JNS-13412; No of Pages 9 Journal of the Neurological Sciences xxx (2014) xxx–xxx

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Review article

Neurological manifestations of dengue infection: A review Rajesh Verma ⁎, Ritesh Sahu, Vikram Holla Neurology, King George Medical University, Lucknow, UP, India

a r t i c l e

i n f o

Article history: Received 3 June 2014 Received in revised form 4 August 2014 Accepted 29 August 2014 Available online xxxx Keywords: Dengue infections Encephalitis Myositis Myelitis Guillain–Barre syndrome Hypokalaemic paralysis

a b s t r a c t 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. © 2014 Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . 2. Epidemiology . . . . . . . . . . . . . . . . . . 3. Epidemiological trends in India . . . . . . . . . . 4. Dengue transmission . . . . . . . . . . . . . . . 5. Clinical spectrum . . . . . . . . . . . . . . . . . 6. Dengue fever and severe dengue . . . . . . . . . 7. Neurological complications . . . . . . . . . . . . 8. Pathogenesis . . . . . . . . . . . . . . . . . . 9. Encephalopathy and encephalitis . . . . . . . . . 10. Myelitis . . . . . . . . . . . . . . . . . . . . . 11. Acute disseminated encephalomyelitis . . . . . . . 12. Guillain–Barré syndrome . . . . . . . . . . . . . 13. Myositis . . . . . . . . . . . . . . . . . . . . . 14. Hypokalaemic paralysis . . . . . . . . . . . . . . 15. Other neurological manifestations . . . . . . . . . 16. Laboratory diagnosis of dengue infection . . . . . . 17. Management . . . . . . . . . . . . . . . . . . 18. Management of unusual manifestations/complications 19. Conclusion . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction ⁎ Corresponding author at: Department of Neurology, King George Medical University, Lucknow, UP 226003, India. Tel.: +91 9335915823. E-mail address: [email protected] (R. Verma).

Dengue is caused by an infection with one of the 4 serotypes of dengue virus, family Flaviviridae, genus Flavivirus (single-stranded

http://dx.doi.org/10.1016/j.jns.2014.08.044 0022-510X/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Verma R, et al, Neurological manifestations of dengue infection: A review, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.08.044

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R. Verma et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx

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 [2–4]. 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.

2. 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, proliferation of breeding sites for Aedes mosquitoes and the lack of effective mosquito control are potential reasons for the global resurgence and spread of dengue fever [10]. The rapid evolution of dengue viruses with more virulent genotypes of the virus replacing the less virulent ones may also be contributing to the rapid spread of infection [11]. Dengue is now the most rapidly spreading mosquito-borne viral disease in the world [12]. The disease is now endemic in more than 100 countries in Africa, America, Eastern Mediterranean, South-east Asia and the Western Pacific and approximately 2.5 billion people are at risk (two fifths of the world's population). The World Health Organization (WHO) estimates that 50 to 100 million infections occur annually [12]. An estimated 500,000 people with severe dengue require hospitalisation each year, a very large proportion of whom are children. About 2.5% of those affected die [12]. Not only is the number of cases increasing as the disease is spreading to new areas, but explosive outbreaks are also

