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Indian Pediatr 2017;54: 319-325 |
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Exploration of
Association between Litchi Consumption and Seasonal Acute
Encephalopathy Syndrome
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Source Citation:
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 Jan 30. pii: S2214-109X(17)30035-9.
doi:10.1016/S2214-109X(17)30035-9.
Section Editor:
Abhijeet Saha
|
Summary
In this hospital-based surveillance and nested
age-matched case-control study, authors performed laboratory
investigations to assess potential infectious and non-infectious causes
of acute neurological illness in children (age ≤15 y) who were admitted
with new-onset seizures or altered sensorium to two hospitals in
Muzaffarpur, India. Age-matched controls were residents of same area who
were admitted to the same hospitals for a non-neurologic illness within
seven days of the date of admission of the case. Clinical specimens
(blood, cerebrospinal fluid, and urine) and environmental specimens
(litchi fruits) were tested for evidence of infectious pathogens,
pesticides, toxic metals, and other non-infectious causes, including
presence of hypoglycin A or methylenecyclopropylglycine (MCPG) –
naturally occurring fruit-based toxins that cause hypoglycemia and
metabolic derangement. Out of 390 patients meeting the case definition
admitted to the two referral hospitals, 122 (31%) died. On admission,
204 (62%) of 327 had blood glucose concentration
≤70 mg/dL. In
comparison of 104 cases with 104 age-matched controls, litchi
consumption (matched odds ratio [mOR] 9.6; 95% CI 3.6, 24) and absence
of an evening meal (mOR 2.2; 95% CI 1.2, 4.3) in the 24 h preceding
illness onset were associated with illness. The absence of an evening
meal significantly modified the effect of eating litchis on illness (OR
7.8; 95% CI 3.3, 18.8 without evening meal; and OR 3.6; 95% CI 1.1, 11.1
with an evening meal). Metabolites of hypoglycin A, MCPG, or both were
detected in 48 (66%) of 73 urine specimens from cases and none from 15
controls; 72 (90%) of 80 case-patient specimens had abnormal plasma
acylcarnitine profiles, consistent with severe disruption of fatty acid
metabolism. In 36 litchi arils tested, hypoglycin A concentrations
ranged from 12.4 µg/g to 152.0 µg /g, and MCPG ranged from 44.9 µg/g to
220.0 µg/g. Authors concluded that outbreak of acute encephalopathy in
Muzaffarpur was associated with both hypoglycin A and MCPG toxicity.
Commentaries
Evidence-based Medicine Viewpoint
Relevance: For the past two decades, seasonal
outbreaks of an acute encephalopathy syndrome (AES) affecting children,
have been reported from a few districts in Bihar, notably Muzaffarrpur
[1-3]. The disease is associated with high mortality rate, and has
several public health implications. Initial investigations suggested
causes such as heat stroke, unidentified viral infection, and toxins
present in litchis [1,4]. Investigations into the outbreaks of 2013 and
2014 pointed more firmly towards a hypoglycemic encephalopathy, possibly
related to methylenecyclopropylglycine (MCPG) found in litchis [4,5] and
previously associated with hypoglycemia in animal experiments. A recent
publication [6] attempted to confirm the role of litchi consumption in
the seasonal encephalopathy.
Critical appraisal: The study [6] was described
as a case-control design, comparing potential exposure factors among
children with the acute encephalopathy syndrome (cases) versus
age-matched children without neurological illness (controls). Besides
this component, the authors undertook several additional prospective
investigations to identify (or rule out) alternate cause(s) of the
syndrome. Thus strictly speaking, this study is a combination of a
case-control design and prospective cohort study. The significance of
this distinction is highlighted subsequently. Table I
presents a critical appraisal of the case-control component of the study
using a criteria derived from an excellent tool designed for the purpose
[7].
