| Abstract|| |
Background: Migraine is the most common type of episodic headache. Migraine can affect the pediatric patients' life through absence from school and restricting inside-home and social activities. Objective: This study was done with the objective of investigating the prophylactic effect of levetiracetam on pediatric migraine headaches. Materials and Methods: In this before-after clinical trial, 30 children aged 4–14 years with migraine headache were included and followed for 6 months. The required data were gathered through observation, examination, paraclinical studies, and interview. The data were entered into a checklist. Furthermore, the Pediatric Migraine Disability Assessment (PedMIDAS) questionnaire was used to assess disability. Levetiracetam tablet was administered for 6 months. The frequency and duration of migraine headaches as well as migraine-related symptoms and possible side effects were documented. The data were then analyzed by the SPSS software (ver. 20.0, IBM Company). Results: The frequency of headaches, their severity, and duration decreased significantly at the end of the study (P < 0.001). After 6 months of treatment, migraine attacks were recovered completely in six patients (20%). Only three patients (10%) showed side effects such as nagging and negotiating, poor sleep, and lack of appetite which neither resulted in cessation of the medication. Furthermore, the PedMIDAS score decreased significantly at the end of the study (P < 0.001). Conclusion: Levetiracetam had acceptable efficacy and tolerability to be used for prophylaxis of migraine headache in children and can be a good substitute in such patients.
Keywords: Children, levetiracetam, migraine, prophylactic treatment
|How to cite this article:|
Sediqi M, Yavari B, Almasi A. Prophylactic efficacy of levetiracetam on migraine headaches in children aged 4–14-year-old. Ann Trop Med Public Health 2017;10:1547-51
|How to cite this URL:|
Sediqi M, Yavari B, Almasi A. Prophylactic efficacy of levetiracetam on migraine headaches in children aged 4–14-year-old. Ann Trop Med Public Health [serial online] 2017 [cited 2019 Jan 22];10:1547-51. Available from: http://www.atmph.org/text.asp?2017/10/6/1547/222666
| Introduction|| |
Headache constitutes the most common reason for children to visit pediatric neurology clinics. It is essential that physicians have a systematic approach to manage children who complain of headaches. Headache is quite common during childhood and its frequency increases in adulthood. Before puberty, headache is more frequent in boys, but after puberty, it becomes more common in girls. Migraine is the most common form of recurrent headaches and is characterized by recurrent moderate-to-severe headache attacks associated with symptoms such as nausea, vomiting, photophobia, and phonophobia. Migraine is generally categorized as migraine without aura (common migraine), migraine with aura (classic migraine), and chronic migraine. Migraine headaches usually occur over the course of several hours to days (1–72 h). Younger children usually complain of headaches in the afternoon and after school hours. At early teenager years, headaches usually occur at lunchtime. Older teenagers usually experience adult pattern of headaches which usually are morning headaches. In 75% of the children, report of at least one severe headache attack before 15 years of age is present. Recurrent headaches are less common but are still prevalent. Migraine has been reported in 10.6% of 5–15-year-old children and among 28% of older teenagers. Treatment options for migraine are abortive treatments in acute attacks, prophylactic ones, and biobehavioral interventions. Treatment of an acute migraine attack includes alleviation of headache and return to normal activity. This abortive therapy includes two groups of medications: nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans. Most childhood migraine headaches respond properly to correct dosages of NSAIDs when they are administered at an early stage of headache onset. However, when headaches are recurrent (for example, once or more per week) or disabling, prophylactic treatment becomes necessary. The aim of prophylactic therapy is to decrease the frequency of headaches and their related disability. Several prophylactic treatments have been used for migraine prophylaxis. Amitriptyline and beta-blockers are among these medications. Recently, antiepileptic medications have been used more frequently for migraine prophylaxis. It has been demonstrated that topiramate, valproic acid, and levetiracetam are efficacious agents in adults who suffer from migraine. Although limited studies have been done about the utility of antiepileptic drugs in children, the safety and tolerability of these medications in children with epilepsy have been evaluated.
