Anastasia Martinez-Esteve Melnikova1&Michela G. Schäppi2&Christian Korff1
Received: 31 March 2015 / Revised: 8 July 2015 / Accepted: 13 July 2015
#Springer-Verlag Berlin Heidelberg 2015
Abstract Cyclic vomiting syndrome is an episodic disor-der considisor-dered to be a migraine variant. Riboflavin is efficient in the prophylactic treatment of migraines in adults. We describe the effectiveness and tolerance of ri-boflavin treatment in three children with cyclic vomiting syndrome. All of them fulfilled the diagnosis criteria for cyclic vomiting syndrome. They received prophylactic monotherapy with riboflavin for at least 12 months.
Excellent response and tolerability was observed.
Conclusion: Based on clinical observation in three cases, riboflavin may be an effective and safe prophylactic treatment for children with cyclic vomiting syndrome.
What is Known:
•CVS is one of the“childhood periodic syndromes”classified as a migraine subtype by the International Headache Society.
•Riboflavin is currently used as a prophylactic treatment in patients with migraine.
What is New:
•Riboflavin may be an effective and safe prophylactic treatment for children with CVS.
•Increasing doses of riboflavin and long periods of prophylaxis may be needed in some children..
Keywords Cyclic vomiting syndrome . Migraine . Riboflavin . Periodic syndromes . Children
Abbreviations
Cyclic vomiting syndrome (CVS) is a periodic syndrome characterized by stereotyped recurrent episodes of vomiting separated by symptom-free periods [14]. It is a severe and debilitating condition that often requires extensive evalua-tions, repeated hospitalizaevalua-tions, and long-term psychological support. Diagnosis is based on the description of the clinical presentation and the exclusion of secondary etiologies. It can affect patients of all age categories. Its prevalence is estimated at 1.9 to 2.3 % of school children [15].
The International Headache Society classifies CVS as a migraine subtype—one of the “childhood periodic syn-dromes”that also include abdominal migraine, benign parox-ysmal vertigo of childhood, and benign paroxparox-ysmal torticollis (ICHD-II Appendix1.3.3) [14,10]. These paroxysmal condi-tions of childhood are reported to precede the subsequent ap-pearance of migraine in later childhood [14,10].
The etiology of CVS remains unknown. Like for migraine, one hypothesis is an acute deficient supply of mitochondrial energy reserves in stressful situations, as a result of mtDNA mutations [6]. Riboflavin (vitamin B) is a cofactor involved Revisions received: 04 June 2015 / 09 July 2015
* Anastasia Martinez-Esteve Melnikova
1 Pediatric Neurology, Child and Adolescent Department, Geneva University Hospitals, Geneva, Switzerland
Eur J Pediatr
DOI 10.1007/s00431-015-2597-2
used as a prophylactic treatment in patients with migraine [13, 22].
No data about riboflavin prophylaxis for pediatric CVS was found using the keywords “riboflavin” and “cyclic vomiting”in a PubMed search; all resources being solicited without restriction. We report on the effectiveness and toler-ance of riboflavin treatment in three children with CVS.
Case reports Patient 1
This 12-year-old boy was suffering from attacks of vomiting since the age of 2 months. He initially vomited sporadically at irregular intervals; since the age of 1 year, he started vomiting several times per episode and presented up to 20 episodes per day at intervals of 1 week. Between the age of 7 and 9 years, the episodes were less frequent and more irregular.
The patient was otherwise healthy and developing normal-ly. He did not complain of headache. He did not present any academic or behavioral problems. Medical history revealed that he was positive for hepatitis C, probably transmitted dur-ing pregnancy. No further information about the patient’s fam-ily was available, as he had been adopted at 6 months.
