Generalized Mechanical Nerve Pain Hypersensitivity in Children With Episodic Tension-type Headache Daniel M.

Fernndez-Mayoralas, Csar Fernndez-de-las-Peas, Ricardo Ortega-Santiago, Silvia Ambite-Quesada, Rodrigo Jimnez-Garca and Alberto Fernndez-Jan Pediatrics 2010;126;e187; originally published online June 7, 2010; DOI: 10.1542/peds.2010-0012

The online version of this article, along with updated information and services, is located on the World Wide Web at:
http://pediatrics.aappublications.org/content/126/1/e187.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Generalized Mechanical Nerve Pain Hypersensitivity in Children With Episodic Tension-type Headache
AUTHORS: Daniel M. Ferna ndez-Mayoralas, MD, PhD,a,b Ce sar Ferna ndez-de-las-Pen as, PT, PhD,c,d,e Ricardo Ortega-Santiago, PT,c,d Silvia Ambite-Quesada, PT, MSc,f Rodrigo Jime nez-Garca, MD, PhD,g and Alberto Ferna ndez-Jae n, MDa,b
aDepartment of Neuropediatry, Hospital Quiro n de Madrid, Madrid, Spain; bDepartment of Neuropediatry, Centro CADE, Madrid, Spain; cDepartment of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, dEsthesiology Laboratory, fDepartment of Anatomy, and gPreventive Medicine and Public Health Teaching and Research Unit, Department of Health Sciences, Universidad Rey Juan Carlos, Alcorco n, Spain; and eCentre for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

WHATS KNOWN ON THIS SUBJECT: Some studies suggest the presence of central sensitization in children with headache; however, conicting results have been found. Furthermore, previous studies focused on muscle tissues but not on nerve tissues. WHAT THIS STUDY ADDS: This is the rst study to reveal bilateral and generalized pressure hypersensitivity over both trigeminal and nontrigeminal nerves in children with FETTH.

KEY WORDS tension-type headache, pressure pain threshold, sensitization, children ABBREVIATIONS PPTpressure pain threshold CNS central nervous system FETTHfrequent episodic tension-type headache NPRSnumerical pain rate scale BDI-IIBeck Depression Inventory, Second Edition TTSTotal Tenderness Score CI condence interval ANOVAanalysis of variance www.pediatrics.org/cgi/doi/10.1542/peds.2010-0012 doi:10.1542/peds.2010-0012 Accepted for publication Mar 24, 2010 Address correspondence to Ce sar Ferna ndez de las Pen as, PT, PhD, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avenida de Atenas s/n, 28922 Alcorco n, Madrid, Spain. E-mail: cesar.fernandez@urjc.es PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2010 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.

abstract
OBJECTIVES: The objective of this study was to analyze the presence of generalized pressure pain hypersensitivity over nerve tissues in trigeminal and nontrigeminal regions in children with frequent episodic tension-type headache (FETTH). METHODS: Thirty children, 7 boys and 23 girls (mean age: 8.8 1.7 years) with FETTH and 50 age- and gender-matched healthy children (14 boys, 36 girls; mean age: 8.5 2.1 years; P .743) were recruited. Pressure pain thresholds (PPTs) were bilaterally assessed over supraorbital (V1), infra-orbital (V2), mental (V3), median (C5), radial (C6), and ulnar (C7) nerves by an assessor who was blinded to the patients condition. RESULTS: The analysis of variance showed that PPT levels were significantly bilaterally decreased over both trigeminal (supra-orbital, infraorbital, and mental) and nontrigeminal (median, ulnar, and radial) nerves in children with FETTH as compared with control subjects (all sites, P .001). There was a greater magnitude of PPT decrease within trigeminal nerves as compared with nontrigeminal nerves (P .03). PPTs over infra-orbital (rs 0.4, P .05) and radial (rs 0.5, P .01) nerves were negatively correlated with the duration of headache attacks (P .05). CONCLUSIONS: Our study revealed bilateral and generalized pressure hypersensitivity over both trigeminal and nontrigeminal nerves in children with FETTH. Diffuse hypersensitivity of peripheral nerves evidences the presence of hyperexcitability of the central nervous system in children with FETTH. Pediatrics 2010;126:e187e194

