TOPIC OF THE ISSUE: REVIEW ARTICLE
|Year : 2010 | Volume
| Issue : 4 | Page : 585--591
Encephalitis in the clinical spectrum of dengue infection
Neuropathology Group, Department of Clinical Neurology, University of Oxford, United Kingdom
Pembroke College, Oxford, OX1 1DW
Dengue viral infections are common worldwide. Clinical manifestations form a broad spectrum, and include uncomplicated dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Encephalopathy has been well reported and has classically been thought to result from the multisystem derangement that occurs in severe dengue infection; with liver failure, shock, and coagulopathy causing cerebral insult. However, there is increasing evidence for dengue viral neurotropism, suggesting that, in a proportion of cases, there may be an element of direct viral encephalitis. Understanding the pathophysiology of dengue encephalopathy is crucial toward developing a more effective management strategy. This review provides an overview of the clinical spectrum of dengue infection, and examines evidence supporting the existence of dengue encephalitis.
|How to cite this article:|
Varatharaj A. Encephalitis in the clinical spectrum of dengue infection.Neurol India 2010;58:585-591
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Varatharaj A. Encephalitis in the clinical spectrum of dengue infection. Neurol India [serial online] 2010 [cited 2019 Jan 17 ];58:585-591
Available from: http://www.neurologyindia.com/text.asp?2010/58/4/585/68655
Four out of every ten people in the world are at risk for dengue virus infection  The features of infection range from an asymptomatic state to a severe hemorrhagic disorder with multisystem involvement. Encephalopathy and neurologic complications are well reported but poorly understood. Increasing evidence suggests that encephalopathy may result from direct viral infection of the central nervous system. This review examines the place of encephalitis in the clinical spectrum of dengue infection.
A literature search was performed using PubMed with the terms "dengue" AND "encephalitis"; "encephalopathy"; and "central nervous system." Relevant publications from the World Health Organization (WHO) and the UK National Travel Health Network and Centre (NaTHNaC) were also included in the review.
Dengue is endemic to over 100 countries [Figure 1] and approximately 2.5 billion people are at risk. It is estimated that 50-100 million infections and 25,000 fatalities occur worldwide every year.  World Health Organization (WHO) surveillance shows that global incidence is increasing.  The primary vector is the mosquito Aedes aegypti, found in abundance from latitudes 35°N to 35°S.  Dengue does not occur naturally in the United Kingdom, but is an important differential for fever in the traveler returning from the Tropics.
Dengue is a single-stranded RNA virus of the flavivirus genus. There are four viral serotypes, named DEN-1 to DEN-4. The serotypes are sufficiently heterogeneous that infection with one does not confer immunity to the others. In fact, secondary infection with a different serotype is usually more severe; perhaps due to preferential activation of memory T cells from the primary infection, at the expense of initiating a new and more specific immune response ("original antigenic sin").  After transmission, dengue infects and replicates within the cells of the immune system, especially macrophages and monocytes. Host immune responses play a crucial role in pathogenesis, as outlined in a review by Malavige et al. 
Clinical Spectrum of Dengue Infection
The manifestations of dengue infection represent a wide spectrum of clinical states, as shown in [Table 1].
Dengue fever (DF) classically presents with a rapid onset of fever, malaise, headache, and retro-orbital pain, with severe myalgia and arthralgia ("break-bone fever"). Erythema of the face, neck, and chest is typical, as is a generalized maculopapular rash. In children the presentation is nonspecific, with prominent coryza and gastrointestinal upset. Symptoms usually begin 5-8 days after the bite, last for 2-7 days, and are typically followed by complete recovery.
Dengue hemorrhagic fever (DHF) usually results from secondary infection. Although largely indistinguishable from DF in the initial stages, vascular leak and derangement of clotting become manifest after a few days. There is easy bruising and bleeding, with widespread petechiae. Vascular leak results in hemoconcentration, serous effusions, and hypoproteinemia. The liver is often inflamed, and liver failure may occur. Blood tests show thrombocytopenia and elevated hematocrit. Fever persists for 2-7 days, after which most patients experience spontaneous resolution. In more severe cases, however, the disease progresses to a state of critical vascular leak and circulatory collapse known as dengue shock syndrome (DSS). Untreated, death usually occurs within 12-24 h from the onset of shock. 
