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REVIEW ARTICLE
Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 16-18

Decoding mystery disease “litchi as idiopathic triggering cause of hypoglycemia-induced (LITCHI) encephalitic syndrome” – Are the evidence of association adequate?


1 Department of Community and Family Medicine, AIIMS, Raipur, Chhattisgarh, India
2 Centre for Community Medicine, AIIMS, New Delhi, India
3 Department of Community Medicine, Dr. Baba Saheb Ambedkar Hospital, New Delhi, India

Date of Web Publication4-Jul-2019

Correspondence Address:
Vineet Kumar Pathak
Department of Community and Family Medicine, AIIMS, Raipur, Chhattisgarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJCFM.IJCFM_19_19

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  Abstract 

There has been an increase in reports of outbreak of encephalopathy in children presenting with a syndrome of sudden onset of high fever and altered sensorium in and around the peak of Indian summer months in geographical regions that flourish in Litchi plantation. In the light of the increased mortality and morbidity due to the mystery disease and the speculations surrounding litchi consumptions, a study was conducted in the litchi production hub of Muzaffarpur district Bihar in India by the NCDC in technical collaboration with US CDC. The variables that were significantly associated were litchi consumption (OR: 9.6 [3.8-24.1]), visiting a fruit orchard (OR: 6 [2.7-13.4]), and absence of an evening meal (OR: 2.2 [1.2-4.3]) in the 24-h preceding illness onset. The recommendations that have been advocated are to avoid eating unripe litchi or its seed and always preferring fresh and ripe ones, children should not to go to sleep without a proper dinner meal during the litchi season and cases of altered sensorium should be always be checked for blood glucose levels and prompt correction should be done if levels suggest hypoglycemia in hospitals.

Keywords: Acute encephalitis, children, hypoglycemia, litchi


How to cite this article:
Pathak VK, Yadav K, Majhi J. Decoding mystery disease “litchi as idiopathic triggering cause of hypoglycemia-induced (LITCHI) encephalitic syndrome” – Are the evidence of association adequate?. Indian J Community Fam Med 2019;5:16-8

How to cite this URL:
Pathak VK, Yadav K, Majhi J. Decoding mystery disease “litchi as idiopathic triggering cause of hypoglycemia-induced (LITCHI) encephalitic syndrome” – Are the evidence of association adequate?. Indian J Community Fam Med [serial online] 2019 [cited 2019 Jul 20];5:16-8. Available from: http://www.ijcfm.org/text.asp?2019/5/1/16/262116


  Summary Top


There has been an increase in reports of outbreak of encephalopathy in children recently from the eastern part of India, where it is characterized by a syndrome of sudden onset of fever of high grade and associated with altered sensorium. The reporting of such incidences increases in and around the peak of Indian summer months confined to the geographical regions that flourish in litchi plantation for the past couple of decades.

Etiology of disease was many a times proposed to be of viral (non-Japanese encephalitis [JE] virus) origin,[1] sequelae to heat stroke,[2] emerging bat virus,[3] or the residual after-effects of pesticides.[4] These speculated etiologies are yet to be proven for causality for the outbreak of encephalopathy. These unexplained cases of encephalopathy have been conveniently labeled as “mystery disease” as no definitive clinical diagnosis consistent with the International Classification of Diseases has been made for two decades.

Recent evidence put forwarded by various studies show an association with the litchi fruits belonging to the Sapindaceae family of plants that bear methylenecyclopropylglycine (MCPG) which is an analog of hypoglycin A in the seeds[5],[6],[7] which have the potential to cause hypoglycemia leading to consequent encephalopathy in laboratory animals.[8],[9]

In the light of the increased mortality and morbidity of children due to the mystery disease and the widely believed speculations surrounding litchi consumptions, this study was conducted in the litchi agricultural/harvesting hub of Muzaffarpur district in Bihar, India, by the National Centre for Disease Control in technical collaboration with US Centre for Disease Control.[10] Factors such as presence of infectious pathogen (JE virus, West Nile virus, etc.), pesticides, and heavy metal content were analyzed by collection of samples (blood, urine, and cerebrospinal fluid [CSF]) from cases presenting with the symptoms over a period of 2 consecutive years from 2013 to 2014 and controls over the same period with similar conditions from hospital and community from the surrounding areas.

This was a case–control study in which they have recruited cases and controls from two different hospitals which were the only known hospitals to provide treatment to such mystery disease cases presenting with or referred with acute neurological symptoms in the region. As per protocol of the study design, the cases and controls were matched, with the only differentiating factor that, the controls were without any history of neurological symptoms in present or in their lifetime.

The treating physicians were communicated about the recruitment criteria of “patients aged ≤15 years presenting with new-onset seizures or altered sensorium in the past 7 days,” and the management of each case was guided as per the physicians' discretion which led to the nonuniformity of diagnostic tests in the participants.

Finally, in the summer of 2014 during the months of May–July, 104 cases were selected with 104 matched controls for the study. Probing questionnaire also covered the practices followed by the participants such as consumption of food items, cleaning of food prior consumption, time spent in agricultural fields or litchi orchards, and consumption of a regular dinner meal or litchi.

