Advertisement

Chikungunya encephalitis, a case series from an endemic country

Published:December 19, 2020DOI:https://doi.org/10.1016/j.jns.2020.117279

      Highlights

      • Clinical findings of Chikungunya encephalitis: Seizures, stupor, headache,
      • Neuroimaging findings: MRI: Bilateral white matter lesions. Focal temporal lobe hyperintensities. CT scan: Brain edema.
      • Description of the neuropathological findings in the postmortem brain examination:
      • Inflammatory infiltrates of lymphocytes in the brainstem, hippocampus and frontal lobes.

      Abstract

      Background

      The Chikungunya Virus (CHIKV) was introduced into Honduras in 2015. Since then the WHO has reported more than 14,000 suspected cases in the country. Objective: To describe the clinical, laboratory, neuroimaging, and pathological features of CHIKV encephalitis.

      Patients and methods

      We evaluated all consecutive cases of CHIKV infection meeting encephalitis criteria at Hospital Escuela Universitario at Tegucigalpa, Honduras, during 2015. Who case definition was used: patient with neurological manifestations meeting clinical criteria (fever >38.5 °C, joint pain); resident/visitor in the last 15 days to an endemic area; laboratory confirmation with IgM/ELISA. Other etiologies were excluded by ancillary studies.

      Results

      Out of 95 cases with suspected CHIKV infection, 7 (7%) cases with CHIKV encephalitis were identified; mean age was 56 years and four were men. The mean latency from onset of symptoms to diagnosis was 5 five days. Clinical manifestations were: fever/arthralgia, headache/alteration of consciousness and status epilepticus. The EEG demonstrated slow background activity and generalized epileptiform discharges in three patients. Brain MRI showed bilateral white matter hyperintensities and one with focal encephalitis; CSF analysis demonstrated lymphocytic pleocytosis and hyperproteinorrachia. Two patients died. Postmortem brain examination of one patient revealed lymphocytic infiltrates with focal necrosis in hippocampus, frontal lobes and medulla oblongata.

      Conclusions

      Neurological complications of CHIKV are infrequent, but may be severe. In this case series, the neurological manifestation was encephalitis. Predominant symptoms and signs were fever, behavioral abnormalities, headache and seizures. Because of the potential morbidity and mortality of CHIKV encephalitis, these patients should be admitted to hospital urgently.

      Keywords

      1. Introduction

      Chikungunya Virus (CHIKV) is a mosquito-borne alphavirus, and was first isolated after a 1952–1953 epidemic in present-day Tanzania [
      • Charrel R.N.
      • Leparc-Goffart I.
      • Gallian P.
      • de Lamballerie X.
      Globalization of chikungunya: 10 years to invade the world.
      ]. It is usually transmitted to humans by Aedes aegypti mosquitoes. In 2005, a strain of the virus was detected in the islands in the southwest of the Indian Ocean.
      The first evidence in the Americas of infection by CHIKV occurred in December 2013, on Saint Martin Island [
      • Ramon-Pardo P.
      • Cibrelus L.
      • Yactayo S.
      • et al.
      Chikungunya: case definitions for acute, atypical and chronic cases. Conclusions of an expert consultation.
      ,
      • Tang B.L.
      The cell biology of chikungunya virus infection.
      ]. In 2015 PAHO / WHO reported 87,577 confirmed cases of CHIKV infection with 54 deaths in Latin America up to September 2 of that year (epidemiological week number 5) [
      • de la Salud O.P.
      Número de casos reportados de chikungunya en países o territorios de las Américas 2015 (por semanas) Semana Epidemiológica/SE 36 (actualizada al 11 de septiembre de 2015).
      ]. Honduras was the country with the most reported cases in Central America with 14,325 suspected cases [
      • de la Salud O.P.
      Número de casos reportados de chikungunya en países o territorios de las Américas 2015 (por semanas) Semana Epidemiológica/SE 36 (actualizada al 11 de septiembre de 2015).
      ]; At that time, there was no record of atypical cases in Honduras; however, in other regions atypical cases have been observed with a prevalence of approximately 0.5%. Reported neurological manifestations of CHIKV include encephalitis, Guillain-Barré syndrome (GBS) [
      • Thiruvengadam K.V.
      • Kalyanasundaram V.
      • Rajgopal J.
      Clinical and pathological studies on chikungunya fever in Madras city.
      ,
      • Wielanek A.C.
      • De Monredon J.
      • El Amrani M.
      • Roger J.C.
      • Serveaux J.P.
      Guillain-Barré syndrome complicating a chikungunya virus infection.
      ], encephalomyelitis, seizures, and optic neuritis [
      • Cerny T.
      • Schwarz M.
      • Schwarz U.
      • Lemant J.
      • Gérardin P.
      • Keller E.
      The range of neurological complications in chikungunya fever.
      ] [
      • C. OPS
      Preparedness and Response for Chikungunya Virus Introduction in the Americas.
      ], Other reported complications of CHIKV include gastrointestinal, cardiovascular and renal manifestations [
      • C. OPS
      Preparedness and Response for Chikungunya Virus Introduction in the Americas.
      ,
      • Rajapakse S.
      • Rodrigo C.
      • Rajapakse A.
      Atypical manifestations of chikungunya infection.
      ].
      The Hospital Escuela Universitario (HEU) in Tegucigalpa is the most important Hospital in Honduras and has the most experience diagnosing and treating patients with CHIKV infection. A review of these patients demonstrated that several of them experienced atypical neurological manifestations. In this report we describe the clinical, pathological and neuroimaging characteristics of these cases.

