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Efficacy of flunarizine in the prophylaxis of cyclical vomiting syndrome and abdominal migraine
European Journal of Paediatric Neurology (2005) 9, 23–26
www.elsevier.com/locate/ejpn
CASE STUDY
Efficacy of flunarizine in the prophylaxis of cyclical vomiting syndrome and abdominal migraine Sanjeev V. Kothare* Department of Pediatrics, Division of Neurology, St Christopher’s Hospital for Children, Drexel University College of Medicine, Erie Avenue at Front Street, Philadelphia, PA 19134, USA Received 9 September 2004; accepted 15 November 2004
KEYWORDS Abdominal migraine; Cyclical vomiting; Flunarizine
Summary Cyclical vomiting syndrome (CVS), and abdominal migraine (AM) are relatively unusual periodic syndromes, generally believed to be migraine equivalents, and are characterized by recurrent and severe paroxysmal episodes of vomiting and/or abdominal pain lasting hours to days, separated by weeks to months of no symptoms. Flunarizine is a calcium channel-blocking agent that has been used successfully as a prophylactic agent in the prevention of both childhood and adultonset migraine syndromes. The purpose of this study was to evaluate the efficacy of flunarizine as a prophylactic/preventive agent in the treatment of CVS and AM. Eight children with CVS and 10 children with AM were included in the study. The mean dose of flunarizine was 5 mg/day in children with CVS, and 7.5 mg/day in children with AM. Follow-up ranged from 6 to 24 months (mean 13 months). There was a 57% reduction in frequency and 44% reduction in duration of attacks of CVS, and a 61% reduction in frequency and 51% reduction in duration of attacks of AM. Sixty-four percent of patients with CVS and AM had history of episodic recurrent headaches with 60% reduction in frequency of attacks on treatment. Flunarizine showed to be equally efficacious than previously tried therapies in the prophylaxis of a small cohort of patients with CVS and AM. Q 2004 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
Introduction Cyclical vomiting syndrome (CVS), and abdominal migraine (AM) are relatively unusual periodic syndromes, characterized by recurrent and severe paroxysmal episodes of vomiting and/or abdominal pain lasting hours to days separated by weeks to months of no symptoms. They have recently been * Tel.: C1 215 427 8372; fax: C1 215 427 4393. E-mail address: [email protected].
re-classified in the 2nd edition of the International Classification of Headache Disorders (ICHD) as childhood periodic syndromes that are common precursors of migraine.1 Treatment of both CVS and AM is focused on preventing attacks with various prophylactic medications including cyproheptadine, pizotifen, erythromycin, phenobarbital, propranolol, and amytriptiline.2 Flunarizine is a calcium channel-blocking agent that has been used successfully as a prophylactic agent in the prevention of both childhood and adult-onset
1090-3798/$ - see front matter Q 2004 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. doi:10.1016/j.ejpn.2004.11.002
24 migraine syndromes.3 The purpose of this study was to evaluate the efficacy of flunarizine as a prophylactic/preventive agent in the treatment of CVS and AE.