Blood, CSF, and urine samples were collected for the evaluation of infectious pathogens, pesticides, and heavy metal toxicology along with investigation for hypoglycin A and MCPG in urine samples of the enrolled cases and controls. 64% and 45% of the samples from cases demonstrated the presence of hypoglycin A and its metabolite MCPG in urine samples versus 0 levels in the controls. The independent variables that were significantly associated with the illness on matched bivariate analysis were litchi consumption (matched odds ratio [mOR]: 9.6 [95% confidence interval (CI): 3.8–24.1]), visiting a fruit orchard (mOR: 6 (95% CI: 2.7-13.4)), and absence of an evening meal (mOR: 2.2 [95% CI: 1.2–4.3]) in the 24-h preceding illness onset. Stratified analysis controlled for age and absence of an evening meal in the previous 24 h significantly modified the relation between litchi consumption and illness (OR: 7·8 [95% CI: 3.3–18.8], without evening meal; OR: 3.6 [95% CI: 1.1–11.1] with evening meal).


  Comments Top


A maximum number of cases (37%) were reported during June 8–14 which coincided with the harvesting season where there is abundant litchi on trees. Children often consume them irrespective of ripen or unripen state due to its delicacy. Small children might not be able to distinguish between rotten and ripen litchi fallen on the ground. Parents/guardians of the cases have reported that most of the children had spent their playtime in the litchi orchards prior to presentation in the hospitals with the symptoms of encephalopathy which had a strong association of having a large amount of litchi consumed during the previous day which led to skipping of a regular meal later in the evening and subsequent development of hypoglycemia following early morning due to the high levels of hypoglycin A and its metabolites. This event might have triggered the development of acute neurological syndrome between 3:00 AM and 8:00 AM in the morning precipitating in the form of seizures or altered sensorium in a participant without any previous history of febrile seizures or altered sensorium.

The results of the study may hamper the economy of Indian agriculturists and farmers by labeling the tropical fruit litchi as a precursor agent prone to cause seizure episode in small children consequently reducing the demand of the fruit in the international market by negative publicity and at the same time depriving an agricultural community that have an opportunity to harvest and earn from the ephemeral yields of litchi only for a single season in a year. Now that we are aware of clues and conditions that mediate to cause this “mystery disease,” further studies can be planned to investigate and establish conclusive evidences before labeling litchi to be the seed of the disease.

Thus, litchi consumption by children should be controlled by parents/guardians, especially residing in the vicinity of litchi cultivation areas; they must avoid eating unripe litchi or its seed (as toxins are found in greater amounts in unripe fruits than in fully ripe ones) and should always prefer eating fresh and ripe ones. Furthermore, children should never miss a meal, particularly dinner. In case of any illness during the “season,” the blood glucose levels should be checked “ first/soon after admission” to gain a healthy lead time improving the prognosis of the “mystery disease,” and if required, glucose can be administered promptly to correct low levels during the course of treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Samuel PP, Muniaraj M, Thenmozhi V, Tyagi BK. Entomo-virological study of a suspected Japanese encephalitis outbreak in Muzaffarpur district, Bihar, India. Indian J Med Res 2013;137:991-2.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Sahni GS. The recurring epidemic of heat stroke in children in Muzaffarpur, Bihar, India. Ann Trop Med Public Health 2013;6:89-95.  Back to cited text no. 2
  [Full text]  
3.
Dinesh DS, Pandey K, Das VN, Topno RK, Kesari S, Kumar V, et al. Possible factors causing acute encephalitis syndrome outbreak in Bihar, India. Int J Curr Microbiol Appl Sci 2013;2:531-8.  Back to cited text no. 3
    
4.
Biswas SK; International Centre for Diarrhoeal Diseases Research. Outbreak of illness and deaths among children living near lychee orchards in Northern Bangladesh. Bangladesh ICDDRB Health Sci Bull 2012;10:15-22.  Back to cited text no. 4
    
5.
Shah A, John TJ. Recurrent outbreaks of hypoglycaemic encephalopathy in Muzaffarpur, Bihar. Curr Sci 2014;107:570-1.  Back to cited text no. 5
    
6.
John TJ, Das M. Acute encephalitis syndrome in children in Muzaffarpur: Hypothesis of toxic origin. Curr Sci 2014;106:1184-5.  Back to cited text no. 6
    
7.
Gray DO, Fowden L. Alpha-(Methylenecyclopropyl) glycine from litchi seeds. Biochem J 1962;82:385-9.  Back to cited text no. 7
    
8.
Melde K, Buettner H, Boschert W, Wolf HP, Ghisla S. Mechanism of hypoglycaemic action of methylenecyclopropylglycine. Biochem J 1989;259:921-4.  Back to cited text no. 8
    
9.
Melde K, Jackson S, Bartlett K, Sherratt HS, Ghisla S. Metabolic consequences of methylenecyclopropylglycine poisoning in rats. Biochem J 1991;274(Pt 2):395-400.  Back to cited text no. 9
    
10.
Shrivastava A, Kumar A, Thomas JD, Laserson KF, Bhushan G, Carter MD, et al. Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: A case-control study. Lancet Glob Health 2017;5:e458-66.  Back to cited text no. 10
    




 

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