      2. Clinical cases

      We conducted a consecutive case study of adults who were evaluated in the Emergency Department at HEU from April to September 2015. We used the PAHO case definition of CHIKV infection with neurological manifestations: Specifically, this is a person with neurological manifestations who satisfies the clinical (acute fever ˃38.5 °C and joint pain), epidemiological (resident or visitor in the last 15 days of an area with local transmission of CHIKV) and laboratory (confirmation by PCR, serology or viral culture) criteria for CHIKV infection [
      • Ramon-Pardo P.
      • Cibrelus L.
      • Yactayo S.
      • et al.
      Chikungunya: case definitions for acute, atypical and chronic cases. Conclusions of an expert consultation.
      ].
      For serological confirmation of CHIKV, we used IgM antibody detection by ELISA (RUO CHIKjjDetectTM IgM ELISA, InBiOS International Inc. Seattle USA). Additionally, we performed serological screens for specific IgM antibodies to exclude other etiologies such as Herpes simplex virus types I and II, Dengue, malaria, Cytomegalovirus (CMV), Epstein Barr virus (EBV), Leptospira and HIV. These serological tests as well as Gram stain and cultures of CSF to look for bacteria, mycobacteria and fungi were negative in all cases. Neuroimaging studies of brain (CT and MRI) and EEG were also obtained.
      There were 95 patients suspected of CHIKV infection, seven of whom (7%) satisfied the PAHO / WHO criteria of CHIKV infection with neurological manifestations. None had a prior history of febrile illness, and none had been in another known endemic country for CHIKV; therefore, none had developed immunological memory for CHIKV. Table 1 summarizes the characteristics of these seven cases.
      Table 1Characteristics of patients with CHIKV encephalitis in Tegucigalpa, Honduras, April–September 2015.
      CaseAgeSexOriginClinicCTMRICSFOutcome
      175MComayaguaStupor

      Fever
      NAHP

      L
      Recovered
      264MOlanchoStuporNA1HP

      L
      Recovered
      343FComayaguaStatus epilepticus

      Fever
      EEHP

      Recovered
      485FFrancisco MorazánStupor

      Headache

      Fever

      Myalgias
      AtrophyNAHP

      L
      Death after 25 days.
      563MOlanchoStupor

      Headache

      Fever

      Althralgias
      NAHP

      L
      Recovered
      636MFrancisco MorazánStatus epilepticus

      Fever

      Rash
      NNHPRecovered
      728MComayaguaStupor

      Headache

      Frontal signs

      Fever

      Althralgias

      Rash
      ENAHPDeath after 3 days
      CT: computed tomography scan, MRI: magnetic resonance imaging, M:, Male, F: female, N: normal, A: periventricular lesions, A1: hyperintensity in right hippocampus, E: Cerebral edema, NA: not available, HP: hyperproteinorrachia, L: lymphocytic pleocytosis.
      The mean age was 56 years with a range of 28 to 85 years; 57% were men (4/7) and 43% were women (3/7).
      The time from onset of fever to neurological manifestations was 5 days (range: 3 to 10 days; SD = 2.51). Glasgow Coma Scale (GCS) at admission was 10 (range 4–14 points; SD = 4.61). The mean hospitalization days was 9 (range 0–30; SD = 7.91).
      Regarding the co-morbid disease background of the cases, 71% (5/7) had chronic hypertension, 57% (4/7) had type 2 diabetes mellitus and 29% (2/7) suffered from chronic alcoholism. Initial routine laboratory studies were within normal limits except for relative lymphopenia in 43% (3/7).
      The Cerebrospinal Fluid (CSF) showed lymphocytic pleocytosis in 4/7 cases with a mean cell count of 56.70xmm3 (SD = 44.40); hyperproteinorrachia was found in 7/7 cases with a mean of 137.30 mg / dL, (SD = 25.87).
      Electroencephalography (EEG) was performed in 43% (3/7) of the patients, and in all of them generalized epileptiform discharges and slow background activity were found.