Levetiracetam is a pyrrolidine derivative and its use in partial myoclonic seizures, and primary generalized tonic-clonic seizures in both children and adults have been approved by the Food and Drug Administration. Levetiracetam can be used even in neonates and is used as the second or third medication in the treatment of neonatal seizures. Levetiracetam selectively binds to synaptic vesicle protein. The function of this protein is unknown, but probably levetiracetam modulates the vesicles to release synaptic glutamate and gamma-aminobutyric acid. Levetiracetam is tolerated well and the most common side effects reported are somnolence, asthenia, and dizziness. Less common side effects include complaints of aggressive behavior and anxiety and rarely idiosyncratic reactions. Drug interactions are minimal as levetiracetam is not metabolized by the hepatic cytochrome P450 system. Both oral and parenteral preparations are available. Oral absorption is relatively complete and rapid and is not affected by food ingestion. It reaches its peak plasma concentration in 1.3 h.
Miller studied the efficacy of levetiracetam on migraine in children and showed that frequency of headaches before treatment which was 6.3 attacks per month decreased to 1.7 attacks per month after treatment. This reflected efficacy of levetiracetam on pediatric migraine. Pakalnis et al. studied the efficacy of levetiracetam on pediatric migraine including children aged 6–17 years and showed that the mean number of headache attacks decreased from 6 attacks per month to two attacks per month after treatment. However, limited studies have been done regarding the prophylactic effect of levetiracetam on pediatric migraine headaches. There has been no study involving Iranian children. If efficacy and tolerability of this medication is demonstrated, it could be a good option for prophylactic treatment of migraine.
Here, we decided to study the efficacy and tolerability of levetiracetam on pediatric migraine headaches and to study its side effects.
| Materials and Methods|| |
In this before-after clinical trial, 30 children with migraine headaches were included and followed for 6 months. The study population was children aged 4–14 years who presented to the pediatric clinic of our university hospital in 2013 for 1-year period. The patients had complaints of headache and migraine-associated symptoms. Other causes of headaches were excluded using appropriate diagnostic methods such as laboratory tests, brain electroencephalogram (EEG), or brain imaging. These studies were done considering defined indications in reference pediatric textbooks. Then, the diagnosis of migraine headache was made based on the criteria of the International Headache Society. After getting medical history and performing pertinent physical examinations, if according to International Classification of Headache Disorders (ICHD III) criteria, headache was diagnosed as migraine, the patient was considered to be included in the study. After getting informed consent, if agreed, the patient was included in the study.
The inclusion criteria were age range of 4–14 years, diagnosis of migraine based on the ICHD III criteria, score of higher than 20 on Pediatric Migraine Disability Assessment (PedMIDAS) questionnaire, and headache attacks of more than once per week. Children with any of the following factors were excluded: having abnormal brain imaging or EEG result, concomitant seizure disorder, abnormal neurologic examination, recent history of head trauma, taking narcotics, headaches secondary to infection (sinusitis, otitis media, etc.), having mood disorder, and history of allergy to antiepileptic medications. Furthermore, those who were on migraine prophylaxis were included only if migraine headache was not controlled.
If headaches were repeated more than once per week or headaches were disabling, the PedMIDAS questionnaire was administered. If the PedMIDAS score was higher than 20, levetiracetam tablet with the minimum dose recommended in pediatric textbooks was administered (20 mg per kg). The tablets used here were similar for all patients and were delivered by a single pharmaceutical company.
