Recently a number of outbreaks of what is often called ‘mystery disease’ or disease caused by a ‘mystery virus’ has been reported in India, in newspapers and newsmagazines. The most recent outbreak was in May to July 2003, occurring in various districts of Andhra Pradesh (AP)(1,2). In one magazine it was reported that 79 (53%) among 148 ill children died due to the ‘mysterious disease’(1). Apparently a similar outbreak with high fatality occurred in the neighboring region of Maharashtra also. The number of children who died in these outbreaks was 116 in AP and 54 in Maharashtra(2). Although suspected to be viral encephalitis, on investigation only 3 children were found to have recent infection with Japanese encephalitis (JE) virus in AP, and the Maharashtra outbreak was "proved JE negative", thus excluding JE as the outbreak disease in either State(1,2). Therefore, the disease was undiagnosed, hence called ‘mysterious’ by the media.

There was disagreement among doctors about the illness being encephalitis(2,3). The newspaper stated that the Director General of Health Services had concluded that the outbreak was JE, but it quoted Dr. Nagabhushana Rao (Professor of Neurology at Osmania University) disagreeing on account of major clinical and epidemiological differences between the current illness and JE. Dr. Rao had pointed out that in the past the season of JE was August to December, while this outbreak was in June, when the mosquito density was unlikely to have reached sufficient level to function as the vector. Moreover, he said that the two diseases differ in terms of the frequency of diarrhea and convulsions, and the speed with which brain edema developed and death ensued(3). Children affected with the ‘mystery disease’ died within one day, which does not happen in JE. It was reported that the "health officials feel the epidemic is similar to the ‘mutant measles viral’ outbreak that plagued Warangal last May-June"(3).

The reports on the clinical picture of the disease in the media are as follows. "Almost all children who died were in the 2-12 age group and death came within 36 hours of their hospitalization"(1). "Diarrhea followed by high fever, convulsions and then irreversible coma are some of the common symptoms of this killer disease"(2). "Most alarmingly, children…..have been succumbing within 10 to 12 hours". "The mortality rate has been almost 60%"(2).

A review of the case histories of children who had died with the illness, with pediatricians of the District Hospital in Karimnagar and the Teaching Hospital of Osmania University in Hyderabad, has corroborated the clinical features described above (John T.J. Unpublished Report to the Government of AP, 18 July 2003). Typically a rural child, between 2 and 15 years of age, goes to bed normally, but develops vomiting in the early hours of the morning. Loss of consciousness follows and deteriorates to deep coma and decerebrate posturing, within several hours. Death ensues within 48-72 hours from start. Other common features included fever (occasionally very high), one or two loose motions, irrelevant talking, combative limb movements or posturing and generalized convulsions.

Investigations in a proportion of children included lumbar puncture and examination of the cerebrospinal fluid (CSF), blood tests for glucose level and CT scan of the head. In children with the above clinical description, the CSF was clear and under high pressure, without pleocytosis, often with reduced glucose but normal protein content. Blood glucose level was lowered in most children. Brain edema was found on scan. Case fatality varied, but was over 60%, but those who recovered did so very rapidly and without any sequel.

It is easy to recognize the clinical and laboratory information fitting with the diagnosis of "acute encephalopathy with fatty degeneration of the viscera" or in other words, the "Reye’s syndrome"(4,5). The similarities and differences between Reye’s syndrome and viral encephalitis are given in Table I. The quality of management and care would alter some of the features, but not of pathology.