      Brain CT showed diffuse cerebral edema in 29% (2/7) and was normal in 71% (5/7) cases. Brain MRI was performed in 71% (5/7) of cases and in 29% (2/7) showed bilateral punctate white matter lesions visible in the diffusion-weighted imaging (DWI) sequences (Fig. 1) and focal temporal encephalitis (Fig. 2); Brain MRI was normal in 29% (2/7). Magnetic resonance arteriography (MRA) was normal in all cases, and no study demonstrated abnormal contrast enhancement.
      Fig. 1
      Fig. 1Cerebral Magnetic Resonance Imaging of a case with encephalitis by Chikungunya virus.
      Brain MRI of a 75-year-old male patient with punctate lesions in the Diffusion sequence and insinuating in the Flair.
      Fig. 2
      Fig. 2Cerebral Magnetic Resonance Imaging of a case with focal encephalitis by Chikungunya virus.
      : Brain MRI of 65 year old man revealed predominantly right medial temporal lobe hyperintensities in FLAIR sequences (2b). Upon administration of gadolinium(2a), right medial cortical temporal lobe enhancement was observed.
      During hospitalization, the following medical complications occurred: hypernatremia and acute kidney failure in 43% (3/7); pneumonia and respiratory failure in 29% (2/7); hyperosmolar state and urinary tract infection in 14% (1/7). Seventy-one percent (5/7) improved and 29% (2/7) of the patients died.
      Both of the patients who died were women. One was 28 years old without comorbidities. She suffered a rapid decrease of consciousness, and serial brain CT scans showed progressive diffuse cerebral edema. She died after three days of illness. The second patient was 85 years old. She presented with a five-day course of fever and chills accompanied by severe progressive suprapubic abdominal pain. She had a past medical history of a thyroid mass, which had not been evaluated, and also suffered from chronic obstructive pulmonary disease (COPD). Upon admission to hospital, her GCS was 14 without any other abnormality in the neurological exam; Cultures of blood and CSF were negative. During hospitalization she had a further deterioration of consciousness that coincided with hypernatremia (160 meq / L) and exacerbation of COPD. CSF examination showed pleocytosis of 30 cells/ml (100% lymphocytes), and protein of 123 mg/dl. Four days later, she developed acute tetraplegia with global hyperreflexia. Brain CT showed only generalized atrophy, and it was not possible to perform brain or spinal MRI. She had a cardio-respiratory arrest and died.
      Her postmortem examination of brain revealed the following:
      Gross examination of brain showed narrow cerebral sulci and slightly flattened gyri in a generalized manner. Microscopic examination showed arachnoid vascular congestion and edema of the hippocampus, basal ganglia and frontal lobes. Microglial aggregates were seen, and there was a significant increase in perivascular spaces with inflammatory infiltrates of lymphocytes and plasma cells in blood vessels (Fig. 3a ). At the brainstem level, there was mild interstitial edema. In the medulla, and sparse lymphocytic inflammatory cells with foci of necrosis of 0.3 mm in the anterior part were seen (Fig. 3b).
      Fig. 3
      Fig. 3Autopsy findings of a case with encephalitis by Chikungunya virus.
      3a: Lymphocytic perivascular inflammatory infiltrate in hippocampus and widening of the Virchow-Robin space. 3b: A 0.3 mm necrotic focus in the anterior part of the medulla with gliosis as well as subarachnoid vessels with lymphocytic inflammatory infiltrate.
      Management: All patients were administered empirical treatment with intravenous acyclovir until herpes simplex virus infection was excluded. All patients were provided standard symptomatic and supportive care with appropriate management of intercurrent medical complications.

