Dengue Virus Encephalitis

Abstract

In this chapter, we will draw attention to the possibility of viral encephalitis caused by a common pathogen: dengue. To this end, it includes necessary knowledge of diagnosis and therapeutic management, such as general notions of infections in the central nervous system; viral encephalitis—diagnostic and therapeutic investigation; arboviruses and their relevance; dengue as an endemic disease; diagnostic methods and treatment; its possible clinical presentations and complications, among them, dengue encephalitis.

1. Introduction

In this chapter, the authors focus their efforts primarily on understanding encephalitis, especially those caused by viral pathogens, as well as their neurological repercussions. It brings fundamental concepts for understanding diagnostic reasoning and prognosis. Besides the various viruses already well known and with possible and consecrated research and therapeutics, it also intends to draw attention to less prevalent etiologies. However, it is of fundamental importance for the medical community and is of paramount importance for neurology.

Among the pathogens, the chapter draws attention mainly to dengue virus encephalitis, due to the high incidence of dengue cases in endemic countries and encephalitis being a rare consequence but difficult to diagnose and extremely important for medical knowledge in the scope of diagnosis differences in countries where dengue is endemic.

2. Central nervous system infections

Infections of the central nervous system (CNS) present a wide variety of situations, ranging from common diseases to serious and rare diseases, from benign manifestations to severe neurological impairments, which often determine sequelae and cause the patient’s death, in addition to acute, subacute, and chronic diseases.

The main clinical manifestations of infections are characterized by headache, fever, and altered mental status. Vomiting and focal signs may occur, but even so, these symptoms are common to several other neurological diseases that mimic meningitis and encephalitis. For the diagnosis, a complete anamnesis, epidemiological history, and accurate clinical and neurological examinations are essential to glimpse signs that may suggest a probable diagnosis (Figure 1) [1].

Figure 1.

Patient with stroke after acute dengue infection. Right: Brain MRI in diffusion sequence. Left: Brain MRI in FLAIR sequence. Both show the presence of an extensive lesion with diffusion restriction and hypersignal on the images, respectively, in the territory of the middle cerebral artery, with involvement of the ipsilateral thalamus and mass effect with midline shift. In addition, the presence of a right temporal parietal lesion is observed. Extracted from: http://www.rmmg.org/article/details/2631.

3. Viral encephalitis

Encephalitis is the term used to describe the involvement of the brain tissue by a viral etiological agent, while bacterial, fungal, or focal parasitic infections involving the brain tissue are classified as cerebritis or abscess, depending on the presence or absence of a capsule [2]. It is characterized by the presence of an inflammatory process in the brain parenchyma, associated with clinical evidence of brain dysfunction. This process is often caused by a viral infection. The main viruses that cause encephalitis in immunocompetent patients belong to the group of herpes viruses, arboviruses, and enteroviruses [1].

Although, by definition, in cases of meningitis, the infectious/inflammatory process is limited to the meninges, in encephalitis, not rarely, the process is not restricted to the brain parenchyma, and the involvement of the meninges can also be present [2].

Some authors consider that up to 2/3rd of encephalitis cases will not have an etiological definition [3]. Among cases with identified etiologies, viruses represent the largest share of encephalitis cases. The true incidence of these infections is difficult to determine, as a diagnosis may not be considered at first or a specific viral etiology may not be confirmed due to the lack of laboratory structure for this [4].

Several viruses can penetrate the central nervous system, causing, among other conditions, encephalitis. Herpes Simplex Virus (HSV1) is a relatively common cause of encephalitis, which together with Varicella Zoster are described in the medical literature as classic etiologies [5]. Other viral pathogens may be suggested by local epidemiology, as is the case with the dengue virus. Acute arbovirus infection occurs 5 to 15 days after the bite of the transmitting mosquito. CNS invasion can occur during the initial phase of viremia with infection of capillary endothelial cells and subsequent infection of neurons. The viral infection spreads from one neuron to another through dendrites and axons, predominantly affecting the gray matter of the cerebral cortex and the basal ganglia [1].

Viral encephalitis can also be classified, according to the stage of infection, into viral and post-viral. In direct viral infection, it is possible to find genetic material or the virus itself in the histology of the affected brain tissue. In postinfectious encephalitis, the virus does not directly attack neurons, but the intense immune-mediated inflammatory response can lead to demyelination and neuronal damage [6].