Methods Retrospective analysis of all the records of patients seen in a pediatric neurology clinic by a single physician (author) in Bombay, India, between 2000 and 2002 was performed. Patients who satisfied the diagnosis of CVS and AM according to established diagnostic criteria (Table 1) and who were started on flunarizine were identified. All patients had an extensive diagnostic evaluation to rule out alternate etiologies including MRI brain, EEG, abdominal ultrasounds, upper and lower GI series, metabolic work up, stool examinations as described in Table 2, all of which were normal. A total of 18 children were included in the study. Table 1 Diagnostic criteria for cyclical vomiting syndrome and abdominal migraine.6,10 Cyclical vomiting syndrome Essential Recurrent severe, discrete episodes of vomiting Varying intervals of normal health between episodes Duration of vomiting episodes from hours to days No apparent cause of vomiting (negative laboratory, radiographic and endoscopic testing) Supportive Stereotypical pattern of each episode with time of onset, intensity, duration, frequency, associated symptoms within individuals Self limiting episodes resolving spontaneously if left untreated Associated symptoms of nausea, abdominal pain, headache, motion sickness, photophobia, lethargy Associated signs of pallor, diarrhea, dehydration, fever, excessive salivation, social withdrawal Abdominal migraine Pain is severe enough to interfere with normal daily activities Pain is described as dull or sore in nature Pain is periumbilical or poorly localized Pain is associated with two of the following: anorexia, nausea, vomiting, pallor Each attack lasts for at least 1 h There is complete resolution of symptoms between attacks Attacks occur at least twice a year The diagnosis is excluded if any of the following: nonmidline pain, burning pain, persistence of symptoms between attacks, attacks last less than 1 h, symptoms suggestive of an alternative etiology
S.V. Kothare Table 2
Differential diagnosis of CVS and AM.10
Differential diagnosis Gastrointestinal Peptic Ulcer disease including esophagitis Inflammatory Bowel disease Malabsorption syndromes Malrotation Hepatobiliary Pancreatitis Chronic appendicitis Renal Hydronephrosis Nephrolithiasis Urinary tract infection Neurological Increased intracranial pressure Abdominal epilepsy Endocrine Addison’s disease Diabetes mellitus Metabolic Organic acidemias Aminoaciduria Urea cycle disorders Acute intermittent porphyria Disorders of fatty acid oxidation Mitochondrial disorders Others Pregnancy Mu ¨nchausen-by-proxy Anxiety, depression
Results Eight children (5 girls and 3 boys) ages 2–8 years (mean age: 3.5 years) had CVS and 10 children (6 girls and 4 boys) ages 4–11 years (mean age: 6 years) had AM. Flunarizine dose were 2.5–10 mg flunarizine (mean dose: 5 mg/day) in CVS patients and 2.5–15 mg flunarizine (mean dose 7.5 mg/day) in AM patients. Flunarizine was administered as once a day in 75% and twice a day in 25% patients. Follow up ranged from 6 to 24 months (mean 13 months). Frequency (frequency of attacks per month) and duration of attacks before treatment and on treatment with flunarizine in children with CVS and AM is shown in Table 3. On flunarizine, there was a 57% (0.57/1) reduction in frequency and 44% (1.32/3) reduction in duration of attacks of CVS, while there was a 61% (0.49/0.8) reduction in frequency and 51% (7.4/14) reduction in duration of attacks of AM. Sixty four percent of patients with CVS and AM had history of episodic recurrent headaches. Frequency of headaches dropped from
Efficacy of flunarizine in the prophylaxis of cyclical vomiting syndrome and abdominal migraine Table 3
CVS AM
25
Results of frequency and duration of attacks. Frequency of attacks before treatment
Frequency of attacks on flunarizine
Duration of attacks before treatment
Duration of attacks on flunarizine
0.3–2/month, mean: 1/month 0.4–2/month, mean: 0.8/ month
0.2–1.5/month, mean: 0.57/month 0.2–1/month, mean: 0.49/month
2 h–7 days, mean: 3 days 4–48 h, mean: 14 h
6 h–4 days, mean: 2.2 days 3–36 h, mean: 7.4 h
CVS, cyclical vomiting syndrome; AM, abdominal migraine.
4 attacks per month (range 2–8 per month) to 2.4 attacks per month (range 1.5–5 per month) on treatment with flunarizine. Overall, there was a 60% (2.4/4) reduction in frequency of headaches on flunarizine. Twenty-one percent discontinued the medication because of weight gain (15%), or perceived lack of efficacy (6%).
