CASE
A 45-year-old Australian male visited Bali, Indonesia, for 10 days during the wet season in January (staying at resort hotels in Seminyak and Canggu). His medical history included asthma and restless leg syndrome, treated with pramipexole, levodopa, and carbidopa. Before travel, he received diphtheria/tetanus/pertussis (acellular) and typhoid vaccines and commenced doxycycline for malaria prophylaxis. Aside from a day trip to Ubud, holiday activities were primarily resort based, without any camping or other outdoor activities. Despite this, the patient recalled multiple mosquito bites. He had no previous travel to a Japanese encephalitis virus (JEV)–endemic area.
One day after returning to Australia, he developed fever, vomiting, and myalgia. On day 4 of symptom onset, he developed confusion and expressive dysphasia and was admitted to hospital. On examination, he was afebrile, disoriented, dysphasic, and had bilateral conjunctival injection with no rash noted. The patient underwent ophthalmological assessment. Visual acuity was 6/6 in the right eye and 6/7.5 in the left. Slit-lamp biomicroscopy showed fine keratic precipitates on the corneal endothelium and moderate anterior chamber inflammation. Examination of the posterior pole revealed bilateral vessel tortuosity and bilateral pale chorioretinal lesions (Figure 1 left eye). Peripheral intraretinal hemorrhages were also seen in both eyes.
Left eye shows the chorioretinal lesions (see arrow).
Citation: The American Journal of Tropical Medicine and Hygiene 103, 4; 10.4269/ajtmh.19-0330
Left eye shows the chorioretinal lesions (see arrow).
Citation: The American Journal of Tropical Medicine and Hygiene 103, 4; 10.4269/ajtmh.19-0330
Left eye shows the chorioretinal lesions (see arrow).
Citation: The American Journal of Tropical Medicine and Hygiene 103, 4; 10.4269/ajtmh.19-0330
Cerebrospinal fluid (CSF) microscopy on day 5 of symptoms revealed lymphocytes 243 × 106 cells/L and polymorphonuclear leukocytes 18 × 106 cells/L. The CSF protein was 1.4 g/L (normal range, 0.1–0.3) and normal glucose 3.4 mmol/L. Magnetic resonance imaging (MRI) showed signal changes in bilateral, asymmetrical mesial temporal lobe involving the cortex and some subcortical white matter, the right thalamus, and the left head of caudate nucleus (Figure 2). Intravenous acyclovir and ceftriaxone were commenced but ceased after blood and CSF bacterial cultures were negative, and CSF herpes simplex viruses 1 and 2, cytomegalovirus, and varicella zoster viruses were not detected using PCR tests. Cerebrospinal fluid cryptococcal antigen was negative. Chikungunya (and other alphaviruses), hendra/nipah virus, leptospira, and toxoplasma were not detected using PCR on CSF.
Magnetic resonance imaging scan demonstrating signal changes in the mesial temporal lobe involving the cortex and some subcortical white matter (see thin horizontal arrow), the right thalamus (see thick arrow), and the left head of caudate nucleus (see diagonal arrow).
Citation: The American Journal of Tropical Medicine and Hygiene 103, 4; 10.4269/ajtmh.19-0330
Magnetic resonance imaging scan demonstrating signal changes in the mesial temporal lobe involving the cortex and some subcortical white matter (see thin horizontal arrow), the right thalamus (see thick arrow), and the left head of caudate nucleus (see diagonal arrow).
Citation: The American Journal of Tropical Medicine and Hygiene 103, 4; 10.4269/ajtmh.19-0330
Magnetic resonance imaging scan demonstrating signal changes in the mesial temporal lobe involving the cortex and some subcortical white matter (see thin horizontal arrow), the right thalamus (see thick arrow), and the left head of caudate nucleus (see diagonal arrow).
Citation: The American Journal of Tropical Medicine and Hygiene 103, 4; 10.4269/ajtmh.19-0330
Two weeks into admission, he developed right face and arm myoclonic jerks associated with delirium and psychotic features. Risperidone was trialed with no improvement. Electroencephalography showed diffuse slowing, suggestive of underlying diffuse encephalopathy. After 3 weeks in rehabilitation, the patient’s delirium resolved; however, he had ongoing impairment in memory and concentration.
