The syndrome of acute encephalitis in children in India: Need for new thinking

Definition, clinical description and differential diagnoses

Acute encephalitis is the clinical diagnosis of children with acute onset of symptoms and signs of inflammatory lesions in the brain. Changes in sensorium, seizures and upper motor neuron type of altered muscle tone point to cerebral dysfunction. Brain tissue would show the pathology, but at the bedside, inflammation is surmised from pleocytosis of the cerebrospinal fluid (CSF) to predominantly lymphocytes, since the aetiology is mostly non-pyogenic infection1. The clinical picture usually consists of a prodromal phase (one to three days) with fever, malaise and headache and an encephalitic phase with continued fever, decreasing level of consciousness, seizures, abnormal movements or paralysis. Signs of meningeal inflammation are absent or minimal. Many children may succumb, but others recover through a post-encephalitic phase, the fortunate ones more or less completely, but others with sequelae of cognitive deficiencies, muscle paralysis, abnormal movements, etc.

Acute encephalopathy and acute meningitis - pyogenic, tubercular, fungal or viral - are other examples of acute central nervous system (CNS) diseases due to infectious or non-infectious aetiologies that can and must be differentiated from acute encephalitis. In acute encephalopathy, brain pathology is non-inflammatory, often biochemical; hence, CSF shows no pleocytosis. Onset is often without prodromal phase and tends to be in the morning hours, the child having been well the previous evening. Changes in sensorium, seizures and upper motor neuron-type muscle tone abnormalities and abnormal movements point to cerebral dysfunction. Encephalopathy occurring in clusters is often conflated with acute encephalitis outbreak234. Acute meningitis is diagnosed when the clinical presentation points to meningeal inflammation - with fever, headache, neck rigidity, positive Kernig and Brudzinski signs and high pleocytosis in CSF. In pyogenic meningitis, CSF cells are predominantly polymorphonuclear leucocytes, while in most others, these are predominantly lymphocytes. While viral meningitis is often self-limited, bacterial and fungal meningitis will progress to severe brain dysfunction and death, if left untreated. When features of encephalitis and meningitis co-exist, the disease is called meningoencephalitis1.

Some systemic infectious diseases with their own distinct clinical features may occasionally present with brain function derangement. Some are due to invasion of the pathogens into CNS, as with dengue fever5, chikungunya6, scrub typhus7 and leptospirosis8, but even in such instances, these should be labelled as a complication of the primary disease, instead of acute encephalitis.

Cerebral malaria, a mimicker of encephalitis, is a complication of Plasmodium falciparum malaria. Some CNS complications of diseases are of unclear pathogenesis, such as encephalopathy of typhoid fever, shigellosis, influenza and varicella. Children given acetyl salicylic acid for such illnesses have increased risk of encephalopathy (Reye syndrome), for which reason the drug is prohibited in children below 12 years2. In some, pathogenesis is immune-mediated inflammation, as in post-measles and post-varicella encephalitis, also called acute demyelinating encephalomyelitis (ADEM)9.

Intracranial abscess (brain/subdural) and subarachnoid haemorrhage are relatively uncommon, but for the affected child, accurate diagnosis offers the possibility of life-saving treatments. Septicaemia of various aetiologies may present with cerebral dysfunction, which, unless picked up and treated early, may be life-threatening.

In summary, all that presents with fever and cerebral dysfunction are not acute encephalitis. No single syndrome will accommodate all these disparate clinical conditions. Each clinical entity must be diagnosed and managed according to the modern medical recommendations both for individual healthcare and community control. Many of the above are medical emergencies and must be diagnosed promptly for saving life and preserving brain functions. Misclassification or delay can entail risk to the patient.

Causative infections of acute encephalitis

We confine our attention to children with normal immune functions; children with immunodeficiency may have opportunistic agents that are by and large non-pathogenic to others. Acute encephalitis is mostly caused by any of the many ‘neurotrophic’ viruses, many of which are vector-transmitted (arthropod-borne) arboviruses. In India, Japanese encephalitis (JE) virus is the predominant aetiology10. Due to its ecological features, namely, the requirement of ‘amplifying hosts’ (pigs, herons and egrets) and vectors (Culex species mosquitoes), there are geographic restriction to some parts of the country, mostly rice paddy growing areas, and seasonal restriction determined by vector density, mostly post-monsoon.