Table I Critical Appraisal of the Case-Control Component of the Study
Criteria |
Appraisal |
Did the study address a clearly focused issue?
|
Yes. The authors outlined their objectives to identify risk
factors associated with the seasonal acute encephalopathy
syndrome, and also examine whether toxins (specifically
hypoglycin and MCPG) could be involved. They also intended to
confirm that the syndrome was not infectious in origin.
|
Did the authors use an appropriate to answer their question?
|
Yes. The case-control design is an acceptable method to work
backwards and identify method associations between exposure to
potential risk factors, and the disease condition, especially
because prospective observational studies (although
methodologically superior) would be time-consuming,
prohibitively expensive and logistically challenging. |
Were the cases recruited in an acceptable way? |
Case was defined clinically as a child (<15 y) with new seizure
or sensorial alteration originating within 7 days of
presentation to either of the referral two hospitals in the
region. In that sense, cases were recruited through passive
(rather than active) surveillance. However, only those cases who
survived beyond six hours of presentation were enrolled in this
study. Thus more severe cases, and those with early fatal
outcome were automatically excluded. Further, not all cases were
included; for logistic reasons, only every fourth case was
included in the study. Thus 104 cases were recruited from a
total of 390 affected children. Sample size calculation was done
a priori to ensure adequate power. |
Were the controls recruited in acceptable way?
|
Yes. Controls were (age-matched) children, admitted to the same
referral hospitals (within 7 an days of a case) but without
acute neurological illness. Although the authors intended to
recruit both community and hospital-based controls for each
case, they excluded the former and restricted to hospitalized
controls. The authors cited ‘over-matching’ for excluding
community controls; however it is unclear why or how this could
be a problem. In a case-control study, it would be ideal if
cases and controls were identical in all respects, except the
outcome. Hence near-complete matching would be welcome. Further,
there is no description of the controls recruited in this study. |
Was the exposure accurately |
measured to minimize bias? Ascertainment of exposure was done by
‘asking’ cases and controls about potential risk factors
including litchi consumption. Presumably these questions were
directed towards attendants/family members of the affected
children, raising the possibility of recall bias. Further, since
most of the exposure(s) were unwitnessed, some of the responses
could at best be speculative or presumptive. Although the
methods used were not ideal, alternate approaches would have
been difficult. |
What confounding factors have authors accounted for?
|
Although not explicitly stated, the authors attempted to account
for obvious confounding the factors such as age, area of
residence, nutritional status, etc. Limited statistical
adjustments were also performed although multivariate analysis
and logistic regression are not described. |
What are the results of this study? How precise are the results?
|
Cases vs Controls: Consumption of litchi: matched OR 9.6 (95% CI
3.8, 24.1); Consumption of unripe litchi: matched OR 7.9 (95% CI
1.1, 347.0); Consumption of rotten litchi: matched OR 7.4 (95%
CI 1.5, 69.8); Consumption of fallen litchis: (22 cases vs no
controls); Consumption of partially eaten litchis (17 cases vs
no controls); Absence of meal after 7 PM: matched OR 2.2 (95% CI
1.2, 4.3); Litchi consumption without evening meal: OR 7.8(95%
CI 3.3, 18.8); Litchi consumption with evening meal: OR 3.6 995%
CI 1.1, 11.1); Biting/chewing/consumption of litchi seed: Data
not presented Visiting fruit orchard(s): matched OR 6.0 (95% CI
2.7, 13.4); Parental visit to fruit orchard: matched OR 2.3 (95%
CI 1.1, 4.8) Washing fruits / vegetables before consumption :
matched OR 0.13 (95% CI 0.05, 0.40); Below poverty
line (BPL) status: matched OR 1.4 (95% CI 0.8, 2.4); Data
pertaining to consumption of raw vegetables, source of drinking
water, exposure to chemicals/insecticides/pesticides, etc are
not presented.
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Do you believe the results?
|
The results are impressive and difficult to ignore. Some issues
that are not taken into account are presented below. Appraisal
of potentially causal relationship using the Bradford Hill
criteria is presented in Table II.
|
Can the results be applied to the local population?
|
Yes.
|
Do the results of this study fit with other available evidence?
|
See text for detailed analysis of this point. |
Table II Bradford Hill Criteria [8] for Assessment of Causality
Criteria |
Assessment |
Strength of association |
A very strong association was demonstrated between direct and
indirect markers of litchi consumption, and the acute
encephalopathy syndrome.
|
Temporalitya |
On the one hand, temporality is clearly demonstrated as the
majority of cases presented within 12-18 hours of litchi
consumption. On the other hand, litchi consumption by children
is unlikely to be a one-time event; hence presuming that the
affected children had similar behaviour patterns on other days
also, it is unclear why/how they were not affected. In any
case, the encephalopathy outbreak coincided with the litchi
harvesting season. |
Consistency |
There is data from other settings (notably Vietnam and
Bangladesh) that litchi consumption could be associated with
similar acute encephalopathy syndromes [9,10]. Further, another
fruit from the same family as litchi was implicated in metabolic
encephalopathy in Haiti, Surinam and French Guyana [11,12].