      3. Discussion

      The first reports of CHIKV encephalitis were probably from India in 1965 [
      • Robinson M.
      An epidemic of virus disease in Southern Province, Tanganyika territory, in 1952–1953.
      ,
      • Lemant J.
      • Boisson V.
      • Winer A.
      • Thibault L.
      • André H.
      • Tixier F.
      • Lemercier M.
      • Antok E.
      • Cresta M.P.
      • Grivard P.
      • Besnard M.
      • Rollot O.
      • Favier F.
      • Huerre M.
      • Campinos J.L.
      • Michault A.
      Serious acute chikungunya virus infection requiring intensive care during the Reunion Island outbreak in 2005-2006.
      ]. Since that time several descriptions of fatal encephalitis related to CHIKV have been described [
      • Rajapakse S.
      • Rodrigo C.
      • Rajapakse A.
      Atypical manifestations of chikungunya infection.
      ,
      • Lemant J.
      • Boisson V.
      • Winer A.
      • Thibault L.
      • André H.
      • Tixier F.
      • Lemercier M.
      • Antok E.
      • Cresta M.P.
      • Grivard P.
      • Besnard M.
      • Rollot O.
      • Favier F.
      • Huerre M.
      • Campinos J.L.
      • Michault A.
      Serious acute chikungunya virus infection requiring intensive care during the Reunion Island outbreak in 2005-2006.
      ,
      • Economopoulou A.
      • Dominguez M.
      • Helynck B.
      • Sissoko D.
      • Wichmann O.
      • Quenel P.
      • Germonneau P.
      • Quatresous I.
      Atypical chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005-2006 outbreak on Réunion.
      ]); But, there are relatively few published case series of CHIKV encephalitis with histopathological findings (Table 2).
      Table 2Previous CHIKV encephalitis case series.
      PapersYearNo. cases
      Ernould, S, Walters, H.200886
      Robin. S., Ramful, D.200812
      Ganesan, K., Diwan, A.20082
      Lemant, J., Boisson, V.200813
      Rampal, M. Sharda200720
      Chandak, N., Kashyap, R.200927
      Chusri, S., Siripaitoon, P.20111
      Taraphdar, D.20153
      Gérardin, P., Couder, T.201624
      Crosby L., Perreau, C.201628
      Nagpal K., Agarwa, P.20171
      Rocha, V., de Oliveira, A.20171
      Scott, S., Braga, P.20172
      Pereira, LP., Villas-Bôas, R20172
      Samra JA, Hagood NL.201734
      Khatri, H., Shah, H.20181
      Jain RS, Khan I.20182
      Bonifay T, Prince C.20184
      Rocha, VFD.20181
      Singh R, Kaur R.20191
      Anand KS, Agrawal AK201912
      The pathophysiological mechanism of central nervous system (CNS) damage from CHIKV is not certain [
      • van Duijl-Richter M.K.S.
      • Hoornweg T.E.
      • Rodenhuis-Zybert I.A.
      • Smit J.M.
      Early events in chikungunya virus infection-from virus cellbinding to membrane fusion.
      ]. The two major theories are direct infection by CHIKV or secondary immune-mediated damage. These two mechanisms are not mutually exclusive, and both could be involved in the pathogenesis of CHIKV encephalitis. Since CHIKV neurotropism and direct neural invasion have not been demonstrated, an immunological and secondary inflammatory reaction may be responsible for the CNS manifestations [
      • Tang B.L.
      The cell biology of chikungunya virus infection.
      ,
      • Cerny T.
      • Schwarz M.
      • Schwarz U.
      • Lemant J.
      • Gérardin P.
      • Keller E.
      The range of neurological complications in chikungunya fever.
      ]. In our study, we found clear evidence of encephalitis. This is concordant with the conclusions of a systematic review of atypical manifestations of CHIKV from six studies that were carried out on the Island of Réunion and India [
      • Rajapakse S.
      • Rodrigo C.
      • Rajapakse A.
      Atypical manifestations of chikungunya infection.
      ], where encephalitis is the most frequent manifestation of atypical CHIKV. Based upon the epidemiological data from these studies, the incidence of CHIKV encephalitis ranged from 11 to 18/100,000 inhabitants.
      In most series, men are affected more often than women [
      • Chandak N.H.
      • Kashyap R.S.
      • Kabra D.
      • Karandikar P.
      • Saha S.S.
      • Morey S.H.
      • Purohit H.J.
      • Taori G.M.
      • Daginawala H.F.
      Neurological complications of chikungunya virus infection.
      ] [
      • Thiruvengadam K.V.
      • Kalyanasundaram V.
      • Rajgopal J.
      Clinical and pathological studies on chikungunya fever in Madras city.
      ,
      • Rampal M.
      • Sharda H. Meena
      Neurological complications in chikungunya fever.
      ,
      • Ray P.
      • Ratagiri V.H.
      • Kabra S.K.
      • Lodha R.
      • Sharma S.
      • Sharma B.S.
      • Kalaivani M.
      • Wig N.
      Chikungunya infection in India: results of a prospective hospital based multi-centric study.
      ,
      • Ernould S.
      • Walters H.
      • Alessandri J.L.
      • Llanas B.
      • Jaffar M.C.
      • Robin S.
      • Attali T.
      • Ramful D.
      • Combes J.C.
      Aspects pédiatriques de l’épidémie de Chikungunya à l’île de la Réunion.
      ],; [
      • Tournebize P.
      • Charlin C.
      • Lagrange M.
      Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island.
      ] which is similar to what was found in our series. Tournebize et al. in 2009, reported an average age of 58.6 years in infected adults [
      • Tournebize P.
      • Charlin C.
      • Lagrange M.
      Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island.
      ,
      • Nagpal K.
      • Agarwal P.
      • Kumar A.
      • Reddi R.
      Chikungunya infection presenting as mild encephalitis with a reversible lesion in the splenium: a case report.
      ], which is similar to what was found in our study.
