Of Encephalitis, Litchis and Blood Sugar: Bihar's AES Outbreak Explained

Over a 100 children have died in Bihar due to AES – or acute encephalitis syndrome – a deceptively straightforward umbrella term for infections that cause swellings on the brain.

An outbreak of infections classified as acute encephalitis syndrome (AES).

What is AES?

AES is an umbrella term of infections that cause swellings on the brain. Its symptoms typically include headache, vomiting, confusion and seizures, and complications include memory loss, coma and even death.

Can we treat AES?

It depends. Since AES is an umbrella term for a variety of infections, doctors need to know the specific type of infection before they can consider treatment options. Not all forms of AES can be treated equally well. For example, Japanese encephalitis, caused by the Japanese encephalitis virus, can be prevented using a vaccine of the same name; once it has infected a person, treatment is usually only of the symptoms, not of the cause itself.

Other viruses known to cause encephalitis include the Nipah virus and the Chandipura virus.

Why are some people talking about litchi?

Following outbreaks between 2012 and 2015, different research groups from India and the US were able to determine that many of those diagnosed with AES – used as an umbrella term – had a specific condition called hypoglycaemic encephalopathy. Encephalitis and encephalopathy sound the same because of their common root, enképhalos, Greek for ‘brain’, but otherwise play out differently different.

As T. Jacob John, a retired professor of virology from the Christian Medical College, Vellore, wrote in The Hindu on June 19, the primary pathology of encephalitis is in the brain where of encephalopathy, it is not. And with encephalopathy, researchers found that the litchi fruit, grown aplenty in Bihar, could be one of the causes, particularly because the outbreak overlaps with the fruit’s harvest season.

But the litchi fruit can’t be poisonous. We eat it!

As one line of reasoning goes, it depends on whether or not you can afford to eat food regularly and on time.

Every summer, estate owners employ labourers to harvest and basket litchis before it is transported. A controversial 2017 study identified two toxins in the fruit’s seed, called methylene cyclopropyl acetic acid (MCPA) and methylene cyclopropyl glycine (MCPG). Both toxins block a metabolic pathway called gluconeogenesis, which the body uses to maintain blood sugar levels. Some of the leftovers of this set of interrupted reactions are chemical substances that, to use John’s words, “are highly toxic to the brain cells”.

Because the families often can’t afford food, it is plausible that their children eat stray litchis that fall to the ground during harvest on an empty stomach. And because they haven’t been eating regularly and on time, their blood sugar levels are already low, as is the amount of reserve glycogen in their livers. In these circumstances, the body starts gluconeogenesis, only for it to be interrupted by the MCPA/MCPG. This leads to a condition called aminoacidaemia that then damages their brains.

But the toxin is in the seeds, not in the pulp.

Priyanka Pulla reported in 2015 that Padmini Srikantiah, of the US Centres for Disease Control, was investigating whether some varieties of litchi contained MPCA in the pulp as well. In February 2019, researchers from the Indian Institute of Toxicology Research, Lucknow, and the Banaras Hindu University reported finding amounts of MCPG in ripe and semi-ripe litchi fruits in Muzaffarpur that John, writing in his article, called “generous”.

So are all AES cases actually encephalopathy cases?

No. In fact, some questions remain of the encephalopathy claim as well. For example, Vipin Vashistha, a paediatrician at the Mangla Hospital and Research Centre, Uttar Pradesh, pointed out to The Wire in 2017 that unripe litchis contained more of the toxins than ripe or semi-ripe litchis, and that a child would have to consume such a large quantity of the fruit to develop encephalopathy that they would also have osmotic diarrhoea. He has also disputed quality control measures used in study as well as some of the assumptions, and has been joined by researchers from the National Research Centre on Litchi, Muzaffarpur.

In turn, John and others have stood firm on there being a causal link between the consumption of litchis and the annual AES outbreaks in Bihar, contingent on the affected children not being able to replenish their blood sugar levels on time. That said, litchi-related hypoglycaemic encephalopathy remains in consideration as one of the infections under the annual AES outbreaks in Bihar (and other states).

Even more broadly speaking, a review article published in 2012 in the National Medical Journal of India noted:

While most studies from 1975 to 1999 identified [Japanese encephalitis virus] as the main cause of AES, many studies published after 2000 identified Chandipura and enteroviruses as the most common agents, in both outbreaks and surveillance studies. … The landscape of AES in India has changed in the previous decade [2000-2010], and both outbreak investigations and surveillance studies have increasingly reported non-JEV aetiologies. Because of these findings, there is a need to explore additional strategies to prevent AES beyond vector control and JEV vaccination.

