Viral encephalitis in travellers
ABSTRACT
Viral infections are the commonest cause of encephalitis, and the purpose of this article is to inform UK clinicians of the presentation, diagnosis and management of viral encephalitis in travellers returning to the UK. The classical presentation is as a triad of fever, headache and altered mental state. There may be other findings either on examination or on imaging which, together with a travel history, may give clues as to the aetiology. It is important to note that in high- and middle-income countries the commonest cause of viral encephalitis is herpes simplex. This, coupled with the fact that untreated herpes simplex encephalitis (HSE) has a mortality of over 70%, means that aciclovir should always be included in the treatment of patients with suspected encephalitis, regardless of their history of travel. In the UK, the Rare and Imported Pathogens Laboratory (RIPL) at Public Health England can perform specific polymerase chain reaction (PCR) analyses on blood and CSF samples for many imported causes of viral encephalitis.
Key points
Herpes simplex encephalitis is the commonest cause of viral encephalitis in high- and middle-income countries and must always be included in the differential diagnosis.
Treatment in cases of suspected viral encephalitis should include prompt administration of aciclovir 10 mg/kg three times daily intravenously.
A thorough travel history in the returning traveller will give clues as to the causative agent in cases of arboviral encephalitis.
The Rare and Imported Pathogens Laboratory at Public Health England can perform specific PCR analyses on blood and CSF samples for most recognised causes of imported viral encephalitis.
Presentation of viral encephalitis in immunocompromised individuals may be atypical or subacute, and the differential diagnosis should be broadened to include other infectious causes.
Epidemiology
It should be noted that the commonest viral causes of encephalitis in the UK are unrelated to travel: herpes simplex viruses (HSV) 1 and 2, varicella-zoster virus (VZV), enteroviruses and (in the unvaccinated) mumps and measles. HSV encephalitis (HSE) is the most frequently diagnosed encephalitis in high- and middle-income countries, and the annual incidence of HSE in the general UK population is 0.2–0.4/100,000.1 The vast majority of HSE is due to HSV-1. A recent multicentre, population-based prospective study, recruiting patients with encephalitis over a period of 2 years from 24 hospitals in London, the south-west and north-west of England, found that HSV was the infectious agent in 19% of cases. The majority of cases were in children and young adults, with 50% of all cases of HSE occurring in children younger than 5, and 80% of cases occurring in patients under the age of 64.2
In the industrialised world, enteroviruses are a major cause of aseptic meningitis and sporadic cases of hand, foot and mouth (HFM) disease. However, enterovirus 71 has caused a number of large outbreaks of HFM in South-East Asia, with a small proportion of young children developing a severe brainstem encephalitis.3 In travellers, arthropod-borne encephalitis viruses (arboviruses) are important causative agents in those returning from endemic areas. These viruses are transmitted to human beings by the bites of arthropods (particularly mosquitos and ticks) and are a leading cause of encephalitis globally. Arboviruses, such as West Nile virus and Japanese encephalitis virus, have spread to new areas, and West Nile virus has caused outbreaks in the Americas and southern Europe.4 Tick-borne encephalitis (TBE) virus is endemic in a large geographical area spanning from northern China and Japan through far-eastern Russia and into Europe, and causes thousands of cases of TBE per year in Europe alone.5 Outbreaks of chikungunya virus have been reported in several African countries, the Indian subcontinent and South-East Asia,6 and an outbreak was recently reported in Italy.7 Whilst rare, neurological complications from this infection have been reported.8
Clinical presentation
Viral encephalitis classically presents with a flu-like prodrome, which develops into an illness with fever, severe headache and altered mental status. Additional features include vomiting, motor or sensory deficits, and speech and movement disorders. While the clinical syndrome of meningitis and encephalitis can overlap, it is important to note that the presence or absence of normal brain function is the main distinguishing factor and has important therapeutic and prognostic implications. Viral meningitis requires no treatment and outcomes are invariably good, but physicians must be careful to exclude even minor degrees of cognitive impairment which may indicate incipient encephalitis and the requirement for antiviral (aciclovir) therapy.
In addition to enquiring about symptoms, a thorough travel history and vaccination history are essential, in particular for suggesting arboviruses as the causative agent (see Table 1). This information may need to be obtained from relatives if the patient is confused or obtunded. Unvaccinated individuals are at higher risk of acquiring infections, such as measles or mumps, in countries with ongoing outbreaks. A history of a rash, in the patient or a household member, may give clues as to the aetiology in cases of measles or VZV. It should be noted that a history of recurrent labial or genital herpes simplex infection occurs no more commonly in patients with HSE than controls.9 Reports of noting strange smells may indicate olfactory hallucinations from frontotemporal involvement in HSE.4 Symptoms of parotitis, testicular pain or abdominal pain from pancreatitis may be suggestive of mumps virus as the causative agent. A history of an animal bite in a rabies endemic country points to rabies virus as a possible cause.