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Tension-type headache is the most common form of headache,1 and its chronic form is 1 of the most neglected2 and difcult headaches to treat. It has been shown that on the World Health Organizations ranking of the worlds most disabling disorders, headache is among the 10 most disabling disorders for both genders.3 Several studies have been conducted of adults with tension-type headache, but less has been conducted of children. In an epidemiologic study, the 6-month prevalence of headaches was 53.2% among children from 7 to 14 years of age.4 Lewis et al5 estimated that 20% of the children with primary headache need medical therapy. Although there has been an increasing interest in the pathogenic mechanisms of tension-type headache, the true patho-anatomic mechanisms remain inconclusive.6 It is clear that hyperexcitability of peripheral and central nociceptive pain pathway plays an important role in this condition.7 These sensitization mechanisms result in increased muscle tenderness8 and pressure pain hyperalgesia,911 particularly in adults with tension-type headaches; however, the results from studies that included children who presented with tension-type headache are controversial. An early study reported that children with migraine but not with tension-type headache showed increased tenderness of pericranial, neck, and shoulder muscles.12 In a more recent study, the same authors found that children with neither migraine nor episodic tension-type headache had increased extracephalic zun et al14 muscle hypersensitivity.13 Tu showed pressure pain hyperalgesia (lower pressure pain threshold [PPT] levels) in the upper trapezius muscle in adolescents with chronic tensiontype headache compared with healthy children. Discrepancies between studies may be related to differences bee188 NDEZ-MAYORALAS et al FERNA

tween child populations with headache (episodic versus chronic tensiontype headache) or to the fact that sensitivity to manual palpation of muscle tissues may be not sensitive to reect central sensitization in children with headache. There is increasing evidence that sensitization of pain pathways leads to mechanical pain hypersensitivity of nerve tissues. In fact, lower PPTs over different peripheral nerves in patients with whiplash,15 chronic tension-type headache,16 lateral epicondylalgia,17 unilateral migraine,18 or temporomandibular pain disorders19 as sign of heightened pain sensitivity and hyperexcitability of the central nervous system (CNS)20 has been found. To our knowledge, no previous studies have assessed generalized pressure hypersensitivity over peripheral nerves in children with tension-type headache. To investigate central nociceptive processing gain in children with tensiontype headache, we aimed to analyze the presence of generalized pressure pain hyperalgesia over nerves within symptomatic (trigeminal) and nonsymptomatic (upper extremity) regions in children with frequent episodic tension-type headache (FETTH).

[NPRS]), and no aggravation of headache during physical activity. Only 1, either photophobia or phonophobia, was permitted. No children reported vomiting or evident nausea during pain attacks. Other primary headaches were excluded. Each child fullled the criteria for FETTH, and no apparent evidence of secondary headaches was present. Medication overuse headache, according to International Headache Society criteria, was excluded.21 None of the children was taking any prophylactic drug; however, they could continue with their acute drug therapy during headache attacks. In addition, age- and gender-matched children without history of head or neck pain symptoms were recruited from volunteers who responded to a local announcement. Ethical approval was granted by local ethics committee (URJC/FHA043). Informed consent was obtained from both children and parents, and all procedures were conducted according to the Declaration of Helsinki. Self-reported Measures Children completed a headache diary for 4 weeks to complement the diagnosis.22 An 11-point NPRS23 (0 no pain, to 10 maximum pain) was used to assess headache intensity. The headache diary was used to calculate the following variables: (1) headache intensity, calculated from the mean of the NPRS of the days with headache; (2) headache frequency, calculated by dividing the number of days with headache by the number of the analyzed weeks (days per week); and (3) headache duration, calculated by dividing the sum of the total hours of headache by the number of days with headache (hours per day). The Beck Depression Inventory, Second Edition (BDI-II), a 21-item selfreport measure that assesses affective, cognitive, and somatic symptoms

METHODS
Subjects Consecutive children who received a diagnosis of FETTH by an experienced neuropediatrist from the Neurology Department of Hospital Quiro n were screened for eligibility criteria. For all children, headache features, temporal prole, and family history were assessed from the clinical history. To be included, children had to describe the characteristics that are typical of FETTH following the common criteria of the International Headache Society21: bilateral location, pressing or tightening pain, mild/moderate intensity (6 on a numerical pain rate scale