occurring. The estimated global mortality rate is 25,000 patients annually [13]. A change in the serotypes of prevalent dengue viruses results in major dengue epidemics [14]. In Asian regions, the predominant dengue serotype of DEN-2 has been replaced with DEN-3 [15]. In 1998, a new DEN-3 virus subtype (subtype III) emerged and expanded from the Indian subcontinent, resulting in a major pandemic of dengue viral infections affecting more than fifty countries [16]. 3. 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 serotypes were found to be co-circulating [19]. In the year 2006 also, an epidemic of dengue infection occurred in northern India and more than three thousand confirmed cases are reported from Delhi only. Dengue infection is prevalent as an endemic infection since 2006 in India. Most cases were reported in the post-monsoon season and young adults (21–30 years) were predominantly affected. 4. 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 vector originated in Africa and spread to tropical and subtropical areas. A. polynesiensis and A. scutellaris are common in South Pacific regions. A. albopictus is native to the tropical and subtropical regions of Asia. But due to an increase in international travel and through transportation of goods this vector has spread all over the world thereby leading to a geographical expansion of the dengue endemic area. These vectors are mainly a container breeder and day biting mosquitos are active during dusk and dawn [20]. Although these vectors can breed and bite during any part of the year, significant increases in the mosquito larval populations are seen during and after the rainy season. This is because the eggs can survive months during the dry season and they turn into larvae when they are washed by rain water. This causes post-monsoon epidemics of dengue in the South and Southeast Asian countries [21]. Infected humans are the main carriers and multipliers of the virus (primary reservoirs), serving as a source of the virus for uninfected mosquitoes. Dengue virus can also pass vertically into eggs thus surviving the dry season inside eggs. Nonvector-borne modes of dengue transmission are also identified such as vertical transmission from mother to foetus, transfusion-related transmission, transplantation-related transmission, and needle-stick-related transmission [22]. But these are very uncommon. 5. Clinical spectrum Clinical manifestations range from an asymptomatic subclinical state to the most severe dengue fever with plasma leakage, bleeding manifestations and multisystem involvement. 6. 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

Please cite this article as: Verma R, et al, Neurological manifestations of dengue infection: A review, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.08.044

R. Verma et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx

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 classify dengue into three groups; dengue without warning signs; dengue with warning signs; and severe dengue (dengue with severe plasma leakage, severe bleeding, or organ failure) (Table 1). Dengue with warning signs includes those patients who tend to deteriorate during defervescence thereby warranting extra care and observation. If these cases are not treated promptly they may land into severe dengue manifestation. WHO has recognised the CNS involvement of dengue and has mentioned altered sensorium as one of the criteria of severe dengue.

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On the basis of pathophysiology, neurological complications in dengue infection is classified as: 1) secondary to systemic complications such as electrolyte imbalance, microcapillary haemorrhage, release of toxic products, and hepatic and renal failure; 2) a post-infectious immune mediated mechanism such as GBS and neuralgic amyotrophy, and 3) a direct neurotropic effect of the virus manifesting as encephalitis, myelitis or myositis. CNS manifestations classically described in dengue are headache, sleeplessness, somnolence, dizziness, restlessness and altered sensorium. Seizures, signs of meningitis and paresis are not so common. CNS manifestations can develop before or after the development of haemorrhagic manifestations. 8. Pathogenesis

7. 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 frequently during epidemics than in isolated cases; in DHF/DSS and in younger patients. Central nervous system complications comprise 95% of neurological complications. Encephalopathy and encephalitis are the most commonly reported neurological complications of dengue, with a calculated incidence varying between 0.5% [2] and 6.2% [24]. The neurological complications of dengue infection can be categorised in three groups: mild non-specific symptoms of headache, dizziness, inattention, slight alteration in sensorium, decreased sleep, and restlessness; severe syndromes of depressed sensorium, lethargy, confusion, seizures, meningismus, myelitis, encephalitis or encephalopathy; and delayed syndromes of paralysis of extremities, Guillain–Barré syndrome or bulbar palsy, seizures, memory impairment, loss of sensation and various psychiatric manifestations [25]. Table 1 Spectrum of dengue viral infection (WHO guidelines, 2009). Criteria for dengue Live in /travel to dengue endemic area Fever and 2 of the following criteria – Nausea, vomiting – Rash – Aches and pains – Tourniquet test positive – Leukopenia – Any warning sign Warning signs – Abdominal pain or tenderness – Persistent vomiting – Clinical fluid accumulation – Mucosal bleed – Lethargy, restlessness – Liver enlargement N2 cm – Laboratory: increase in HCT concurrent with rapid decrease in platelet count Severe dengue Severe plasma leakage leading to – Shock (DSS) – Fluid accumulation with respiratory distress Severe bleeding as evaluated by clinician Severe organ involvement – Liver: AST or ALT ≥1000 IU/l – CNS: impaired consciousness – Heart and other organs