      In our series, the latency from the beginning of symptoms until the neurological manifestations was comparable with that reported by Taraphdar (4.5 days) [
      • Taraphdar D.
      • Roy B.K.
      • Chatterjee S.
      Chikungunya virus infection amongst the acute encephalitis syndrome cases in West Bengal, India.
      ] and Cerny et al. 2017 [
      • Cerny T.
      • Schwarz M.
      • Schwarz U.
      • Lemant J.
      • Gérardin P.
      • Keller E.
      The range of neurological complications in chikungunya fever.
      ], Rampal (2 to 3 days) [
      • Rampal M.
      • Sharda H. Meena
      Neurological complications in chikungunya fever.
      ], Chandack (20 days) [
      • Chandak N.H.
      • Kashyap R.S.
      • Kabra D.
      • Karandikar P.
      • Saha S.S.
      • Morey S.H.
      • Purohit H.J.
      • Taori G.M.
      • Daginawala H.F.
      Neurological complications of chikungunya virus infection.
      ] and Lemant (4 to 5 days) [
      • Lemant J.
      • Boisson V.
      • Winer A.
      • Thibault L.
      • André H.
      • Tixier F.
      • Lemercier M.
      • Antok E.
      • Cresta M.P.
      • Grivard P.
      • Besnard M.
      • Rollot O.
      • Favier F.
      • Huerre M.
      • Campinos J.L.
      • Michault A.
      Serious acute chikungunya virus infection requiring intensive care during the Reunion Island outbreak in 2005-2006.
      ].
      Based upon previous studies, the main neurological manifestations in adults with CHIKV encephalitis are alteration of consciousness, seizures, cranial neuropathies, and extensor plantar responses [
      • Chandak N.H.
      • Kashyap R.S.
      • Kabra D.
      • Karandikar P.
      • Saha S.S.
      • Morey S.H.
      • Purohit H.J.
      • Taori G.M.
      • Daginawala H.F.
      Neurological complications of chikungunya virus infection.
      ,
      • Rampal M.
      • Sharda H. Meena
      Neurological complications in chikungunya fever.
      ,
      • Tandale B.V.
      • Sathe P.S.
      • Arankalle V.A.
      • Wadia R.S.
      • Kulkarni R.
      • Shah S.V.
      • Shah S.K.
      • Sheth J.K.
      • Sudeep A.B.
      • Tripathy A.S.
      • Mishra A.C.
      Systemic involvements and fatalities during chikungunya epidemic in India, 2006.
      ]. In our study, most of the patients presented with headache, behavioral changes and status epilepticus. Seizures were most commonly of the generalized tonic-clonic variety, coinciding with those reported by Tournebize [
      • Tournebize P.
      • Charlin C.
      • Lagrange M.
      Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island.
      ]. In our study, the Glasgow Coma Score (GCS) on admission was slightly higher than that found by Lemant in 2008 [
      • Lemant J.
      • Boisson V.
      • Winer A.
      • Thibault L.
      • André H.
      • Tixier F.
      • Lemercier M.
      • Antok E.
      • Cresta M.P.
      • Grivard P.
      • Besnard M.
      • Rollot O.
      • Favier F.
      • Huerre M.
      • Campinos J.L.
      • Michault A.
      Serious acute chikungunya virus infection requiring intensive care during the Reunion Island outbreak in 2005-2006.
      ].
      The hematological profiles of our patients were mostly normal, which is in agreement with the results of other studies [
      • Tournebize P.
      • Charlin C.
      • Lagrange M.
      Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island.
      ,
      • Ernould S.
      • Walters H.
      • Alessandri J.-L.
      • Llanas B.
      • Jaffar M.-C.
      • Robin S.
      • Attali T.
      • Ramful D.
      • Combes J.-C.
      Chikungunya in paediatrics: epidemic of 2005-2006 in Saint-Denis, Reunion Island.
      ]. But, several studies noted lymphopenia in some of the patients [
      • Cerny T.
      • Schwarz M.
      • Schwarz U.
      • Lemant J.
      • Gérardin P.
      • Keller E.
      The range of neurological complications in chikungunya fever.
      ,
      • Ernould S.
      • Walters H.
      • Alessandri J.-L.
      • Llanas B.
      • Jaffar M.-C.
      • Robin S.
      • Attali T.
      • Ramful D.
      • Combes J.-C.
      Chikungunya in paediatrics: epidemic of 2005-2006 in Saint-Denis, Reunion Island.
      ,
      • Staikowsky F.
      • Talarmin F.
      • Grivard P.
      • Souab A.
      • Schuffenecker I.
      • Le Roux K.
      • Lecuit M.
      • Michault A.
      Prospective study of Chikungunya virus acute infection in the Island of La Réunion during the 2005–2006 outbreak.
      ].
      Several abnormal findings in the CSF have been described. The most common findings in CSF were lymphocytic pleocytosis, hyperproteinorrachia, and normal or slightly low glucose [
      • Lemant J.
      • Boisson V.
      • Winer A.
      • Thibault L.
      • André H.
      • Tixier F.
      • Lemercier M.
      • Antok E.
      • Cresta M.P.
      • Grivard P.
      • Besnard M.
      • Rollot O.
      • Favier F.
      • Huerre M.
      • Campinos J.L.
      • Michault A.
      Serious acute chikungunya virus infection requiring intensive care during the Reunion Island outbreak in 2005-2006.
      ,
      • Chandak N.H.
      • Kashyap R.S.
      • Kabra D.
      • Karandikar P.
      • Saha S.S.
      • Morey S.H.
      • Purohit H.J.
      • Taori G.M.
      • Daginawala H.F.
      Neurological complications of chikungunya virus infection.
      ,
      • Tournebize P.
      • Charlin C.
      • Lagrange M.
      Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island.
      ,
      • Ernould S.
      • Walters H.
      • Alessandri J.-L.
      • Llanas B.
      • Jaffar M.-C.
      • Robin S.
      • Attali T.
      • Ramful D.
      • Combes J.-C.