Discussion CVS, first described by Gee in 1882, is characterized by recurrent stereotypical episodes of intense nausea and vomiting lasting hours to days, which are separated by symptom-free intervals.4 The average age of onset ranges between 2 and 9 years, with an average frequency of 12 attacks per year. It affects about 2% of school-aged children. The criteria for diagnosis of CVS are listed in Table 1. AM was first described in 1921 by Buchanan, and it is characterized by recurrent acute-onset incapacitating non-colicky midline abdominal pain lasting hours to days, and accompanied by pallor, vomiting and anorexia, with complete recovery between attacks.5 The mean age for presentation at 7 years is slightly higher than seen in CVS, and it has a prevalence of 4% in school-aged children. Symon et al. further refined the diagnostic criteria.6 These have been summarized in Table 1. Thirty-six percent of patients with AM or CVS have associated headaches, while 70% of either of these periodic syndromes eventually evolve into adult-onset migraine.7 In the current series, 64% of patients with CVS and AM had history of recurrent episodic headaches, with 60% reduction in frequency of attacks on flunarizine treatment. The diagnosis of these syndromes is one of exclusion, and involves extensive diagnostic testing to rule out varied etiologies, which are summarized in Table 2. When either of these conditions is accompanied by altered sensorium, abdominal
epilepsy (AE) has to be considered in the differential diagnosis.8 The treatment of CVS and AM involves abortive therapy and when indicated preventive prophylaxis. Prophylaxis is indicated when the frequency of incapacitating attacks is O1 attack per month or when the duration of the attack lasts long (usually O24 h).2 Flunarizine is a non-selective calcium antagonist that has an established efficacy in migraine prophylaxis, which has been confirmed in several open and controlled trials.3 Although it is unavailable in the US, it has been used extensively in several other countries including India. The long half-life with once a day dosing and good safety profile makes it an attractive alternative for migraine prophylaxis. Since CVS and AM are considered migraine equivalents, flunarizine therapy was initiated on a small population of patients with either CVS or AM in this study group. There was a significant reduction in frequency and duration of attacks in both conditions. The efficacy of flunarizine shown in our series is comparable to various prophylactic medications including cyproheptadine, pizotifen, erythromycin, phenobarbital, propranolol, and amitryptiline that have been used in previous open labeled studies in the treatment of CVS or AM.2,9 Also, the efficacy of flunarizine in our study in both these conditions is comparable to its efficacy in common and classical migraine.3 Overall, flunarizine was well tolerated. This is the first study to show the efficacy of flunarizine in the prophylaxis of a small cohort of patients with CVS and AM. Larger prospective studies need to be done in the future to confirm this observation.
References 1. Headache classification committee of the International Headache Society. The international classification of headache disorders. Cephalgia 2004;24:1–160.
26 2. Worawattanakul M, Rhoads JM, Lichtman SN, Ulsen MH. Abdominal migraine: prophylactic treatment and follow-up. J Pediatr Gastroenterol Nutr 1999;28:37–40. 3. Centonze V, Tesauro P, Trizio T, et al. Efficacy and tolerability of flunarizine in the prophylaxis of migraine. Cephalgia 1985;5(Suppl 2):165–8. 4. Gee S. On fitful or recurrent vomiting. St Bartholomew’s Hospital Rep 1882;18:1–6. 5. Buchanan JA. The abdominal crises of migraine. J Nerv Ment Dis 1921;54:406–12. 6. Symon DNK, Russell G. Abdominal migraine: a childhood syndrome defined. Cephalgia 1986;6:223–8.
S.V. Kothare 7. Abu-Arafeh I, Russell G. Prevalence and clinical features of abdominal migraine compared with those of migraine headache. Arch Disease Childhood 1995;72:413–7. 8. Garcia-Herrero D, Fernandez-Torre JL, Barrasa J, et al. Abdominal epilepsy in an adolescent with bilateral perisylvian polymicrogyria. Epilepsia 1998;39:1370–4. 9. Forbes D, Withers G. Prophylactic therapy in cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr 1995;21(Suppl 1): S57–S9. 10. Li Buk, Balint JP. Cyclical vomiting syndrome: evolution in our understanding of a brain-gut disorder. Adv Pediatr 2000; 47:117–60.
