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Description of the neuropathological findings in the postmortem brain examination:
Inflammatory infiltrates of lymphocytes in the brainstem, hippocampus and frontal lobes.
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.
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.
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.
]; 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) [
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 [
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.
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.
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).
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.
The first reports of CHIKV encephalitis were probably from India in 1965 [
]. 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 [
]. 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 [
], 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]; 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.
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.
To professor Marco Tulio Medina (National Autonomous University of Honduras) for his advice and scientific guidance.
de Lamballerie X.
Globalization of chikungunya: 10 years to invade the world.