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 CNS lead to the development of encephalopathy. But a recent demonstration of an IgM antibody to dengue in the cerebrospinal fluid (CSF) and reports of virus isolation from brain tissue and CSF of patients with dengue infection suggest a direct virus invasion of the CNS and the neurotropism of dengue virus [6–8]. It has been observed that dengue virus can infect cultured mouse neurons in vitro. The membrane receptor appears to facilitate invasion only for specific neurons, since astrocytes were spared from use in the same experiment [27]. So, neurological involvement can be related to the neurotropic effect of the virus and the systemic complication of infection and can also be immune mediated. 9. 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 infection. Encephalopathy is a broad term, used to describe a clinical picture of reduced consciousness which can be sometime caused by encephalitis. The presence of focal neurological deficits on clinical examination, focal abnormalities in neuroimaging or focal EEG abnormalities usually suggests encephalitis. Encephalopathy can be a manifestation of metabolic complications such as liver failure, renal impairment, electrolyte imbalance, hypoxia and shock. Coagulation disorders in dengue haemorrhagic fever and dengue shock syndrome can lead to bleeding and altered sensorium (Fig. 1). Encephalopathy is more related to these indirect effects of dengue infection, rather than direct viral invasion which results in encephalitis. Up to 80% of neurological complications are due to encephalopathy. Fever, headache, seizures, altered consciousness and focal neurologic signs are classical findings in patients of dengue encephalitis. Median time of onset of neurological symptoms ranged from 3 to 7 days from the start of fever [28]. In a study from India, Misra et al. reported 11 patients with confirmed dengue infection who presented with a clinical picture suggestive of encephalopathy. In this study, the authors had excluded all nonencephalitic causes and suggested dengue encephalitis as the likely aetiology; however no provision was made to detect dengue virus in the cerebrospinal fluid [3]. In another study from India published by Manimala Rao et al., comparing 24 patients of dengue fever without encephalitis with 25 patients of dengue fever with encephalitis, they

Please cite this article as: Verma R, et al, Neurological manifestations of dengue infection: A review, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.08.044

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Fig. 1. Magnetic resonance imaging (MRI) of the brain of a young male presenting with a neurological deficit due to subdural bleeding secondary to dengue infection induced thrombocytopenia showing right sided subdural haematoma in T1 weighted (A), T2 weighted (B) and gradient recoil echo (C) image.

noticed no significant difference in platelet count or packed cell volume, but SGOT and SGPT were significantly increased in the encephalitis group with SGPT more compared to SGOT. Only 2 among the total of 25 patients with encephalitis succumbed to death while the others completely recovered [29]. Verma et al. had reported a case of dengue encephalitis leading to epilepsia partialis continua [30]. A few studies had demonstrated the dengue virus or an antibody in the CSF, making dengue encephalitis a true entity. Solomon et al. made a diagnosis of dengue encephalitis in nine patients. All had dengue confirmed in the serum and the virus or an antibody was found in the CSF of only two of these patients [7]. Araújo et al. studied 201 patients with suspected viral meningitis or meningoencephalitis and found CSF positivity for dengue in 8 patients (3.8%) showing that dengue virus can also lead to meningitis [31]. Evidence of dengue infection in serum can be demonstrated in almost every patient of suspected dengue encephalitis; however dengue infection could not be confirmed in the CSF in a majority of the patients. The reason for this mismatch remained unexplained. Low viral load/ titre of antibodies in the CSF may be a possible explanation [28,32]. Further studies are required to settle this issue, which will also bring further insight into the pathogenesis of dengue encephalitis. Magnetic resonance imaging (MRI) is the preferred neuroimaging modality (Fig. 2). Many encephalitis causing viruses have a propensity to involve particular brain structures, which results in characteristic imaging patterns. These patterns may help in the differential diagnosis of