Clinical/epidemiological features

Encephalitis

Reye’s syndrome

Affected age group

Under 15

Under 15

Prodromal period

1 or 2 days

None

Brain function affected

Severely

Severely

Deteriorating sensorium

Yes

Yes

Progressing to deep coma

Often

Almost always

Convulsions

Less frequent

More frequent

Focal neurological signs

Often

Absent

Duration of illness

Days to weeks

Hours to days

Case fatality

10-30%

Over 50%

Brain damage on recovery

Common

Absent

Frequency

Mostly outbreaks

Mostly sporadic

Outbreaks

Often

Occasional

Seasonality

Depends on mosquitoes

Reason unknown

Geographic distribution

Mostly rural

Rural or urban

Sibling affected

Almost never

Occurs occasionally

CSF pressure

Mild elevation

Marked elevation

Cells in CSF (per cu mm)

Increased  (More than 10)

Normal (less than 5)

Protein content of CSE

Mild elevation

Normal

Glucose level in CSF

Normal

Often reduced

Blood glucose level

Normal

Often reduced

Liver enzymes

Normal

Markedly elevated

Blood ammonia level

Normal

Often elevated

Brain scan

Typical changes

Only edema

Liver biopsy pathology

None

Microvescicular fat

Brain pathology

Inflammation

No inflammation

Viral studies

Positive

Negative

Table I explains the reason why clinicians may confuse between the two illnesses. The clinical features of the encephalopathy syndrome clearly suggest an acute brain disease of children in outbreaks, for which reason the illness is often mistakenly diagnosed as encephalitis. Since JE virus is the widely recognized common cause of encephalitis, especially in outbreaks, physicians and public health and administrative officials have a tendency to attribute all outbreaks of brain disease in children to JE virus. Careful consideration of the fine points of differ-entiation between the two clinical entities is often a casualty of the heavy workload of the attending pediatrician, pressure from families of ill children, superiors and the media, and the anguish of watching many children die. Expert teams visiting and calling it meningo-encephalitis, collecting serum and CSF samples for identifying the hypothetical virus causing the disease and hectic anti-mosquito measures to kill off the putative vectors transmitting the hypothetical virus, reinforce the misdiagnosis of encephalitis(1-3).

During my investigation, both in Karimnagar and Hyderabad in AP, it was found that doctors were diagnosing ‘encephalitis’ in spite of documenting the absence of pleocytosis in the CSF and finding gross brain edema in CT scans, hypoglycemia and low CSF sugar values, rapid deterioration and death within 24-48 hours - all recognized features of Reye's syndrome. Having made the erroneous diagnosis of encephalitis, the tests of Reye’s syndrome, namely liver function enzymes, blood ammonia level and liver biopsy to identify microvescicular fat in hepatocytes were not performed.

There was another important cause that perpetrated the confusion between encephalo-pathy and encephalitis. As is often the case in any JE endemic region, a few cases of encephalitis were also hospitalized during the same period as that of the outbreak of Reye’s syndrome. This made the doctors believe that the two clinical patterns were caused by one disease, due to a single pathogen, even though the two clinical patterns are mutually exclusive. In Karimnagar, there was one child with 105 cells per cu mm. of CSF, 99% being lymphocytes, but her case was clubbed with those of the outbreak, in spite of the most likely diagnosis of aseptic meningitis (A. Rao, Personal communication, 2003). In Hyderabad, there were several cases of encephalitis confounding the more frequent cases of encephalopathy (S. N. Rao, Personal communication, 2003). In addition there were a few children with fever, skin rash, purpuric skin bleeding, shock like state and death (S. N. Rao, Personal communication, 2003). This clinical picture, although described as another form in which the outbreak disease presented itself, was clearly different from encephalopathy or encephalitis, but was most probably due to Dengue Haemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS). In summary, different diseases of children affecting the brain and sensorium and causing death were clubbed together on account of the fact that they occurred in the same time period of May to July, assuming that all of them represented one epidemic. This was done to fulfill the saying that ‘one outbreak is due to one disease, caused by one agent’ (S. N. Rao, Personal communication, 2003). My recommendation to the concerned doctors was to review all case records and try to reclassify each of them with the best fit diagnosis of either Reye’s syndrome, encephalitis or DHF/DSS. This would allow a search for cases not accounted for in these diagnostic categories.