www.elsevier.com/locate/ejpn
CASE STUDY
Efficacy of flunarizine in the prophylaxis of cyclical vomiting syndrome and abdominal migraine Sanjeev V. Kothare* Department of Pediatrics, Division of Neurology, St Christopher’s Hospital for Children, Drexel University College of Medicine, Erie Avenue at Front Street, Philadelphia, PA 19134, USA Received 9 September 2004; accepted 15 November 2004
KEYWORDS Abdominal migraine; Cyclical vomiting; Flunarizine
Summary Cyclical vomiting syndrome (CVS), and abdominal migraine (AM) are relatively unusual periodic syndromes, generally believed to be migraine equivalents, and are characterized by recurrent and severe paroxysmal episodes of vomiting and/or abdominal pain lasting hours to days, separated by weeks to months of no symptoms. Flunarizine is a calcium channel-blocking agent that has been used successfully as a prophylactic agent in the prevention of both childhood and adultonset migraine syndromes. The purpose of this study was to evaluate the efficacy of flunarizine as a prophylactic/preventive agent in the treatment of CVS and AM. Eight children with CVS and 10 children with AM were included in the study. The mean dose of flunarizine was 5 mg/day in children with CVS, and 7.5 mg/day in children with AM. Follow-up ranged from 6 to 24 months (mean 13 months). There was a 57% reduction in frequency and 44% reduction in duration of attacks of CVS, and a 61% reduction in frequency and 51% reduction in duration of attacks of AM. Sixty-four percent of patients with CVS and AM had history of episodic recurrent headaches with 60% reduction in frequency of attacks on treatment. Flunarizine showed to be equally efficacious than previously tried therapies in the prophylaxis of a small cohort of patients with CVS and AM. Q 2004 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
Introduction Cyclical vomiting syndrome (CVS), and abdominal migraine (AM) are relatively unusual periodic syndromes, characterized by recurrent and severe paroxysmal episodes of vomiting and/or abdominal pain lasting hours to days separated by weeks to months of no symptoms. They have recently been * Tel.: C1 215 427 8372; fax: C1 215 427 4393. E-mail address: [email protected].
re-classified in the 2nd edition of the International Classification of Headache Disorders (ICHD) as childhood periodic syndromes that are common precursors of migraine.1 Treatment of both CVS and AM is focused on preventing attacks with various prophylactic medications including cyproheptadine, pizotifen, erythromycin, phenobarbital, propranolol, and amytriptiline.2 Flunarizine is a calcium channel-blocking agent that has been used successfully as a prophylactic agent in the prevention of both childhood and adult-onset
1090-3798/$ - see front matter Q 2004 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. doi:10.1016/j.ejpn.2004.11.002
24 migraine syndromes.3 The purpose of this study was to evaluate the efficacy of flunarizine as a prophylactic/preventive agent in the treatment of CVS and AE.