      Chikungunya in paediatrics: epidemic of 2005-2006 in Saint-Denis, Reunion Island.
      ,
      • Rocha V.F.D.
      • de Oliveira A.H.P.
      • Bandeira A.C.
      • Sardi S.I.
      • Garcia R.F.
      • de Magalhães S.A.
      • Sampaio C.A.
      • Soares G. Campos
      Chikungunya virus infection associated with encephalitis and anterior uveitis.
      ]. These results coincide in a general way with the results of this study. EEG patterns were also similar among the different studies with slowing of background rhythms and occasional epileptiform abnormalities [
      • Tournebize P.
      • Charlin C.
      • Lagrange M.
      Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island.
      ,
      • Ernould S.
      • Walters H.
      • Alessandri J.-L.
      • Llanas B.
      • Jaffar M.-C.
      • Robin S.
      • Attali T.
      • Ramful D.
      • Combes J.-C.
      Chikungunya in paediatrics: epidemic of 2005-2006 in Saint-Denis, Reunion Island.
      ,
      • Pereira L.P.
      • Villas-Bôas R.
      • de Scott S.S.O.
      • Nóbrega P.R.
      • Sobreira-Neto M.A.
      • de Castro J.D.V.
      • Cavalcante B.
      • Braga-Neto P.
      Encephalitis associated with the chikungunya epidemic outbreak in Brazil: report of 2 cases with neuroimaging findings.
      ].
      In most of the published studies of CHIKV encephalitis where brain CT was done, the CT was usually normal with the exception of a few cases (28.6%) with diffuse cerebral edema [
      • Chandak N.H.
      • Kashyap R.S.
      • Kabra D.
      • Karandikar P.
      • Saha S.S.
      • Morey S.H.
      • Purohit H.J.
      • Taori G.M.
      • Daginawala H.F.
      Neurological complications of chikungunya virus infection.
      ,
      • Rampal M.
      • Sharda H. Meena
      Neurological complications in chikungunya fever.
      ,
      • Ernould S.
      • Walters H.
      • Alessandri J.-L.
      • Llanas B.
      • Jaffar M.-C.
      • Robin S.
      • Attali T.
      • Ramful D.
      • Combes J.-C.
      Chikungunya in paediatrics: epidemic of 2005-2006 in Saint-Denis, Reunion Island.
      ]. Most studies describe that brain MRI was also normal; however, in some cases bilateral white matter lesions [
      • Chandak N.H.
      • Kashyap R.S.
      • Kabra D.
      • Karandikar P.
      • Saha S.S.
      • Morey S.H.
      • Purohit H.J.
      • Taori G.M.
      • Daginawala H.F.
      Neurological complications of chikungunya virus infection.
      ,
      • Pereira L.P.
      • Villas-Bôas R.
      • de Scott S.S.O.
      • Nóbrega P.R.
      • Sobreira-Neto M.A.
      • de Castro J.D.V.
      • Cavalcante B.
      • Braga-Neto P.
      Encephalitis associated with the chikungunya epidemic outbreak in Brazil: report of 2 cases with neuroimaging findings.
      ,
      • de Scott S.S.O.
      • Braga-Neto P.
      • Pereira L.P.
      • Nóbrega P.R.
      • de Assis Aquino Gondim F.
      • Sobreira-Neto M.A.
      • Schiavon C.C.M.
      Immunoglobulin-responsive chikungunya encephalitis: two case reports.
      ], as well as spinal cord lesions have been found [
      • Maity P.
      • Roy P.
      • Basu A.
      • Das B.
      • Ghosh U.S.
      A case of ADEM following chikungunya fever.
      ,
      • Chusri S.
      • Siripaitoon P.
      • Hirunpat S.
      • Silpapojakul K.
      Case reports of neuro-chikungunya in southern Thailand.
      ,
      • Samra J.A.
      • Hagood N.L.
      • Summer A.
      • Medina M.T.
      • Holden K.R.
      Clinical features and neurologic complications of children hospitalized with chikungunya virus in Honduras.
      ]. The findings in our study mirror these results except that spinal MRI was not performed in our patients.
      The clinical outcome of patients with CHIKV encephalitis has previously been reported as generally favorable.; Previous studies have reported a mortality rate of approximately 4% (2/49) in India [
      • Chandak N.H.
      • Kashyap R.S.
      • Kabra D.
      • Karandikar P.
      • Saha S.S.
      • Morey S.H.
      • Purohit H.J.
      • Taori G.M.
      • Daginawala H.F.
      Neurological complications of chikungunya virus infection.
      ] and 8.7% (2/23) in La Isla de la Réunion [
      • Tournebize P.
      • Charlin C.
      • Lagrange M.
      Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island.
      ]. But, in our study, the mortality rate was 28.57% (2/7), a figure that should alert us to the potential severity of atypical cases in adults.
      There are several case reports on brainstem encephalitis related to CHIKV, Gauri and Musthafa described cases of adults with neurological symptoms related to CHIKV, both of whom obtained laboratory confirmation with IgM by ELISA [
      • Gauri L.A.
      • Ranwa B.L.
      • Nagar K.
      • Vyas A.
      • Fatima Q.
      Post chikungunya brain stem encephalitis.
      ,
      • Musthafa A.K.M.
      • Abdurahiman P.
      • Jose J.
      Case of ADEM following chikungunya fever.
      ]. Two cases of encephalo-myeloradiculitis related to CHIKV have been reported. In both cases, periventricular white matter lesions, cerebral edema, microglial aggregates, and perivascular lymphocytic infiltrates were noted in brain [
      • Ganesan K.
      • Diwan A.
      • Shankar S.K.
      • Desai S.B.
      • Sainani G.S.
      • Katrak S.M.
      Chikungunya encephalomyeloradiculitis: report of 2 cases with neuroimaging and 1 case with autopsy findings., AJNR.
      ]; These findings agree partially with what was found in the postmortem brains of our series. They confirm the presence of encephalitis, but they are not pathognomonic of a specific virus, and therefore serological confirmation is necessary.

