The death of more than 130 children in Muzaffarpur, Bihar during the summer months of 2019 due to Acute encephalitis syndrome (AES) has raised an intense debate on the probable etiology of the killer disease. The recurrent outbreaks of the disease are reported since 1995, and several attempts have already been made by the different teams to clinch the exact etiology [1,2]. The key recent investigations were performed by three sets of expert-groups – John, et al. [3], the Natioal Center for Disease Control (NCDC), India, and Centre for Disease Control (CDC), United State (US) group [4], and by the pediatrician in-charge of Shri Krishna Medical College Hospital (SKMCH), Muzaffarpur [5]. While the first two groups identified litchi toxins, namely methylene cyclopropylglycine (MCPG) and methylene cyclopropy-lalanine (MCPA or hypoglycin A), responsible for the development of an acute hypoglycemic encephalopathy (AHE) amongst malnourished, poor, rural children [3,4], the latter suggested extremely high environmental temperature and humidity in the region resulting in ‘heat stroke’ that led to encephalopathy [5]. Due to the lack of documented hyperpyrexia in all the cases, and early morning onset of symptoms, there were few takers for the heat stroke theory. The litchi-toxins theory was more acceptable and the Bihar State Health Ministry started following the preventive measures as suggested by the groups who put forward this theory. The number of cases and deaths declined sharply in the following four years, 2015 to 2018 only to resurface in a much significant number in 2019.

A previous similar recurrent epidemic in many districts of Western Uttar Pradesh (UP), the so-called ‘Saharanpur encephalitis’ [6], was investigated by an independent group of investigators and the etiology was identified as toxicity due to oral ingestion of a local weed [7]. There are many similarities between the western UP and Muzaffarpur outbreaks; yet the approach, investigations and the outcomes are quite different (Table I).

TABLE I Comparative Analysis of Investigations of Western UP Aka ‘Saharanpur’ and ‘Muzaffarpur’ Outbreaks

In the Western UP outbreak, step-wise investigation approach was adopted and as a first step a proper ‘case definition’ with exclusion and inclusion criteria was formed. Based on its strict application, the disease was initially identified as an encephalopathy [6]. The next step was the histopathological examination of few target organs, which hinted toward toxin-mediated necrosis of liver and muscles (thus the term (acute hepato-myoencephalopathy (HME) syndrome) [6,7]. The differences in approaches in the two outbreak investi-gations are presented in (Table I).

With the re-emergence of the outbreak in Muzaffarpur this year, the debate on the exact etiology has reignited. While the role of any microbiological agent as the main trigger has been abandoned by most investigators, the focus is now on the litchi toxins and heat stroke as probable theories. Despite many ‘missing links’ like inconsistent findings of hypoglycemia and hyperthermia, lack of profuse vomiting (a hallmark of MCPA toxicity), ‘mismatched’ seasonality (paucity of unripe fruits at the peak of the outbreaks when the entire crop is matured), no clarity on toxic levels (LD50) of toxins that cause dose-dependent toxicity, occurrence in children too young to eat the fruit, lack of hepatic dysfunctions despite mitochondrial involvement, flawed selection of controls in case-control study, lack of study of toxins in the body fluids of healthy siblings and peers living in the same household or village, the doubtful role of rapid correction of hypoglycemia on prevention of deaths, the litchi toxin theory was considered as the most plausible one.

A detailed case-control study in western UP helped in identifying the putative toxin which turned out to be anthraquinone derivatives contained in the beans of the weed, Cassia occidentalis [7]. Previous published literature confirmed the biological plausibility of causation in vertebrates. The cause-effect relationship of the Cassia occidentalis with acute HME syndrome in Wistar rats was subsequently demonstrated [8]. These detailed studies also helped in further outbreaks like the one in Sylhet, Bangladesh (2007-08) [9] and another in Malkangiri, Orissa (2016).

Currently, the outbreak investigations in India are at the crossroads. The need is to conduct investigations which are detailed and comprehensive, and performed in a coordinated and step-wise manner without any fixed notion.

1. Yewale VN. Misery of mystery of Muzaffarpur. Indian Pediatr. 2014;51:605-6.

2. Vashishtha VM. Encephalitis outbreaks in Muzaffarpur: Five blind men describing an elephant! Indian Pediatr. 2014; 51:936.

3. John TJ, Das M. Acute encephalitis syndrome in children in Muzaffarpur: hypothesis of toxic origin. Curr Sci 2014;106:1184-5.

4. 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-e466.

5. Sahni GS. Recurring epidemics of acute encephalopathy in children in Muzaffarpur, Bihar. Indian Pediatr 2012;49:502-03.

6. Vashishtha VM, Nayak NC, John TJ, Kumar A. Recurrent annual outbreaks of a hepato-myo-encephalopathy syndrome in children in western Uttar Pradesh, India. Indian J Med Res. 2007;125:523-33.

7. Vashishtha VM, Kumar A, John TJ, Nayak NC. Cassia occidentalis poisoning causes fatal coma in children in western Uttar Pradesh. Indian Pediatr 2007; 44:522-5.

8. Panigrahi G, Tiwari S, Ansari KM, Chaturvedi RK, Khanna VK, Chaudhari BP, et al. Association between children death and consumption of Cassia occidentalis seeds: clinical and experimental investigations. Food Chem Toxicol. 2014;67:236-48.