When Reye and colleagues described the new disease in 1963 and named it acute encephalopathy and fatty degeneration of the viscera, it was thought to occur only rarely(6). By the time we reported the disease for the first time in India in Vellore, only 130 cases had been recognized globally, mostly from countries in which every illness is diagnosed with criteria and laboratory studies(4). Since then many authors have reported sporadic cases in several regions in India, in the south and north(7-10). Thus, many had come to believe that Reye’s syndrome occurs only sporadically. Facts speak to the contrary, and many outbreaks have been reported, but many have also been left at the ‘mystery disease’diagnosis, or attributed to varied etiologies like JE virus or measles virus.

One recent report in the media had alluded to an epidemic of disease similar to the outbreak in AP, but caused by ‘mutant measles virus’ that plagued Warangal, AP, in May-June of 2002(3). However, the source of the information was not given(3). There was an outbreak of a brain disease typical of ence-phalopathy in children in Warangal in 1997, and the National Institute of Virology had claimed that it was also caused by measles virus (NS Wairaghkar, Personal communication 1999). In a large outbreak of Reye's syndrome in Haryana, Punjab and Chandigarh in 1997, measles virus was attributed as the cause(5,6). The outbreak, diagnosed as Reye’s syndrome at the Postgraduate Institute in Chandigarh, involved 129 children from 10 districts, in the months of September and October of 1997, with case fatality of 72 %(5). The measles virus aetiology has been questioned since the outbreak was clearly due to Reye’s syndrome(5,11,12).

There was an outbreak of a brain disease of children with high case fatality in Saharanpur district and nearby areas of Uttar Pradesh (UP) during October to November 2002 (V.M. Vasishta, Personal communication, 2003). It affected about 300 children in a wide area covering various districts of UP and Uttaranchal, contiguous with the areas affected in the 1997 outbreak. The clinical features were closely similar to those of the recent outbreak in AP, and the CSF was without pleocytosis. Elevated liver enzymes and low blood sugar were documented, but liver biopsy was not done. The case fatality was about 80%. Children who recovered did so rapidly and had no sequel suggesting brain damage. All these features indicate that the actual diagnosis was not encephalitis, but Reye’s syndrome. This outbreak was also called ‘mystery disease’ at first, presumably on account of the differences from encephalitis, the more familiar diagnosis. However, later it was attributed to JE virus even though the disease was clearly encephalopathy and not encephalitis (V.M. Vasishta, Personal communication, 2003).

From about 1958, outbreaks of what was then called ‘Nagpur encephalitis’ occurred with some regularity annually in eastern Maharashtra(13-15). It had been investigated for JE etiology and it was ruled out. Later it was investigated for enterovirus etiology in 1968(14,15). Results clearly showed that the disease was an encephalopathy syndrome and not encephalitis as believed popularly until then(14,15). Tissue biopsy specimens held frozen in the virus laboratory were examined and were confirmed to contain intracellular microvesicular fat accumulation, and thus the disease was found to be indistinguishable from Reye’s syndrome(15). In short, many outbreaks of Reye’s syndrome have been reported in India; many have gone unreported also. Historically, the first outbreak of Reye’s syndrome was recognized in Thailand and was called Udorn encephalopathy, after the district worst affected(16,17). However, way back in 1954, Late Dr. Najib Khan had described an outbreak of a new disease, which he named Jamshedpur fever, with clinical characteristics identical to those of Reye’s syndrome(18). In summary, this disease has been occurring in large outbreaks in different parts of the country over the last four to five decades. Except for the documentation by N. Khan of the outbreak in 1953 as a new disease (Jamshedpur fever), the recognition that outbreaks of ‘Nagpur encephalitis’ in 1967 and 1968 were actually due to encephalopathy indistinguishable from Reye’s syndrome, and the report of the 1997 outbreak in Haryana, Punjab and Chandigarh as Reye’s syndrome, all other outbreaks had remained undiagnosed, but carried labels of encephalitis, often with the etiology defined as JE virus or of mystery disease.