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of depression, was also used.24 Children, with the help of the parents, were asked to choose from a group of sentences that best described how they had been feeling in the preceding 2 weeks. For example, to assess sadness, they could choose either, I do not feel sad, I feel sad much of the time, I am sad all the time, or I am so sad or unhappy that I cannot stand it. The BDI-II has shown good internal consistency ( .86), with higher scores indicating higher levels of depressive symptoms.25,26 Pericranial Tenderness Examination Total Tenderness Score (TTS) was used to assess pericranial tenderness.27 Briey, 8 pairs of muscles and tendon insertions (masseter, temporal, frontal, trapezius, sternocleidomastoid, and suboccipital muscles and coronoid and mastoid processes) were palpated.27 Manual palpation was conducted with small rotational movements of the assessors second and third ngers during 4 to 5 seconds. Tenderness was scored on a 4-point (0 3) scale at each location (local tenderness score). A TTS is calculated from the sum of scores from both sides (total maximum score: 48).27 PPT Assessment PPT is dened as the minimal amount of pressure where a sensation of pressure rst changes to pain.28 An electronic algometer (Somedic AB, Farsta, Sweden) was used to measure PPT (kPa). The pressure was applied approximately at a rate of 30 kPa/second. All participants were instructed to press the switch when the sensation changed from pressure to pain. The mean of 3 trials (intraexaminer reliability) was calculated and used for the main analysis. A 30-second resting period was allowed between each measurement. The reliability of pressure algometry has been found to be
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high (intraclass correlation coefcient 0.91 [95% condence interval (CI): 0.82 0.97]).29 Children attended a preliminary session for familiarization with the pressure test procedures. Children were tested on headache-free days. PPT levels were measured bilaterally over supra-orbital (V1), infra-orbital (V2), mental (V3), median (C5), ulnar (C7), and radial (C6) nerves by an assessor ho was blinded to the childrens condition. The order of assessment was randomized among the participants. All nerves were identied by manual palpation and marked with a pencil. The supra-orbital nerve (V1) was located over the supra-orbital foramen (at the junction between the lateral and medial third of the upper part of the margin of the orbit), the infraorbital nerve (V2) was located over the infra-orbital foramen above the canine fossa, and the mental nerve from the mandibular nerve (V3) was located over the mental foramen on the anterior surface of the mandible. The median nerve (C5) was located over the cubital fossa medial to and adjacent to the tendon of biceps, the ulnar nerve (C7) was located in the groove between the medial epicondyle and the olecranon, and the radial nerve (C6) was marked where it passes through the lateral intermuscular septum between the medial and lateral heads of triceps to enter the middle to lower third of the humerus. Sample Size Determination The sample size determination and power calculations were performed with an appropriate software (Taman o de la Muestra 1.1 [Madrid, Spain]). The calculations were based on detecting, at least, signicant clinically differences of 20% on PPT levels between both groups30 with an level of .05 and a desired power of 80% and an estimated interparticipant coefcient of

variation for PPT measures of 20%. This generated a sample size of at least 16 participants per group. PPT Data Management In this study, the magnitude of sensitization was investigated to assess the differences of absolute and relative PPT values between groups. For relative values, we calculated a PPT index by dividing PPT of each participant at each point by the mean of PPT score of the control group at the same point. A PPT index 100% indicate pressure pain sensitization. Statistical Analysis Data were analyzed with the SPSS 14.0 (SPSS Inc, Chicago, IL). Results are expressed as means and 95% CI. The Kolmogorov-Smirnov test was used to analyze the normal distribution of the variables (P .05). Quantitative data without a normal distribution (pain history, headache intensity, frequency, or duration) were analyzed with nonparametric tests, and data with a normal distribution (PPTs) were analyzed with parametric tests. The intraclass correlation coefcient was used to assess intraexaminer reliability of PPT data. Differences in TTS between study groups were assessed with the unpaired Students t test. A 3-way analysis of variance (ANOVA) test was used to investigate the differences in PPT levels with point (supra-orbital, infraorbital, mental, median, radial, and ulnar nerves) and side (dominant or nondominant) as within-participant factors and group (FETTH or control subjects) as between-participant factors. A 2-way ANOVA test was also used for assessing differences in PPT index with side (dominant/nondominant) as a within-patient factor and with point (supra-orbital, infra-orbital, mental, median, radial, ulnar nerves) as a between-patient factor. Posthoc comparisons were done with the Tukey test. Finally, the Spearmans rho (rs)
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test was used to analyze the association between PPTs and the clinical variables relating to pain symptoms. The statistical analysis was conducted at a 95% condence level, and P .05 was considered statistically signicant.

TABLE 1 Differences in PPTs (kPa) Over the Supra-orbital (V1), Infra-orbital (V2), and Mental (V3)
Nerve Trunks Between Children With Tension-type Headache and Healthy Control Subjects
Parameter Children with FETTH Dominant Nondominant Children without headache Dominant Nondominant Supra-orbital Nerve (V1)a Infra-orbital Nerve (V2)a Mental Nerve (V3)a

132.2 30.3 (120.1144.3) 152.6 29.5 (140.5164.7) 185.1 35.7 (173.1197.2) 126.6 27.1 (114.5138.7) 147.9 30.4 (135.8160.1) 185.8 39.7 (173.7197.9) 269.1 21.1 (260.0278.1) 272.1 22.8 (263.1281.1) 291.4 24.7 (282.3300.4) 263.1 21.3 (254.0272.1) 271.2 20.1 (262.1280.2) 288.7 27.7 (279.6297.7)