      4. Conclusions

      Neurological manifestations in patients with CHIKV are infrequent, but may be severe. All of our cases manifested a CHIKV encephalitis. In our adult patients, chronic comorbidities were frequent. The clinical presentation usually consisted of fever, behavioral changes, headache, decreased level of consciousness, and seizures. Considering the potential lethality of CHIKV encephalitis, these patients should be admitted to hospital and provided the best supportive and symptomatic therapy available. Many of these patients require neurointensive care, and if possible, should be referred to a tertiary care medical center.

      Acknowledgments

      To professor Marco Tulio Medina (National Autonomous University of Honduras) for his advice and scientific guidance.

      References

        • Charrel R.N.
        • Leparc-Goffart I.
        • Gallian P.
        • de Lamballerie X.
        Globalization of chikungunya: 10 years to invade the world.
        Clin. Microbiol. Infect. 2014; 20: 662-663https://doi.org/10.1111/1469-0691.12694
        • Ramon-Pardo P.
        • Cibrelus L.
        • Yactayo S.
        • et al.
        Chikungunya: case definitions for acute, atypical and chronic cases. Conclusions of an expert consultation.
        Managua, Nicaragua, 20–21 May 2015, Wkly. Epidemiol. Rec. 2015; 90 (Accessed September 7, 2015): 410-414
        • Tang B.L.
        The cell biology of chikungunya virus infection.
        Cell. Microbiol. 2012; 14: 1354-1363https://doi.org/10.1111/j.1462-5822.2012.01825.x
        • de la Salud O.P.
        Número de casos reportados de chikungunya en países o territorios de las Américas 2015 (por semanas) Semana Epidemiológica/SE 36 (actualizada al 11 de septiembre de 2015).
        in: PAHO. 2015
        • Thiruvengadam K.V.
        • Kalyanasundaram V.
        • Rajgopal J.
        Clinical and pathological studies on chikungunya fever in Madras city.
        Indian J. Med. Res. 1965; 53 (Accessed September 13, 2015): 729-744
        • Wielanek A.C.
        • De Monredon J.
        • El Amrani M.
        • Roger J.C.
        • Serveaux J.P.
        Guillain-Barré syndrome complicating a chikungunya virus infection.
        Neurology. 2007; 69: 2105-2107https://doi.org/10.1212/01.wnl.0000277267.07220.88
        • Cerny T.
        • Schwarz M.
        • Schwarz U.
        • Lemant J.
        • Gérardin P.
        • Keller E.
        The range of neurological complications in chikungunya fever.
        Neurocrit. Care. 2017; https://doi.org/10.1007/s12028-017-0413-8
        • C. OPS
        Preparedness and Response for Chikungunya Virus Introduction in the Americas.
        OPS, Washington2010: 14
        • Rajapakse S.
        • Rodrigo C.
        • Rajapakse A.
        Atypical manifestations of chikungunya infection.
        Trans. R. Soc. Trop. Med. Hyg. 2010; 104: 89-96https://doi.org/10.1016/j.trstmh.2009.07.031
        • Robinson M.
        An epidemic of virus disease in Southern Province, Tanganyika territory, in 1952–1953.
        Trans. R. Soc. Trop. Med. Hyg. 1955; 49: 28-32https://doi.org/10.1016/0035-9203(55)90080-8
        • Lemant J.
        • Boisson V.
        • Winer A.
        • Thibault L.
        • André H.
        • Tixier F.
        • Lemercier M.
        • Antok E.
        • Cresta M.P.
        • Grivard P.
        • Besnard M.
        • Rollot O.
        • Favier F.
        • Huerre M.
        • Campinos J.L.
        • Michault A.
        Serious acute chikungunya virus infection requiring intensive care during the Reunion Island outbreak in 2005-2006.
        Crit. Care Med. 2008; 36: 2536-2541https://doi.org/10.1097/CCM.0b013e318183f2d2
        • Economopoulou A.
        • Dominguez M.
        • Helynck B.
        • Sissoko D.
        • Wichmann O.
        • Quenel P.
        • Germonneau P.
        • Quatresous I.
        Atypical chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005-2006 outbreak on Réunion.
        Epidemiol. Infect. 2009; : 534-541https://doi.org/10.1017/S0950268808001167
        • van Duijl-Richter M.K.S.
        • Hoornweg T.E.
        • Rodenhuis-Zybert I.A.
        • Smit J.M.
        Early events in chikungunya virus infection-from virus cellbinding to membrane fusion.
        Viruses. 2015; 7: 3647-3674https://doi.org/10.3390/v7072792
        • Chandak N.H.
        • Kashyap R.S.
        • Kabra D.
        • Karandikar P.
        • Saha S.S.
        • Morey S.H.
        • Purohit H.J.
        • Taori G.M.
        • Daginawala H.F.
        Neurological complications of chikungunya virus infection.
        Neurol. India. 2009; 57: 177-180https://doi.org/10.4103/0028-3886.51289
        • Rampal M.
        • Sharda H. Meena
        Neurological complications in chikungunya fever.
        J. Assoc. Physicians India. 2007; 55 (Accessed September 13, 2015): 765-769
        • Ray P.
        • Ratagiri V.H.
        • Kabra S.K.
        • Lodha R.
        • Sharma S.
        • Sharma B.S.
        • Kalaivani M.
        • Wig N.
        Chikungunya infection in India: results of a prospective hospital based multi-centric study.
