Travel Medicine and Infectious Disease (2014) 12, 189e193

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Neurological manifestations of dengue:A cross sectional study

Praveen Nilendra Weeratunga b,*,Manjula Chandragomi Caldera a, Inuka Kishara Gooneratne a,Ranjanie Gamage a, Priyankara Perera a

a Institute of Neurology, National Hospital of Sri Lanka, Colombo, Sri LankabUniversity Medical Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka

Received 14 April 2013; received in revised form 23 October 2013; accepted 1 November 2013Available online 27 November 2013

Summary Background: Dengue is an infectious disease caused by a virus of the flaviviridae

family. It is a multi systemic illness causing considerable morbidity and mortality. A spectrumof neurological manifestations has been associated with dengue.Methods: This was a descriptive cross sectional study including patients diagnosed with Denguefever (DF), Dengue with warning signs and severe dengue with neurological sequale presentingto the Institute of Neurology, National Hospital of Sri Lanka from June 2011 to August 2012. Allpatients underwent serology testing for Dengue IgM in blood and CSF as confirmation of thediagnosis.Results: Seven patients were included. 1/7 had bilateral optic neuritis (ON), 3/7 had a cere-bellar syndrome (CS), 2/7 had transverse myelitis (TM) and 1/7 had cranial nerve palsy.

The patient with ON had a post-infectious pattern and protracted recovery.All patients with CS had bilateral involvement. All had a self limiting course with complete

recovery. Two were associated with acute infection.Both patients with TM had longitudinally extensive disease with one patient experiencing

complete recovery. The patient with cranial nerve involvement had isolated 6th nerve palsy.Conclusions: Neurological manifestations of dengue are diverse. It is important to considerdengue as a cause for the above neurological presentations in hyper endemic territories forthe disease.ª 2013 Elsevier Ltd. All rights reserved.

* Corresponding author. 291/34B Havelock Gardens, Colombo, SriLanka. Tel.: þ94 773579142.

E-mail address: prav782@yahoo.com (P.N. Weeratunga).

1477-8939/$ - see front matter ª 2013 Elsevier Ltd. All rights reservedhttp://dx.doi.org/10.1016/j.tmaid.2013.11.001

Introduction

Dengue is an infectious disease caused by a flavivirus.Dengue is recognized as a significant health burden in Asiawith considerable morbidity and mortality. With increasing

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190 P.N. Weeratunga et al.

travel to the region it is imperative to attain a better un-derstanding of the disease including its rare manifestations.

Sri Lanka is hyper endemic for the disease with 28,473cases being reported [1] in 2011. A spectrum of neurologicalmanifestations has been associated with dengue and recentstudies report an increasing incidence of these neurologicalsequale [2]. This study describes the neurological sequaleof dengue in Sri Lankan patients and relates it to findings inthe region and to those in other hyper endemic territories.

Method

This was a descriptive cross sectional study among patientsadmitted to the Institute of Neurology at the National Hos-pital of Sri Lanka in Colombo. This is the largest tertiary careneurology referral center in Sri Lanka. This study includedserologically confirmed cases of dengue with neurologicalsequale admitted to the above unit from June 2011 to August2012. The diagnosis and classification of patients was per-formed based on the revised WHO classification of 2009 asdengue, dengue with warning signs and severe dengue [3].Only patients >16 years of age were included.

These patients were diagnosed as having dengueconcurrently or within a 2-week period. All patients un-derwent testing for Dengue IgM in blood and CSF. Patientswere evaluated clinically and with investigations including:full blood count, liver function tests, renal function tests,serum electrolytes, coagulation profile. Regional imagingwith MRI was performed in all patients. Viral antibodies inblood and CSF (i.e.: Varicella zoster, Epstein Barr, measles,mumps, rubella, herpes simplex, HIV, Japanese encephali-tis and Coxsackie viruses), autoimmune screening (ESR,antinuclear antibody) and visual evoked potentials (VEP)were performed based on clinical presentation. All patientsunderwent fluid management based on current local andWHO guidelines. Other specific management is mentionedwith the cases.

Results

Seven patients fulfilling entry criteria were included in thestudy. All patients were serologically confirmed cases ofdengue.

The patient and disease related characteristics aretabulated (Table 1). As demonstrated 6/7 patients weremale. One case had a diagnosis of dengue fever while 5/7had a diagnosis of dengue with warning signs. One had

Table 1 Description of patient characteristics and neurological

Patient Presentation Age Gen

1 ON 21 M2 Cerebellar 40 F3 Cerebellar 28 M4 Cerebellar 25 M5 TM 39 M6 TM 31 M7 CN 65 M

severe dengue with evidence of shock. Cases of severedengue with hepatic, cardiac or multiorgan involvementwere not encountered. Four patients developed neurolog-ical sequale during the acute illness while the remainderdeveloped them post-infection.