RESULTS
Demographic and Clinical Data of the Sample Fifty-two consecutive children who presented with headache between September and December 2009 were screened for eligibility criteria. Twenty-two (42%) children were excluded: migraine (n 7), hemicranial headache (n 7), higher levels of depression (BDI-II 15), and anxiety (n 8). Finally, a total of 30 children, 7 boys and 23 girls, aged 5 to 11 years (mean: 8.6 2.1 years) satised all of the inclusion criteria and agreed to participate. In our sample, headache history was 1.8 years (95% CI: 1.52.1 years), mean headache period per day was 4.1 hours (95% CI: 3.2 4.9 hours), mean intensity per episode was 5.1 (95% CI: 4.75.5), and number of days per week with headache was 3.5 (95% CI: 2.8 3.8). No signicant associations between headache parameters (intensity, frequency, or duration) were found (P .7). Children were tested on headache-free days and when at least 5 days had elapsed since the last head pain attack to avoid possible related allodynia. Five children usually took ibuprofen during acute headaches. Finally, the BDI-II score was 3.8 (95% CI: 3.2 4.3). In fact, a signicant positive relation (rs 0.503, P .005) between BDI-II and headache frequency was found: the greater the frequency of headache attacks, the greater the level of depression. In addition, 50 age- and gender-matched children without headache, 14 boys and 36 girls, aged 5 to 11 years (mean: 8.5 2.1 years) participated (P .743).
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Data are means SD (95% CI). a Signicant differences between patients and control subjects (2-way ANOVA test).

Pericranial Tenderness Children with FETTH showed a signicantly (t 15.986; P .001) greater TTS (mean SD: 19.4 5.8) as compared with healthy children (mean SD: 3.8 2.9). No signicant association between TTS and clinical features of headache were found (P .3). Pressure Pain Sensitivity Over Peripheral Nerves The intraexaminer repeatability of PPT readings for nerve trunks ranged from 0.90 to 0.93 for the dominant side and from 0.91 to 0.94 for the nondominant side. The SE of measurement ranged from 4.3 to 5.0 kPa for the dominant side and from 4.8 to 5.5 kPa for the nondominant side. The ANOVA revealed signicant differences between groups (F 319.8, P .001) and points (F 430.2, P .001) but not sides (F 0.219, P .640). A signicant interaction between group and point was also found (F 4.434, P .001). In such a way, over each nerve, patients showed bilateral lower PPT levels

than did healthy control subjects (P .001). In addition, trigeminal nerves showed lower PPT as compared with nontrigeminal nerves (P .001). The posthoc analyses revealed an increasing PPT gradient from supra-orbital (V1), infra-orbital (V2), mental (V3), median (C5), radial (C6), and ulnar (C7) nerves in both groups (P .01). Table 1 summarizes PPT assessed over trigeminal nerves for both sides within each study group, and Table 2 shows PPT levels over nontrigeminal nerves in both groups. PPT Indices The ANOVA showed signicant differences for PPT indices between points (F 22.723, P .001) but not sides (F 0.136, P .712). Furthermore, no signicant side * points interaction (F 0.198, P .963) was found. Posthoc analysis revealed that PPT indices in the trigeminal nerves (supraorbital: 49% [95% CI: 44%53%]; infraorbital: 55% [95% CI: 50%59%]; mental: 63% [95% CI: 59% 69%]) were signicantly more impaired (P .03)

TABLE 2 Differences in PPTs (kPa) Over the Median (C5), Radial (C6), and Ulnar (C7) Nerve Trunks
Between Children With Tension-type Headache and Healthy Control Subjects
Parameter Children with episodic frequent tension type headache Dominant Nondominant Children without headache Dominant Nondominant Median Nerve (C5)a Radial Nerve (C6)a Ulnar Nerve (C7)a

204.6 37.1 (192.6216.7) 201.2 39.5 (189.1213.2) 336.8 50.4 (327.8345.8) 334.6 32.1 (325.5343.6)

227.8 51.4 (215.8239.9) 225.7 48.2 (213.7237.8) 350.4 22.0 (341.3359.4) 359.2 23.3 (350.2368.3)

286.7 55.2 (274.6298.8) 292.9 49.7 (280.8304.9) 410.1 29.2 (400.9419.1) 409.6 26.6 (400.5418.6)

Data are means SD (95% CI). a Signicant differences between patients and control subjects (2-way ANOVA test).

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0.46, P .013; Fig 2) and over the radial (dominant: rs 0.601, P .001; nondominant: rs 0.556, P .002) nerves were found: the longer the duration of headache attacks, the lower the PPT levels. No signicant correlation between TTS and headache clinical parameters were found (P .1).