As another review article published in 2016 in the Annals of Neuroscience put it, the history of AES in the country had “three phases”:

… (a) period before 1975 when a few cases with JE aetiology were identified; (b) between 1975 and 1999 when more JEV cases were reported with frequent outbreaks that resulted in the development of JE endemic regions near the Gangetic plains and in parts of Deccan and Tamil Nadu; (c) between 2000 and 2010, a dramatic change was observed in the AES scenario, which saw the rise in non-JE outbreaks mostly caused by viruses such as Chandipura virus, Nipah virus, and other enterovirus

Image: Ann Neurosci. 2016 Sep; 23(3): 131–133.

Image: Ann Neurosci. 2016 Sep; 23(3): 131–133.

Are there any other causes of interest?

Yes. For example, researchers have been checking if scrub typhus could explain AES outbreaks in Assam after 2010. To quote from the abstract of a paper published in 2017 in the journal Emerging Infectious Diseases (edited for brevity and clarity):

Scrub typhus is a miteborne bacterial disease. Clinical features generally include fever, headache, and myalgia, with or without eschar/rash. In the Indian context, scrub typhus was first reported in Assam during World War II across the India-Myanmar border. The northeastern region of India then experienced decades without the disease until it reemerged in 2010. Assam … is recognised as an endemic zone for AES, especially that caused by Japanese encephalitis virus. However, the aetiology of >50% of the AES cases in Assam remains unrecognised.

(The paper then proceeds to examine the possibility of scrub typhus being able explain the infections.)

Can we treat encephalopathy?

We can treat hypoglycaemic encephalopathy, at least according to John and others. As the authors of the 2016 review wrote:

In [some] cases, although encephalitis was not confirmed, pathogenesis lead to encephalopathy with hypoglycaemia. Sixty-three percent of 390 patients suffered from hypoglycaemia with low blood glucose level of 70 mg/dl, and it was observed that only treatment for hypoglycaemia reduced the number of deaths from 44% in 2013 to 26% in 2014.

Srikantiah says as much in Priyanka Pulla’s report as well.

The treatment for hypoglycaemia is to supply dextrose – a simple sugar very much like glucose – through intravenous means. John writes in The Hindu that other measures include ensuring children eat cooked meals before going to bed and keeping children, through parental supervision, from eating too many litchis during the harvest season. In fact, as a result of these measures, John claims that the number of cases in 2016-2018 were lower than in 2014-2015.

Why did the number of deaths rise again this year?

We don’t know, especially since a number of factors are in play. For example, even among those people being hospitalised with brain damage due to encephalopathy, John and his peers have alleged a common problem. He writes:

To correct mild hypoglycaemia, 5% glucose is enough, but here the problem is not hypoglycaemia alone, but aminoacidaemia as a result of blocked gluconeogenesis. … if ill children are infused with 10% glucose within four hours of onset of brain dysfunction, recovery is fast and complete. If only 5% glucose is given, or if 10% glucose is not administered within four hours, recovery is unlikely. I do not have detailed information from the field, but there seem to have been some human slip-ups this time.

Curiously enough, according to a paediatrician at the SKMCH Hospital in Muzaffarpur, many of whose patients are being treated for AES, the litchi connection does not pan out because some AES cases have been reported in other months as well.

(On a separate note, a litchi grower has said pinning the encephalopathy blame on the fruit is a ploy by the mango lobby to discourage business.)

Should we blame the doctors?

Not at all. It is important to remember that we are now in an emergency situation. In such situations, doctors respond as quickly as possible to save as many lives as possible and don’t have as much time to dwell on what the exact issue might be. As a result, they typically respond by administering a variety of treatments in the hope that one or the other among them will protect the patient.

But someone has to take the blame.

Emergency situations are like wartime; there is little point dissecting how we respond if we don’t prepare for it in peacetime, especially when we know war is coming.

For example, the Kerala government took measures following the Nipah virus outbreak last year to ensure it isn’t caught off-guard again, even though it responded admirably at the time itself.

Unlike with the AES outbreaks in northern India, government doctors knew by the time the third patient was diagnosed that they were dealing the Nipah virus, and could promptly begin the right treatment protocols. Officials tracked down every single person a patient had come in contact with and monitored them for symptoms. All those suspected of being infected with the Nipah virus were moved to purpose-built isolation wards Government Medical College (GMC), Kozhikode, where all medical personnel were equipped with safety equipment.

The outbreak was contained within five weeks; 16 people had died but it could have been many, many more.

As K.P. Aravindan, a former professor at GMC Kozhikode, wrote for The Wire at the time:

Many of those who contracted the illness acquired it in a hospital. Some were merely visitors who had come to see other patients. It is, therefore, time to examine how we can decongest our hospitals. Instituting a strict referral system and controlling visitors are sorely needed reforms. Bystanders who help out with many routine hospital chores can be reduced by appointing more caring staff. Infection control protocols within hospitals also need to be followed with intent, with universal precautions for health workers in dealing with any patient.