Methods Retrospective analysis of all the records of patients seen in a pediatric neurology clinic by a single physician (author) in Bombay, India, between 2000 and 2002 was performed. Patients who satisfied the diagnosis of CVS and AM according to established diagnostic criteria (Table 1) and who were started on flunarizine were identified. All patients had an extensive diagnostic evaluation to rule out alternate etiologies including MRI brain, EEG, abdominal ultrasounds, upper and lower GI series, metabolic work up, stool examinations as described in Table 2, all of which were normal. A total of 18 children were included in the study. Table 1 Diagnostic criteria for cyclical vomiting syndrome and abdominal migraine.6,10 Cyclical vomiting syndrome Essential Recurrent severe, discrete episodes of vomiting Varying intervals of normal health between episodes Duration of vomiting episodes from hours to days No apparent cause of vomiting (negative laboratory, radiographic and endoscopic testing) Supportive Stereotypical pattern of each episode with time of onset, intensity, duration, frequency, associated symptoms within individuals Self limiting episodes resolving spontaneously if left untreated Associated symptoms of nausea, abdominal pain, headache, motion sickness, photophobia, lethargy Associated signs of pallor, diarrhea, dehydration, fever, excessive salivation, social withdrawal Abdominal migraine Pain is severe enough to interfere with normal daily activities Pain is described as dull or sore in nature Pain is periumbilical or poorly localized Pain is associated with two of the following: anorexia, nausea, vomiting, pallor Each attack lasts for at least 1 h There is complete resolution of symptoms between attacks Attacks occur at least twice a year The diagnosis is excluded if any of the following: nonmidline pain, burning pain, persistence of symptoms between attacks, attacks last less than 1 h, symptoms suggestive of an alternative etiology
S.V. Kothare Table 2
Differential diagnosis of CVS and AM.10
Differential diagnosis Gastrointestinal Peptic Ulcer disease including esophagitis Inflammatory Bowel disease Malabsorption syndromes Malrotation Hepatobiliary Pancreatitis Chronic appendicitis Renal Hydronephrosis Nephrolithiasis Urinary tract infection Neurological Increased intracranial pressure Abdominal epilepsy Endocrine Addison’s disease Diabetes mellitus Metabolic Organic acidemias Aminoaciduria Urea cycle disorders Acute intermittent porphyria Disorders of fatty acid oxidation Mitochondrial disorders Others Pregnancy Mu ¨nchausen-by-proxy Anxiety, depression
Results Eight children (5 girls and 3 boys) ages 2–8 years (mean age: 3.5 years) had CVS and 10 children (6 girls and 4 boys) ages 4–11 years (mean age: 6 years) had AM. Flunarizine dose were 2.5–10 mg flunarizine (mean dose: 5 mg/day) in CVS patients and 2.5–15 mg flunarizine (mean dose 7.5 mg/day) in AM patients. Flunarizine was administered as once a day in 75% and twice a day in 25% patients. Follow up ranged from 6 to 24 months (mean 13 months). Frequency (frequency of attacks per month) and duration of attacks before treatment and on treatment with flunarizine in children with CVS and AM is shown in Table 3. On flunarizine, there was a 57% (0.57/1) reduction in frequency and 44% (1.32/3) reduction in duration of attacks of CVS, while there was a 61% (0.49/0.8) reduction in frequency and 51% (7.4/14) reduction in duration of attacks of AM. Sixty four percent of patients with CVS and AM had history of episodic recurrent headaches. Frequency of headaches dropped from
Efficacy of flunarizine in the prophylaxis of cyclical vomiting syndrome and abdominal migraine Table 3
CVS AM
25
Results of frequency and duration of attacks. Frequency of attacks before treatment
Frequency of attacks on flunarizine
Duration of attacks before treatment
Duration of attacks on flunarizine
0.3–2/month, mean: 1/month 0.4–2/month, mean: 0.8/ month
0.2–1.5/month, mean: 0.57/month 0.2–1/month, mean: 0.49/month
2 h–7 days, mean: 3 days 4–48 h, mean: 14 h
6 h–4 days, mean: 2.2 days 3–36 h, mean: 7.4 h
CVS, cyclical vomiting syndrome; AM, abdominal migraine.
4 attacks per month (range 2–8 per month) to 2.4 attacks per month (range 1.5–5 per month) on treatment with flunarizine. Overall, there was a 60% (2.4/4) reduction in frequency of headaches on flunarizine. Twenty-one percent discontinued the medication because of weight gain (15%), or perceived lack of efficacy (6%).