Limited data from the annual Muzaffarpur outbreaks also
implicated litchis [4,5].
|
Theoretical plausibility.
|
On the one hand, there is theoretical plausibility as (i) two
toxins were demonstrated in urine of a few affected patients, as
well as randomly analysed fruit samples; (ii) metabolic markers
of fatty acid oxidation pathway were deranged in some of the
affected cases vs none of the controls, and (iii) alternate
explanations including viral meningo-encephalitis, environmental
exposure to other toxins, and heat stroke appear unlikely.
However, it is unclear why there is no clustering of cases (as
litchi orchards are apparently ubiquitous in Muzaffarpur),
how/why young infants were affected, and whether siblings and/or
parents of index cases (presumably having similar behaviour
patterns) were affected.
|
Coherence |
There appears to be coherence between the results of the
case-control component of the study and the multiple lines of
inquiry pursued in the prospective component; although it can be
argued that there were methodological limitations with respect
to the number of cases and/or controls studied.
|
Specificity in the causes.
|
There are threats to specificity including: (i) absence of
clustering of cases, (ii) lack of involvement of family
members, (iii) lack of data on relationship between toxic levels
and clinical outcome, (iv) protective effect of washing
fruits/vegetables when the toxin acts through ingestion, rather
than contact etc. |
Dose response relationship. |
This component has not been demonstrated. |
Experimental evidence.
|
There is experimental evidence in animals supporting the
hypothesis that MCPG can cause a metabolic encephalopathy, but
no direct demonstration through litchi consumption. Further, the
levels of hypoglycin A and MCPG demonstrated in a few litchi
samples in this study have not been correlated with toxicity
levels in previous studies [13].
|
Analogy |
Previous reports of metabolic encephalopathy from ackee fruit
[11,12] are considered analogous.
|
The observational component focused on five distinct
lines of inquiry: (i) measurements of hypoglycin A and MCPG
metabolites in biological specimens of affected cases, (ii)
measurement of markers of fatty acid metabolism (since the two toxins
act through disruption of this metabolic pathway), (iii)
confirmation of the absence of viral etiology through detailed CSF
analysis and/or cerebral imaging techniques, (iv) demonstration
of elevated concentrations of hypoglycin and MCPG in representative
litchi samples, and (v) exclusion of environmental metabolic
encephalopathies by measurement of plasma and RBC cholinesterase
activity, as well as analysis of litchi samples for pesticide levels.
These efforts and the procedures used within each line of inquiry are
indeed laudable. However, three points should be noted: (i) not
all the affected children were uniformly subjected to all the clinical
tests (thereby creating an inadvertent element of selection bias), (ii)
the control group were either not subjected to the complete extensive
clinical workup, or the data are not shown, and (iii) the methods
for selecting fruit samples for analysis are not described. Table
III presents data from the prospective component of the study.
Table III Additional Analyses in the Prospective Component of the Study
Line of inquiry |
Summary of results |
Presence of Hypoglycin A and MCPG metabolites in urine |
Cases vs controls: Hypoglycin A metabolite: 47/73 vs 0/15;
MCPG metabolite: 33/73 vs 0/15 |
Markers of fatty acid metabolism |
Cases vs controls: Abnormal acylcarnitine analysis: 72/80 vs not
mentioned; Abnormal urinary organic acid analysis: 67/75 vs 0/15 |
Confirmation of the absence of viral or alternate etiology |
17 CSF samples from cases were negative for JE and West Nile
viruses (by PCR);12 CSF samples were negative for 11
(unspecified) viruses by PCR; Sequencing for viruses in 40 CSF
and 40 serum samples were negative in 39 each; CSF was examined
in 62 cases, but hypoglycorrhachia was detected in only 79%.
Cerebral imaging (MRI) was done in only 16 cases. No specific
abnormalities were detected. EEG was done in only 30
cases. No pattern(s) suggesting a specific etiology were
observed. |
Exclusion of environmental metabolic encephalopathies |
Neither pesticide nor metals were detected in 80 case samples.
