conjoint Health Research Ethics Board. Guidelines for treatment Patients were advised to avoid analgesic (such as acetaminophen and ibuprofen) overuse by limiting their use to a maximum of two or three times per week or eight times per month, and to avoid any opiate medications. Light exercise was encouraged if PCS persisted for 3 months or longer post injury. Prophylactic medications were selected based on comorbidities by a neurologist with expertise in acquired brain injury and headache disorders. Melatonin or amitriptyline was typically prescribed if sleep disruption was a significant comorbidity. Melatonin was started at 3mg and increased to a maximum of 10mg. Amitriptyline was started at 5mg and titrated to a maximum of 1mg/kg depending on response. 23 Topiramate is often used when obesity is a comorbidity and was avoided as a first-line prophylactic medication if the mtbi was associated with significant cognitive dysfunction. It was commenced at 12.5mg/day and slowly titrated to 1.5 2mg/kg/day to a maximum of 200mg/day. 24 Valproic acid is not used as a first-line medication in our paediatric clinic. A reduction in headache frequency of 50% or greater was defined as a successful response to treatment. Prophylactic medications were continued for 3 months following headache resolution and then gradually discontinued. Typically, efficacy is assessed after 2 to 3 months, and to allow medication to be changed if necessary. Statistical analysis The Statistical Package for the Social Sciences (version 19.0; SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. The Kolmogorov Smirnov test was used to determine which variables were normally distributed and which were not. In the case of normally distributed data, t-tests and analysis of covariance were used to examine group differences, whereas v 2 tests and the Wilcoxon- Mann Whitney U test were used to conduct group comparisons on non-normally distributed data. Logistic regression was used to examine whether symptom resolution (i.e. treatment response status) was predicted by time in follow-up. RESULTS Cohort of emergency department attendees Initial follow-up Twenty per cent of the mtbi cohort and 16% of the extracranial injury cohort had pre-existing headaches. Seventy-five children (11%; 95% confidence interval [CI] %) in the mtbi population-based cohort were 638 Developmental Medicine & Child Neurology 2013, 55:

4 symptomatic with acute PTH at a mean of 15.8 days (SD 11.6d; median 14d; IQR 9d) post injury. The headaches were rated as 2.5 (SD 0.98; median 2; IQR 2) on the PCSI (when compared with pre-injury status). 3-month follow-up Fifty-two children with mtbi (7.8%; 95% CI %) were symptomatic with chronic PTH at 3 months post injury and with headaches rated as 2 (SD 0.85; median 2; IQR 2) on the PCSI. Headache was more commonly reported in those children who continued to have PCS over time. PTHs were present in 75% of children with symptoms at 6 months post injury, and 100% of children with symptoms at 1 year post injury. Thirty-nine out of 52 children with persistent PCS (20 males, 19 females; mean age 11y 1mo, SD 4y 3mo) were evaluated in the clinic. Thirteen families declined to participate. The demographic and injury details are shown in Table I. The characteristics of the headaches are shown in Table II. Daily headache was reported in 44% of children, and 18% had headaches lasting longer than 4 hours. Fiftyone per cent had pre-existing headaches, and 31% had migraine/probable migraine pre-injury. Forty-four per cent of children satisfied criteria for migraine (one with aura) and 3% for probable migraine; in 8% headache was unclassified. Ten children had a new-onset migraine-like disorder attributed to the mtbi, four of whom had a family history of migraine. Treatment cohort Forty-four children with PTH seen in a brain injury clinic (29 females, 15 males; mean age 14y 1mo, SD 3y 1mo) and who received prophylactic medication for their headaches were studied to determine their response to treatment. The demographic, clinical, and headache details are presented in Tables I and II. These children were older and had symptoms for a longer period (p<0.01) than the children in the emergency department cohort, but otherwise their clinical characteristics were similar. Sixty-one per cent (95% CI 47 74%) experienced daily headaches post injury. Headaches satisfied criteria for migraine in 39% of children, and 9% were classified as chronic tension-type headaches (Table II). Twenty-three per cent of children had pre-existing headaches, and 14% had migraine or probable migraine pre-injury. Overall, 64% of the treatment cohort had a successful response to medication. Twenty-two children (50%) reported a marked reduction in the frequency of their headaches post treatment. Forty-five per cent reported complete resolution of their headaches with treatment, and