3.1 Clinical presentation

Viral encephalitis should be suspected in the presence of a febrile illness accompanied by headache, altered level of consciousness, and also signs and symptoms of brain dysfunction, such as: cognitive dysfunction (memory), disorientation, hallucinations, agitation and changes in behavior, and focal neurological alterations (hemiparesis, aphasia), in addition to epileptic seizures. Some clinical findings may suggest an etiology, such as rash in the case of arboviruses, parotitis (mumps), gastroenteritis (enterovirus), and upper airway infections (influenza and HSV1) [1].

3.2 Diagnosis

After clinical suspicion, a complementary arsenal should be used, such as cerebrospinal fluid (CSF) puncture associated with neuroimaging. The European Federation of Societies of Neurology, EFNS, recommends that CSF investigations include basic chemical and cytological analysis and research of specific viruses using the polymerase chain reaction technique.

Laboratory tests (hemogram, VHS, C-reactive protein), in addition to blood cultures, chest X-rays, and examinations for other possible sources of infection such as clinical evaluation, electroencephalography (EEG), and brain biopsy, should only be indicated if the previous tests are not conclusive [1].

3.3 Radiological presentation of encephalitis

A plethora of infectious and non-infectious inflammatory diseases affect the central nervous system (CNS). The normal brain responds to these injuries in a limited way, often causing injuries to the parenchyma. Initially, there is an increase in cerebral perfusion caused by the release of inflammatory factors and cytokines, later, and as a consequence, the capillaries leak, leading to edema but without pain, unless the meninges are affected. In most cases, there is a concomitant abnormality of the blood-brain barrier with the associated enhancement. Later, if the insult results in neuronal death, the tissue shrinks and becomes atrophic [7].

Imaging techniques are relatively sensitive for detecting an abnormality, localizing it, and, in many cases, categorizing the lesion into infectious/inflammatory versus neoplastic or vascular disease. The location of the lesions is the critical first step in the differential diagnosis. Lesions may occur in a variety of locations, such as the epidural, subdural, subarachnoid, intraventricular, or intraparenchymal space; white matter; gray matter; gray-white junction; or deep gray matter. The lesions may be confined to a particular region of the brain, such as the temporal lobe, or they may be scattered, affecting different areas and presenting numerous clinical manifestations. Among the various imaging methods, including magnetic resonance spectroscopy (MRE), perfusion-weighted imaging, and single-photon emission computed tomography (SPECT) examination, only DWI had an impact on the diagnostic suggestion of infectious/inflammatory conditions, because diffusion restriction is characteristic of some stages of some infections [7].

3.4 Initial conduct

The European Federation of the Neurological Societies (EFNS) also recommends performing neuroimaging, preferably MRI, before lumbar puncture in patients with immunosuppression, previous CNS disease, recent seizure, papilledema, altered level of consciousness (Glasgow coma scale <10), or focal neurological (except cranial nerve palsy).

For conceptual reasons, the neuroimaging exam is almost always the first one to be performed. Regardless of whether the lumbar puncture is performed, if there is clinical suspicion of acute viral encephalitis, good practice establishes the initiation of treatment with acyclovir at a dose of 10 mg/kg intravenously (IV) every 8 hours for at least 14 days before a diagnosis is confirmed. Etiology is possible. The rationale for this practice is that acyclovir is a relatively safe treatment and, when administered in herpetic encephalitis before the patient falls into a coma, reduces mortality and morbidity in treated patients. Thus, acyclovir treats the most common and severe viral encephalitis, as well as covers varicella zoster virus (VZV) infection.

All cases of acute viral encephalitis should be managed in an intensive care unit (ICU) with mechanical ventilation available. Regardless of the etiology, clinically supportive therapy is one of the mainstays of the treatment of acute viral encephalitis.

Epileptic seizures should be controlled with IV phenytoin or other drugs that are necessary. Extreme attention should be given to maintaining breathing, heart rhythm, and fluid balance; prevention of deep venous thrombosis and aspiration pneumonia; and clinical control of intracranial hypertension (ICH), and secondary bacterial infections [1].

