Review article
Neurological manifestations of dengue infection: A review

https://doi.org/10.1016/j.jns.2014.08.044Get rights and content

Highlights

  • There is a rising trend of neurological complications of dengue virus infection.

  • Host, epidemiological and viral factors are responsible for neurotropicity.

  • Systemic involvement, immune mediation and tissue invasion are core factors.

  • A better understanding of neurological involvement will reduce morbidity/mortality.

Abstract

Dengue is a common arboviral infection in tropical and sub-tropical areas of the world transmitted by Aedes mosquitoes and caused by infection with one of the 4 serotypes of dengue virus. Neurologic manifestations are increasingly recognised but the exact incidence is unknown. Dengue infection has a wide spectrum of neurological complications such as encephalitis, myositis, myelitis, Guillain–Barré syndrome (GBS) and mononeuropathies. Encephalopathy is the most common reported complication. In endemic regions, dengue infection should be considered as one of the aetiologies of encephalitis. Even for other neurological syndromes like myelitis, myositis, GBS etc., dengue infection should be kept in differential diagnosis and should be ruled out especially so in endemic countries during dengue outbreaks and in cases where the aetiology is uncertain. A high degree of suspicion in endemic areas can help in picking up more cases thereby helping in understanding the true extent of neurological complications in dengue fever. Also knowledge regarding the various neurological complications helps in looking for the warning signs and early diagnosis thereby improving patient outcome.

Introduction

Dengue is caused by an infection with one of the 4 serotypes of dengue virus, family Flaviviridae, genus Flavivirus (single-stranded nonsegmented RNA viruses). Annually, there are millions of infections and thousands of deaths related to dengue infection and global incidence is increasing [1]. Dengue is transmitted by mosquitoes of the genus Aedes. Clinical manifestations range from an asymptomatic state to severe dengue with plasma leakage, bleeding or organ impairment.

Classical dengue fever is characterised by a rapid onset of fever, headache, retro-orbital pain with severe myalgia and arthralgia. Dengue fever can have more severe forms termed dengue haemorrhagic fever (DHF) and dengue shock syndrome [DSS]. The World Health Organization (WHO) has given new guidelines of case definitions consisting of dengue fever, dengue fever with warning signs and severe dengue. Hence, the terminology of dengue haemorrhagic fever and dengue shock syndrome is better avoided as they are no longer preferred and used.

Apart from the common manifestations of dengue fever, various neurological manifestations including encephalitis, myelitis, Guillain–Barré syndrome (GBS) and myositis have been well reported in dengue infection. Neurological complications were thought to result from the multisystem derangement leading to encephalopathy [2], [3], [4]. Although dengue virus initially was considered a non-neurotropic virus [5], neuroinvasion has been demonstrated by detection of dengue virus antigen in the brain by immunohistochemistry in fatal cases of dengue encephalopathy [6] and also by PCR (polymerase chain reaction) and IgM antibody tests in CSF (cerebrospinal fluid) in patients with dengue encephalitis [7], [8]. Despite the recent increase in reporting of neurological complications the exact extent of these complications are lacking. Also clinical research has not been conclusive and pathogenesis of neurological manifestations is still controversial regarding various clinical syndromes. Better knowledge both in endemic and nonendemic countries regarding neurological involvement can go a long way in early diagnosis, treatment and referral of these cases to specialised centres leading to a better treatment outcome. So a detailed review of various neurological manifestations that are reported in literature is necessary. This helps in understanding the different neurological syndromes that are being attributed to dengue infection. Also the review can help in making way for further research and clinical study to better understand the various links between dengue fever and neurological manifestation. The literature was searched through Pubmed and Google scholar for various case reports, series and observation studies on neurological manifestations of dengue. These data was then classified based on type of clinical syndromes and then analysed individually.

Section snippets

Epidemiology

The first record of a case of probable dengue fever is in a Chinese medical encyclopaedia from the Jin Dynasty (265–420 AD) where it was referred as “water poison” associated with flying insects. The earliest report of neurological involvement was probably by Benjamin Rush, who published an account of a probable dengue fever epidemic that had occurred in Philadelphia in 1780 [9]. Population explosion, uncontrolled urbanisation in tropical and subtropical countries with poor sanitation,

Epidemiological trends in India

In India, dengue has been endemic for over two centuries. Recently, there is an increasing frequency of outbreaks. Since the first epidemic in Kolkata during 1963–64, dengue has emerged as a major public health problem [17]. The first major outbreak of dengue in India was reported in 1991 and one of the largest outbreaks in North India occurred in Delhi in the year 1996. It was mainly due to the dengue-2 virus [18]. In the year 2003, another outbreak occurred in Delhi and all four dengue virus

Dengue transmission

Dengue viruses are transmitted to humans through the bites of infective female Aedes mosquitoes. Mosquitoes generally acquire the virus while feeding on the blood of an infected person [12]. Aedes mosquitoes namely, Aedes aegypti, Aedes albopictus, Aedes scutellaris and Aedes polynesiensis are known to act as vectors in the transmission of dengue infection. It is important to note that each vector has a particular ecology, behaviour and geographical distribution. A. aegypti, the most important

Clinical spectrum

Clinical manifestations range from an asymptomatic subclinical state to the most severe dengue fever with plasma leakage, bleeding manifestations and multisystem involvement.

