Table 5.

Emerging Issues in Encephalitis (Selected Agents)

Agent	Challenge	Recent Progress	Recommendations/Future Directions
Arboviruses
	Epidemiology: Re-emergence/ resurgence (WNV); Expansion of geographic range (JEV, LACV);	Use of spatial and temporal statistics to impute etiologiesa	Enhanced surveillance, data mining, and utilization of a wider panel of arbovirus diagnostic assays
	Epidemiology: Under-recognition of arboviruses as agents of neurologic disease	Increased awareness among physicians to include a variety of arboviruses in differential diagnosis	Ongoing research to better understand arbovirus pathogenesis, ecology, and the factors contributing to emergence, activity, and outbreaks
	Prevention: Vaccines unavailable for many arboviruses	Some success with vaccination against JEV and TBEV	Improved public health messaging regarding personal preventative measures to decrease risk for exposure; increased use of JEV vaccine for prevention in children in risk areas
		Four WNV vaccines currently in human trialsb	Further development of a vaccine for WNV targeted at vulnerable populations
		Tetravalent dengue vaccine showed modest efficacy; large scale studies are in progressc	Further development and validation of dengue vaccine to induce long-term protective immunity against all 4 dengue serotypes simultaneously
	Treatment: Lack of specific therapeutics	Advances in the study of pathogenesis and informed drug design, with several candidate therapeutic platforms being evaluatedd,e	More effective bridging of in vitro and animal studies with translational research/clinical trials
Rabies (Lyssavirus)	Epidemiology: Need for enhanced surveillance	Recognition of “milder” forms of disease and broader understanding as a continuum	Wider inclusion in the differential diagnosis of encephalitis even without a history of animal exposure
	Prevention: Optimization of prevention programs	Experimentation with abbreviated and lower-dose vaccination schedules to lower cost and improve accessibilityf	Improved animal control and more widespread vaccination programs towards human rabies prevention and canine rabies elimination
	Treatment: Lack of specific therapeutics	“Milwaukee protocol” reported to show some promise, though subsequent reports inconclusiveg	Evaluation of inhibitors of RNA replication, neuroprotectants and better understanding of pathogenesis
Free living amoebae	Epidemiology: Relatively few cases and low level surveillance impedes our understanding of disease	Recognition of nasal irrigation for medical or religious purposes as a risk factor for PAMh	Serosurveys to define prevalence of disease; more widespread environmental testing to delineate reservoirs of disease
	Diagnosis: Limited recognition and availability of diagnostic testing	Consistent case definitions agreed upon by CDC and Council of State and Territorial Epidemiologists (CSTE)	More rapid diagnostics are critical given short therapeutic window
	Treatment: Lack of widely available and robust treatments	Miltefosine treatment for GAEi; Corifungin for FLA in vitroj	Further evaluation of miltefosine, corifungin, and other agents in humans

Abbreviations: CDC, Centers for Disease Control and Prevention; FLA, free living amoebae; GAE, granulomatous amoebic encephalitis; JEV, Japanese encephalitis virus; LACV, La Crosse Virus; PAM, primary amoebic meningoencephalitis; TBEV, Tick-borne encephalitis virus; WNV, West Nile virus.

^a Kulkarni et al., Epidemiology and Infection 2012 (epub ahead of print).

^b De Filette et al., Vet Res 2012; 43:16.

^c Sabchareon et al. Lancet 2012; 380:1559–67.

^d Lee et al., J Gen Virol 2012; 93:20–26.

^e Suthar et al., Nat Rev Microbiol 2013; 11:115–28.

^f Wieten et al., Clin Infect Dis 2013; 414–19.

^g Jackson AC, Antiviral Res 2013 (epub ahead of print).

^h Yoder et al. Clin Infect Dis 2012; 55:e79–85.

ⁱ Kim et al., Antimicrob Agents Chemother 2008; 52:4010–16.

^j Debnath et al. Antimicrob Agents Chemother 2012; 56:5450–57.