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To the Editor: The spice Chinese star anise (Illicium verum f Hook) is used in many cultures. Caribbean and Hispanic cultures use a tea infusion of its star-shaped fruit as treatment for infant colic.¹ A closely related species, Japanese star anise (Illicium anisatum L), however, has been reported to cause neurologic and gastrointestinal toxicities.^1-2 Possible adulteration of I verum with I anisatum has led to recalls of these products in several countries.³ During the past 2 years at our institution, 7 cases of adverse neurologic reactions have been reported among infants aged 2 weeks to 3 months who were exposed to star anise tea. The presentation consisted of signs of acute-onset irritability, jitteriness, clonus or myoclonus, increased deep tendon reflexes, nystagmus, vomiting, and seizures. All of the cases had normal laboratory and electroencephalography findings. Symptoms in all of the cases resolved within 24 hours of presentation. None of the infants had further neurologic episodes at follow-up. We were able to obtain samples of the anise from 3 of these cases to determine whether they had been contaminated with I anisatum.

Methods
All fruits were inspected for the defining structures of I anisatum. Following microscopic examination, each sample was ground to a fine powder followed by a modified extraction procedure for anisatin compounds.⁴ The sesquiterpene lactone fraction was isolated, and liquid chromatography mass spectroscopy (LC-MS) analysis was performed (Finnigan Aqua Navigator, San Jose, Calif). The volatile fraction from each sample was also examined for the presence of safrole and eugenol, compounds found in all toxic Illicium species, but not in I verum.⁵ The volatile oil samples were also examined for the presence of anethole, found in I verum in concentrations of 72% to 92%.⁶ Other Illicium species typically have anethole concentrations lower than 40%.⁵ Subsequently, all samples were ground to a fine powder and sealed in gas-chromatography vials with Teflon septa. Solid-phase microextraction (SPME) headspace sampling was used in combination with gas chromatography mass spectroscopy (GC-MS) (Agilent 6890, Palo Alto, Calif).

Results
Microscopic examination of the samples did not prove suitable for a definitive determination of I anisatum adulteration due to inherent variation observed in the hundreds of I verum fruits examined. In the volatile compound isolation from the first case, anethole was found to comprise at least 75% of the essential oil. It was impossible to discern whether safrole was present in low concentration since the separation equipment could not resolve the safrole peak from anethole, when anethole is present in high concentrations. Chromatographic analysis of samples from the second case detected eugenol, although anethole was again found in high concentrations, preventing the identification of safrole. The volatile compound profile in the third case was significantly different from that in the first 2 cases, due to the presence of safrole and eugenol with a low concentration of anethole.

Analysis by LC-MS of the sesquiterpene lactone fraction of each sample was performed to determine the presence of anisatin, neoanisatin, and veranisatins A, B, and C. Anistatin and neoanisatin are potent neurotoxins found in I anisatum.⁴ Although I verum is considered safe for consumption, this species also contains the toxic compounds, veranisatin A, B, and C.⁷ Anisatin compounds are thought to act as picrotoxin-like noncompetitive -aminobutyric acid (GABA) antagonists.⁸ The mass spectral pattern of each sample was similar in the number, type, and concentration of these compounds. Extracts from the third case, however, suggested the presence of an Illicium species other than I verum.

Comment
Given our laboratory findings, the symptoms we have described may be attributed to an overdose of I verum, contamination with I anisatum, or a combination of both. Illicium verum has been considered safe because it contains veranisatins in low concentrations.⁷ However, relatively small quantities in infants may be sufficient to produce adverse neurologic reactions.⁹

Ingestion of star anise should be considered in the differential diagnosis of infants presenting with acute-onset irritability, vomiting, and seizures. Based on these cases and the finding of I verum contamination, we recommend against administering star anise to infants. Stricter regulation may also be warranted.

Diego Ize-Ludlow, MD
Department of Pediatrics
Miami Children's Hospital
Miami, Fla

Sean Ragone, MD; Jeffrey N. Bernstein, MD
Florida Poison Control Center
Jackson Memorial Hospital
University of Miami School of Medicine

Isaac S. Bruck, PhD
Center for Ethnobiology and Natural Products
Florida International University
Miami

Michael Duchowny, MD
Department of Neurology
Miami Children's Hospital
University of Miami School of Medicine

Barbara M. Garcia Peña, MD, MPH
barbara.pena{at}mch.com
Division of Emergency Medicine
Miami Children's Hospital

1. Garzo Fernandez C, Gomez Pintado P, Barrasa Blanco A, Martinez Arrieta R, Ramirez Fernandez R, Ramon Rosa F, Grupo de Trabajo del Anis Estrellado. Cases of neurological symptoms associated with star anise consumption used as a carminative [in Spanish]. An Esp Pediatr. 2002;57:290-294. PUBMED 2. Biessels GJ, Vermeij FH, Leijten FS. Epileptic seizure after a cup of tea: intoxication with Japanese star anise. Ned Tijdschr Geneeskd. 2002;146:808-811. PUBMED 3. 2002/75/EC: Commission Decision of 1 February 2002 laying down special conditions on the import from third countries of star anise (notified under document number C[2002] 379). Off J Eur Communities. 2002:L33-L34. 4. Yamada K, Takada S, Nakamura S, Hirata Y. The structures of anisatin and neoanisatin: toxic sesquiterpenes from Illicium anisatum L. Tetrahedron. 1968;24:199-229. FULL TEXT 5. Okuyama E, Nakamura T, Yamazaki M. Convulsants from star anise (Illicium verum Hook. F.). Chem Pharm Bull (Tokyo). 1993;41:1670-1671. PUBMED 6. Kudo Y, Oka JI, Yamada K. Anisatin, a potent GABA antagonist, isolated from Illicium anisatum. Neurosci Lett. 1981;25:83-88. FULL TEXT | ISI | PUBMED 7. Cok WB, Howard AS. The essential oil of Illicium anisatum. Can J Chem. 1966;44:2461-2464. 8. Shinozaki H, Ishida M, Kudo Y. Effects of anisatin on the GABA action the crayfish neuromuscular junction. Brain Res. 1981;222:401-405. FULL TEXT | ISI | PUBMED 9. Montoya-Cabrera MA. Poisoning by star anise (Illicium verum) tea [in Spanish]. Gac Med Mex. 1990;126:341-342. PUBMED

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2004;291:562-563.

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