No abnormal cholinesterase activity was detected in 27 cases. No
pesticide residue was found in 14 litchi samples |
Hypoglycin and MCPG in representative litchi samples |
36 litchi arils were tested from Muzaffarpur, although samples
were not taken from homes of cases and controls. Hypoglycin A
levels varied from 12.4-152.0 mg/g. MCPG level varied from
44.9-220.0 mg/g. Data comparing unripe vs ripe fruit are
presented for only 3 arils and showed that the former had higher
levels of both compounds. |
Critical appraisal of this report [6] raises several
issues that could have been addressed in this otherwise excellent study.
First, it is safe to assume that children visit litchi orchards (and
consume fruit), accompanied by siblings and friends. Therefore, if the
exposure occurs as described by the authors, family and community
clustering of cases would be evident. It is surprising why this was not
observed. Second, it would have been interesting to see the
age-stratified data of affected cases, to determine whether toxin levels
were distributed similarly across all age groups. Presumably older
children have greater capacity for consumption, and this could be
reflected in clinical data as well as laboratory measurements of toxin
levels. Third, it would be interesting to learn whether adolescent girls
were affected similarly, as younger girls and/or age-matched boys, as it
is unlikely that adolescent girls would visit orchards alone. Fourth,
assuming that adults also consume litchi in excess during the harvesting
season, and there was a strong association with parental visits to
orchards, it is important to learn whether any adults (or household
contacts) in the family of affected children, were similarly afflicted.
Further, the exposure is likely to occur for several days/weeks rather
than a single day. In such a scenario, what tips the balance towards a
potentially fatal disease on a given day, but not on other days? Last,
but not the least, the disease could have occurred by consumption of
litchis at home also; hence laboratory testing of samples from homes of
cases and controls would have added value.
The authors emphasized that the absence of an evening
meal was associated with disease. They attributed this to a relative
fasting state where hypoglycemia induced fatty acid oxidation could not
occur due to the toxins. However, the reasons for skipping the evening
meal have to be understood. If children are ‘too full’ with litchis as
the authors propose, it is only an indirect indicator of a large(r)
quantity of litchis consumed (hence greater amount of toxin in the
system). If it is because of hypoglycemia caused by the toxins, cases
should have occurred as frequently during the daytime also as children
could consume litchis during the morning hours and skip lunch. This
conundrum could have been resolved by comparing the blood glucose level,
toxin levels and clinical outcomes in those who did and those who did
not have the evening meal.
It is surprising that washing of fruits/vegetables in
households was protective, as the toxin is present within the fruit
(especially within seeds) and not the surface. Further, the hypoglycemia
hypothesis necessitates consumption of the toxin, rather than contact;
hence it is unclear how washing could help. On the other hand, each
year, the onset of rains is associated with abatement of the epidemic,
suggesting that either consumption declines dramatically, or the fruit
(surface) is (naturally) washed.
This study had an excellent opportunity to compare
survivors among the recruited children with those who died. This would
help to determine risk factors for adverse outcome, a possible
dose-response relationship with the toxin levels and/or markers of
abnormal fatty acid oxidation, and/or other clinical or biochemical
markers. Unfortunately, no data on fatal cases have been presented.
Finally, it should be emphasized that the association
between litchi consumption and the acute encephalopathy in this study is
not derived solely from the case-control component, but also the
multiple additional lines of investigation. In fact, the Bradford-Hill
criteria are not entirely fulfilled from the data presented. Further,
the contribution of previous studies in excluding alternate cause(s) for
the clinical syndrome [1,4,5,14,15], has to be emphasised. It is
commendable that the authors themselves described their impressive
findings as an association, rather than a causal relationship.
Extendibility: The study was conducted in
the epidemiological source of the clinical condition; hence the data are
easily applicable. It would be interesting to observe whether similar
observations are made in other litchi growing areas of the country.
Conclusion: This well-designed study strongly
suggests that the seasonal acute encephalopathy syndrome occurring in
Muzaffarpur India, is associated with toxins present in litchi fruits.
Funding: None; Competing interest:
None stated.
References
1. Sahni GS. Recurring epidemics of acute
encephalopathy in children in Muzaffarpur, Bihar. Indian Pediatr.
2012;49:502–3.
2. Yewale V. Misery of mystery of Muzaffarpur. Indian
Pediatr. 2014;51:605-6.
3. Shah A, John TJ. Recurrent outbreaks of
hypoglycaemic encephalopathy in Muzaffarpur, Bihar. Curr Sci.
2014;107:570-1.
4. John TJ, Das M. Acute encephalitis syndrome in
children in Muzaffarpur: hypothesis of toxic origin. Curr Sci.
