Migraine is frequent in children and adolescents ... - Wiley Online Library

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Pediatrics International (2014) 56, 865–867

doi: 10.1111/ped.12375

Original Article

Migraine is frequent in children and adolescents with neurofibromatosis type 1 Ricardo Silva Pinho,1 Eduardo Ferracioli Fusão,1 Joelma Karina Sagica Fernandes Paschoal,1 Eliana Maria Monteiro Caran,2 Thaís Soares Cianciarullo Minett,3 Luiz Celso Pereira Vilanova1 and Marcelo Rodrigues Masruha1 1 Department of Neurology and Neurosurgery, 2Department of Pediatrics/Pediatric Oncology Institute and Support Group for Children and Adolescents with Cancer, Federal University of São Paulo, São Paulo, Brazil, and 3Department of Public Health and Primary Care, Cambridge University, Cambridge, UK Abstract

Background: Despite the high prevalence of headache in patients with neurofibromatosis type 1 (NF1), little data exist regarding the classification and characterization of headaches experienced by these patients. This paper describes a study of headache in patients with NF1 compared with healthy controls. Methods: In this transversal study, participants (aged 4–19 years) were classified into two groups: NF1 patients or control subjects. The diagnosis of NF1 was performed according to the diagnostic criteria of the National Institutes of Health Consensus Conference, and the headache diagnosis was performed according to the diagnostic criteria of the International Classification of Headache Disorders, Second Edition. All participants underwent physical and neurologic evaluation and completed a detailed headache questionnaire. Results: The comparison of 50 patients with NF1 and 50 age-matched controls revealed that the complaint of headache was significantly more frequent in the NF1 group than in the control group (CG) (62% vs 14%, χ2(1) = 22.4; P < 0.001). Migraine was significantly more frequent in patients with NF1 than in the CG (54% vs 14%, χ2(1) = 17.82; P < 0.001). No differences were found between the two groups regarding the use of simple analgesics (NF1: 14% vs CG: 5%, χ2(1) = 1.18; P = 0.276). Conclusions: Children and adolescents with NF1 are prone to migraines. Complaints of headache are very frequent in this population.

Key words: adolescents, children, headache, migraine disorders, neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is one of the most frequent (1 per 2500–3000 persons worldwide),1 ubiquitous, and clinically relevant autosomal dominant human diseases.2 The gene for NF1 was cloned on chromosome 17q11.2 and comprises 60 exons spanning 350 kb of genomic DNA.1,3 Half of the patients with NF1 have inherited their NF1 mutation, and the other half of NF1 cases are caused by a de novo NF1 mutation.4 The criteria for the diagnosis of NF1, which were developed by the National Institutes of Health (NIH) Consensus Conference5 in 1987, are generally accepted for routine clinical use.6 In addition to the clinical signs that are commonly stated for these criteria, others signs may be present in varying proportions; headache has been reported variably from 15% to 47% in several surveys.2,7–10 Despite the high prevalence of headache in this population, little data exist regarding the classification and characterization

Correspondence: Marcelo Rodrigues Masruha, MD PhD, Department of Neurology and Neurosurgery, Botucatu Street 720, Federal University of São Paulo, São Paulo 04023-900, Brazil. Email: mmasruha @ig.com.br Received 11 February 2014; revised 21 April 2014; accepted 30 April 2014.

© 2014 Japan Pediatric Society

of headaches experienced by patients with NF1.10 This article describes a study of headaches in patients with NF1 compared with healthy controls.

Methods In this transversal study, all participants (aged 4–19 years) were classified into two groups: NF1 patients and control subjects. The NF1 patients were regularly followed at the Child Neurology Division and at the Pediatric Oncology Institute, both of the Federal University of São Paulo, Brazil. The control subjects were healthy individuals recruited in schools who were of similar age ranges. The diagnosis of NF1 was performed according to the diagnostic criteria of the National Institutes of Health Consensus Conference,5 and the headache diagnosis was performed according to the diagnostic criteria of the International Classification of Headache Disorders, Second Edition (ICHD-2);11 chronic migraine (CM) was defined according to the 2006 appendix criteria.12 Subjects were considered to have recurrent headaches if they were present at least 3 times per year and were not associated with infections or head trauma. Medication overuse was defined

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in terms of treatment days per month as follows: ergotamine, triptan or opioid overuse required 10 or more days per month on a regular basis for 3 or more months; and simple analgesics (or any combination of different acute drugs) required 15 or more days per month (also on a regular basis for 3 or more months). The exclusion criteria were the presence of other chronic diseases, such as asthma, or a previous history of radiotherapy. All subjects or their guardians provided written consent for the research, which was approved by the Ethics Committee of the Federal University of São Paulo. All participants underwent physical and neurologic evaluation and completed a detailed headache questionnaire. All patients with NF1 received at least one routine brain magnetic resonance imaging (MRI) during their follow up. When the headache started after the date of the routine MRI or if an important change in the headache characteristics occurred, a new MRI was performed. Data analysis

The χ2-test (without Yates’s correction) was used for the categorical data comparisons. The mean values of the two patient groups were compared using the independent Student’s t-test (t). A P-value of less than 0.05 was considered statistically significant, and all tests were two-tailed. Ninety-five percent confidence intervals (CI) were calculated for the differences between means. Statistical analyses were performed using stata 13.0.