viral encephalitis. There are no specific MRI features which characterise dengue encephalitis [33]. MRI may be normal in many cases especially in the early part of the disease or it may show scattered focal abnormality, haemorrhage and edema [2]. MRI showed hyperintense areas in the globus pallidus in one out of nine patients with dengue encephalitis [3]. The thalamic involvement simulating Japanese encephalitis had also been reported on CT scan in a dengue case after excluding Japanese encephalitis by relevant serological tests. It is important to note that the lesions in MRI in a patient of dengue makes encephalitis more likely than encephalopathy although changes like haemorrhage, infarct and oedema can be present without encephalitis. In Cam's study of dengue encephalopathy, MRI demonstrated focal ‘encephalitis-like’ changes in four patients [2]. In a recent study of brain imaging (20 MRI + 1 CT) done by Bhoi et al. in 21 patients of confirmed dengue fever with altered sensorium, the lesions were seen in 10 patients. The imaging findings in the study were cerebellar bleed, subdural haematoma, signal changes in the thalamus, basal ganglia, white matter, and cortical area and meningeal enhancement. The imaging pattern did not affect the outcome [34]. Coagulation and bleeding abnormality caused by thrombocytopenia and platelet dysfunction can lead to vascular stroke in the form of intracranial haemorrhages and ischemic infarcts in dengue infection. Intracranial haematoma can cause altered sensorium and focal weakness. The majority of the studies have shown good recovery and better prognosis in patients of dengue encephalitis [7,28]; however the study by Misra et al. reported a poor outcome and suggested encephalitis as

Fig. 2. Magnetic resonance imaging (MRI) of the brain of a 28 year old male presenting with dengue encephalitis showing hyperintense signal changes involving bilateral basal ganglia in T2 weighted (A) and FLAIR image (B) with no post gadolinium enhancement (C).

Please cite this article as: Verma R, et al, Neurological manifestations of dengue infection: A review, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.08.044

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Table 2 Encephalopathy in patients of acute dengue fever.

Hendarto et al. [27] Cam et al. [2] Mishra et al. [3]

Verma et al. [60]

Cases of encephalopathy

CSF serology

Mortality

Clinical features

152 encephalopathy from a total of 2441 dengue fever 27 of 5400 encephalopathy

No CSF serology

No data

CSF serology positive in 14 of 22 No CSF serology

22%

10 patients had either hemiparesis, quadriparesis or optic atrophy. Many had altered sensorium or convulsions MRI showed cerebral edema in most and encephalitis like changes in few Seizure in 3, EEG slowing in 8, CSF pleocytosis in 8 and myoclonus in 1. Another 6 had motor weakness

CSF serology positive in all encephalopathy patients

None

11 of 17 dengue patients with neurological manifestation over 2003–2005 4 cases of encephalopathy out of 26 dengue patients with neurological manifestation

the most severe complication of dengue infection [3]. In this study by Misra et al., 3 patients died and 3 patients had partial recovery (Table 2). Another study of 150 patients suspected of infectious disease with fatal outcomes found 84 patients with dengue positivity. All 150 patients underwent CSF analysis for dengue virus of which 41 (48.8% of 84) were dengue positive. This study showed that neurological complications in dengue were one of the important causes of fatal outcome [35].

10. 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 myelitis [37]. Myelitis is probably caused by direct viral invasion. Intrathecal synthesis of dengue IgG antibodies may indicate viral neurotropism for the spinal cord and may be contributing to the pathogenesis of the myelitis [38]. The immune related mechanism may be important in the pathogenesis of postinfectious myelopathy, acute disseminated encephalomyelitis and neuromyelitis optica [39]. Kunishige et al., reported a rare case where spinal cord involvement was limited to the grey matter of the spinal cord, preferentially to the anterior

27.3%

Of 26 patients with neurological manifestation apart from encephalopathy, 10 had brachial neuritis, 3 had GBS, 3 had hypokalaemic paralysis, 2 had opsoclonus myoclonus syndrome, 2 had myositis, 1 had ADEM and 1 had myelitis

horn only, similar to poliomyelitis. Anti-dengue virus antibodies for dengue virus type 1 were detected in the CSF in this patient [40]. 11. 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 [41–43]. 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 the patient described by Brito et al. [42]. Yamamoto et al. also described a patient with a demyelinating lesion in the thoracic spinal cord [33]. Autoimmune response towards myelin or other selfantigens, via molecular mimicry by cross-reacting antibodies may be the probable mechanism for acute disseminated encephalomyelitis [44]. 12. 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

Fig. 3. Magnetic resonance imaging of the cervical spine (sagittal (A) and axial (B) view) showing hyperintense signal changes involving the long segment of the cervical cord in a patient with myelitis associated with dengue infection.