Secondary neurological complications in the presence of viral encephalitis are frequent and include cerebral infarction, cerebral venous thrombosis, syndrome of inappropriate secretion of antidiuretic hormone, aspiration pneumonia, upper digestive hemorrhage, urinary tract infection, and disseminated intravascular coagulation (DIC). Isolation in acute viral encephalitis is only indicated for patients who are very immunocompromised, with rabies encephalitis or with rashes and contagious hemorrhagic fever.

3.5 Treatment

When the clinical history and thorough general physical and neurological examinations raise the suspicion of acute viral encephalitis without directing to a particular etiology, good practice recommends the empiric initiation of acyclovir for the reasons mentioned above. However, when there are clinical and laboratory data that guide the etiological diagnosis for a given virus, the treatment must be adapted.

In the case of herpetic encephalitis in an adult patient, acyclovir is maintained at a dose of 10 mg/kg IV every 8 hours for at least 14 days. VZV encephalitis can also be treated with this regimen, and when severe, usually associated with encephalic vasculitis, high-dose dexamethasone or pulse therapy with methylprednisolone for 3 to 5 days should be associated. In the case of CMV encephalitis, treatment with ganciclovir at a dose of 5 mg/kg, IV, every 12 hours, associated with foscarnet at a dose of 60 mg/kg, IV, every 8 hours, or 90 mg/kg, EV, every 12 hours, for a period not yet determined in studies. If the patient has AIDS, antiretroviral treatment should be initiated or maintained, independing on the case [1].

So far, acute viral encephalitis caused by other viruses has no recommended specific treatment, and the patient must receive intensive clinical support until the natural resolution of the process. A summary of the specific antiviral treatments available is shown in Table 1.

Virus	Antivirals	Duration (days)
HSV-1, VZV, HSV-2 (adults)	Acyclovir 10 mg/ kg IV every 8 hours	14–21
COGS	Ganciclovir 5 mg/ kg IV every 12 hours + foscarnet 60 mg/ kg IV every 8 hours or 90 mg/ kg IV every 12 hours	indefinite

Table 1.

Specific antiviral regimens and mean duration of treatment.

HSV: herpes simplex virus; VZV: varicella zoster virus; and CMV: cytomegalovirus.

4. Arbovirosis

Arboviruses are diseases of viral etiology, caused by Arboviruses, transmitted from infected hematophagous arthropod vectors [8]. Arboviruses (Arthropod-borne virus) have part of their replication cycle, especially the initial one, in such insects and can be transmitted to mammals and other animals through bites. It is considered that around 150 different arboviruses cause diseases in humans [9].

After the bite of the infected insect, the dendritic cells of the skin are initially affected. After initial replication, migration to lymph nodes occurs, and the period of viremia begins, with variable duration, which can occur 3–5 days. Arboviruses disseminate to the liver, spleen, and bone marrow and may reach other organs [3].

Such agents can cause a series of diseases with different clinical presentations, ranging from mild and self-limiting forms to severe forms characterized by syndromes such as shock due to plasma leakage and even invasion of the central nervous system, causing encephalitis [10].

4.1 Epidemiology and geographical distribution of arboviruses

Arboviruses are distributed throughout the globe, with the exception of Antarctica, and predominate, above all, in regions of the globe with a tropical and subtropical climate. Such distribution respects the biomes in which the vectors tend to have better adaptation [8].

Until the 1970s, dengue was considered a disease restricted to some countries in the Caribbean and Southeast Asia. From that time on, there was a lack of control of the vector Aedes aegypti, with its migration to other countries. Today, it is estimated that 2.5 billion people live in risk areas in approximately 100 countries. About 50 million dengue virus infections occur annually, with 500,000 cases of dengue hemorrhagic fever and 22,000 deaths. There have been two major recent pandemics, in 1998 and between 2001 and 2002, with twice as many cases of dengue hemorrhagic fever reported in the last pandemic than in 1998. The lack of an available vaccine, the presence of four antigenically distinct serotypes, and the lack of specific therapy make combating the mosquito vector the only effective measure to control the disease [11].

Arthropod-borne encephalitis viruses represent a significant public health problem in most tropical and subtropical countries. These viruses belong to the Flaviviridae, Togaviridae, Bunyaviridae, and Reoviridae families. Such agents are highly adaptive to specific reservoir hosts and are transmitted from animal to animal through the bite of an infected arthropod [9].