The patients were asked to prepare a headache diary. They were asked to write down the days when they experience headache, duration of headache, migraine-associated symptoms, and duration of migraine-associated symptoms. Then, the patients were contacted monthly by phone call, or if needed, they were visited in person. This follow-up continued for 6 months, and the frequency and severity of headaches were compared to baseline time point. The PedMIDAS questionnaire was completed every 3 months (i.e., at baseline, at 3 months, and at 6 months). During the study, if needed, the dosage of levetiracetam was increased. If side effects occurred, visiting by phone call or in person was done. In addition to prophylactic treatment, acute headache attacks were treated by NSAIDs or triptans. The administered medications for acute attacks were similar among the patients. None of the patients received biobehavioral interventions.
If no response to levetiracetam was observed, the patient was considered as nonresponder to levetiracetam, and another prophylactic medication was substituted.
The required data were gathered through observation, physical examination, paraclinical tests, interview, and filling out the checklist and the PedMIDAS questionnaire. The gathered data were analyzed by the SPSS software for Windows (ver. 20.0, IBM Company) using appropriate statistical tests. To compare quantitative variables and in case of normal distribution at measurement time points, repeated measure test, and to control the effect of confounding variables, the linear mixed model was used. In performing unadjusted comparisons of before and after study, the paired t-test was used. Furthermore, analysis was done in two forms, one by ITT (in patients who took at least one dosage of levetiracetam) and by per protocol method (for patients who completed the study) to study the efficacy of the treatment. Furthermore, the size effect was calculated and the significance levels of the tests were considered as P < 0.01 and P < 0.05.
| Results|| |
The mean (±standard deviation [SD]) age of the patients was 9.3 (±2.5) years (range, 5–14 years). The mean ages of the girls and boys were 8.38 and 10.36 years, respectively. There were 16 girls (53.3%) and 14 boys (46.7%). The mean weight of the sample was 30.483 Kg (range, 15–53 Kg).
Only two patients did not have familial history of headache (one boy and one girl). Furthermore, there was no significant difference regarding familial history of headache between boys and girls (P = 0.92, Fisher's exact test).
Regarding the location of headache, most children (21 participants, 70%) had bilateral headaches. Regarding the quality of headaches, the most prevalent type was pulsating headache (17 cases, 56.7%). In terms of the time that the most severe headache experienced, most children (25 cases, 83.3%) experienced headaches in the afternoon. Furthermore, 29 children (96.7%) stated that the headaches were not so intense to awake them from sleep. Headache in 28 cases (93.3%) was without aura [Table 1].
|Table 1: The frequency distribution of headache characteristics in boys and girls|
Click here to view
According to the Fisher's exact test, no significant difference existed between boys and girls regarding pain location, quality, the time of the most severe pain, awaking from sleep because of pain, and aura (P > 0.05).
[Table 2] presents the frequency and percentages of migraine-associated symptoms. According to the Cochran's Q-test, no significant difference existed regarding vomiting, abdominal pain, and dizziness at three measurement time points (P > 0.05). However, there were significant differences regarding photophobia, phonophobia, and nausea at the studied three time points (P < 0.05).
|Table 2: The frequency distribution of migraine-associated symptoms at three studied time points|
Click here to view
The pairwise comparisons showed that a significant difference existed regarding nausea at 3 months compared to baseline (P = 0.01) and also at 6 months compared to baseline (P < 0.001). No significant difference existed between nausea occurrence at 3 months' and at 6 months' time points. With regard to photophobia, a significant difference existed at 3 months compared to 6 months after initiating levetiracetam (P = 0.026) and also 6 months after treatment in comparison to baseline time point (P < 0.001). No significant difference was observed regarding photophobia 3 months after starting treatment versus baseline time point (P = 0.57). Regarding photophobia, a significant difference existed 3 months after treatment compared to baseline time point (P = 0.004) and also 6 months after starting treatment compared to baseline time point (P = 0.001). No significant difference existed regarding photophobia 3 months and 6 months after starting levetiracetam (P = 0.231).