Please cite this article as: Verma R, et al, Neurological manifestations of dengue infection: A review, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.08.044

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invasion by dengue virus, however, mild lymphocytic infiltration to foci of severe myonecrosis has been shown in dengue infection [50] (Fig. 4). Even rhabdomyolysis [51] and myocarditis [52] following dengue infection have been reported. Recently Salgado et al. have demonstrated infection of heart tissues in vivo; and of striated muscle, in vitro by dengue virus [53]. In a recent study, Paliwal et al. described 7 patients of dengue myositis. 3 patients were having severe involvement, very high CPK levels and had respiratory muscle involvement also. Two of them required mechanical ventilation and later on succumbed to the illness. All patients were having raised CPK levels. The authors concluded that severe myalgia, early respiratory muscle involvement and very high CPK levels suggest a severe form of dengue myositis with poor prognosis [54] (Table 3). 14. Hypokalaemic paralysis Fig. 4. Haematoxyline & eosin staining of muscle biopsy specimen showing lymphocytic infiltration in dengue myositis.

acute infection evokes an aberrant immune response which causes nerve damage. Dengue infection may trigger an abnormal immune response, which can cross-react with the peripheral nerve via molecular mimicry [47]. Recent infections with Campylobacter jejuni, cytomegalovirus, Epstein–Barr virus, and Mycoplasma pneumoniae are commonly implicated to cause Guillain–Barré syndrome [48]. However, in patients presenting with Guillain–Barré syndrome without any usual antecedent infections, screening for dengue virus infection may help in identifying a rare cause.

13. 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 CPK levels were elevated in all patients. The nerve conduction studies were normal in all patients and EMG was myopathic in one patient. Six patients recovered completely and one who needed ventilator support had poor recovery [4]. Muscle biopsy in 1 patient was suggestive of myositis. Muscle biopsy studies have not demonstrated direct

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 secondary hypokalaemic paralysis presenting to the hospital with 4 out of 15 cases [57]. Around 35 cases of hypokalaemic paralysis are published in literature from India. Redistribution of potassium in cells or increased urinary potassium wasting due to renal tubular abnormalities can result in hypokalaemia, leading to paralysis. Increased catecholamine levels in response to stress of the infection and secondary insulin release may result in an intracellular shift of potassium and hypokalaemia [56]. The prognosis is good with almost all recovering within 12 h of potassium correction with complete recovery in a few days. So, in addition to myositis and Guillain–Barré syndrome, hypokalaemic paralysis may also be responsible for the acute pure motor quadriparesis in patients with dengue infection. 15. 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,

Table 3 Acute muscle weakness in patients of dengue fever. Proportion of cases

Investigations

Prognosis

Kalita et al. [4]

7 of 16 cases of dengue with neurological manifestation had pure motor weakness

6 improved completely; 1 required ventilator support till 1 month

Misra et al. [3]

6 cases had motor weakness out of 17 dengue patients with neurological manifestation over 2003–2005 2 cases of hypokalaemic paralysis 3 cases of hypokalaemic paralysis 3 cases of hypokalaemic paralysis and 2 cases of acute myositis out of 26 dengue patients with neurological manifestation. 7 cases of dengue myositis

CPK raised in all. EMG showed a myopathic pattern in 1 case; all the rest were normal; muscle biopsy done in 1 patient showed myophagocytosis CPK was elevated in 5 patients; EMG in 1 patient was myopathic; muscle biopsy done in 1 patient was suggestive of myositis No data No data CPK was raised in all myositis cases and was normal in hypokalaemic paralysis. NCS was normal in all. EMG was not done All had raised CPK. No data for NCS or EMG

Gupta et al. [54] Jha et al. [55] Verma et al. [60]

Paliwal et al. [53]

Garg et al. [56]

4 of 29 cases of hypokalaemic paralysis were confirmed dengue fever

CPK was not raised. NCS EMG was not done

All improved completely

All recovered All recovered completely All improved completely

3 had fulminant myositis with respiratory muscle weakness out of which 2 patients died; the rest recovered All cases recovered