2014;106:1184-5.
5. Das M, Asthana S, Singh SP, Dixit S, Tripathi A,
John TJ. Litchi fruit contains methylene cyclopropyl-glycine. Curr Sci.
2015;109:2195-7.
6. 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 Jan 30. pii:
S2214-109X(17)30035-9. doi:10.1016/S2214-109X(17)30035-9.
7. Critical Appraisal Skills Programme (CASP): 11
questions to help you make sense of a case control study. Available
from: http://media.wix.com/ugd/dded87_63fb65dd4e0548
e2bfd0a982295f839e.pdf. Accessed September 14, 2015.
8. No authors listed. The Bradford Hill Criteria.
Available from:
http://www.southalabama.edu/coe/bset/johnson/bonus/Ch11/Causality%20criteria.pdf.
Accessed March 10, 2017.
9. Paireau J, Tuan NH, Lefrancois R, Buckwalter MR, Nghia
ND, Hien NT, et al. Litchi-associated acute encephalitis in
children, Northern Vietnam, 2004–2009. Emerg Infect Dis.
2012;18:1817-24.
10. 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.
11. Joskow R, Belson M, Vesper H, Backer L, Rubin C.
Ackee fruit poisoning: An outbreak investigation in Haiti 2000-2001, and
review of the literature. Clin Toxicol (Phila). 2006;44:267-73.
12. Gaillard Y, Carlier J, Berscht M, Mazoyer C, Bevalot
F, Guitton J, et al. Fatal intoxication due to ackee (Blighia
sapida) in Suriname and French Guyana. GC-MS detection and
quantification of hypoglycin-A. Forensic Sci Int. 2011; 206: e103-7.
13. Vashistha V. Outbreaks of hypoglycemic
encephalopathy in Muzaffarpur, India: Are these caused by toxins in
litchi fruit? Counterpoint. Indian Pediatr. 2016;53:399-402.
14. 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.
15. Shrivastava A, Srikantiah P, Kumar A, Bhushan G,
Goel K, Kumar S, et al. Outbreaks of unexplained neurologic
illness - Muzaffarpur, India, 2013-2014. MMWR Morb Mortal Wkly Rep.
2015;64 49-53.
Joseph L Mathew
Department of Pediatrics,
PGIMER, Chandigarh, India.
Email:
[email protected]
Pediatric Infectious Disease Specialist’s Viewpoint
This paper is an important contribution,
re-confirming the discovery of a new disease in India by a team of
Indian investigators [1-3]. Additionally, it provides information on a
few missing details of previous reports. Re-confirmation by independent
investigators is how science progresses. In August 2014, then President
of Indian Academy of Pediatrics had highlighted the failure of
prestigious agencies such as National Centre for Disease Control (NCDC,
New Delhi) and US Centers for Disease Control and Prevention (CDC), to
diagnose the disease that occurred seasonally every year and took a
heavy toll of lives of young children, in Muzaffarpur [4]. He was
skeptical of the veracity of the diagnosis of the disease as
hypoglycemic encephalopathy and its cause as Litchi fruit consumption by
malnourished children who missed the evening meal [1-3]. Therefore,
independent re-confirmation of the nature of the disease and its cause
is welcome news [1-3].
Muzaffarpur district in Bihar, famous for Litchi
orchards, has had annually recurring acute brain disease of children
with high mortality, believed by most pediatricians, health ministry
officials and NCDC/CDC scientists as viral encephalitis. As no virus was
found in spite of repeated search, the disease was called ‘acute
encephalitis syndrome’ (AES) by professionals and ‘mystery disease’ by
the public [1,4]. Disappointed by lack of help from NCDC/CDC for saving
the lives of children, a pediatric infectious disease specialist was
called in by Bihar health ministry officials [1]. During the 2013
outbreak season, he led a team (hereafter referred to as the Bihar team)
that identified the disease as ‘hypoglycemic encephalopathy’, a form of
metabolic coma that is non-infectious [1-3]. This was received by other
investigators and health ministry officials as total surprise, some with
scepticism [4]. Until then, clinical diagnosis according to
International Classification of Diseases had not been attempted in
Muzaffarpur, the thrust of NCDC/CDC being sophisticated laboratory tests
for possible viral and pesticide causes of AES [5]. Searching for the
cause before making clinical diagnosis is like tying the bullock to the
back of the cart; the cart will not move forwards [5].