Dengue infection has the capacity to cause a multisystem disorder. Numerous neurologic manifestations have been reported, including transverse myelitis,  Guillain-Barré syndrome,  acute disseminated encephalomyelitis,  and myositis;  however, the most widely reported is encephalopathy. The incidence is unclear; calculations range from 0.5%  to 6.2%  of DHF cases. Kankirawatana et al. reported that 18% of children with suspected encephalitis in a Thai hospital were found to have dengue infection.  Several studies report that DEN-2 and DEN-3 have the highest propensity to neurologic complications. ,,
Strictly speaking, encephalitis is a histologic diagnosis of inflammation of the brain parenchyma, commonly due to viral infection. Organisms that are capable of infecting neurons are described as neurotropic. Encephalitis typically presents with fever (if infective), reduced consciousness, headache, seizures, and focal neurologic signs. In contrast, encephalopathy is a clinical picture of reduced consciousness, which can be caused uncommonly by encephalitis but more commonly by other infections, metabolic derangements, alcohol, or drugs. 
Encephalopathy in dengue infection is well recognized, however, to-date it remains unclear whether the virus is neurotropic; it is unclear whether encephalopathy is mediated by direct infection of the nervous system, or indirectly via other mechanisms [Table 2]. In particular, hepatic encephalopathy is well reported in dengue.  However, if these indirect mechanisms are carefully excluded, a subset of patients remain. This suggests that dengue encephalitis may be a distinct clinical entity.
Isolating Dengue Encephalitis
Dengue has classically been thought not to be neurotropic.  However, the discovery of dengue virus ,, and antidengue IgM ,,, in the cerebrospinal fluid (CSF) of patients with encephalopathy suggests that dengue is capable of central nervous system (CNS) infection. Clinical research has not been conclusive and much of the published literature is limited to case reports. A few studies purporting to address encephalitis did not adequately exclude other causes of encephalopathy and hence were not suitable for consideration in this review. However, 4 studies with appropriate exclusion criteria were identified and are discussed below.
In India, Misra et al. described 11 encephalopathic patients with confirmed dengue infection.  Care was taken to exclude patients with nonencephalitic causes, making true encephalitis the likely etiology. Unfortunately, no provision was made to identify virus in the CSF, presence of which would have strengthened the case. That said, eight patients had a lymphocytic pleocytosis of the CSF, suggesting a viral meningoencephalitic process. Interestingly, Misra et al also identified a second group of dengue patients presenting a picture of acute neuromuscular paralysis with intact mental status resembling the Guillain-Barré syndrome (GBS). Serum creatine kinase (CK) was raised in five of the six patients, and after excluding differentials, they inferred that the etiology was a generalized dengue myositis. Some patients had features of both encephalitis and myositis, leading the authors to propose a 'continuum' of neurological involvement between the two syndromes.
In Vietnam, Solomon et al. made a clinical diagnosis of dengue encephalitis in nine encephalopathic patients.  All had dengue confirmed in the serum and all had either CSF pleocytosis, focal neurologic signs, or seizures. None had an identifiable nonencephalitic diagnosis. However, virus and/or antibody were found in the CSF of only two of these patients. Unusually, seven patients showed no classic features of dengue infection, leading the authors to suggest that dengue be considered in all encephalitic patients in endemic areas, regardless of the presence or absence of classical features.
In two similar studies, Kankirawatana et al.  and Kularatne et al.  identified eight and six patients, respectively, in whom dengue encephalopathy was without identifiable cause. These are included in the discussion below.
Clinical Features of Dengue Encephalitis
From the studies described above, we may extract the features that characterize dengue encephalitis [Figure 2]. The common features that emerge are classically encephalitic; fever, headache, reduced consciousness, and seizures. Other features identified include meningism, ,, extensor plantars,  frontal release signs,  abnormal posturing,  facial nerve palsy,  and tetraparesis.  Isolated case reports describe more esoteric features ranging from altered sensorium  to bilateral hippocampal encephalitis presenting as amnesia in a traveler. 
Three of the studies reported the relative frequency of primary and secondary dengue infection in encephalitic patients, revealing a preponderance of secondary infections [Figure 3]. Three of the studies reported the time of onset of neurologic symptoms [Figure 4]. Median time of onset ranged from 3-7 days from the start of fever.
All studies made observations regarding the outcomes [Table 3]. Misra et al. found that recovery was complicated, leading the authors to propose that encephalitis lies at the severe end of the spectrum of dengue infection.  This is at odds with the other studies, which suggest a more benign disease. ,, Whether this represents heterogeneity in disease, management, or patients is difficult to determine.
Clinical diagnosis is supplemented by laboratory tests. As for viral diseases in general, laboratory diagnosis of dengue infection rests on either detection of the virus itself, or of the host immune response. Methods currently in use are summarized in [Table 4].
The 'gold-standard' method for viral detection has traditionally been viral culture, although it is difficult and time-consuming. Newer methods of viral RNA detection by polymerase chain reaction (PCR) assay are quicker, more widely available, and allow discrimination between viral serotypes. Singh et al found the specificity of one PCR assay to be 100%, with a sensitivity of 70% when samples were taken in the first five days of fever.  The third option is detection of viral antigens by immunochemistry. Dussart et al have achieved a sensitivity of 89% with an assay for NS1 antigen  . This test is rapid, reliable, and, crucially, cheaper than PCR.