Serum JEV IgM was detected on day 4 of symptoms. Seroconversion was demonstrated for JEV (IgG not detected by immunofluorescence at day 4 of symptom onset; titer > 160 on day 11 and > 1,280 on day 30)1 but not for potentially cross-reacting flaviruses including dengue virus, Murray Valley encephalitis virus (MVEV), West Nile virus (WNV), and Zika virus (Table 1).
Serology results
| Days from symptom onset | |||
|---|---|---|---|
| Day 5 | Day 11 | Day 30 | |
| Japanese encephalitis virus | |||
|  IgG | < 10 (negative) | > 160 (positive) | > 1,280 (positive) |
|  IgM | Detected | Detected | Detected |
| Bartonella IgG | – | < 128 | – |
| Chikungunya virus | |||
|  IgG | < 10 (negative) | – | < 10 (negative) |
|  IgM | ND | – | ND |
| Dengue virus | |||
|  IgG | ND | Low positive | – |
|  IgM | ND | ND | – |
|  NS1 antigen | ND | ND | – |
| HIV antigen/antibody | ND | – | – |
| West Nile virus total antibody | – | ND | – |
| Murray Valley encephalitis virus total antibody | – | ND | – |
| Zika | |||
|  IgG | – | – | ND |
|  IgM | – | – | ND |
Cerebrospinal fluid JEV IgG and PCR were negative at day 5. Flaviviruses were negative using PCR on CSF: dengue types 1, 2, and 3 virus, MVEV, WNV, Kunjin strain, and yellow fever virus.
DISCUSSION
Japanese encephalitis virus belongs to the family Flaviviridae and is transmitted between animals and human host by Culex mosquitoes. In the tropics, JEV transmission occurs year-round, whereas seasonal epidemics begin during the rainy seasons when the mosquito density is maximum.2 Most JEV infections are asymptomatic or mild. The WHO estimates 68,000 clinical cases of JE globally each year. Approximately 1 in 250 infections of serologically confirmed JE develops severe symptoms. Neurologic disease typically develops in patients after an incubation period of 5–15 days (although this period can be as brief as 2–3 days) and a short, nonspecific febrile prodrome.3 About 30% of patients admitted to hospital with JE die, and around half of the survivors have severe neurological sequelae.4 In areas with better hospital facilities, there is a reduction in mortality but a concomitant increase in the number of patients with sequelae.4
Very few cases of JE have been described in Australian travelers since the first report in 1998.4 In this case, the presence of serum JEV-specific IgM antibody and IgG seroconversion with greater than 4-fold rise in titer of JEV-specific antibody at least 14 days apart (between days 11 and 30 of symptom onset) fulfills the WHO laboratory confirmation of a JEV infection.5 A false-positive result is unlikely without recent JE vaccination and absence of serological evidence of other potentially cross-reacting flaviviruses. Magnetic resonance imaging findings in bilateral thalami are characteristic of flavivirus encephalitides; however, other areas of involvement may also be seen.6,7
To our knowledge, this is the first description of chorioretinitis associated with JE and highlights the importance of a detailed ocular examination when there is clinical suspicion of JE. Viral and bacterial arthropod vector-borne infections, namely, WNV, Rift Valley fever phlebovirus, dengue virus, chikungunya virus, and rickettsia have been associated with ocular manifestations. The pathophysiology is almost always hematogenous spread of infection from another part of the body to the highly vascular uvea, with a breach in the blood–eye barrier.8 West Nile virus is closely related to JEV and is associated with common ocular manifestations including chorioretinitis, retinal hemorrhages, and vitritis.9 Typical bilateral or rarely unilateral multifocal chorioretinitis is the most common ocular manifestation of WNV associated in almost 80% of patients with acute WNV-associated neurological illness.10 Most patients have no ocular symptoms or present with mildly reduced vision or floaters.
For most travelers who travel to Asia, the risk of JE is very low but varies based on destination, length of travel, season, and activities.2 Japanese encephalitis vaccine is recommended for travelers who plan to spend 1 month or more in endemic areas during JEV transmission season. It should also be considered for shorter term travelers traveling during the wet season, if there is considerable outdoor activity or the accommodation is not mosquito-proof.11
Indonesia is a popular tourist destination for Australians and others, in particular Bali, where JEV is endemic. Although JE is uncommon in returned travelers,12 its high mortality rate and serious permanent neurologic sequelae should prompt consideration for JE immunization. With newer, safer, single-dose vaccines, JEV prevention and vaccination should be part of pretravel counseling.
Acknowledgment:
We would like to thank Linda Santamaria for feedback received.
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