At 9 years, he was hospitalized due to an exacerbation of vomiting episodes (up to 20 per day), accompanied by slight hematemesis. An esophagogastroduodenoscopy showed mild gastroesophagitis, a gastric biopsy showed no evidence for Helicobacter pylorior malignancy, and esophageal pH mon-itoring showed functional dyspepsia. Metabolic tests and CNS imaging were normal (Table1). The patient was discharged with the diagnosis of CVS and was prescribed a prophylactic treatment of cyproheptadine (8 mg twice/day) and an acute treatment of nasal sumatriptan (10 mg/dose). Both treatments were abandoned, as no efficacy was observed after four addi-tional episodes.
At his first visit to our unit, at 12 years, vomiting episodes were occurring every 7–10 days, proceeded by nausea, head-ache, and tiredness. They began around 5 a.m., lasted 24–72 h, and were triggered by stress. Oral riboflavin was prescribed in monotherapy as a compounded medication at the dose of 20 mg twice a day. Although the episodes decreased to one episode per 15 days, the dose was increased to 400 mg/day after 1 year of treatment. At the age of 14 years, i.e., 24 months after beginning the treatment, he presented one single and mild vomiting episode every 3 months. Therapeutic compli-ance was good, per parents’report.
Patient 2
This 12-year-old girl had presented with recurrent attacks of vomiting since the age of 7 years. She presented two vomiting
episodes per month, each one lasting for 2–4 days, but was completely asymptomatic between attacks. A few isolated ep-isodes had appeared during a plane flight. No other apparent physical or psychological precipitating factors were detected.
The patient had a history of esophageal atresia operated on the second day of life and reoperated at 9 months for esoph-ageal narrowing. Since then, she was treated with omeprazole.
She also had scoliosis and strabismus and required a psychi-atric follow-up for depression. Family history was positive for migraines in her mother.
An extensive evaluation excluded secondary narrowing and vestibular dysfunction, as well as other common differen-tial diagnoses (Table1). She was diagnosed with CVS at 12 and a prophylactic treatment of riboflavin was administered, prescribed as a compounded medication. She received doses of 30 mg twice a day for 1 month. Although the episodes were shorter, with duration of 2 to 3 h, they were still observed at the frequency of three episodes in 2 months. The doses were increased to 50 mg twice a day, and, after 1 month, to 400 mg/
day. After 15 months of treatment with good compliance per parents’report, not a single episode of vomiting had been reported.
Patient 3
This 4-year-old girl presented stereotyped recurrent attacks of vomiting every 2–3 weeks since the age of 3 years. The epi-sodes usually began early in the morning or at night and could last 24–36 h. During these attacks, she also complained of unusual tiredness, loss of appetite, and headaches. She was completely asymptomatic between episodes.
The patient was carrying a ventriculoperitoneal (VP) shunt for hydrocephalus that had developed following a perinatal intraventricular hemorrhage. She also presented a mild devel-opment delay. A history of migraine was present in several members of the family.
Multiple investigations were realized during repeated hos-pitalizations, notably to exclude intracranial hypertension sec-ondary to VP shunt dysfunction: the several CT-scans that were performed never showed any signs consistent with that diagnosis; the drainage system was nevertheless completely revised and changed, which did not improve the clinical pre-sentation. Basic metabolic tests were normal, as well as all additional blood tests performed (Table1).
CVS was diagnosed at the age of 4 and the patient was prescribed prophylactic monotherapy with riboflavin at 10 mg/day (VITAMINE B2 Streuli® drag 10 mg) for 12 months. The compliance was good, per parent’s report.
The patient presented her last vomiting episode 10 days after the beginning of the treatment. Since then, no other episodes of vomiting or headache occurred during the 4 years that followed cessation of treatment.
Eur J Pediatr
Discussion
Our three pediatric patients fulfilled the diagnostic criteria for CVS [14]. The extensive evaluations (Table 1), real-ized during the acute episodes, and the spontaneous re-covery of the three children allowed excluding other eti-ologies, such as infectious diseases, electrolyte and acid-base imbalance, bowel obstruction, hepatitis, pancreatitis, biliary and urinary tracts anomalies, gallbladder disease, increased intracranial pressure and inborn errors of metab-olism [14]. Patient 2 and patient 3 benefited of additional evaluations in order to exclude any complication of their underlying problems that could have alternatively ex-plained the vomiting episodes.