The mean duration of symptoms was 6.83 h at baseline which decreased to 0.73 h 6 months later [Table 3]. According to repeated measures analysis of variance (ANOVA), a significant difference existed regarding duration of symptoms at three time points (baseline, after 3 months, and after 6 months); significant Mauchly's W-test, P < 0.001; the Greenhouse-Geisser test was used to compare the changes at three time points. The results of pairwise comparison test (LSD = least significant difference) showed significant difference regarding duration of symptoms at baseline and after 3 months (P = 0.001), between baseline and 6 months later (P < 0.001), and also between 3 months and 6 months after starting levetiracetam (P = 0.001).
|Table 3: Characteristics of headache and the Pediatric Migraine Disability Assessment score in the studied children at three time points|
Click here to view
The mean headache duration time was 8.40 h at baseline which decreased to 1.15 h 6 months later [Table 3]. Furthermore, according to paired t-test, a significant decrease in headache at 3 and 6 months after starting treatment in comparison to pretreatment time and also between 6 months and 3 months after staring treatment was seen (P < 0.001).
According to repeated measures ANOVA, a significant difference existed regarding headache frequencies at baseline, 3 months, and 6 months later (Mauchly's W-test; P < 0,001); The Greenhouse-Geisser test was used to compare the changes at three time points. The results of pairwise comparison test used (LSD test) showed significant differences regarding the frequency of headaches at baseline and after 3 months (P < 0.001), at baseline and after 6 months (P < 0.001), and between 3 and 6 months after starting treatment (P < 0.001).
At baseline, the mean PedMIDAS score was 34.77, which decreased to 4.4 after 6 months [Table 3]. According to repeated measures ANOVA, a significant difference was observed with regard to the PedMIDAS scores at baseline, 3 months, and 6 months after initiating treatment (Mauchly's W-test, P < 0,001); The Greenhouse-Geisser test was used to compare the changes at three time points. The results of pairwise comparison test used (i.e., LSD test) showed significant differences regarding the differences in PedMIDAS score at baseline and after 3 months (P < 0.001), at baseline and after 6 months (P < 0.001), and between 3 and 6 months after starting treatment (P < 0.001).
At 3 months, the frequency of headaches became zero in two patients and migraine resolution occurrence ratio was calculated as 6.7%. After 6 months, this figure reached 6 patients and resolution rate was 20%. Furthermore, two patients who had aura at baseline did not have aura any more after 6 months. Only three patients showed side effects such as nagging and negotiating, poor sleep, and lack of appetite which neither resulted in cessation of the medication. Hence, it could be stated that tolerability rate of levetiracetam was 100%.
| Discussion|| |
This study was carried out with the purpose of evaluating the prophylactic efficacy of levetiracetam on migraine headaches and its possible side effects among children aged 4–14 years old. Headache is the most common neurologic complaint in children and migraine is the most common type of headache. As migraine can affect adversely personal, educational, and social life of children, diagnosis of patients who require prophylactic treatments and providing appropriate prophylactic treatment is important in improving their quality of life and preventing their headaches to become resistant in the future.
The obtained findings showed that a meaningful decrease in headache frequency and the PedMIDAS score occurred after treatment with levetiracetam for 6 months. Furthermore, a significant decrease in the duration of headaches and migraine-associated symptoms was observed. Plus, migraine was resolved completely in six patients (20%). In Miller on 19 children with migraine, in conformity to what we observed here, a considerable response was seen in terms of decrease in headache frequency. He observed migraine resolution in 10 patients (50%) which is higher than our findings. He reported that two patients did not resume taking levetiracetam because of its adverse reactions including asthenia, dizziness, irritability, and hyperactivity. However, in our study, the medication was not discontinued in any of the patients.
In Pakalnis et al. study, a significant decrease in headache frequency and the PedMIDAS scores was seen which is in compatible with our results. Of the 20 children studied, migraine resolved in four children which is in conformity with our results. Furthermore, similar to our study, none of the children required discontinuation of levetiracetam.