The main viral agents responsible for encephalitis in humans and belonging to the Flaviviridae family are distributed heterogeneously across the globe. Dengue viruses DENV-1, DENV-2, DENV-3, and DENV-4 are transmitted by Aedes aegypti or Aedes albopictus mosquitoes. The worldwide distribution of vectors and different serotypes has increased dramatically over the last decade, and PAHO/WHO data suggest that 3.9 billion people are subject to infection. In 2015, dengue virus infections in Southeast Asia, the Americas, and the Eastern Pacific totaled 3.2 million, and the incidence rate in the Philippines reached 24%. South Asian countries have reported seropositivity for antibodies against the dengue virus ranging from 60 to 80%. In Africa and the eastern Mediterranean, data are scarce due to underreporting; however, the vectors are present in 15 countries. In Europe, transmission is low, with most cases being travelers from endemic countries. In 2020, 5 cases of local transmission were reported in Italy. Regarding the neurological involvement by dengue, about 1% of those infected evolve with this outcome, with brain involvement being predominant, ranging from 58.8 to 71.4% in case report studies [12, 13, 14].

Other members of the Flaviviridae family are extremely important in cases of encephalitis worldwide. The Japanese encephalitis virus is responsible for 68,000 cases in Asia. Murray Valley encephalitis virus affects countries in Oceania, and its incidence is underestimated, since only 1 in 150–1000 infected people develop the disease. Encephalitis of St. Louis has, in outbreaks, an incidence of 5 to 200 cases per 100,000 people, and in the last 50 years, it has affected more than 10,000 people. West Nile encephalitis virus is widely distributed in Africa, South Asia, the Middle East, and Europe [9].

4.2 Major arboviroses

We can list 4 main families responsible for encephalitis in humans. They are: Flaviviridae, Togaviridae, Bunyaviridae, and Reoviridae.

4.2.1 Flaviviridae

The Flaviviridae family comprises about 70 species, 40 of which are responsible for diseases in Homo sapiens. Classically, the Flavivirus family is divided into 4 main branches: tick encephalitis complex, Japanese encephalitis complex, yellow fever, and dengue. All representatives of the family can be responsible for infections in humans, with possible neurological repercussions [15].

Flaviviruses have particles that vary between 40 and 60 nm and have an icosahedron-shaped capsid covered by a lipid envelope with membrane proteins and glycoprotein spikes. Positive single-stranded RNA makes up its genome. Its replication is cytoplasmic, using host machinery and producing a strand of reverse polarity, used as a template.

The encephalitis virus of St. Louis has a tropism for the nervous system, with direct invasion and neuronal damage. It causes illness with nonspecific symptoms of encephalitis, such as seal signs, fever, and headache. Regarding mortality, data ranging from 5 to 20% have already been recorded. In Brazil, descriptions of co-infection with dengue have already been registered, and the picture presents with hemorrhagic lesions and positive tourniquet test, with unfavorable outcome.

The West Nile virus is also neurotropic and mainly affects the medulla, pons, thalamus, substantia nigra, and basal ganglia, producing clinical syndromes of the first motor neuron; however, the symptoms may be compatible with other encephalitis. The disease manifests itself more intensely in the elderly and immunosuppressed. The treatment is supportive, intervening in convulsive crises; some case reports predict advantages in the use of corticotherapy and immunoglobulin [15].

Japanese encephalitis is a clinical entity that presents signs and symptoms of nonspecific acute encephalitis. The incubation period for the virus lasts 5 to 10 days, and evolution to neuroinvasive disease occurs in a minority of cases. There is no targeted therapy for Japanese encephalitis virus.

4.2.2 Togaviridae

Togaviruses are a family of single-stranded, enveloped, spherical RNA viruses classified into two genera: Rubivirus and Alphavirus. This includes 40 members, and the genus Rubivirus is composed of a single member, rubella. The main encephalitis-related agents are Western equine encephalitis virus, Eastern equine encephalitis virus, Venezuelan equine encephalitis virus, and Mayaro virus [15].

4.2.3 Bunayviridae

The four genera belonging to the family Bunyaviridae that infect animals are: Orthobunyavirus, Phlebovirus, Nairovirus, and Hantavirus. These viruses are transmitted by mosquitoes, ticks, and rodent excrements [16].