Detection of the host immune response (serology) is commonly achieved by MAC-ELISA (IgM antibody-capture enzyme-linked immunosorbent assay), which measures 'dengue-specific' IgM. Although the presence of anti-dengue antibodies shows only that there has been recent infection (within 24 weeks), it is possible to confirm acute infection by showing rising antibody titres in two serum samples. Serological assays are also relatively simple and can be bought as self-contained kits. The advantages of serological testing are tempered, however, by a reduced specificity due to cross-reactivity with antibodies against other flaviviridae. Singh et al reported the sensitivity of MAC-ELISA at 69%, rising to 90% with repeat convalescent testing. Specificity was 80%. 
Which class of test to use depends very much on timing. During the first stage of infection the patient is febrile and virus may be detected in the serum, whereas in the period after defervescence viraemia is abolished and the antibody response may be detected.  Hence it is sensible to use PCR or immunoassay in the patient with fever for fewer than five days, and MAC-ELISA in the patient with fever for more than five days.
Brain Imaging in Dengue Encephalitis
Although laboratory testing remains the definitive diagnostic tool, brain imaging adds considerable information to the investigation of suspected viral encephalitis. Magnetic resonance imaging (MRI) is the modality of choice as compared to computed tomography (CT), as it provides far greater definition of the brain substance as well as superior visualization of the posterior fossa. Aside from excluding differential diagnoses, general findings consistent with viral encephalitis include cerebral edema, white matter changes, and (later) necrosis and brain atrophy. Infarction or hemorrhage may also be visible. Breakdown of the the blood-brain barrier may be visualized as signal enhancement on MRI with gadolinium contrast. However, it is not uncommon for scans to appear normal early in the disease, and specialist neuroradiological input is required to interpret subtle abnormalities.
In the investigation of the patient with a suspected CNS infection, focal abnormalities on brain imaging are suggestive of encephalitis rather than encephalopathy, which tends to produce more global changes.  Many viral encephalitides display a tropism for particular brain structures, which results in typical imaging patterns [Table 5]. It should be emphasized, however, that these findings are not 'pathognomonic', and deviations from stereotypical presentations may occur.
Are there MRI features which characterize dengue encephalitis? In Misra's eleven patients, MRI was performed on nine; all were normal bar one patient with hyperintense areas in the globus pallidus.  In Cam's study of dengue encephalopathy, MRI scans in eighteen patients showed focal 'encephalitis-like' changes in four,  although the authors made no mention of the distribution of lesions. Kamble et al have described a case featuring JE-like thalamic involvement visualized on CT (JE was excluded by serological tests),  while other authors have reported MRI lesions in the hippocampi,  temporal lobes, , pons,  and spinal cord. , Clearly, much of the data is disparate and a conclusive characterization of the MRI features of dengue encephalitis is not yet possible, although the focal nature of imaging abnormalities adds weight to the theory of viral neurotropism.
The Case for Dengue Encephalitis
The evidence from published studies suggests that dengue encephalitis is a distinct clinical entity. A case definition is proposed in [Table 6]. When one considers that the flavivirus genus includes numerous members that cause encephalitis, among them West Nile and Japanese encephalitis viruses, that dengue should have the potential for encephalitis is perhaps unsurprising. However, the importance of other mechanisms, particularly liver failure, is not to be downplayed, and it would appear that true encephalitis represents only a subset of dengue encephalopathy cases.
A large part of the evidence for dengue neurotropism is the presence of virus and/or antibody in the CSF. Given that vascular leak is a central feature of DHF, does this constitute proof of neurotropism? One could imagine that dengue simply leaks into the CSF through damaged cerebral vascular endothelium. However, the correlation of virus in the CSF with otherwise unexplainable encephalopathy would point strongly toward CNS infection. Some patients have virus in the CSF but not in the serum,  which is inconsistent with the idea of passive viral leak into the CSF during viremia. A few studies have also shown viral RNA  and antigens  in CNS biopsies, directly confirming viral infiltration of brain parenchyma. There is a paucity of data on the mechanisms by which dengue may penetrate the blood-brain barrier, however, entry through infected macrophages  and histamine release  have been implicated.
