Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that emerged in the islands of the Indian Ocean about a decade ago and has become widely disseminated. Clinically similar to dengue fever, CHIKV is generally considered a nonfatal disease with spontaneous recovery, although some patients have arthralgias that persist for months. Gerardin and colleagues reported their experience of central nervous system (CNS) involvement after a large CHIKV outbreak that occurred on Reunion Island between September 2005 and June 2006.
The study was a retrospective cohort that included all patients hospitalized at a single hospital on Reunion Island with CHIKV infection and neurological symptoms who had a lumbar puncture. Patients with a positive cerebral spinal fluid (CSF) CHIKV PCR or anti-CHIKV IgM were used to fulfill the specific case definition. The investigators followed the International Encephalitis Consortium criteria to classify patients according to a current definition of encephalitis. These combine the major criterion of change in mental status with several minor criteria, including fever within 72 hours of presentation; seizures not related to epilepsy; new onset of focal neurological deficits; CSF leukocyte count ≥ 5/mm3; brain parenchyma on neuroimaging suggestive of encephalitis; and EEG consistent with encephalitis and not attributable to another cause. Probable CHIKV-associated encephalitis was defined as the major criterion and at least three minor criteria; possible CHIKV-associated encephalitis was defined as the major criterion and two minor criteria. Every patient with CHIKV CNS disease was followed for 3 years to assess for neurological sequelae.
During the CHIKV outbreak, 129 patients developed neurological signs, of which 57 were enrolled in the study after various exclusions. The cohort contained 21 adults (age range 33-88 years, mean age 63.9 years) and 36 infants (age range 4 days-5.4 months, mean age 1.6 months). The adults were more likely to have experienced decreased consciousness, coma, focal neurological signs, seizures, or death, while the infants were more likely to have experienced fever, behavior changes, rash, and survival. The cumulative incidence rate of CHIKV-associated encephalitis was 8.6 per 100,000 persons (95% confidence interval [CI], 6.9-10.4) with a U-shaped distribution pattern that affected mostly those younger than 5 years old and older than 65 years. Six adult patients died during hospitalization, and eight were discharged with neurologic sequelae. Of the 10 adults available for follow up at 3 years, three of them had neurologic sequelae attributable to CHIKV. Of the 17 infants available for follow up at 3 years, one had severe cerebral palsy and blindness after a full-term normal gestation, and four had poor neurodevelopmental performance. Because of the high attrition in the follow-up period, the burden of neurologic sequelae could not be precisely calculated. However, poor prognosis (i.e., death or sequelae) was more prominent in adults compared to children (52.6% vs 18.2%, respectively; P = 0.020).
COMMENTARY
This report adds to the increasing body of evidence that CHIKV can cause severe neurological disease. The finding of a number of cases of CNS involvement and encephalitis in the Reunion Island cohort questions the conventional belief that CHIKV infection causes a painful yet self-limited illness. Notably, the cumulative incidence rate of CHIKV-associated encephalitis in the cohort was higher than what has been observed with West Nile virus. The outcomes data were similar to what has been reported for other virus-associated encephalitides, dispelling hope that CHIKV-associated encephalitis might lead to less neurological sequelae. Further research is needed to elucidate the neurological tropism mechanisms of CHIKV, which could possibly be targets for antiviral therapy.
What are the clinical implications of the study? CHIKV should be considered in the differential diagnosis of travelers with fever and neurological symptoms, especially in those returning from tropical and subtropical regions. This is illustrated by a recent case report of a 57-year-old man from the island of Tonga who presented to Stanford Hospital with 1 day of fever and altered mental status after a week of diffuse joint pains, headache, abdominal pain, and rash.1 Initial testing for HIV antibody/antigen, IgM for dengue virus, West Nile virus, measles and rubella, syphilis immunoassay, and CSF PCRs for enterovirus, herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, and cytomegalovirus were negative. These were followed by nucleic acid amplification tests for dengue virus, Plasmodium species, Zika virus, and Leptospira species, which were also negative. Next, serum and plasma specimens were tested for CHIKV, yellow fever virus, dengue virus, and Rift Valley fever virus using a multiplex, real-time reverse transcriptase PCR, which detected CHIKV RNA. On the second hospital day, the patient defervesced and improved with supportive care, including antiepileptic drugs and IVIG. After his discharge, anti-CHIKV IgM was detected in serum from hospital day 2 by the Division of Vector-Borne Infectious Diseases at the CDC.
REFERENCE
- Nelson J, et al. Encephalitis caused by chikungunya virus in a traveler from the Kingdom of Tonga. J Clin Microbiol 2014;52:3459-3461.
A retrospective cohort study of a major chikungunya virus outbreak found a significant incidence of central nervous system disease, with patients < 1 year of age and > 65 years of age at most risk for chikungunya virus-associated encephalitis.
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