Cyclic vomiting syndrome versus inborn errors of metabolism: A review with clinical recommendations

Pediatric neurologists are often asked to determine whether a child having spells has a “migraine variant” or a “childhood periodic syndrome”. These migrainous disorders include things like benign paroxysmal torticollis, benign paroxysmal vertigo, abdominal migraine, and cyclic vomiting syndrome (CVS) and are now referred to in the International Classification of Headache Disorders III edition (beta version) as “Episodic syndromes that may be associated with migraine”1. The clinical phenotypes of these childhood periodic syndromes are reviewed in this issue of Headache Currents by Drs. Rothner and Parikh. The purpose of this manuscript is to review the main metabolic disorders, such as inborn errors of metabolism, than can mimic cyclic vomiting syndrome in order to provide the clinician with an overview of the metabolic differential and a practical guide to initial screening tests for these. Cyclic vomiting syndrome is the main migrainous periodic syndrome phenotype that might mimic presentation of a metabolic disorder. Because of some overlap in clinical symptomatology, abdominal migraine might also be thought of similarly. Both of these disorders are now under the same subheading in ICHD-III beta, 1.6.1 Recurrent gastrointestinal disturbance. The other periodic syndromes are unlikely to raise significant suspicion for a metabolic disorder. Benign paroxysmal vertigo attacks are most commonly less than five minutes in duration, thus generally too brief to be a manifestation of a metabolic disturbance1–3. In infants with benign paroxysmal torticollis, the differential is generally focused on seizure, reflux, structural brain lesion, or dystonia1. Glutaric aciduria has reportedly been considered in the differential in infants with benign paroxysmal torticollis, but to our knowledge no case has been reported4. Children with cyclic vomiting syndrome manifest with periodic attacks of nausea with frequent vomiting. Attacks can last from hours to days. Typically attacks have a certain periodicity and are stereotyped within an individual1. Onset is most commonly around age five years5, 6. A personal or family history of migraine is common7 and this relationship has been recognized since the 1800’s8. Abdominal migraine typically has its onset in school-aged children around age seven9. Attacks are characterized by abdominal pain that is dull or “just sore” in quality and peri-umbilical or poorly localized. Children may have associated nausea, vomiting, pallor and anorexia with attacks1. In the child who has prominent abdominal pain and very frequent vomiting during their attacks, the abdominal migraine and cyclic vomiting phenotypes may overlap. From here forward we will just refer to the cyclic vomiting phenotype, but the metabolic evaluation decision-making could be applied in either. For a patient presenting with a cyclic vomiting phenotype, there is a broad differential to consider beyond migraine associated cyclic vomiting syndrome. In addition to inborn errors of metabolism, other potential causes include gastrointestinal, renal10 and epileptic disorders (such as Panayiotopoulus syndrome in a young child11), and in the adolescent or adult patient cannabinoid hyperemesis syndrome would be a possibility12. Another important diagnostic consideration would be migraine itself1. In some children, the vomiting component of attacks may be most prominent and therefore the chief complaint, but careful history taking will reveal that they also have headache and sensitivity features during attacks and meet ICHD criteria for migraine, albeit with a notable periodicity to attacks. It is problematic that the term “cyclic vomiting” may sometimes be used erroneously in the literature to refer to a child or adult whose vomiting pattern is simply recurrent, severe, or frequent. This makes it difficult to determine how often migrainous cyclic vomiting syndrome, in which there is a true periodicity to attacks which are stereotyped in an individual and independent of acute intercurrent illnesses, truly phenotypically overlaps with presentations of recurrent emesis due to inborn errors of metabolism. The concern for metabolic disorders is really about ensuring we do not miss a disorder that could come to cause serious morbidity or mortality down the line in an adult or child who presents with a cyclic or recurrent vomiting phenotype. A key feature of migrainous periodic syndromes is that the children are completely well between attacks. Children with developmental delay, developmental regression, seizures, poor growth, an abnormal neurologic examination, or a progressive clinical course do not fit this phenotype and presence of these features in a child with a cyclic vomiting phenotype should prompt further evaluation for inborn errors and other etiologies.