FIGURE 1
PPT indices in both trigeminal and extratrigeminal points. The boxes represent the mean and percentile scores, and the error bars represent the SD.

as compared with PPT indices in the nerves of the nontrigeminal area (median: 60% [95% CI: 56% 65%]; radial: 63% [95% CI: 59% 68%]; ulnar: 70% [95% CI: 66%75%]). Furthermore, the PPT index of the ulnar nerve was less impaired than PPT indices in the median and radial nerves (P .05; Fig 1).

Pressure Sensitivity and Clinical Features in Children With Tensiontype Headache Signicant negative correlations between duration of headache with PPT over the infra-orbital (dominant: rs 0.41, P .033; nondominant: rs

DISCUSSION The main nding of this study was bilateral and generalized pressure pain hypersensitivity over trigeminal and nontrigeminal nerves in children with FETTH when compared with healthy children. In fact, generalized hypersensitivity of peripheral nerves supports the presence of hyperexcitability of the CNS in children with FETTH. The decrease in PPTs, particularly over trigeminal nerves, was associated with the duration of headache attacks, supporting a role of nerve peripheral nociception in the sensitization mechanisms.
In this study, PPT was signicantly decreased bilaterally over the supraorbital, infra-orbital, mental, median, ulnar, and radial nerves in children with FETTH as compared with control subjects, suggesting both trigeminal

FIGURE 2

Scatter plots of relationships between duration of headache attacks and PPT levels over infra-orbital nerve (n 30).

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and extratrigeminal sensitization of afferent inputs from neural tissues. Our results agree with previous studies conducted of whiplash,31 lateral epicondylalgia,17 unilateral migraine,18 and temporomandibular pain disorders,19 which showed a generalized decrease in PPTs over peripheral nerves as sign of hyperexcitability of the CNS.20 The presence of pressure hypersensitivity over extratrigeminal areas can be considered a manifestation of sensitization of second-order (or higher) nociceptive neurons in the CNS. In fact, the presence of generalized lower PPT levels found in children with FETTH may be a common nding of central sensitization in other forms of chronic pain, such as chronic abdominal pain, sickle cell disease, chronic arthralgias, and bromyalgia. It would be interesting to investigate whether the identied sensitization mechanisms found in this study in children with FETTH are also present in children with other chronic pain syndromes. Previous studies determined that neurogenic inammation during headache attacks, particularly migraine, may activate trigeminal afferents that project to brain areas that are involved in nociceptive processing.32 That trigeminal neurons release calcitonin generelated peptide under conditions that mimic neurogenic inammation supports its role in pain perception during headache attacks.33 In fact, a neurogenic inammation triggered by antidromic discharges that originate from the CNS could sensitize peripheral nerve trunks,34 which may depolarize nociceptive second-order (or higher) neurons.35 Over time, this might affect the physical condition of the nerves and would lower the threshold of the nociceptive bers of the nervi nervorum (nerves that innervate the connective tissue layers of the nerve itself). Finally, low-threshold Aber inputs in states of central sensie192 NDEZ-MAYORALAS et al FERNA

tization could depolarize nociceptive second-order neurons, and this will enhance head pain perception36; however, the potential role of the calcitonin generelated peptide and neurogenic inammation has been extensively studied in migraine but not in tension-type headache. Nevertheless, these mechanisms also may be implicated in tension-type headache pain according to the continuum theory between these headaches, in which tension-type headache would be a mild expression of migraine.37 An interesting result of this study was that the magnitude of PPT changes in children with FETTH was greater within the trigeminal nerves (supra-orbital: 49%; infra-orbital: 55%; mental: 63%) as compared with nontrigeminal nerves (median: 60%; radial: 62% 65%; ulnar: 70%). Our results suggest that the sensitization process is restricted not only to the trigeminal second-order neurons but also to extratrigeminal nociceptive neurons in children with FETTH. Nevertheless, the degree of sensitization within the trigeminal area was greater, which supports a role of peripheral sensitization mechanisms. In fact, because hyperexcitability of the CNS is considered a dynamic condition that is inuenced by various factors, particularly peripheral nociceptive inputs,38 it may be possible that peripheral nociceptive barrage contributes to this sensitization process. In this study, PPT levels over the infra-orbital nerve were negatively associated with the duration of headache attacks, suggesting a potential role of prolonged peripheral nociception in the sensitization process. In such scenario, the sensitization of nerve nociceptors may result in spontaneous neural discharges,39,40 which contribute to the irritation of the trigeminal nerve nucleus caudalis. This phenomenon may be related to the fact that many pain circuits are bipolar