While sporadic cases of acute encephalo-pathy and fatty degeneration of the viscera are widely recognized and called as Reye’s syndrome, the correct name of outbreaks of this encephalopathy syndrome, based on prece-dent, is Jamshedpur fever. It would be a fitting tribute to Late Dr. Khan to name it as Khan’s disease.

It is generally accepted that at the time of onset of the illness no particular infection is involved in the pathogenesis. Evidently, there is no ‘encephalitis’ and it is not a CNS infection, although many clinicians have conflated encephalitis with the acute encephalopathy and this confusion persists even today, as illustrated in Saharanpur (2002), AP and Maharashtra (2003). However, an infectious disease in the preceding two weeks appears to be a common feature if history is taken carefully. In most instances it is an upper respiratory disease. Two specific infectious diseases are associated with the development of Reye’s syndrome - chickenpox and influenza due to type B virus. In the vast majority of the Indian cases the history of preceding illness was not sought or reported. In addition, a co-factor in the pathogenesis seems to be the exposure to a noxious substance, the best known one being aspirin. Precisely, for this reason aspirin is not used in children below 12 years of age. However, clandestine use of aspirin appears to be prevalent as found in the 1997 outbreak in northern India(5). A few children had salicylate in the blood in spite of obtaining no history of its use by the physicians who had treated minor illnesses in the affected children(5).

Other noxious substances have also been incriminated in its pathogenesis. They include isopropyl alcohol, aflatoxin, margosa oil, pesticides etc. In rural India there is ample opportunities for exposure to a variety of chemicals used in agriculture and such risk factors deserve urgent and diligent investiga-tion in every outbreak of the encephalopathy syndrome. The widespread use of insecticides against mosquitoes should also be considered among the risk factors of epidemic encephalo-pathy. Why would a non-infectious disease occur as an outbreak or epidemic? The most likely explanation is the widespread exposure to a triggering factor, such as a putative chemical toxin. Whether it is salicylate, aflatoxin, insecticide or another substance must be investigated in every such outbreak. It is a pity that the disease is usually investigated thoroughly for a viral etiology, but the real risk factor is not investigated.

The pathogenesis is a temporary and self-limited derangement of mitochondrial archi-tecture and functions. Consequently, the fat metabolism is disrupted within cells. Biopsy of liver or kidney would show intracellular fat inclusion bodies in a microvescicular manner. The accumulated fat induces cytotoxic edema. But for brain edema, the disease would have been inconsequential, since recovery is both rapid and complete. The clinical manifesta-tions of brain disease are entirely due to brain edema, obviously of cytotoxic type. The brain edema resembles that of heat hyperpyrexia, for which reason it had been suggested as one cause of the outbreaks of acute encephalopathy(19). Early diagnosis and appropriate steps taken to reduce brain edema is life saving. The common mistakes are to hydrate the child and not to give adequate anti-edema treatment. If fluids are restricted to less than two-thirds of normal requirement, but given intravenously as hypertonic dextrose (10 or 15%), and mannitol and dexamethasone are given at appropriate doses, children tend to recover in a matter of several hours. Otherwise mortality may be as high as 50-75%.

It is imperative that the Academy establishes continuing education for members in the States affected with recurrent outbreaks of the acute encephalopathy syndrome so that the lives of hundreds of children may be saved in spite of falling ill with this disease. If the Academy will join force with the Indian Council of Medical Research and the local medical colleges where children with acute encephalopathy are hospitalized, we can resolve the causative factor(s) and solve the problem of recurrent outbreaks that take a heavy toll of the lives of our children. Meanwhile, it is important to educate all professional colleagues on the diagnosis and management of such outbreaks and help the Public Health and government officials to refrain from bringing bad name to India by declaring that this disease has mysterious origin, a concept discarded by Ayurveda in ancient times and by science in modern times.

T. Jacob John,
439, Civil Supplies Godown Lane,
Kamalakshipuram, Vellore,
Tamilnadu 632 002,
India.
E-mail: vlr–[email protected]