Optic neuritis (ON)

A 21-year-old male presented with bilateral loss of visionwith ocular pain worsened with eye movements. There wasno perception of light bilaterally. The patient had denguefever with warning signs 10 days prior to his visual symp-toms. No episodes of hypotension or compensated shockwere documented during this episode. He did not demon-strate clinical evidence of autoimmune disease and theautoimmune profile including antinuclear antibodies (ANA)were unremarkable. There was not history of prior expo-sure to drugs, toxins or alcohol. The patient did notdemonstrate evidence of nutritional deficiencies.

The patient had dilated slightly reactive pupils andnormal ophthalmoscopy. The rest of neurological exami-nation was normal. VEP was un-recordable bilaterally. Adiagnosis of retrobulbar neuritis was made. MRI brain andspine was normal excluding demyelination and spaceoccupying lesions. Lumbar puncture was unremarkable.Intravenous methyl-prednisolone was given for 3 days fol-lowed by oral prednisolone for 11 days. The patient had 6/18 visual acuity (VA) bilaterally after one year. The patientdid not develop recurrences or other neurological mani-festations such as transverse myelitis within the studyperiod.

Cerebellar syndrome (CS)

Three patients demonstrated evidence of bilateral cere-bellar dysfunction. They presented with dysarrthria andataxia and were found to have bilateral nystagmus anddysmetria on clinical examination. Alternate causes ofcerebellar syndrome were excluded by means of serologyfor Varicella zoster, Epstein Barr, measles, mumps, rubella,herpes simplex, HIV, Japanese encephalitis and Coxsackieviruses in blood and CSF. Autoimmune screen was negative.

The onset of CS in the 3 cases ranged from 2 days to 2weeks from onset of illness (Table 2). All cases showed aself limiting, resolving pattern. The CSF in all cases wasunremarkable. MRI showed T2 hyper-intense lesions in thecerebellum in only case 3. The MRI in other patients wasnormal.

presentations.

der Diagnosis Timing

Dengue with warning signs PostSevere dengue with shock AcuteDengue with warning signs PostDengue with warning signs AcuteDengue with warning signs PostDengue fever AcuteDengue with warning signs Acute

Fig. 1 T2 weighted MRI image demonstrating longitudinallyextensive transverse myelitis extending from T5eT12.

Table 2 Clinical, cerebrospinal fluid findings and imagingfeatures in patients with cerebellar syndrome.

Patient Presentation Time CSF Imaging Recovery

1 Bilateral 5 Normal Normal 2 months2 Bilateral 14 Normal Normal 1 week3 Bilateral 2 Normal T2 lesions 2 weeks

Neurological manifestations of dengue 191

Transverse myelitis (TM)

Two patients presented with subacute paraparesis, sensorydysfunction, and bladder and bowel incontinence. Clinicalexamination was consistent with transverse myelitis withsensory levels at C5 and T8 respectively.

Case 1 demonstrates a post-infectious TM while case 2developed TM during the disease itself (Table 3). Both caseshad longitudinally extensive myelitis on MRI. Case 1 had MRIevidence of cord inflammation extending from T5 to T12(Fig. 1) and from C5 to T8 in case 2. Specific changes notedwere cord edema with high signal intensity and peripheralcontrast enhancement. T2 hyperintensities were also notedin both patients. The MRI brain in all patients was normal.VEPs in both patients were normal. Both patients werepulsed with methyl-prednisolone (1 g daily for 3 days). Case1 regained normal lower limb function within 1 week.However recovery was poor in case 2 at 3 months. Duringthe study patients did not develop recurrences or otherneurological manifestations such as ON. Aquaporin-4 anti-bodies were not performed due to unavailability.

Cranial nerve palsy

A 65-year-old male without preceding divergent squint inchildhood presented with dengue with warning signs for 6days and acute onset diplopia for 2 days. Examinationrevealed right 6th nerve palsy. MRI brain with contrast andCSF and were unremarkable. Spontaneous resolution wasnoted after 3 month of follow up.

Discussion

The total number of 4678 serologically confirmed cases ofdengue presented to the above tertiary care neurology unitwithin the study period (unpublished data procured fromhospital statistics). Therefore the observed frequency ofneurological sequale of dengue is noted to be 0.15% duringthe period of study.

The findings of this study are discussed in light of othersimilar studies from the region and from other hyperendemic countries for dengue. Misra et al. [4] and Verma

Table 3 Clinical, cerebrospinal fluid findings and imagingfeatures in patients with transverse myelitis.

Patient Age Time Level ofinvolvement

Imaging CSF Recovery

1 39 14 T8 T7eT12 Normal Good2 31 7 C5 C2 D Proteins

lowPoor

et al. [2] from India report encephalopathy as a commonneurological manifestation of dengue. A Thai study alsoreported encephalopathy as the commonest manifestation[5]. Solomon et al. [6]. in a study of patients presentingwith suspected central nervous system infections report 9/16 patients with encephalitis due to dengue with prominentneurological manifestations being loss of consciousness andconvulsions. Other manifestations reported in this study aremetabolic encephalopathy mainly attributed to hepaticderangement and two cases of transverse myelitis.

In contrast we did not encounter patients with enceph-alitis/encephalopathy due to dengue. A possible reasoncould be that the serotypic pattern of Sri Lankan dengue hasa different neurological predisposition from that observed inother hyper-endemic territories for the disease.