Based on the mitochondrial hypothesis explained below and the benefits observed in adults with migraine in some studies [2,17,23], we used riboflavin as prophylactic treat-ment in our patients. Riboflavin was administered alone (i.e., not as part of a multivitamin preparation), in monotherapy and for at least 12 months in all of them. The elder patients (pa-tients 1 and 2) received increasing doses of riboflavin two times a day and up to 400 mg/day, the maximal dose utilized in previous studies with adult’s migraine and in patients with mitochondriopathies [19, 21, 23, 24]. The youngest patient (patient 3), who received smaller doses, rapidly showed pos-itive results. Based on parents’report, the compliance was
noticed in one patient and a complete disappearance of symp-toms was observed in the other two, without adverse effects.
The pathophysiology of migraine remains incompletely understood. However, biochemical studies and studies with phosphorus magnetic resonance spectroscopy (31P-MRS) have shown the presence of an impairment of the brain oxida-tive energy metabolism in patients with migraine. These find-ings suggest a dysfunction of mitochondria in the brain of patients with migraine, decreasing its ability to respond to bigger energy demand during interactions with environmental triggers [1,25]. On this basis, certain authors proposed ribo-flavin as a prophylactic treatment in migraine [18,23].
Riboflavin is a precursor of flavin mononucleotide and flavin-adenosine-dinucleotide, cofactors for multiple reduction-oxidation enzymes that play important roles in ox-idative reactions in mitochondria respiratory chain complexes.
This mechanism suggests that replenishing migraine patients’
mitochondrial energy stores using riboflavin could influence mitochondrial phosphorylation. Administering riboflavin in patients with classic mitochondriopathies has been shown to bring clinical and biochemical improvement [19, 21, 24].
Similarly, the efficacy and safety of riboflavin in migraine have been described in several studies [2,17,23]. Studies in adults showed more promising results than those in children [7,9,16]. It is possible that methodological difficulties and pharmacokinetic consideration of riboflavin could explain Table 1 Evaluation in three patients with CVS
Patient 1 Patient 2 Patient 3
Blood tests Blood count, Na, K, Cl, Mg, calcium, phosphate, glucose, ammonium, lactate, creatinine, BUN, acid-base status.
Blood count, Na, K, Cl, Mg, calcium, phosphate, glucose, ammonium, lactate, acid-base status.
Blood count, Na, K, Cl, Mg, calcium, phosphate, glucose, ammonium,
Metabolic tests Plasma and urine amino acids. Urine organic acids. Acylcarnitine profile analysis.
– Plasma and urine amino acids. Urine
organic acids.
Abdominal ultrasound. Abdominal X-ray. Abdominal X-ray.
24-h esophageal pH monitoring:
functional dyspepsia.
– –
CNS evaluation Cerebral computed tomography. – Cerebral computed tomography.
Fundoscopic examination. Fundoscopic examination. Fundoscopic examination.
Cerebral MRI. Cerebral MRI. Cerebral MRI.
– – Shuntography.
Others – Vestibular functions. –
BUNblood urea nitrogen,ASTaspartate transaminase,ALTalanine transaminase,CNScentral nervous system Eur J Pediatr
evidence on this subject, the American Academy of Neurology and the Canadian Headache Society have recog-nized riboflavin as a prophylactic treatment for migraine pa-tients [13,22].
Given the fact that CVS is classified as a subtype of mi-graine, the question as to whether beneficial effects of ribofla-vin might be observed in CVS patients seems legitimate.