neurons, so stimulation or sensitization of peripheral elements communicates centrally; therefore, once central sensitization is established, nociceptive inputs that originate from trigeminal nerve trunks may become a perpetuating factor for central sensitization in children with FETTH. Undoubtedly, other triggers for FETTH exist. In addition to sensitization mechanisms, the results from this study reect a dysfunctional state of endogenous pain modulatory systems, which has been previously reported in adults with chronic tension-type headache.41,42 Furthermore, recent studies highlight the importance of risk genes for enhanced pain sensitivity (eg, polymorphisms in the gene coding for the cathecol-o-methyl-transferase) have been associated with headache in adult populations.43,44 We do not know whether a combination of sensitization mechanisms, descending pain modulation, and genetics can be implicated in the development of FETTH in children. We should recognize some limitations of this study. First, we included a subgroup of children who had FETTH with high frequency of headache attacks (3.5 per week) and lower levels of depression according to the BDI-II. One of the main reasons for controlling the degree of depression in children with FETTH is that depression induces an increased effect on pressure pain sensitivity.45 We recognize that the BDI-II has good psychometric properties in children aged 12 to 13 years26,4648; however, no study has investigated psychometric properties of the BDI-II in children aged 12 years, so our results related to lower level of depression should be considered with caution. Moreover, we did not assess anxiety levels in our children with FETTH, which may inuence painenhanced sensitivity. We do not know whether our results would be similar

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in other subgroup of patients with FETTH or children with chronic tensiontype headache. In addition, children from a specialized neurologic clinic may not represent the characteristics of the general population of children with headache; therefore, extrapolation of our results should be conducted with caution. Population-based epidemiologic studies with larger samples are needed to permit a more generalized interpretation of these results. Second, we included both girls and boys with FETTH. It has been shown that women have greater susceptibility to the development of temporal summation of chemical,49 mechanical,50 and thermal51 pain and less efcient diffuse pain inhibitory pathways52,53 than men. Because we REFERENCES
1. Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur J Neurol. 2005;12(suppl 1):127 2. Bendtsen L, Jensen R. Tension type headache: the most common, but also the most neglected headache disorder. Curr Opin Neurol. 2006;19(3):305309 3. Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3): 193210 4. Kro ner-Herwig B, Heinrich M, Morris L. Headache in German children and adolescents: a population-based epidemiological study. Cephalalgia. 2007;27(6): 519 527 5. Lewis D, Ashwal S, Dahl G, et al. Practice parameter: evaluation of children and adolescents with recurrent headaches report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2002;59(4): 490 498 6. Fumal A, Schoenen J. Tension-type headache: current research and clinical management. Lancet Neurol. 2008;7(1):70 83 7. Ferna ndez-de-las-Pen as C, Arendt-Nielsen L, Simons DG, Cuadrado ML, Pareja JA. Sensitization in tension type headache: a pain model. In: Ferna ndez-de-las-Pen as C, Arendt-Nielsen L, Gerwin R, eds. Tension

included 7 boys with FETTH, we could not compare pressure pain hypersensitivity between genders. Future studies should analyze gender differences in these sensitization mechanisms. Finally, another limitation of this study is that we can speculate on the mechanisms (peripheral or central) that are responsible for the increased mechanical pain sensitivity only over peripheral nerves. Additional studies are required to dene the potential role of nerve tissue hypersensitivity in the perpetuation of central sensitization in children with tension-type headache.

healthy children. Generalized pain hypersensitivity of peripheral nerves supports the presence of a state of hyperexcitability of the CNS in children with FETTH. The decrease in PPT levels, particularly over trigeminal nerves, was associated with the duration of headache attacks, supporting a role of nerve peripheral nociception in the sensitization mechanisms. Additional studies are required to dene the potential role of nerve tissue hypersensitivity in the perpetuation of central sensitization in children with tensiontype headache.

CONCLUSIONS
We found bilateral and generalized pressure hypersensitivity over trigeminal and nontrigeminal nerves in children with FETTH when compared with

ACKNOWLEDGMENTS This study received funds from a grant conceded by the Universidad Rey Juan Carlos and Comunidad de Madrid (reference CCG10-URJC BIO-5011).

