Lychee-associated acute hypoglycaemic encephalopathy outbreaks in Muzaffarpur, India
Authors: Mukul Das, T Jacob John
Journal: The Lancet Global Health (2017)

The article by Aakash Shrivastava and colleagues in The Lancet Global Health (April, 2017)1Shrivastava A Kumar A Thomas JD et al.Association of acute encephalopathy with litchi consumption in an outbreak in Muzzaffarpur, India, 2014: a case control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar is timely, and presents an important finding: validation of lychee-associated hypoglycaemic encephalopathy. First described in India,2John TJ Das M Acute encephalitis syndrome in children in Muzaffarpur: hypothesis of toxic origin.Curr Sci. 2014; 106: 1184-1185Google Scholar, 3Shah A John TJ Recurrent outbreaks of hypoglycaemic encephalopathy in Muzaffarpur, Bihar.Curr Sci. 2014; 107: 570-571Google Scholar, 4Das M Asthana S Singh SP Dixit S Tripathi A John TJ Litchi fruit contains methylene cyclopropyl-glycine.Curr Sci. 2015; 109: 2195-2197Crossref Google Scholar the disease is caused by lychee (also spelled litchi) consumption after a prolonged fast by undernourished children due to the presence of a hypoglycaemic agent, methylene cyclopropyl glycine (MCPG). The President of the Indian Academy of Pediatrics expressed scepticism when cases of encephalopathy were first linked with lychee consumption in 2014.5Yewale V Misery of mystery of Muzaffarpur.Indian Pediatr. 2014; 51: 605-606Crossref PubMed Scopus (9) Google Scholar The different methodological approaches to the problem, by the Indian National Centre for Disease Control (NCDC) and our research group, offer important lessons in the investigation of diseases of unknown cause. Researchers had been investigating the annually recurring, seasonal outbreaks of CNS disease with high case fatality in children in the Muzaffarpur district of Bihar for nearly two decades.6Directorate General of Health Services, Ministry of Health and Family Welfare, Governemnt of India. Report on the national programme for prevention and control of Japanese encephalitis (JE)/acute encephalitis syndrome (AES). New Dehli, India; 2014.Google Scholar The NCDC assumed the outbreak to be viral encephalitis, because, superficially, it resembled Japanese encephalitis, which is very common in India.7National Centre for Disease Control. Outbreak of acute encephalitis syndrome in Bihar, 2012. NCDC Newsletter 2012; 1 (Oct): 3–4.Google Scholar, 8Srikantiah P. Outbreak of acute neurological syndrome in Muzaffarpur, Bihar, 2013. National Centre for Disease Control Newsletter, 2013; 2 (Sept): 1–3.Google Scholar, 9Srikantiah P, Shrivastava A. NCDC-CDC Muzaffarpur encephalopathy outbreak investigations, 2013–2014. National Centre for Disease Control Newsletter; 2014, 3 (Sept): 6–7.Google Scholar No prevention or treatment could be proposed without a diagnosis.9Srikantiah P, Shrivastava A. NCDC-CDC Muzaffarpur encephalopathy outbreak investigations, 2013–2014. National Centre for Disease Control Newsletter; 2014, 3 (Sept): 6–7.Google Scholar Meanwhile, the media accused the Bihar State Health Ministry of neglect and inaction; and, consequently, in 2012, the Bihar State Health Ministry asked a paediatric infectious disease specialist (T Jacob John) for urgent help. A small team was formed in response, which took an entirely different (and rapidly fruitful) approach during the next (2013) outbreak season.2John TJ Das M Acute encephalitis syndrome in children in Muzaffarpur: hypothesis of toxic origin.Curr Sci. 2014; 106: 1184-1185Google Scholar Common CNS diseases in children are classified into diagnostic categories with mutually exclusive criteria: encephalitis (ie, mostly viral), encephalopathy (ie, mostly biochemical or toxic), meningitis (ie, pyogenic, tuberculous, or viral), and cerebral malaria. In 2013, we clinically classified the disease to guide our search for a cause—infectious or otherwise. We diagnosed the outbreak disease, unequivocally, as encephalopathy, which was non-infectious and biochemical in pathogenesis.2John TJ Das M Acute encephalitis syndrome in children in Muzaffarpur: hypothesis of toxic origin.Curr Sci. 2014; 106: 1184-1185Google Scholar, 3Shah A John TJ Recurrent outbreaks of hypoglycaemic encephalopathy in Muzaffarpur, Bihar.Curr Sci. 2014; 107: 570-571Google Scholar, 4Das M Asthana S Singh SP Dixit S Tripathi A John TJ Litchi fruit contains methylene cyclopropyl-glycine.Curr Sci. 2015; 109: 2195-2197Crossref Google Scholar The disease closely resembled metabolic coma of acyl-CoA dehydrogenase deficiency and ackee-related Jamaican vomiting sickness, due to interrupted fatty acid β-oxidation cycle and neo-glucogenesis.2John TJ Das M Acute encephalitis syndrome in children in Muzaffarpur: hypothesis of toxic origin.Curr Sci. 2014; 106: 1184-1185Google Scholar, 