Discussion CVS, first described by Gee in 1882, is characterized by recurrent stereotypical episodes of intense nausea and vomiting lasting hours to days, which are separated by symptom-free intervals.4 The average age of onset ranges between 2 and 9 years, with an average frequency of 12 attacks per year. It affects about 2% of school-aged children. The criteria for diagnosis of CVS are listed in Table 1. AM was first described in 1921 by Buchanan, and it is characterized by recurrent acute-onset incapacitating non-colicky midline abdominal pain lasting hours to days, and accompanied by pallor, vomiting and anorexia, with complete recovery between attacks.5 The mean age for presentation at 7 years is slightly higher than seen in CVS, and it has a prevalence of 4% in school-aged children. Symon et al. further refined the diagnostic criteria.6 These have been summarized in Table 1. Thirty-six percent of patients with AM or CVS have associated headaches, while 70% of either of these periodic syndromes eventually evolve into adult-onset migraine.7 In the current series, 64% of patients with CVS and AM had history of recurrent episodic headaches, with 60% reduction in frequency of attacks on flunarizine treatment. The diagnosis of these syndromes is one of exclusion, and involves extensive diagnostic testing to rule out varied etiologies, which are summarized in Table 2. When either of these conditions is accompanied by altered sensorium, abdominal
epilepsy (AE) has to be considered in the differential diagnosis.8 The treatment of CVS and AM involves abortive therapy and when indicated preventive prophylaxis. Prophylaxis is indicated when the frequency of incapacitating attacks is O1 attack per month or when the duration of the attack lasts long (usually O24 h).2 Flunarizine is a non-selective calcium antagonist that has an established efficacy in migraine prophylaxis, which has been confirmed in several open and controlled trials.3 Although it is unavailable in the US, it has been used extensively in several other countries including India. The long half-life with once a day dosing and good safety profile makes it an attractive alternative for migraine prophylaxis. Since CVS and AM are considered migraine equivalents, flunarizine therapy was initiated on a small population of patients with either CVS or AM in this study group. There was a significant reduction in frequency and duration of attacks in both conditions. The efficacy of flunarizine shown in our series is comparable to various prophylactic medications including cyproheptadine, pizotifen, erythromycin, phenobarbital, propranolol, and amitryptiline that have been used in previous open labeled studies in the treatment of CVS or AM.2,9 Also, the efficacy of flunarizine in our study in both these conditions is comparable to its efficacy in common and classical migraine.3 Overall, flunarizine was well tolerated. This is the first study to show the efficacy of flunarizine in the prophylaxis of a small cohort of patients with CVS and AM. Larger prospective studies need to be done in the future to confirm this observation.
References 1. Headache classification committee of the International Headache Society. The international classification of headache disorders. Cephalgia 2004;24:1–160.
26 2. Worawattanakul M, Rhoads JM, Lichtman SN, Ulsen MH. Abdominal migraine: prophylactic treatment and follow-up. J Pediatr Gastroenterol Nutr 1999;28:37–40. 3. Centonze V, Tesauro P, Trizio T, et al. Efficacy and tolerability of flunarizine in the prophylaxis of migraine. Cephalgia 1985;5(Suppl 2):165–8. 4. Gee S. On fitful or recurrent vomiting. St Bartholomew’s Hospital Rep 1882;18:1–6. 5. Buchanan JA. The abdominal crises of migraine. J Nerv Ment Dis 1921;54:406–12. 6. Symon DNK, Russell G. Abdominal migraine: a childhood syndrome defined. Cephalgia 1986;6:223–8.
S.V. Kothare 7. Abu-Arafeh I, Russell G. Prevalence and clinical features of abdominal migraine compared with those of migraine headache. Arch Disease Childhood 1995;72:413–7. 8. Garcia-Herrero D, Fernandez-Torre JL, Barrasa J, et al. Abdominal epilepsy in an adolescent with bilateral perisylvian polymicrogyria. Epilepsia 1998;39:1370–4. 9. Forbes D, Withers G. Prophylactic therapy in cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr 1995;21(Suppl 1): S57–S9. 10. Li Buk, Balint JP. Cyclical vomiting syndrome: evolution in our understanding of a brain-gut disorder. Adv Pediatr 2000; 47:117–60.