Type and Cervicogenic Headache: Pathophysiology, Diagnosis and Treatment. Baltimore, MD: Jones & Bartlett Publishers; 2009:97106 8. Ferna ndez-de-las-Pen as C, Cuadrado ML, Ge HY, Arendt-Nielsen L, Pareja JA. Increased peri-cranial tenderness, decreased pressure pain threshold, and headache clinical parameters in chronic tension type headache patients. Clin J Pain. 2007;23(4): 346 352 9. Bendtsen L, Jensen R, Olesen J. Decreased pain detection and tolerance thresholds in chronic tension type headache. Arch Neurol. 1996;53(4):373376 10. Schoenen J, Bottin D, Hardy F, Gerard P. Cephalic and extra-cephalic pressure pain thresholds in chronic tension type headache. Pain. 1991;47(2):145149 11. Ashina S, Babenko L, Jensen R, Ashina M, Magerl W, Bendtsen L. Increased muscular and cutaneous pain sensitivity in cephalic region in patients with chronic tension-type headache. Eur J Neurol. 2005;12(7):543549 12. Anttila P, Metsahonkala L, Mikkelsson M, et al. Muscle tenderness in pericranial and neck-shoulder region in children with headache: a controlled study. Cephalalgia. 2002;22(5):340 344 13. Metsahonkala L, Anttila P, Laimi K, et al. Extra-cephalic tenderness and pressure

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15.

16.

17.

18.

19.

pain threshold in children with headache. Eur J Pain. 2006;10(7):581585 Tu zun EH, Karaduman A, Eker L. Pressure pain thresholds in adolescent patients with chronic tension-type headache. Pain Clinic. 2005;17(2):127131 Sterling M, Jull G, Vicenzino B, Kenardy J. Sensory hypersensitivity occurs soon after whiplash injury and associated with poor recovery. Pain. 2003;104(3): 509 517 Ferna ndez-de-las-Pen as C, Coppieters MW, Cuadrado ML, Pareja JA. Patients with chronic tension type headache demonstrate increased mechano-sensitivity of the supra-orbital nerve. Headache. 2008;48(4): 570 577 Ferna ndez-Carnero J, Ferna ndez-de-lasPen as C, De-La-Llave-Rinco n AI, Ge HY, Arendt-Nielsen L. Widespread mechanical pain hyper-sensitivity as sign of central sensitization in unilateral lateral epicondylalgia: a blinded, controlled study. Clin J Pain. 2009;25(7):555561 Ferna ndez-de-las-Pen as C, Arendt-Nielsen L, Cuadrado ML, Pareja JA. Generalized mechanical pain sensitivity over nerve tissues in patients with strictly unilateral migraine. Clin J Pain. 2009;25(5):401 406 Ferna ndez-de-las-Pen as C, Gala n-del-Ro F, Ferna ndez-Carnero J, Pesquera J, ArendtNielsen L, Svensson P. Bilateral widespread mechanical pain sensitivity in myofascial

PEDIATRICS Volume 126, Number 1, July 2010

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on May 29, 2013

e193

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

temporomandibular disorder: evidence of impairment in central nociceptive processing. J Pain. 2009;10(11):1170 1178 Zusman M. Central nervous system contribution to mechanically produced motor and sensory responses. Aust J Physiother. 1992; 38(2):195120 Headache Classication Subcommittee of the International Headache Society: The International Classication of Headache Disorders, 2nd edition. Cephalalgia. 2004; 24(suppl 1):9 160 Phillip D, Lyngberg AC, Jensen R. Assessment of headache diagnosis: a comparative population study of a clinical interview with a diagnostic headache diary. Cephalalgia. 2007;27(1):1 8 Jensen MP, Turner JA, Romano JM, Fisher L. Comparative reliability and validity of chronic pain intensity measures. Pain. 1999;83(2):157162 Beck AT, Steer RA, Brown GK. Beck Depression Inventory. 2nd ed. San Antonio, TX: Psychological Corporation; 1996 Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-ve years of evaluation. Clin Psychol Rev. 1988;8(1):77100 VanVoorhis WC, Blumentritt TL. Psychometric properties of the Beck Depression Inventory-II in a clinically-identied sample of Mexican American adolescents. Journal of Child and Family Studies. 2007;789 798 Langemark M, Olesen J. Pericranial tenderness in tension headache: a blind controlled study. Cephalalgia. 1987;7(4):249 245 Vanderweee n L, Oostendorp RB, Vaes P, Duquet W. Pressure algometry in manual therapy. Man Ther. 1996;1(5):258 265 Chesterton LS, Sim J, Wright CC, Foster NE. Inter-rater reliability of algometry in measuring pressure pain thresholds in healthy humans, using multiple raters. Clin J Pain. 2007;23(9):760 766 Prushansky T, Dvir Z, Defron-Assa R. Reproducibility indices applied to cervical pressure pain threshold measurements in healthy subjects. Clin J Pain. 2004;20(5): 341347 Scott D, Jull G, Sterling M. Widespread sensory hypersensitivity is a feature of chronic whiplash-associated disorder but not

32.

33.

34.

35.

36.

37. 38.

39.

40.

41.

42.