In Vaisleib et al. study involving 20 children with migraine, the intensity and frequency of headaches decreased by 50% in six children and by 75% in eight children. In De Souza et al. study, mean headache attacks decreased from 16.8 to 1.5, which is compatible with our results. However, it should be stated that the age range of the patients studied in the mentioned report was 11–19.5 years. Ten patients demonstrated considerable improvement which is higher in comparison to our results (66.6% vs. 20%) and migraine resolved completely in two patients. One patient did not experience any improvement in headache and one patient experienced more headaches during the study period. Four patients experienced fatigue, dizziness, and mood swings. We observed mood swings in three patients. In Rapoport et al. study, 36 adult patients older than 18 years (mean age of 46.5 years) were included and similar results to what we observed regarding decrease in the frequency of headaches were reported.
So far, several medications have been proposed for migraine prophylaxis. Each medication has its own advantages and disadvantages. Hence, there is possibility to study newer medications for this purpose. Regarding appropriate efficacy and tolerability of levetiracetam, we suggest this medication for migraine prophylaxis. The efficacy and safety of levetiracetam in the treatment of seizures have been confirmed in previous studies, and this medication is used even in neonates. It should be mentioned that among antiepileptic drugs in the treatment of seizure disorder, levetiracetam has few side effects, especially in children.
| Conclusion|| |
We observed appropriate efficacy and tolerability of levetiracetam in prophylactic treatment of migraine, this medication can be a suitable option for this purpose. However, it is suggested to conduct more studies with larger sample sizes in Iranian population.
This article is based on a thesis submitted to the graduate studies office in partial fulfillment of requirements for the degree of pediatric physician by Bahare Yavari in Kermanshah University of Medical Sciences, Faculty of Medicine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Swaiman KF, Ashwal S, Ferriero DM, Schor NF. Swaiman Pediatric Neurology. 5th
ed., Vol. 1. Philadelphia: Saunders; 2012. p. 880-99.
Kliegman RM, Behraman RE, Schore NF, St. Geme J, Stanton BF. Nelson Textbook of Pediatrics. 19th
ed. USA: Saunders; 2011. p. 2039-45.
Olesen J, Evers S, Charls A, Hershey A, Lipton R, First M, Bolay H, et al
. Headache classification committee of the international headache society, the international classification of headache disorders, 3rd
ed. Cephalalgia 2013;33:629-808.
Goodman LS, Gilman A, Brunton LL, Chabner B, Knollmann BC. Goodman and Gilman's the Pharmacological Basis of Therapeutics. 12th
ed. New York: McGraw-Hill Medical; 2011. p. 600-1.
Kliegman RM, Behraman RE, Schore NF, Geme JW, Stanton BF. Nelson Textbook of Pediatrics. 19th
ed. USA:Saunders; 2011. p. 2033-7.
Katzung BG, Masters S, Trevor A. Basic and Clinical Pharmacology (LANGE Basic Science). 12th
ed. New York: McGraw-Hill Professional; 2011. p. 414-5.
Miller GS. Efficacy and safety of levetiracetam in pediatric migraine. Headache 2004;44:238-43.
Pakalnis A, Kring D, Meier L. Levetiracetam prophylaxis in pediatric migraine – An open-label study. Headache 2007;47:427-30.
Vaisleib II, Neft RA, Schor NF. Role oflevetiracetam in prophylaxis of migraine headaches in childhood. Neurology 2005;64:A343.
De Souza TG, Shahid A, Waren SP. The use of levetiracetam in the prophylactic treatment of migraine headaches in adolescents. Headache 2005;45:819-20.
Rapoport AM, Sheftell FD, Tepper SJ, Bigal ME. Levetiracetam in the preventive treatmentof transformed migraine: A prospective, open-label, pilot study. Curr Ther Res Clin Exp 2005;66:212-21.
Medical School, Kermanshah University of Medical Sciences, Kermanshah
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]