in six children (14%) the headache frequency decreased to one to three headaches a week. Three children (7%) continued to have severe persisting headaches but did not wish to pursue further medical treatment strategies. The length of time in follow-up was not a significant predictor of symptom resolution (i.e. treatment response status; model v 2 (1) =0.341; p=0.559). Melatonin was found to improve headaches significantly in 9 out of 12 children (75%). A total of 13 out of 18 patients (68%) reported a good effect with amitriptyline (Fig. 1). Seventeen children (39%) received more than one treatment. Indomethacin successfully treated stabbing headache in two children, and in another child occipital neuralgia responded to injections of lidocaine and triamcinolone. Other treatments included self-referred complementary and alternative therapies (16%), physiotherapy (9%), and biofeedback therapy (11%). DISCUSSION To our knowledge, this is the first study to describe the characteristics of PTHs in a large consecutive cohort of children with mtbi, and to document the response of PTH to treatment in a paediatric brain injury clinic cohort. We demonstrated that PTH is common: 11% of all children complain of increased headaches 2 weeks following mtbi and 7.8% at 3 months post injury. This prevalence suggests that PTH is a frequent problem that continues for a long period following injury. Of those Number of patients Unknown No response Partial response Full respone Amitryptiline Nortryptiline Flunarizine Topiramate Melatonin Medication Figure 1: Bar chart demonstrating the response to the most common medications used in the treatment cohort. Post-traumatic Headaches in Children Andrea Kuczynski et al. 639

5 children who reported PCS symptoms in the 3-month period following mtbi, 50% complained of a significant increase in headaches compared with their pre-injury status. PTHs continue to be a significant cause of morbidity in children in whom PCS persists: the proportion of children complaining of headache increased over time, and 100% of symptomatic children at 12 months post injury complained of headaches. This may explain why previous cohorts have reported such variable rates of PTH, for example ranging from 22.5% in studies examining outcome at 2 months to 72% when outcome was evaluated at 1 year following adult mild head injury. 6 In the present study, we found a 7.8% prevalence of increased headache frequency and/or severity at 3 months following mtbi, which is similar to the findings of a previous prospective study by Kirk et al. 17 Blume et al. 7 reported that mtbi is a risk factor for headaches at 3 months post injury (relative risk 1.7; 95% CI ); however, they found that 43% of children with mtbi reported any headache at 3 months post injury, compared with 26.2% of children with an arm injury an increase of 16%. Unfortunately, Blume et al. 7 do not report the prevalence of pre-injury headaches in their sample, which is potentially significant as this is a risk factor for PCS and PTH following mtbi 25 ; nor do they comment on the characteristics of the headaches. Our previous study found that age and severity of the injury, but not sex, were significant risk factors for symptom persistence. 2 In keeping with this, patients in this separate treatment cohort were older and more likely to have experienced a loss of consciousness at the time of injury (p<0.01), and neuroimaging was performed in 54%. This study is the first to present the clinical characteristics of PTH and to further subclassify the headaches using the ICHD-II for children. A wide range of headache characteristics were seen. Headache satisfying criteria for migraine (with or without aura) was the most common type of headache seen (54%), and tension-type headaches were reported in 5% of these children (Table II). Only one previous report characterized PTH in children: of 11 children, five had migraine, five had tension-type headaches, and one child had mixed headaches. 17 Adult cohorts vary markedly in the type of headaches seen depending on whether the patients are selected from headache clinics or have traumatic brain injury: the prevalence of migraine-like headaches ranges from 2 to 41% and of tension-type headaches from 7 to 96%. 6,9,19 In our study, 47% of children with PTH had a history of migraines, although these may not have been recognized previously. Of particular relevance in paediatric practice, in which migraine becomes more problematic in adolescence, is that 82% of the children with persistent headaches in the emergency department cohort and 57% of those in the treatment cohort reported having either pre-existing headache disorders or a family history of migraine. Medication overuse headache (5%) and chronic tensiontype headaches (5%) were seen less commonly than in previous studies. 