43.

chronic idiopathic neck pain. Clin J Pain. 2005;21(2):175181 Parsons A, Strijbos P. The neuronal versus vascular hypothesis of migraine and cortical spreading depression. Curr Opin Pharmacol. 2003;3(1):7377 Durham P. Calcitonin gene-related peptide (CGRP) and migraine. Headache. 2006; 46(suppl 1):S3S8 Daemen M, Kurvers H, Kitslaar P, Slaaf DW, Bullens PH, Van den Wildenberg FA. Neurogenic inammation in an animal model of neuropathic pain. Neurol Res. 1998;20(1): 41 45 Hoheisel U, Mense S, Simons DG, Yu XM. Appearance of new receptive elds in rat dorsal horn neurons following noxious stimulation of skeletal muscle: a model for referral of muscle pain? Neurosci Lett. 1993; 153(1):9 12 Woolf CJ, Thompson SW. The induction and maintenance of central sensitisation is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44(3):293299 Cady RK. The convergence hypothesis. Headache. 2007;47(suppl 1):S44 S51 Herren-Gerber R, Weiss S, Arendt-Nielsen L, et al. Modulation of central hypersensitivity by nociceptive input in chronic pain after whiplash injury. Pain Med. 2004;5(4): 366 376 Bove G, Light A. The nervi nervorum: missing link for neuropathic pain? Pain Forum. 1997; 6(2):181190 Watkins L, Maier S. Neuropathic pain: the immune connection. Pain Clin Update. 2004; 13(1):1 4 Pielstickera A, Haagc G, Zaudigh M, Lautenbachera S. Impairment of pain inhibition in chronic tension-type headache. Pain. 2005; 118(12):215223 Sandrini G, Rossi P, Milanov I, Serrao M, Cecchini AP, Nappi G. Abnormal modulatory inuence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients. Cephalalgia. 2006;26(7): 782789 Park JW, Lee KS, Kim JS, Kim YI, Shin HE. Genetic contribution of catechol-Omethyltransferase polymorphism in pa-

tients with migraine without aura. J Clin Neurol. 2007;3(1):24 30 44. Hagen K, Pettersen E, Stovner LJ, Skorpen F, Zwart JA. The association between headache and Val158Met polymorphism in the catechol-O-methyltransferase gene: the HUNT Study. J Headache Pain. 2006;7(2): 70 74 45. Rhudy JL, Meagher M. Fear and anxiety: divergent effects on human pain thresholds. Pain. 2000;84(1):6575 46. Kapci EG, Uslu R, Turkcapar H, Karaoglan A. Beck Depression Inventory II: evaluation of the psychometric properties and cut-off points in a Turkish adult population. Depress Anxiety. 2008;25(10):E104 E110 47. Basker M, Moses PD, Russell S, Russell PS. The psychometric properties of Beck Depression Inventory for adolescent depression in a primary-care paediatric setting in India. Child Adolesc Psychiatry Ment Health. 2007;1(1):8 48. Steer RA, Kumar G, Ranieri WF, Beck AT. Use of the Beck Depression Inventory-II with adolescent psychiatric outpatients. J Psychopathol Behav Assess. 1998;20(2): 127137 49. Ge HY, Madeleine P, Arendt-Nielsen L. Sex differences in temporal characteristics of descending inhibitory control: an evaluation using repeated bilateral experimental induction of muscle pain. Pain. 2004; 110(12):7278 50. Sarlani E, Greenspan JD. Gender differences in temporal summation of mechanically evoked pain. Pain. 2002;97(12): 163169 51. Fillingim RB, Maixner W, Kincaud S, Silva S. Sex differences in temporal summation but not sensory-discriminative processing of thermal pain. Pain. 1998;75(1):121127 52. Staud R, Robinson ME, Vierck CJ, Price D. Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or bromyalgia patients. Pain. 2003; 101(12):167174 53. Serrao M, Rossi P, Sandrini G, et al. Effects of diffuse noxious inhibitory controls on temporal summation of the RIII reex in humans. Pain. 2004;112(3):353360

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Generalized Mechanical Nerve Pain Hypersensitivity in Children With Episodic Tension-type Headache Daniel M. Fernndez-Mayoralas, Csar Fernndez-de-las-Peas, Ricardo Ortega-Santiago, Silvia Ambite-Quesada, Rodrigo Jimnez-Garca and Alberto Fernndez-Jan Pediatrics 2010;126;e187; originally published online June 7, 2010; DOI: 10.1542/peds.2010-0012
Updated Information & Services References including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/126/1/e187.full.h tml This article cites 50 articles, 8 of which can be accessed free at: http://pediatrics.aappublications.org/content/126/1/e187.full.h tml#ref-list-1 This article has been cited by 2 HighWire-hosted articles: http://pediatrics.aappublications.org/content/126/1/e187.full.h tml#related-urls Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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