Examination
Physical examination may be normal apart from fever and altered mental status. Neurological signs may include drowsiness, paraesthesias, flaccid paralysis, hemiparesis and convulsions. Arboviral infections may be associated with a maculopapular rash. HSV and VZV encephalitis may be associated with the typical cutaneous vesicular eruptions, and genital examination may reveal characteristic blisters or ulcers of HSV. Seizure activity may be subtle and should be carefully looked for, and flaccid paralysis indicates spinal cord involvement. West Nile virus encephalitis and Japanese encephalitis may be associated with tremors, abnormal movements and muscle weakness.10 Lower cranial neuropathies and myoclonus are suggestive of a rhomboencephalitis or basal meningoencephalitis, which is seen with some enteroviruses; a radiculitis in association with encephalitis can be seen with cytomegalovirus (CMV) and Epstein–Barr virus, and deafness has been described with mumps virus.4 A biphasic illness with features of myelitis or spinal paralysis may be seen in cases of tick-borne encephalitis.11
Physical examination may also reveal evidence of compromised immunity, such as seborrheic dermatitis, oral hairy leukoplakia, oral candidiasis or skin lesions of Kaposi's sarcoma in patients with undiagnosed or untreated HIV infection. Patients with impaired immunity due to HIV, solid-organ transplants or chemotherapy may have an atypical or subacute presentation of encephalitis. The differential diagnosis for infective encephalitis in these individuals should be broadened to include HIV infection itself, as well as rarer causes such as mycobacterial, fungal or protozoan infections.
Investigations
Brain imaging and cerebrospinal fluid (CSF) examination are key to diagnosis. CSF examination typically shows macroscopically clear fluid, with increased white cells (majority lymphocytes), normal glucose and a normal-high protein. Samples should be sent to virology for polymerase chain reaction (PCR) detection of herpes viruses, and to reference laboratories for identification of rarer pathogens, as discussed later in the article. While computer tomography (CT) brain scan may show gross abnormalities, such as haemorrhage, it is insensitive and may be completely normal in cases of viral encephalitis. Magnetic resonance imaging (MRI) is more sensitive, showing high signal intensities in affected areas of brain, but may also be normal if performed early in the illness. MRI findings in HSE classically show temporal lobe T2 hyperintensity which spares the basal ganglia, whereas findings in Japanese encephalitis show lesions in the thalami, substantia nigra, basal ganglia, cerebral cortex, cerebellum, brain stem and white matter.12 Encephalitis due to enterovirus 71 is associated with relatively characteristic MRI findings of hyperintensity in the posterior portion of the brainstem on T2-weighted and FLAIR images.13 An electroencephalogram (EEG) will typically show non-specific diffuse high amplitude waves consistent with encephalopathy, but may also show subtle epileptic seizure activity.
Diagnosis
Diagnosis of viral encephalitis relies on detection of the virus in the CSF, most commonly by PCR, in addition to a compatible history and examination. Many UK laboratories now have facilities for performing viral PCR, and can refer on to other centres if they do not have this in house. For rarer causes of encephalitis, such as arboviruses, the Rare and Imported Pathogens Laboratory at Public Health England can perform serology testing and specific PCR analyses on blood and CSF samples (see Table 2). In cases of HSE, CSF samples should be positive for HSV DNA in the first week of illness in approximately 95% of cases, and false negatives most commonly occur within the first 1–2 days of illness or 10–14 days after onset.15
If the cause of encephalitis remains elusive, revisit the history, re-examine the patient and repeat the lumbar puncture; and consider rare causes of meningoencephalitis or conditions with similar symptoms and signs (see Table 3). And remember, all patients with an unexplained neurological illness require an HIV test.
Treatment
Aciclovir is a nucleoside analogue which is highly effective against HSV and some other herpes viruses, including VZV. Because untreated HSE has a reported mortality of over 70%, the empirical treatment of suspected viral encephalitis should always include aciclovir. Treatment with aciclovir substantially reduces mortality to closer to 20%, but nearly two-thirds of patients who survive will still do so with significant neurological sequelae.16 Outcome is closely related to the timeliness of starting treatment, so it is imperative that aciclovir is started as early in the illness as possible. It should be administered intravenously at a dose of 10 mg/kg three times daily for a duration of 14–21 days, as shorter durations of therapy have been shown to be associated with subsequent relapse of HSE.17 Because of the small risk of false-negative results in PCR testing for HSV DNA in the CSF mentioned earlier, aciclovir should be continued pending a repeat CSF examination in 2–3 days if there is a strong suspicion of HSE.
Treatment for other causes of viral encephalitis is mainly supportive. Ganciclovir, foscarnet and cidofovir have been used to treat severe CMV and human herpes virus (HHV)-6 infections, and interferon alpha has been used to treat West Nile virus and other flavivirus infections.4 However, a randomised double-blind placebo-controlled trial published in 2003 showed that interferon alpha is not effective in Japanese encephalitis.18 Infection with rabies virus is nearly always fatal, and all possible cases should be discussed with one of the consultants at the Virus Reference Department at Public Health England, Colindale (contact details available at www.hpa.org.uk).
Prevention
Prevention of viral encephalitis relies mainly on avoidance of the vector through appropriate protective clothing and application of mosquito repellent. Vaccines are available for Japanese encephalitis, tick-borne encephalitis and rabies, and travellers to endemic regions should be encouraged to be vaccinated where appropriate.
- © 2015 Royal College of Physicians
References
- 1.↵
- 2.↵
- 3.↵
- 4.↵
- Solomon T,
- Hart IJ,
- Beeching NJ
- 5.↵
- Mansfield KL,
- Johnson N,
- Phipps LP,
- et al
- 6.↵
- 7.↵
- 8.↵
- Staples JE,
- Breiman RF,
- Powers AM
- 9.↵
- 10.↵
- 11.↵
- 12.↵
- Handique SK,
- Das RR,
- Barman K,
- et al
- 13.↵
- 14.↵
- Public Health England
- 15.↵
- 16.↵
- 17.↵
- Kimura H,
- Aso K,
- Kuzushima K,
- et al
- 18.↵
Article Tools
Citation Manager Formats
Jump to section
Related Articles
- No related articles found.
Cited By...
- No citing articles found.