6 These differences could be a result of the triage and initial evaluation process in our brain injury clinic. For example, patients who are referred to the clinic are contacted within 1 week of referral and families are educated about mtbi and advised of the potential for medication overuse headache, especially after the acute post-injury period has passed. It is also possible that children may differ from adults in the types of headaches they develop following mtbi, or are less likely than adults to develop chronic tension-type headaches. Twenty-one per cent of headaches in the emergency department cohort and 39% of headaches in the treatment cohort were unclassifiable using the ICHD-II, and the only consistent feature in this group was the mtbi. Less common types of headaches were also found in both cohorts, for example cervicogenic headache, occipital neuralgia, exertion headache, and idiopathic stabbing headache. The morbidity associated with PTH was significant. Among the emergency department and clinic cohorts, 44% and 61% of children respectively, were experiencing daily headaches. The children with these types of headache responded well to recognized treatments. This demonstrates that referral to a neurologist or headache specialist is appropriate where symptoms persist. This treatment case series provides additional evidence on the treatment of PTH. Packard 20 retrospectively analysed the response to sodium valproate in a clinic cohort of adult patients with PTH. Improvement was based on patient estimate and a moderate response was reported as a 50% or greater improvement in the headaches. Packard found that 60% had a mild/moderate response, although 14% of patients stopped the medication because of side effects. Sodium valproate is not routinely used to treat headache in our clinic because of the incidence of side effects. 26,27 Erickson 14 reported the efficacy of various treatments used for PTH in US military service members. There was an overall treatment response of 35%, and topiramate was found to be more effective than amitriptyline/ nortriptyline, propranolol, or valproate. As blast-related mtbi accounted for 77% of patients in the Erickson study, it is hard to extrapolate these results to childhood, especially as the mechanism of injury is very different to the fall and sport-related mtbi seen in children and young people. There are no previous studies reporting the response of PTH to treatment in children. We used a variety of treatments depending on the headache characteristics and comorbidities, such as sleep dysfunction (for which amitriptyline or melatonin was more commonly chosen), cognitive dysfunction (in which case topiramate would be avoided), and stabbing headache or Valsalva-induced headaches (treated with indomethacin). However, the numbers receiving individual treatments were small. In contrast to Erickson s study, amitriptyline was effective with 13 out of 19 children (68%) having a positive response and 47% of children reporting no headaches post treatment. Melatonin was also effective in 75% of children. Overall, we found 640 Developmental Medicine & Child Neurology 2013, 55:

6 that 64% of children documented a response to treatment (Fig. 1). We acknowledge the following limitations of this study. The numbers of children receiving individual treatments were small, and it is, therefore, not possible to draw conclusions about relative efficacy of the different agents. Another weakness of this study is the lack of a headache diary and disability score to assess the degree of functional impairment associated with the headaches and treatment response. Further, as this complex population has significant comorbidities (especially mood and cognitive dysfunction), a comprehensive paediatric quality of life measure would also have been useful. Finally, this is an observational, uncontrolled study. Although the children were reviewed at 6.9 months (SD 8.1mo) post injury and the response rates are likely to be higher than what would be expected for the natural history of PCS alone, future studies should ideally be placebo controlled. 2 CONCLUSION In summary, 7.8% of children still report PTH 3 months after mtbi. A family or past medical history of migraine headache was present in 82%. Although migraine headache is the most common type of headache, other cephalgias are not infrequent. Referral to a headache specialist should be considered, especially when the features are not typical of one of the primary headache disorders. Treatment should be tailored to headache type as well as comorbidity. Further research is required to evaluate treatment options in PTH, although our research suggests that children respond to many of the therapies commonly used to treat headache disorders. ACKNOWLEDGMENTS This research was supported by the Alberta Children s Hospital Foundation (RT34396). 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