4.2.4 Reoviridae

Colorado tick fever is the main viral disease caused by a virus of the Reoviridae family, transmitted by the tick Dermacentor andersoni. The symptoms of the infection are mild, and the course is benign in most cases. However, children under 10 years of age may develop encephalitis and hemorrhages [17].

5. Dengue

The dengue virus comprises four serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. It is a virus belonging to the Flaviviridae family, which also includes the yellow fever virus, for example. The dengue virus is enveloped and spherical, with single-stranded RNA [3, 8]. All dengue virus serotypes are transmitted by Aedes aegypti or Aedes albopictus mosquitoes [18]. The infection can be asymptomatic or present with a wide range of clinical manifestations, including mild febrile illness to life-threatening shock syndrome. Numerous viral, host, and vector factors are believed to have an impact on the risk of infection, disease, and disease severity.

Regarding the pathophysiology of the infection, after inoculation of the virus by the vector, the dendritic cells of the skin become infected, thus migrating to the lymph nodes. Subsequently, lymph node migration appears viremia and the acute febrile condition. The invasion of dendritic cells by the virus causes protein-dependent activation of TCD4 and TCD8 lymphocytes, since dendritic cells behave as antigen-presenters, as well as greater immunogenicity. It is believed that the clinical manifestations are due to the release of cytokines, mainly interferon gamma, responsible for bone marrow suppression and drop in platelet count. Viremia can also lead to invasion of the spleen, liver, bone marrow, lung, heart, gastrointestinal tract, and central nervous system [9, 10, 19].

5.1 Clinical presentation

Classically, dengue is a disease that forms part of the wide range of hemorrhagic fevers, presenting a picture similar to that caused by other arboviruses. Clinical manifestations such as fever, accompanied by at least two of the following symptoms: headache, retro-orbital pain, myalgia, arthralgia, prostration, exanthema, nausea, or vomiting, make the diagnosis probable when it occurs in an area with an epidemiological presence of the disease or with a travel history in the last 14 days to an endemic dengue area [10].

The dengue virus behaves similarly to that of yellow fever, with phases of viremia, remission, and disease status. Infection is limited by humoral immunity, which controls the invasion of new cells, and cellular immunity, which eradicates intracellular infection. The dengue virus does not have a specific tropism for a body organ, and what we witness in an epidemic is a variety of clinical conditions such as rash, headache, fever, abdominal pain, diarrhea, or involvement of the respiratory tract; frames that can occur in association or individually. Tissue damage is the result of the cytopathic effect of the virus on infected tissue.

Dengue hemorrhagic fever is a more serious condition that, although not entirely understood, is associated with a second infection by another serotype of the dengue virus, which suggests that there is an immune mechanism much more present than just the viral cytopathic effect. Other conditions associated with an evolution to dengue hemorrhagic fever are serotype 2 infection, malnutrition, black race, and adulthood. It occurs in less than 1% of dengue cases, consisting of fever, hemorrhagic phenomena, hemodynamic instability, and hepatomegaly. Clinical phenomena derive from increased capillary permeability and thrombocytopenia. Increased capillary permeability leads to hypotension and severe shock (dengue shock syndrome), with mortality greater than 12% under optimized therapeutic conditions. Thrombocytopenia may occur in non-severe forms of dengue, which may produce petechiae and ecchymosis; however, in dengue hemorrhagic fever, thrombocytopenia is intense, leading to hematemesis, melena, and metrorrhagia. Hepatic and central nervous system involvement occurs but not as a dominant condition in severe forms of dengue [11].

6. Dengue encephalitis

Although the dengue virus has a high prevalence, especially in countries with tropical and subtropical climates, encephalitis is a relatively little described complication [20]. The involvement of the central nervous system by any of the 4 dengue serotypes is considered uncommon in the medical literature, from encephalitis to polyneuropathies such as Guillan Barre [8].

Viral invasion of the central nervous system (CNS) can result in several clinical syndromes, including encephalitis, the core of this chapter, as well as presentations such as meningitis, myelitis, and neuritis [3]. Encephalitis is defined as an inflammatory process of the brain parenchyma associated with clinical/laboratory evidence of neurological dysfunction.