Please cite this article as: Verma R, et al, Neurological manifestations of dengue infection: A review, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.08.044

R. Verma et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx

out of 26 patients in a tertiary care centre, 10 patients had brachial neuritis. Other neurological manifestations in that study were 4 cases of encephalopathy, 3 cases of GBS, 3 cases of hypokalaemic paralysis, 2 cases of myositis and 1 case each of myelitis and ADEM. There were also 2 cases of opsoclonus myoclonus syndrome associated with dengue seropositivity [61]. Also there are few rare case reports of dengue infection causing an acute cerebellitis like presentation and one case report with a parkinsonism like presentation [62,63].

16. 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 antigen reactivity decreases [64]. Viral isolation by culture, although the gold standard, takes more time compared to other direct methods of investigations for dengue infection diagnosis (1–2 weeks). Viral RNA nucleic acid detection by polymerase chain reaction (PCR) assays is also specific and less time consuming. In a study, the specificity of reverse transcriptase polymerase chain reaction assay was found to be 100% with 70% sensitivity when performed within 5 days of onset of illness [65]. Virus isolation and nucleic acid detection are more costly and labour-intensive but are also more specific than serologic methods used for antibody detection [1]. Also it can differentiate between various serotypes of dengue virus. Viral antigen (NS 1) detection assays are also rapid, reliable and easy to perform [66]. However, these tests cannot distinguish between viral serotypes [64]. NS1 detection assays are now available commercially. ‘Dengue-specific’ IgM antibody (serology) detection by MAC-ELISA (IgM antibody-capture enzyme-linked immunosorbent assay) is also commercially available and the method of choice for diagnosis after the early phase (after 5 days of fever onset). It is not uncommon for an antibody to be negative even after 5 days hence the need for the assay to be repeated. IgM seroconversion and rising titre of IgG in paired sera confirms acute infection. The presence of both IgM positivity and IgG positivity in the acute phase suggests re-infection either with the same or different serotype. Serum, blood, CSF and saliva, but not urine, can be used for detection of IgM [64]. With increased reports of encephalitis due to dengue fever, CSF analysis for dengue virus is being done commonly. Similar to serum, the CSF can be subjected to viral culture, and viral nucleic acid assay or dengue antigen assay can be done early

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in 5–7 days. Thereafter the IgM or IgG serological assays are useful. Isolation of virus from culture, viral nucleic acid positivity, antigen positivity or IgM positivity in the CSF for dengue virus suggests encephalitis rather than just encephalopathy. Apart from these, the CSF analysis can show lymphocytic pleocytosis and/or elevated protein. The patients of malaria, leptospirosis and past dengue infection may sometimes give false positive results and cross-reactivity with other flaviviruses such as Japanese encephalitis (JE), St. Louis encephalitis and yellow fever can also give false positive results [67]. In a hyperendemic region, there are three possibilities in case of co-positivity for both anti-DV IgM and anti-JEV IgM antibodies: co-infection, sequential infection and crossreaction. For co-infection demonstration, (i) a rising antibody titre for both the pathogens should be demonstrated in paired sera, or (ii) the nucleic acid of both the pathogens should be detected in a clinical sample, or (iii) the IgM specific to DV versus JEV should be compared, by measuring neutralising antibodies [68]. Innis et al. proposed that the measurement of Japanese encephalitis and dengue IgM and IgG antibodies upon admission and discharge from hospital care should replace the haemagglutination inhibition assay as the standard dengue serologic technique in regions where these 2 viruses co-circulate. They found that measurement of the anti-dengue IgM to anti-JE IgM ratio correctly identified all patients with defined JE and 98% of patients with dengue infections. Dengue infections could be classified as primary or secondary by determining the ratio of units of dengue IgM to IgG antibody [69]. A haemagglutination-inhibition test is based on the ability of antidengue antibodies in sera to inhibit the agglutination of trypsinized human O RBC by dengue antigens. The potency of this inhibition is measured in an HI test. Along with laboratory confirmation of dengue infection, other haematological tests including platelets and haematocrit values are also commonly measured during the acute stages of dengue infection. Thrombocytopenia (platelet count below 100,000/μl) is commonly seen in dengue haemorrhagic fever and sometimes in classical dengue fever also. Haemoconcentration (increase in haematocrit of 20% or more compared with baseline values) may be seen and may be suggestive of hypovolaemia due to plasma leakage. Total blood count may show a progressive decrease in total white cell count, which may be an early indicator of dengue infection. Progressive leucopoenia followed by thrombocytopenia usually precedes plasma leakage [70].