        PLoS One. 2012; 7: e30025https://doi.org/10.1371/journal.pone.0030025
        • Ernould S.
        • Walters H.
        • Alessandri J.L.
        • Llanas B.
        • Jaffar M.C.
        • Robin S.
        • Attali T.
        • Ramful D.
        • Combes J.C.
        Aspects pédiatriques de l’épidémie de Chikungunya à l’île de la Réunion.
        Arch. Pediatr. 2008; https://doi.org/10.1016/j.arcped.2007.10.019
        • Tournebize P.
        • Charlin C.
        • Lagrange M.
        Neurological manifestations in chikungunya: about 23 cases collected in Reunion Island.
        Rev. Neurol. (Paris). 2009; 165: 48-51https://doi.org/10.1016/j.neurol.2008.06.009
        • Nagpal K.
        • Agarwal P.
        • Kumar A.
        • Reddi R.
        Chikungunya infection presenting as mild encephalitis with a reversible lesion in the splenium: a case report.
        J. Neuro-Oncol. 2017; https://doi.org/10.1007/s13365-017-0515-2
        • Taraphdar D.
        • Roy B.K.
        • Chatterjee S.
        Chikungunya virus infection amongst the acute encephalitis syndrome cases in West Bengal, India.
        Indian J. Med. Microbiol. 2015; 33: 153-156https://doi.org/10.4103/0255-0857.150946
        • Tandale B.V.
        • Sathe P.S.
        • Arankalle V.A.
        • Wadia R.S.
        • Kulkarni R.
        • Shah S.V.
        • Shah S.K.
        • Sheth J.K.
        • Sudeep A.B.
        • Tripathy A.S.
        • Mishra A.C.
        Systemic involvements and fatalities during chikungunya epidemic in India, 2006.
        J. Clin. Virol. 2009; 46: 145-149https://doi.org/10.1016/j.jcv.2009.06.027
        • Ernould S.
        • Walters H.
        • Alessandri J.-L.
        • Llanas B.
        • Jaffar M.-C.
        • Robin S.
        • Attali T.
        • Ramful D.
        • Combes J.-C.
        Chikungunya in paediatrics: epidemic of 2005-2006 in Saint-Denis, Reunion Island.
        Arch. Pediatr. 2008; 15: 253-262https://doi.org/10.1016/j.arcped.2007.10.019
        • Staikowsky F.
        • Talarmin F.
        • Grivard P.
        • Souab A.
        • Schuffenecker I.
        • Le Roux K.
        • Lecuit M.
        • Michault A.
        Prospective study of Chikungunya virus acute infection in the Island of La Réunion during the 2005–2006 outbreak.
        PLoS One. 2009; 4: e7603https://doi.org/10.1371/journal.pone.0007603
        • Rocha V.F.D.
        • de Oliveira A.H.P.
        • Bandeira A.C.
        • Sardi S.I.
        • Garcia R.F.
        • de Magalhães S.A.
        • Sampaio C.A.
        • Soares G. Campos
        Chikungunya virus infection associated with encephalitis and anterior uveitis.
        Ocul. Immunol. Inflamm. 2017; : 1-3https://doi.org/10.1080/09273948.2017.1358378
        • Pereira L.P.
        • Villas-Bôas R.
        • de Scott S.S.O.
        • Nóbrega P.R.
        • Sobreira-Neto M.A.
        • de Castro J.D.V.
        • Cavalcante B.
        • Braga-Neto P.
        Encephalitis associated with the chikungunya epidemic outbreak in Brazil: report of 2 cases with neuroimaging findings.
        Rev. Soc. Bras. Med. Trop. 2017; 50: 413-416https://doi.org/10.1590/0037-8682-0449-2016
        • de Scott S.S.O.
        • Braga-Neto P.
        • Pereira L.P.
        • Nóbrega P.R.
        • de Assis Aquino Gondim F.
        • Sobreira-Neto M.A.
        • Schiavon C.C.M.
        Immunoglobulin-responsive chikungunya encephalitis: two case reports.
        J. Neuro-Oncol. 2017; 23: 625-631https://doi.org/10.1007/s13365-017-0535-y
        • Maity P.
        • Roy P.
        • Basu A.
        • Das B.
        • Ghosh U.S.
        A case of ADEM following chikungunya fever.
        J. Assoc. Physicians India. 2014; 62 (Accessed August 26, 2016): 441-442
        • Chusri S.
        • Siripaitoon P.
        • Hirunpat S.
        • Silpapojakul K.
        Case reports of neuro-chikungunya in southern Thailand.
        Am. J. Trop. Med. Hyg. 2011; 85: 386-389https://doi.org/10.4269/ajtmh.2011.10-0725
        • Samra J.A.
        • Hagood N.L.
        • Summer A.
        • Medina M.T.
        • Holden K.R.
        Clinical features and neurologic complications of children hospitalized with chikungunya virus in Honduras.
        J. Child Neurol. 2017; 32: 712-716https://doi.org/10.1177/0883073817701879
        • Gauri L.A.
        • Ranwa B.L.
        • Nagar K.
        • Vyas A.
        • Fatima Q.
        Post chikungunya brain stem encephalitis.
        J. Assoc. Physicians India. 2012; 60 (Accessed August 17, 2016): 68-70
        • Musthafa A.K.M.
        • Abdurahiman P.
        • Jose J.
        Case of ADEM following chikungunya fever.
        J. Assoc. Physicians India. 2008; 56 (Accessed August 26, 2016): 473
        • Ganesan K.
        • Diwan A.
        • Shankar S.K.
        • Desai S.B.
        • Sainani G.S.
        • Katrak S.M.
        Chikungunya encephalomyeloradiculitis: report of 2 cases with neuroimaging and 1 case with autopsy findings., AJNR.
        Am. J. Neuroradiol. 2008; 29: 1636-1637https://doi.org/10.3174/ajnr.A1133