Dengue fever and severe dengue

Dengue fever is a flu-like illness; it classically starts with an acute onset of high fever, which could be biphasic lasting 3 to 7 days [23]. A moderately intense headache and pain behind the eyes, with severe myalgia and arthralgia (‘break-bone fever’) may be present. Erythema of the face and neck is typical and a generalised maculopapular rash may be present. Young patients may present with coryza, diarrhoea, rash, seizure, vomiting, headache, and abdominal pain. The 2009 WHO guidelines

Neurological complications

Dengue infection has a wide spectrum of clinical presentation (Table 1). Neurological complications can arise in any spectrum of dengue fever such as in dengue fever or in dengue haemorrhagic fever. Any virus serotype may be involved, but serotype-2 and serotype-3 are the most frequently reported as the cause of severe neurological disease [2], [7]. The exact incidence of neurological involvement in dengue infection is still uncertain. The neurological manifestations of dengue fever occur more

Pathogenesis

The pathogenesis of neurological complications in dengue infection is still not well understood. Host immune responses also play a crucial role in the pathogenesis of dengue infection [26]. Indirect effects of other systemic complications such as metabolic abnormality, shock, and liver failure also contribute to neurological complications. Hepatic encephalopathy is a well recognised complication of dengue infection [7]. Previously, it was thought that indirect effects of dengue infection on the

Encephalopathy and encephalitis

Encephalopathy is the most common neurological manifestation of dengue infection. Incidence is not defined clearly. In a study from a Thai hospital, 18% of children with suspected encephalitis were found to have dengue infection [2]. A study from a tertiary care hospital from North India involving children with acute febrile encephalopathy reported that around 20% of cases were having dengue infection. Strictly speaking, encephalitis is an inflammation of the brain parenchyma, usually caused by

Myelitis

Spinal cord can be involved rarely in dengue infection. MRI can help in confirming the spinal cord involvement and may show diffuse signal intensity alteration in the spinal cord (Fig. 3). Usually myelitis in an acute phase of illness will be a flaccid type whereas when it occurs in a delayed phase it is more often spastic. There are reports of spinal cord involvement in dengue infection, presenting as postinfectious myelopathy [36], acute disseminated encephalomyelitis [33] or transverse

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis is an immune mediated illness, usually caused by viral infections or vaccination. Rarely can dengue infection cause acute disseminated encephalomyelitis [41], [42], [43]. MRI features are similar to the findings seen in patients with ADEM due to other aetiologies [40]. Foci of haemorrhages within demyelinating lesions are also evident on MRI [41], [43]. MRI showed signal changes in white matter lesions in the centrum semiovale, corona radiata and thalamus in

Guillain–Barré syndrome

There are a few cases of Guillain–Barré syndrome following dengue infection, reported in literature [45], [46]. In fact Guillain–Barré syndrome is the most common manifestation in the peripheral nervous system. Guillain–Barré syndrome is reported during the recovery phase of illness. Guillain–Barré syndrome is a postinfectious illness in which an acute infection evokes an aberrant immune response which causes nerve damage. Dengue infection may trigger an abnormal immune response, which can

Myositis

Though myalgia is very common in dengue infection, myositis and muscle weakness are distinctly uncommon. A few cases are reported which relate dengue infection with myositis [4], [49]. Kalita et al. reported 7 patients out of 16 patients with dengue infection who presented with acute pure motor quadriparesis. All patients were having fever and the weakness developed within 3–5 days of illness. The weakness was of severe grade in 4 patients and one patient also required ventilator support. The

Hypokalaemic paralysis

Hypokalaemic paralysis following dengue infection is reported in literature but extremely rare [55], [56]. Jha et al. reported 3 patients of confirmed dengue infection who presented with acute onset pure motor quadriparesis with hypokalaemia. All three were having fever and recovered completely with potassium supplementation. All other possible aetiologies of hypokalaemic periodic paralysis were excluded [56]. In another case series, dengue infection was the second most common cause of

Other neurological manifestations

Various post viral neuropathies such as isolated phrenic neuropathy [58] leading to diaphragmatic palsy, long thoracic neuropathy [59] and ophthalmoplegia due to the involvement of the oculomotor nerve [60] are also reported in dengue infection. There are few cases of dengue infection thought to have led to brachial neuritis. In a retrospective study, out of 26 patients in a tertiary care centre, 10 patients had brachial neuritis. Other neurological manifestations in that study were 4 cases of

Laboratory diagnosis of dengue infection

Methods for confirming dengue virus infection may involve detection of the virus, viral nucleic acid, antigens or antibodies (Table 4). Virus detection by culture, viral nucleic acid or antigen detection (Non Structural Protein 1 also called NS1 antigen) can be used to confirm dengue infection in the early (initial 4–5 days) part of the illness. In the later part of the illness, serology (antibodies based test) is more useful and preferred for diagnosis as the sensitivity of virus isolation and

Management

The management of dengue viral infections is primarily symptomatic. Careful monitoring and maintenance of fluid and electrolyte balance is the key to successful management. In classical dengue fever, control of fever by paracetamol or tepid sponging supplemented by oral rehydration if necessary, may be sufficient. The acetylsalicylic acid (aspirin), ibuprofen or other non-steroidal anti-inflammatory agents (NSAIDs) should not be prescribed, as these drugs may aggravate gastritis and bleeding

Management of unusual manifestations/complications

No specific treatment is available for various complications such as encephalopathy or encephalitis. Supportive care and symptomatic treatment such as antiepileptics for seizures, cerebral decongestant including mannitol or diuretics for raised intracranial pressure and inotrope for myocarditis and steroids for myositis in an intensive care unit should be provided. Guillain–Barré syndrome cases due to dengue infection reported in literature responded well to immunomodulators (intravenous

Conclusion

Dengue is a common arboviral infection in tropical and sub-tropical areas of the world transmitted by Aedes mosquitoes. Neurologic manifestations are increasingly recognised but the exact incidence is unknown. Encephalopathy is the most common complication, but dengue infection has a wide spectrum of neurological complications. In endemic regions, dengue infection should always be investigated as the etiological agent in cases of encephalitis, GBS and myelitis and various other neurological

Conflict of interest

There is no conflict of interest.

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