10Saudubray J-M Desguerre I Sedel F Charpentier C A Clinical approach to inherited metabolic diseases.in: Fernandes J Saudubray J-M van den Burghe G Walter JH Inborn Metabolic Diseases, Diagnosis and Treatment. Springer Medizin Verlag, Heidelberg2006: 1-96Crossref Scopus (67) Google Scholar, 11Tanaka K Kean EA Johnson B Jamaican vomiting sickness: biochemical investigations of two cases.New Eng J Med. 1976; 295: 461-467Crossref PubMed Scopus (162) Google Scholar, 12Melde K Buettner H Boschert W Wolf HPO Ghisla S Mechanism of hypoglycaemic action of methylenecyclopropylglycine.Biochem J. 1989; 259: 921-924Crossref PubMed Scopus (39) Google Scholar, 13Melde K Jackson S Bartlett K Sherratt HAS Ghisla S Metabolic consequences of methylenecyclopropylglycine poisoning in rats.Biochem J. 1991; 274: 395-400Crossref PubMed Scopus (58) Google Scholar The outbreak disease had spatial and temporal distribution that matched the seasonal lychee fruit harvest. Other investigators thought the pattern to be irrelevant, or suggestive of viruses from fruit bats or insecticides as the causative agents; however, to us, the association provided a clue to the true nature of the disease. To see this picture clearly, we had to separate the outbreak disease from the background noise of encephalitis, meningitis, and cerebral malaria. The non-sporadic prevalence pattern of the cases of encephalopathy precluded genetic inborn errors of metabolism.10Saudubray J-M Desguerre I Sedel F Charpentier C A Clinical approach to inherited metabolic diseases.in: Fernandes J Saudubray J-M van den Burghe G Walter JH Inborn Metabolic Diseases, Diagnosis and Treatment. Springer Medizin Verlag, Heidelberg2006: 1-96Crossref Scopus (67) Google Scholar Our literature search revealed that ackee and lychee belong to one plant family—Sapindaceae—and that lychee seeds contain MCPG, which is an analogue of ackee's hypoglycin A (methylene cyclopropyl alanine).2John TJ Das M Acute encephalitis syndrome in children in Muzaffarpur: hypothesis of toxic origin.Curr Sci. 2014; 106: 1184-1185Google Scholar Thus, the association of the disease with the lychee harvest became clearer. In India, lychee fruit in bunches are saleable, but single fruits that fall to the ground are collected by children, who then eat and share the fruit with friends. Once we identified MCPG in the edible lychee fruit pulp,4Das M Asthana S Singh SP Dixit S Tripathi A John TJ Litchi fruit contains methylene cyclopropyl-glycine.Curr Sci. 2015; 109: 2195-2197Crossref Google Scholar which was named as hypoglycin G, life-saving treatment and preventive interventions were immediately obvious.3Shah A John TJ Recurrent outbreaks of hypoglycaemic encephalopathy in Muzaffarpur, Bihar.Curr Sci. 2014; 107: 570-571Google Scholar, 4Das M Asthana S Singh SP Dixit S Tripathi A John TJ Litchi fruit contains methylene cyclopropyl-glycine.Curr Sci. 2015; 109: 2195-2197Crossref Google Scholar Before the next outbreak season, we trained all 32 primary health centre medical officers in Muzaffarpur district to recognise encephalopathy early, and to intravenously administer 10% dextrose after the collection of blood for glucose monitoring. Using rural health workers, the Bihar State Health Ministry conducted a public education campaign to encourage parents and carers not to let any child go to sleep without a cooked meal (to avoid long periods of fasting) and to increase parental supervision to minimise lychee consumption by small children (to minimise MCPG ingestion).4Das M Asthana S Singh SP Dixit S Tripathi A John TJ Litchi fruit contains methylene cyclopropyl-glycine.Curr Sci. 2015; 109: 2195-2197Crossref Google Scholar We have been informed that the interventions were successful, and a reduction in disease incidence and deaths of affected children were reported (unpublished minutes of Bihar State Health Ministry Task Force meeting, Nov 29, 2016). The NCDC has now provided evidence in support of our diagnosis of blocked fatty acid β-oxidation cycle, through the documentation of the evidence of organic acidaemia and aciduria in affected children.1Shrivastava A Kumar A Thomas JD et al.Association of acute encephalopathy with litchi consumption in an outbreak in Muzzaffarpur, India, 2014: a case control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar Our success illustrates the importance of methodological appropriateness for the investigation of outbreaks of unknown cause. Based on the evidence,2John TJ Das M Acute encephalitis syndrome in children in Muzaffarpur: hypothesis of toxic origin.Curr Sci. 2014; 106: 1184-1185Google Scholar, 3Shah A John TJ Recurrent outbreaks of hypoglycaemic encephalopathy in Muzaffarpur, Bihar.Curr Sci. 2014; 107: 570-571Google Scholar, 4Das M Asthana S Singh SP Dixit S Tripathi A John TJ Litchi fruit contains methylene