West Nile (WN) virus is common in India and is known to cause acute encephalitis11. However, its geographic prevalence and quantitative contribution to acute encephalitis in India have not been systematically studied, because of considerable antigenic cross-reactivity between JE and WN viruses as well as between them and dengue viruses that are even more widely prevalent.

Anthroponotic viruses such as herpes simplex virus12 and mumps virus1314, a few enteroviruses15 and Epstein-Barr virus16 are other causes of sporadic cases of acute encephalitis. Rarely, measles and rubella may develop a complication by way of encephalitis, but the primary disease would be concurrently evident.

Nipah virus encephalitis had occurred once in Siliguri in West Bengal but was at first misdiagnosed as measles encephalitis1718. Chandipura virus is widely prevalent in India, transmitted by sand flies and mosquitoes, and a few reports of outbreaks of what was called acute encephalitis caused by it have been published1920. Similar outbreaks caused by measles virus, but without clinical measles, also have been reported earlier2122. However, how such widely prevalent viruses cause only rare outbreaks has not been explained. The clinical features of both Chandipura and measles ‘encephalitis’ were very similar to each other but very dissimilar to arbovirus encephalitis. In neither was there a prodromal phase; onset was abrupt and CSF was without pleocytosis as in encephalopathy. However, because a virus was detected in brain tissue or CSF, one has to accept the diagnosis of CNS infection, in spite of the fact that the clinical picture was that of acute encephalopathy without inflammatory pathology in the brain. We recommend caution in concluding that these two viruses are the actual cause of acute encephalopathy until re-confirmed by other investigators.

In the case of the first report on Chandipura virus encephalitis, an alternate pathogenesis has been described, namely, acute vascular pathology or ‘epidemic brain attack’23. Such an explanation may clarify why the clinical picture was that of acute encephalopathy; what is not clear is if the virus infection actually caused cerebral arterial thrombosis23. Among non-viral causes of acute encephalitis, Naegleria is well-recognized to cause ‘primary amebic meningoencephalitis’, affecting people who swim in freshwater ponds or lakes24.

Thus, acute encephalitis is a clinical syndrome with several common features but caused by various infectious agents, mostly but not exclusively viruses. It should be differentiated from all other diseases mentioned above, clinically always and aetiologically when possible. In clinical context, the addition of the word syndrome is superfluous; acute encephalitis is specific and clear enough as is the conventional practice in paediatrics.

Acute encephalitis syndrome (AES), an ambiguous diagnostic term

In recent years, a diagnosis of ‘acute encephalitis syndrome’ (AES) has crept into medical literature in India, with a definition at variance from that of acute encephalitis in paediatric textbooks10142526. For example, AES was defined in one study as ‘clinical neurologic manifestations caused by wide range of viruses, bacteria, fungus, parasites, spirochetes, chemicals and toxins’26. Obviously, the clinical pictures of such various diseases cannot fit into one clinical diagnosis of acute encephalitis, either as a disease or as a syndrome.

The clinical classification into acute encephalitis, encephalopathy, meningitis, ADEM or as complications of any disease that may cause brain dysfunction is an ethical and scientific imperative; correct management will depend on the correct diagnosis. Many of the diseases clubbed into the ‘basket of AES’ are eminently treatable with specific therapies. Antiviral drug is available for herpes simplex encephalitis. Other cases of viral encephalitis can only be treated with supportive care. The risk to the patient in whom AES is diagnosed is that the disease may be presumed to be acute encephalitis, hence viral in origin; further investigations, even spinal tap for CSF examination, may be avoided believing that every so-called AES is viral in origin and without specific therapeutic possibilities.

Conclusion

All acute-onset CNS diseases of children do not constitute one syndrome, but several - not only encephalitis, encephalopathy and meningitis but also CNS complications of systemic diseases, brain abscess, subarachnoid haemorrhage, etc. Each of these diseases must be differentiated from every other since treatment will depend on the specific diagnosis. The tendency to club them together as if they belonged to one syndrome, ‘AES’, must be avoided.