17. 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

Table 4 Laboratory diagnosis in dengue infection.

Direct methods

Serology

Diagnostic method

Time to get result

Preferred time

Diagnostic value

Advantages

Limitations

Viral isolation (culture)

1–2 weeks

1–5 days of onset of symptoms

Confirmatory

Very specific, serotype identification

Nucleic acid detection (PCR)

1–2 days

1–5 days of onset of symptoms

Confirmatory

Highly sensitive and specific, serotype identification

Antigen detection (NS 1) Ig M ELISA (MAC-ELISA) Ig G (paired sera) by ELISA or haemagglutination

1 day

1–6 days of onset of symptoms After 5 days

Not yet determined (probably confirmatory) Probable (seroconversion in paired sera—confirmatory) Confirmatory (fourfold IgG titer increase or seroconversion in paired sera)

Easy to perform, early diagnosis help in patient management Least expensive, easy to perform, differentiate between primary or secondary infection, confirm acute infection

Takes more than 1 week, not possible to differentiate between primary and secondary infection Not possible to differentiate between primary and secondary infection, expensive Less sensitive than PCR (RNA) Need paired sera, delayed confirmation.

1–2 days More than a week

Acute sera—within 5 days, convalescent sera—after 2 weeks

Please cite this article as: Verma R, et al, Neurological manifestations of dengue infection: A review, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.08.044

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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 [64] and may cause Reye's syndrome in children due to aspirin. Platelet counts and haematocrit should be monitored daily from the third day of fever until recovery. Total leukocyte count and liver functions should also be monitored. Fluid balance should be monitored by daily weight and urine output monitoring. In dengue haemorrhagic fever, judicious fluid supplementation may avoid progression to circulatory shock. A more than 20% rise in haematocrit reflects significant plasma loss, mandating aggressive volume replacement. The WHO recommends using crystalloids for volume replacement [1]. The colloids and blood transfusion may be used in unresponsive cases. Ten ml/kg of replacement fluid should be given for every 1% of normal body weight loss [1], in addition to maintenance fluids by the standard weight-based protocol. Platelet transfusions may be needed for significant haemorrhagic manifestations only and not for just low platelet count without haemorrhagic manifestation. Platelet transfusions are required only for significant haemorrhagic manifestations and not for a low platelet rate without bleeding. Electrolyte and metabolic abnormalities, hypoglycemia, liver dysfunction or renal function abnormality should be managed accordingly. There is no specific antiviral treatment available for dengue infection. Various antiviral strategies and the development of a vaccine against dengue are still in the experimental phase. 18. 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 immunoglobulin therapy). Hypokalaemic paralysis recovered completely with potassium supplementation [56]. 19. 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 disorders as described above if the aetiology remains unknown. This review highlights that more and more reports are being made of various manifestations of neurological complications and hence one has to consider dengue in any undiagnosed neurological syndrome in an endemic area especially during an outbreak. Caution also is needed to avoid wrongly associating a particular syndrome to dengue fever because in an endemic area the association may be just coincidental. There is still a paucity of data on various aspects of neurological manifestations of dengue fever. Exact epidemiological data of various neurological complications with their relative frequency is lacking. It is not clear from the review of literature if any serotype predilection to a particular type of manifestation, or secondary infections cause more neurological complications and whether any specific host and viral factors lead to the development of neurological complication. There is an urgent need for a detailed prospective study to look for these neurological complications with predefined specific diagnostic criteria for each neurological manifestation in order to see whether there are any true associations or these are just coincidental findings. Further research in

the pathogenesis of various neurological manifestations should be carried out to find any modifiable factors to better manage these complications.

Conflict of interest There is no conflict of interest.

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