Different etiological hypotheses about the pathogenesis of CVS were proposed in recent years. Certain authors proposed that energy deficits due to mitochondrial dysfunction could initiate the vomiting cascade in individuals with CVS, under common stress conditions, such as infections or psychological stress [6,15]. As CVS is frequently associated with a familial history of migraine in mothers, researchers have explored the possibility of a maternal inheritance of mitochondrial diseases in patients with CVS [4]. mtDNA is generally derived from the ovum. Consequently, individuals related through females share the same mtDNA sequence. In light of this, variations in any mtDNA’s 37 genes, all-critical for oxidative phosphory-lation, could represent risk factors for the development of CVS. Indeed, certain mtDNA polymorphisms were found to be associated with CVS [29, 30]. These data suggest that energy metabolism is an important factor in CVS pathogene-sis, theoretically justifying the use of therapies directed at mitochondrial function. Two mitochondrial-targeted cofac-tors, L-carnitine and coenzyme Q10, have already showed their utility in the prophylactic treatment of CVS [3,5,18,28].
To our knowledge, there is no consensus for prophylactic treatment in CVS in children. Mostly based on small retro-spective clinical series of evidence level II, the North Am erican Society o f Pediatric Gast roent erol ogy, Hepatology, and Nutrition recommends cyproheptadine or propranolol as prophylaxis for children younger than 5 years old and amitriptyline or propranolol for older ones [14]. Other studies also recommend phenobarbital. Unfortunately, all pro-phylactic drugs cited above have potential side effects that may preclude their widespread use in children. In that perspec-tive, riboflavin is of particular interest.
Our observations suggest that riboflavin may be an effec-tive and safe prophylactic treatment for children with CVS.
They also bring additional data about potential beneficial ef-fect of increasing doses of riboflavin in children and suggest that long periods of prophylaxis may be needed in some patients.
Based on the controversial results of previous studies about riboflavin’s efficacy in migraine patients, conclusions would need to be drawn in that disease prior to the development of prospective trials about the efficacy of riboflavin in CVS.
Most of the studies in migraine patients report doses of ribo-flavin between 200 and 400 mg/day in one single administra-tion, following data presented for mitochondrial diseases [12, 16, 17,23]. However, pharmacokinetic data show that the maximal absorption dose of riboflavin in humans is 27 mg
with saturation doses at 30–50 mg and a half-life of 1–2 h [26]. This observation suggests that multiple daily dosing might be required to achieve better efficacy, implying a pos-sible cumulative effect of riboflavin in the mitochondrial stocks. Longer duration of therapy also might be needed in certain patients. Trials designed for a maximum period of 3 months showed controversial results on efficacy of ribofla-vin in migraine, while those designed for more than 3 months showed positive results [2, 9]. This suggests that specific doses of riboflavin might differ from one patient to the next.
In that perspective, one may consider dosing serum levels of riboflavin before and during treatment in each patient in order to determine personal effective serum levels [20].
We did not perform any molecular analysis of mtDNA in our patients. Investigating a potential relationship between specific mtDNA haplogroups and therapeutic response to ri-boflavin in CVS patients may nevertheless be of particular interest, as already studied in migraine patients [11]. Finally, functional and metabolic cerebral imaging studies, such as 31P-MRS, before and under riboflavin administration may also be helpful to understand the pathogenesis of CVS and the effect of riboflavin.
Since our case series is a small observational study, larger-scale double-blind prospective studies of CVS patients are needed to confirm our experience.
Acknowledgments We would like to thank Dr. Charles-Antoine Haenggeli for his careful revision of the manuscript before its initial submission.
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing interests.
Ethical approval This article does not contain any studies with animals performed by any of the authors. For this type of study, formal consent is not required.
Funding source None.
Financial disclosure The authors have no financial relationships rele-vant to this article to disclose.
Authors’contributions Anastasia Martinez-Esteve Melnikova con-tributed to the acquisition, analysis, and interpretation of data; carried out the literature search; conceptualized and designed the study; drafted and critically reviewed the manuscript; and approved the final manuscript as submitted. Dr Schäppi contributed to the acquisition, analysis, and interpretation of data, and to the conceptualization and design of the study; critically reviewed the manuscript and approved the final manu-script as submitted. Christian Korff contributed to the coordination and supervision of data collection at the three sites of acquisition, to the analysis and interpretation of data, to the conceptualization and design the study, and to the review and revision of the manuscript and approved the final manuscript as submitted.
Eur J Pediatr
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