Furthermore prior case series and descriptive studiesinclude pediatric dengue. It is apparent that the cases ofencephalitis reported in dengue are more common inyounger individuals. This study excluded patients <16 yearsof age. Dengue encephalitis may have a predilection forpediatric populations which are not included in this study.

However the true prevalence of encephalitis may beunderestimated as they may be managed in general medicalwardswithout referral to neurology. Furthermore the paucityof cases with severe dengue andmultiorgan involvementwithhepatic and renal derangement may account for the lack ofcases of encephalopathy attributed to dengue.

192 P.N. Weeratunga et al.

Prior neurological manifestations of dengue reportedfrom Sri Lanka are a case of 6th nerve palsy [7] and one ofcerebellar syndrome due to dengue e EBV co infection [8].

ON is rare in dengue. Wen et al. (China) [9], Haritglouet al. [10], Preechawat et al. (Thailand) [11] and De Aragao(Brazil) [12] have all reported cases of bilateral ON with theonset within 1 week of dengue infection and with very poorinitial VA. Rapid recovery of VAwas noted in all. Sanjay et al.(Singapore) reported three patients with unilateral ONpresenting within a week of being diagnosed with denguefever [13]. Recovery in 2 of these cases was poor. ON in ourcase has a similar temporal profile to those patientsdescribed above as it presented a week following dengue.The bilateral nature of the illness is also consistent withprevious reports. Majority of reported cases showed rapidrecovery. However, our patient had a protracted recovery.

CS associated with dengue is unusual. A case report fromBrazil describes a case of post-infectious disseminatedacute encephalitis presenting with CS [14]. EBV-dengue coinfection was implicated in a Sri Lankan patient with CS [8].We encountered a spontaneously resolving CS with a vary-ing temporal profile. The infectious screen for otherimplicated organisms in all patients was negative indicatingdengue as the possible cause. Lack of evidence of inflam-mation in CSF and the self limiting nature of the illness mayindicate a low grade inflammatory process.

TM in dengue was initially reported by Renganthan et al.in a 14-year-old girl with a sensory level at T5/T6 [15].Onset of symptoms in this case was during acute illness. MRIspine was normal. CSF showed marginally elevated protein.Complete recovery was noted 2 weeks after onset.Chanthmat et al. (Singapore) reported a 61-year-old withTM, 6 days following dengue with a sensory level at T9/T10[16]. MRI showed a corresponding segmental lesion. Seetet al. [17] also reported a case of post-infectious TM. It isimportant to highlight that TM in our series were longitu-dinally extensive. Both patients underwent VEP to excludeconcomitant ON. However due to unavailability, aquaporin-4 antibody levels were not performed. Therefore the pos-sibility of NMO triggered by dengue infection cannot besubstantially excluded. The majority of cases reported inthe literature demonstrate an excellent recovery followingdengue TM. However in the above series the outcome ofcase 2 was poor.

Cranial nerve palsy following dengue is extremely rare. Acase report from Sri Lanka documents a case of dengueassociated 6th nerve palsy [7].

It is apparent that this study reports a different spec-trum of neurological sequalae of dengue in comparison withprior case series and descriptive studies. This case seriesreflects the neurological sequalae of dengue in the absenceof major hemodynamic and metabolic derangement andtherefore may be more representative of the true neuro-logical predilection of the virus. The majority of cases showa spontaneous recovery which indicates a good prognosis.Steroids were used in the management of ON and TM butthe clinical application is not well established in thissetting. Patients with cerebellar syndrome demonstratedclinical recovery without specific therapy.

The patients encountered above demonstrate thatdengue can have a wide spectrum of neurological manifes-tations. These neurological manifestations have a varying

temporal profile. The pathogenesis for neurological sequalein dengue is threefold: direct neurotropic effect of thevirus, hypoperfusion of the nervous system due to fluidleakage and delayed immunological sequelae. Multiplepathogenic mechanisms may play a role in the above cases.It is also noteworthy that in 6/7 cases neurological sequalaeoccurred in patients with either DHF or DSS. The patho-physiology of DHF/DSS involves antibody mediatedenhancement of the virus due to pre existing non neutral-izing antibodies against a different serotype to the onecausing the current infection. This results in production ofmultiple cytokines and complement activation. It is possiblethat these factors may be involved in the pathogenesis ofthe neurological sequale of dengue. Further characteriza-tion of the cytokine and antibody profiles in patients withneurological sequale is required. Direct neurotropic invasionof the nervous system could have been established with PCRtesting for dengue which was unfortunately not available.

Conclusion

This study adds to the existing spectrum of neurologicalmanifestations of dengue in the region and in Sri Lanka andstresses the need for consideration of dengue as an aetio-logical agent in the above presentations in the region aswell as returning travelers from the region.

Individual contributions

MCC and RG were involved in conception of the project andselection of patients, PNW, IKG was involved in the analysisof data and preparation of the final manuscript.

Conflict of interest

All authors certify to have no conflicts of interest.

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