cyclopropyl-glycine.Curr Sci. 2015; 109: 2195-2197Crossref Google Scholar, 7National Centre for Disease Control. Outbreak of acute encephalitis syndrome in Bihar, 2012. NCDC Newsletter 2012; 1 (Oct): 3–4.Google Scholar, 8Srikantiah P. Outbreak of acute neurological syndrome in Muzaffarpur, Bihar, 2013. National Centre for Disease Control Newsletter, 2013; 2 (Sept): 1–3.Google Scholar, 9Srikantiah P, Shrivastava A. NCDC-CDC Muzaffarpur encephalopathy outbreak investigations, 2013–2014. National Centre for Disease Control Newsletter; 2014, 3 (Sept): 6–7.Google Scholar it is our judgment that the NCDC asked, “Which virus?”; we asked, “What disease?” The NCDC's approach was research without a sense of urgency—ours was clinical medicine with the immediate goal of diagnosis, treatment, and prevention tailored to cause and risk factors. The NCDC's definition of the disease was too broad, and was meant for high sensitivity (and hence low specificity) as shown in The Lancet Global Health paper1Shrivastava A Kumar A Thomas JD et al.Association of acute encephalopathy with litchi consumption in an outbreak in Muzzaffarpur, India, 2014: a case control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar—cases with and without cerebrospinal pleocytosis and with and without clinical features of metabolic coma of early morning onset and rapid deterioration were included among cases, and children without CNS disease included as controls.1Shrivastava A Kumar A Thomas JD et al.Association of acute encephalopathy with litchi consumption in an outbreak in Muzzaffarpur, India, 2014: a case control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar A case–control study should be uncontaminated with non-cases, for which specificity of case definition is sacrosanct. This error was a continuation of the NCDC's inability to arrive at a clinical diagnosis over many years. Further, as highlighted by Spencer and Palmer14Spencer PS Palmer VS The enigma of litchi toxicity: an emerging health concern in Southeast Asia.Lancet Glob Health. 2017; 5: e383-e384Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar in the same issue of The Lancet Global Health, Srivastava and colleagues did not compare lychee-associated cases with controls from the same community: cases were compared with sick controls and admitted to a case-surveillance hospital less than 7 days from admission of the case. In their research, the NCDC used children admitted to two local hospitals—Sri Krishna Medical College Hospital and Deviprasad Krishnadevi Kejriwal Hospital—but did not include a co-investigator from either hospital.1Shrivastava A Kumar A Thomas JD et al.Association of acute encephalopathy with litchi consumption in an outbreak in Muzzaffarpur, India, 2014: a case control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar Neither of the hospitals were included among the 13 institutions represented by 51 authors of The Lancet Global Health paper.1Shrivastava A Kumar A Thomas JD et al.Association of acute encephalopathy with litchi consumption in an outbreak in Muzzaffarpur, India, 2014: a case control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar Treating clinicians were not acknowledged and thanked by name, which we believe was highly unethical. We declare lychee to be a safe fruit, which is non-toxic to adults and well-nourished children. We thank Bihar State Health Ministry officials for their confidence reposed in us and full support, lychee farmers, parents of affected children, older siblings of children who fell ill, neighbours of such families, lychee-harvesting families, and a number of physicians and paediatricians—all of whom gave us valuable information. We also thank Maya Thomas, Professor of Paediatric Neurology, Christian Medical College, Vellore, for advising us on inborn enzyme defects of fatty acid β-oxidation. We declare no competing interests. Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control studyOur investigation suggests an outbreak of acute encephalopathy in Muzaffarpur associated with both hypoglycin A and MCPG toxicity. To prevent illness and reduce mortality in the region, we recommended minimising litchi consumption, ensuring receipt of an evening meal and implementing rapid glucose correction for suspected illness. A comprehensive investigative approach in Muzaffarpur led to timely public health recommendations, underscoring the importance of using systematic methods in other unexplained illness outbreaks. Full-Text PDF Open AccessLychee-associated acute hypoglycaemic encephalopathy outbreaks in Muzaffarpur, India – Author's replyAs we acknowledged in our study,1 research from T Jacob John and Mukul Das, and others2–4 have contributed essential points to the discussion of the acute toxic encephalopathy outbreaks in Muzaffarpur. Full-Text PDF Open Access