The presence or absence of normal brain function is the important distinguishing feature between encephalitis and meningitis. Patients with meningitis may appear lethargic, yet their brain function is preserved. In encephalitis, abnormalities in brain function are a distinguishing feature, including altered mental status, motor or even sensory deficits, altered behavior, and speech or movement disturbances may be present. Other neurological manifestations of encephalitis may include hemiparesis, flaccid paralysis, and paresthesias [2].

However, the distinction between the two clinical entities is often unclear, given that parenchymal and meningeal processes can occur concomitantly. Some viral agents are more likely to cause aseptic meningitis, and others are more likely to cause encephalitis. Patients with encephalitis may have hallucinations or even be in a psychotic state. Eventually, focal or generalized epileptic seizures occur, depending on the severity of the encephalitis. Commonly, aphasia, myoclonic jerks, and focal deficits are also observed [2].

Regarding the pathophysiological mechanisms, we found some proposed theories. Firstly, a form of encephalopathy due to liver failure and release of neurotoxins and intraparenchymal hemorrhage due to extravasation and failure in the production of coagulation factors are described [19]. Secondly, supported by autopsy findings, direct neurotropic infection and local immune response occur, developing the symptoms of encephalitis due to direct neurological injury similar to other viruses of the Flaviviridae family [12]. In the third, an indirect, post-infectious immune response mechanism due to inflammatory factors filtered in the CSF explains the demyelinating lesion [6].

6.1 Diagnosis

The diagnosis of dengue encephalitis is challenging due to its low prevalence, leading to low suspicion and underdiagnosis. Furthermore, the clinical manifestations and images are nonspecific, and its diagnosis is based on a set of clinical, serological, and radiological findings.

Infection of the central nervous system can be confirmed by the presence in serum of IgM antibodies (dengue IgM), viral antigens (NS1), or viruses through the polymerase chain reaction (PCR) technique, where the viral RNA is identified, associated with neurological symptoms. In relation to imaging findings, there are few descriptions, with the most common findings related to changes identified in the basal ganglia, thalamus, cerebral cortex, cerebellum, and white matter, mainly in magnetic resonance imaging studies, showing restriction of diffusion by DWI and foci of hemorrhage in SWI sequence with low enhancement [19].

Other diagnoses must be ruled out to confirm the diagnosis of dengue encephalitis. In regions where dengue is endemic, a prevalence of 75% of encephalitis due to dengue has been recorded, selecting cases of meningitis and encephalitis with normal cellularity. The classic symptoms of encephalitis are a lowered level of consciousness, headache, and convulsive crises [20].

Alterations in liver function in severe dengue can also generate encephalopathy due to nitrogenous slags, with the increase in liver enzymes and changes in function markers part of the clinical picture, leading to changes in the level of consciousness, changes in behavior and cognition, and convulsions. Another rare manifestation, however, already described, of involvement of the central nervous system by the dengue virus is acute disseminated encephalomyelitis, where the inflammatory response causes acute demyelination of a monophasic course, mainly in the white matter region, usually in the dengue recovery phase [6].

Guillain-Barré syndrome is the most common neuromuscular alteration related to dengue fever. Studies have already demonstrated high incidences, around 30%, of cases of dengue with neurological involvement.

Regarding the treatment of dengue encephalitis, there is no specific targeted therapy to date. Symptom control is carried out with the use of antiemetics and non-steroidal analgesics, and convulsive crises are aborted with classic anticonvulsants, such as benzodiazepines, barbiturates, phenytoin, and prophylaxis performed with valproic acid (always remembering liver monitoring). Case reports have shown a good response to treatment with corticosteroid pulse therapy (dexamethasone or methylprednisolone). Conditions that evolve with Guillain-Barré syndrome seem to benefit from the use of intravenous immunoglobulin, but clinical studies have not yet been carried out [12, 20].

7. Final considerations

Faced with a clinical picture with the causal possibility of encephalitis, considering epidemiological, clinical, environmental issues, among others, the  arboviruses should be considered in the panel of diagnostic possibilities, and among them dengue. It is noteworthy that much of its low incidence and prevalence in endemic areas can be attributed to the diagnostic bias of the lack of consideration of such causative agents. Regarding treatment, there is no specific therapy, except, yes, general care and life support. And given the magnitude of the aforementioned pathology, as well as its various complications, it is necessary to tirelessly search for preventive measures, the most efficient and not yet available being the vaccine.