Although all patients have virus in the serum, it remains to be explained why a relatively large number show no evidence of dengue in the CSF. Could it be that what has been called 'dengue encephalitis' actually results from co-infection with another pathogen, and the occasional presence of dengue in the CSF is an artifact of vascular leak? Although not a parsimonious explanation, this is not impossible; as even though the 4 studies described above were careful to exclude other infections, it is simply not feasible to exclude all known or unknown neurotropic pathogens. There is another possible explanation, however; the absence of evidence of dengue virus in the CSF may be an artifact of detection methods, as although PCR demonstrates a high sensitivity for serum virus this may be diminished in the CSF due to a lower viral load. Anti-dengue antibodies may not be a reliable marker either, due to low titres in the CSF  . The temporal pattern of CSF viral load is not known but is likely to be crucial in determining the timing of CSF testing.
Clearly, further work remains to be done. The issue will not be settled until dengue virus can be reliably shown in the brains of encephalopathic patients in whom no other cause can be identified. A large-scale study, with strict exclusion criteria, careful CSF analysis, and imaging, electroencephalogram, and neuropathology support, would be desirable, as would a greater understanding of the pathogenesis of dengue infection. Can dengue defeat the blood-brain barrier and infect neurons, and if so, how? What factors influence these processes, and can these factors be detected, to identify patients at risk, and can they be modified, to halt encephalitis?
Management of Dengue Encephalitis
Management of dengue infection rests on careful monitoring [Table 7] and replacement of intravascular fluid and electrolyte losses. In uncomplicated DF control of fever may be sufficient, supplemented by oral rehydration if necessary. Observation of hematocrit and platelet count for signs of conversion to DHF/DSS is essential, especially around defervescence. In DHF, on the other hand, early oral or parenteral fluid resuscitation avoids progression to shock. If DSS occurs, urgent expansion of plasma volume is required. Crystalloid (preferably dextrose-saline mixture or Ringer's lactate) should be given as a rapid bolus at a volume of 10-20mg/kg, monitoring closely for improvement.  If unresponsive, colloids and blood transfusion may be used. Blood products may also be required to correct DIC. Management in an intensive care setting is required. Fluid status is best quantified by daily weights, and replacement volumes should be carefully calculated so as to avoid overload (which may worsen cerebral edema). The WHO recommends the use of 5% dextrose diluted with 1-2 volumes of normal saline. 10ml/kg of replacement fluid should be given for every 1% of normal body weight lost,  in addition to maintenance fluids by the standard weight-based protocol.  Also, the kidneys may be damaged by hypoperfusion in DSS, and if acute renal failure occurs dialysis may be required. Damage to lung vasculature may result in acute respiratory distress syndrome (ARDS), necessitating respiratory support. Again, overhydration should be avoided to prevent exacerbation of pulmonary edema.
Cerebral dysfunction secondary to liver failure, shock, electrolyte derangement, or intracranial hemorrhage is well recognized and management follows the appropriate pathway for each. Dengue encephalitis, on the other hand, represents a fundamentally different disorder, and one which may require different management.
General management of viral encephalitis includes monitoring and maintenance of the airway and of adequate oxygenation, hydration, and nutrition. Seizures may be controlled by standard anti-epileptic drugs, and raised intracranial pressure by head-up nursing, mannitol, and steroids.  If bacterial infection remains a possibility then empirical antibiotics appropriate to local organisms should be given. In endemic areas other CNS infections, including cerebral malaria, toxoplasmosis, neurocysticercosis, human immunodeficiency virus (HIV), and tuberculosis should also be excluded, along with local viruses, for example, Japanese encephalitis in Asia and West Nile virus in Africa.
Specific management of viral encephalitis requires antiviral therapy. Given the relative frequency of HSV encephalitis and the mortality benefit that is gained by early treatment, empirical administration of acyclovir is recommended in patients presenting with an encephalitic picture. No such antiviral treatment exists for dengue. Research into the pathogenesis of dengue infection may yield new treatments, and current work has shown inhibition of dengue replication in cell culture by many promising agents, including ribavarin, morpholino oligomers, geneticin, and blockers of viral envelope proteins.  Given the known immunopathogenesis in dengue infection, there may also be a role for immunosuppression.
Dengue viral infections represent a significant burden of disease in the Tropics. Neurologic manifestations are increasingly recognized but remain relatively poorly understood. Acute encephalopathy is the most frequent such manifestation, and although previously thought to be nonencephalitic, increasing evidence of dengue viral neurotropism suggests that a proportion of cases are wholly or partly encephalitic. The primary features of dengue encephalitis are fever, headache, reduced consciousness, and seizures, although other neurologic manifestations may be evident. Classical features of dengue are usually but not invariably present. Virus or antibody is reliably isolated from the serum although CSF samples are often negative. Management combines the principles used across the spectrum of dengue infection with those used in other viral encephalitides, and although no specific antiviral yet exists, there is evidence that the disease may be self-limiting, with most patients making a good recovery. It is hoped that increasing recognition of this condition will lead to an improved understanding of the wide spectrum of dengue infection.
I thank Dr. Alex Tsui for his comments on the manuscript.
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