Sporadic cases of metabolic coma are due to inborn
errors of metabolism, such as acyl-CoA dehydrogenase deficiency,
blocking gluconeogenesis (fatty acid β-oxidation), which itself is
triggered by prolonged fasting [6]. The close similarity, including
early morning onset of encephalopathy, was obvious to the trained eye.
The Bihar team had to explain seasonal increase and temporal/spatial
restriction of cases to Litchi harvests. Ackee fruit in Jamaica is a
known extrinsic causative factor of blocked fatty acid
β-oxidation and
hypoglycemic encephalopathy [7]. The Bihar team found that Ackee and
Litchi belonged to one plant family and that Litchi seeds had been
reported to contain methylene cyclopropyl glycine (MCPG), an analogue of
the Ackee Hypoglycin A [1]. They once again confirmed the disease to be
hypoglycemic encephalopathy prospectively, and demonstrated the presence
of MCPG in the edible fruit pulp of Litchi [2,3].
Armed with all this information, widely shared with
Bihar health ministry, Bihar Task Force on AES, NCDC and the media, the
NCDC/CDC investigators changed tactic and carried out a quick detailed
study in 2014, involving 51 scientists from various fields in USA and
India, and re-confirmed all the earlier published findings, as described
in this Lancet paper. However, it is disturbing to note that no staff of
the two institutions in which they carried out the study – Sri Krishna
Medical College Hospital and Krishnadevi Deviprasad Kejriwal Maternity
Hospital – is included among the 51 authors, and neither institution is
named among the 13 agencies conducting the case-control study. Such
brazen impropriety would not have been tolerated elsewhere; in Bihar,
NCDC and in India CDC are guests, and we in India tolerate such
imperious attitudes of some guests. Indian co-authors should have
defended fairness to Indian colleagues.
The metabolic products accumulating due to blocked
fatty acid
β-oxidation cycle are amino acids and fatty acids that are
toxic to brain cells [6]. Organic acidemia and aciduria are thus
tell-tale signals of blocked fatty acid
β-oxidation cycle, and the
Lancet paper has convincingly shown both in many children. This gap in
the earlier study by the Bihar team has now been filled by the CDC/NCDC
study. Once organic acidemia is established for many hours, brain cells
are apparently permanently damaged, resulting in death of children or
brain function defects in those who survive; hypoglycemia is not the
only or the major cause of the metabolic coma [6].
The Indian team had recommended early intravenous
infusion of 10% dextrose and documented its protection of brain
functions [2]. The Lancet authors repeated this recommendation as ‘rapid
glucose correction’ without realizing that ‘glucose correction’ requires
only 5% dextrose; then why did the Bihar team recommend 10% dextrose?
The purpose is to establish higher than normal blood glucose
concentration to stimulate insulin secretion for turning off the fatty
acid oxidation cycle [6]. The consequences of the absence of a competent
clinical pediatrician among NCDC/CDC investigators were missed diagnosis
for many years, delay in conducting focused investigations, lack of
discriminative case definition to separate encephalopathy from all other
diseases and poorly understood therapeutics.
The Bihar team had recommended that no child should
be allowed to go to sleep without a cooked meal, and that parental
supervision was needed to minimize small children eating Litchi fruits
[1-3]. The Lancet paper repeated these recommendations without
acknowledging that the health ministry had already instituted them long
before the Lancet paper was published. There was a meeting of the Task
Force on AES (Indian Council of Medical Research) in Patna on 29
November 2016, to review AES/JE situation in Bihar. A senior Bihar
health ministry official thanked the Bihar team for solving the mystery
expeditiously and mentioned that by applying the three recommendations,
the disease incidence had been drastically reduced and death almost
completely prevented. Some of the authors of the Lancet paper were
listening, as was myself!
It is a common error to make a broad case definition
for sensitivity, when investigating outbreaks of unknown etiology, as
the Lancet paper illustrates. The broad case definition would allow the
inclusion of encephalitis, encephalopathy, viral and bacterial
meningitis, and cerebral malaria among the study subjects. There cannot
be one etiology for such medley of maladies. Being a quickly
put-together study, and rushing for submission for publication,
apparently the investigators could not sift all cases to include only
acute encephalopathy and exclude all others. The Lancet paper clearly
shows that only a subset of study cases was confirmed with hypoglycemic
encephalopathy, the recurrent outbreak disease. Had they been
discriminative, they need not again have looked for viruses and
pesticides in metabolic coma cases as they had done repeatedly in
previous years – obviously even in 2014, the investigators were not sure
if the ‘outbreak disease’ was infectious or non-infectious. The outbreak
was exclusively encephalopathy. The clinical features were quite typical
of acute encephalopathy (sudden onset, overnight development of severe
disease, rapid progression within hours, absence of CSF pleocytosis and
death or recovery within a few days); they did not at all fit with acute
viral encephalitis or pesticide poisoning [1-3]. When investigating
outbreaks for etiology, the case definition should aim for high
specificity, not sensitivity.