Results A total of 126 subjects were recruited to the study. Of these, 26 subjects were excluded: seven refused to participate, three did not give a reliable history, and 16 met at least one criterion for exclusion. The analysis of the remaining 100 subjects is shown below, of which 50 had NF1 and 50 were the control group (CG). There were no statistically significant differences between the two groups regarding sex (NF1: 38% girls vs CG: 46%, χ2(1) = 0.66, P = 0.418) or age (NF1: 13.2 [4.3], CG: 13.1 [4.3], t(98) = 0.12, P = 0.546). Complaint of headache was significantly more frequent in the NF1 group than in the CG group (62% vs 14%, χ2(1) = 22.4; P < 0.001). The distribution of headache by age is shown in Figure 1. Migraine was significantly more frequent in the patients with NF1 than those in the CG (54% vs 14%, χ2(1) = 17.82 P < 0.001). The headache disorders that were diagnosed in both groups are summarized in Table 1; the headache clinical features are summarized in Table 2. No differences were found between the two groups regarding simple analgesics overuse (NF1: 14% vs CG: 5%, χ2(1) = 1.18; P = 0.276). No participant used ergotamine, triptans or opioids as an option for pain relief. In two patients with NF1, the MRI showed diencephalic astrocytomas. The other brain MRI were otherwise normal or disclosed only spongiotic myelinopathy.

Fig. 1 Distribution of headache in neurofibromatosis type 1 (NF1) patients and in control group (CG) subjects by age group. The frequency of headache among patients with NF1 was significantly higher than controls in both age groups (4–11 years: χ2(1) = 8.53, P = 0.003/12–19 years: χ2(1) = 15.94, P < 0.001).

prevalence is even higher than that reported by previous authors (15–47%).2,8–10,13 To our knowledge, only two previous studies have investigated headache classification and characterization in patients with NF1.2,10 Clementi et al. described 181 patients with NF1;2 headache was present in 30% of these patients. Overall, in the patients with primary headaches, 10% had migraines and 90% had tensiontype headaches. Three patients had brain tumors and obstructive hydrocephalus. However, there were important differences in the

Table 1 Distribution of the types of headaches according to patient group

No headache Migraine without aura Migraine with aura Chronic migraine Tension-type headache Headache attributed to intracranial neoplasm

NF1

CG

n = 50 19 23 4 0 2 2

n = 50 43 4 2 1 0 0

CG, control group; NF1, neurofibromatosis type 1. Table 2 Clinical characteristics of headache in NF1 patients and CG subjects Mean (SD) NF1 CG n = 31 n=7 8.0 (3.9) 7.2 (4.6) 2.5 (3.7) 4 (2.8) 11.3 (5.7) 7.8 (6.3) 6.1 (1.6) 4.8 (2.7)

Discussion

Age of onset (years) Duration (h) Frequency (days) Basal score of pain intensity†

The present study shows a higher prevalence of headache complaint in patients with NF1 (62%) than in controls (14%). This

† On a scale from 0 to 10. CG, control group; NF1, neurofibromatosis type 1.


Migraine and neurofibromatosis type 1 age distribution between our data and those of Clementi et al. Our study did not include any patients over 19 years of age, whereas Clementi et al. included 23 patients older than age 18 years. Surprisingly, they identified only a single patient under 19 who suffered from migraines. This is an extremely low prevalence compared with the general population estimates. Di Mario Jr et al. described 132 patients with NF1.10 Recurrent headache was present in 47% of the patients. Of these patients, 34% had migraine, 45% had nonmigrainous headache, 15% had mixed headache types (both intermittently), and 7.5% had other head pains. Migraine prevalence has been estimated to be 2–7% in preadolescents and 7–11% in adolescents.14 Our study found a prevalence of 14% in the CG, which is in accordance with the published data.14 In the NF1 group, we found that 54% had migraine, which is even higher than the prevalence found by Di Mario Jr.10 Migraine and NF1 may share pathophysiological mechanisms. A number of neurotransmitter systems have been implicated in migraine, most notably serotonergic and calcitonin gene-related peptide. However, there is evidence suggesting that dopamine may be involved in the pathogenicity of migraine. On one hand, dopamine is possibly involved in some of the premonitory symptoms of migraine, such as yawning, nausea, vomiting and gastrokinetic disturbances. On the other hand, dopamine and dopamine agonists may have a therapeutic role in the headache phase of migraine.15 Dopamine dysfunction was also demonstrated in NF1. Diggs-Andrews et al.16 showed that reduced dopamine signaling is responsible for cyclic adenosine monophosphate dependent defects in neuron function and learning in NF1 mice. All physicians that treat patients with NF1 should be aware that migraine is frequent in these individuals. Frequent migraine episodes significantly affect quality of life in children and adolescents.17 Thus, the finding that migraine is frequent in patients with NF1 is very important because current treatment modalities for its treatment can provide a better quality of life for these patients.

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Acknowledgments This study was sponsored by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) – Proc. 2011/50140-8. There are no competing interests.