The Bihar team had found that a large majority of
children with hypoglycemic encephalopathy was from litchi-harvesting
labourers’ families. During harvest season, they camp in the orchards
with children. While fruits harvested in bunches are marketed, single
stray fallen fruits belong to children for collection and hoarding.
Harvesting is during early morning, starting at 4 am. Thus the family
routine is disturbed and children may sleep off without night meal. They
are the ones affected during the night. All cases had consistently early
morning onset, a feature missed by all earlier investigators.
Litchi is a popular and safe fruit. It is a
commercial crop in Muzaffarpur and Litchi orchards provide livelihood
employment for many poor families. Giving Litchi a bad name is
inappropriate and unnecessary, and Bihar Government had advised all
investigators to avoid sensationalizing the Litchi-connection
(unpublished). The MCPG in Litchi is inconsequential in healthy
well-nourished children. What it does is to block the fatty acid
β-oxidation cycle when neo-glucogenesis is demanded on account of failed
glucogenesis by glycogenolysis, for which undernutrition is a
predisposing factor [1]. The Lancet paper flouted the State Government’s
directive. If Litchi market declines, the worst affected would be the
very same families of vulnerable children, pushing them further down the
poverty scale.
Unfortunately the authors of the Lancet paper use
language to imply that the diagnosis, risk factors and preventive
recommendations are their own original contributions. How could the
authors claim they were the first to diagnose the disease and identify
its cause when they had already been published? Their literature search
ended in 2013, while the first two papers of the Bihar team were
published in 2014, and the third in 2015 [1-3]. So they missed them, or
probably timed the literature search deliberately to miss them.
However, they did cite the original papers, which is
proof that they knew of them, but still claimed they diagnosed the
disease first and offered the very same recommendations made by the
Bihar team. Their claims are untenable. But to their credit, they
applied good laboratory analytical methods, much of which was done
overseas. Is not the very purpose of housing CDC scientists in India to
improve the investigative facilities within the country?
Funding: None; Competing interest:
TJJ has been a member of Bihar team and ICMR Task force on Acute
Encephalitis Syndrome.
References
1. John TJ, Das M. Acute encephalitis syndrome in
children in Muzaffarpur: hypothesis of toxic origin. Curr Sci.
2014;106:1184-5.
2. Shah A, John TJ. Recurrent outbreaks of
hypoglycemic encephalopathy in Muzaffarpur, Bihar. Curr Sci.
2014;107:570-1.
3. Das M, Asthana S, Singh SP, Dixit S, Tripathy A,
John TJ. Litchi fruit contains methylene cyclopropyl-glycine. Curr Sci.
2015;109:2195-7.
4. Yewale V. Misery of mystery of Muzaffarpur. Indian
Pediatr. 2014;51:605-6.
5. Srikantiah P. Outbreak of acute neurologic
syndrome in Muzaffarpur, Bihar -2013. In: NCDC Newsletter,
July-September 2013; vol 2, issue 3. Available from:
http://www.ncdc.gov.in/writereaddata/linkimages/Newsltr
04143506613236.pdf. Accessed March 10, 2017.
6. Saudubray JM, Desguerre I, Sedel F, Charpentier C.
A clinical approach to inherited metabolic diseases. In:
Fernandes J, Saudubray JM, van den Burghe G, Walter JH (editors). Inborn
Metabolic Diseases, Diagnosis and Treatment. Heidelberg: Springer, 2006.
p. 1-96.
7. Centers for Disease Control. Toxic hypoglycemic
syndrome – Jamaica, 1989-1991. Morb Mortal Wkly Rep. 1992;41:53-5.
T Jacob John
(Member, Bihar Team; and Member, ICMR Task Force on
Acute Encephalitis Syndrome/
Japanese Encephalitis)
Vellore, Tamilnadu, India.
Email:
[email protected]
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