Which trial do we need? Mannitol therapy in hospitalized adult patients with tick-borne encephalitis and brain oedema: a double-blind placebo-controlled multicentre randomized trial

Tick-borne encephalitis (TBE) is an infection of the central nervous system (CNS) caused by TBE virus (TBEV) [ [1] Mickiené A. Laiškonis A. Günther G. Vene S. Å Lundkvist Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: disease severity and long-term prognosis. Clin Infect Dis. 2002; 35: 650-658https://doi.org/10.1086/342059 Crossref PubMed Scopus (184) Google Scholar , [2] Ruzek D. Avšič Županc T. Borde J. Chrdle A. Eyer L. Karganova G. et al. Tick-borne encephalitis in Europe and Russia: review of pathogenesis, clinical features, therapy, and vaccines. Antivir Res. 2019; 164: 23-51https://doi.org/10.1016/j.antiviral.2019.01.014 Crossref PubMed Scopus (190) Google Scholar ]. In 2020, there were 3734 confirmed cases of TBE in Europe (Russian Federation excluded) and Slovenia had one of the highest incidence rates with 8.9 confirmed TBE cases per 100 000 population [ [3] ECDCTick-borne encephalitis: annual epidemiological report for 2020. 2020 Google Scholar ]. The virus is transmitted to humans principally through tick bites. There are three known subtypes of TBEV: European (EU-TBEV), Siberian and Far Eastern. Of all three subtypes, EU-TBEV causes the mildest disease [ [1] Mickiené A. Laiškonis A. Günther G. Vene S. Å Lundkvist Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: disease severity and long-term prognosis. Clin Infect Dis. 2002; 35: 650-658https://doi.org/10.1086/342059 Crossref PubMed Scopus (184) Google Scholar , [2] Ruzek D. Avšič Županc T. Borde J. Chrdle A. Eyer L. Karganova G. et al. Tick-borne encephalitis in Europe and Russia: review of pathogenesis, clinical features, therapy, and vaccines. Antivir Res. 2019; 164: 23-51https://doi.org/10.1016/j.antiviral.2019.01.014 Crossref PubMed Scopus (190) Google Scholar ]. The majority of infections caused by EU-TBEV are asymptomatic (70%–90%). Among symptomatic cases, approximately 40%–50% develop meningitis, 50% meningoencephalitis and 10% meningoencephalomyelitis [ [4] Kaiser R. Tick-borne encephalitis. Infect Dis Clin North Am. 2008; 22: 561-575https://doi.org/10.1016/j.idc.2008.03.013 Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar ]. The case-fatality rate in EU-TBE ranges from 0.5% to 2%, whereas 30%‒46% of patients report incomplete recovery (residual neurological deficit) manifesting as residual symptoms/signs such as headache, memory and concentration disorders, fatigue, emotional lability, coordination disorders, tremor, hearing loss/tinnitus, and flaccid paresis [1,5‒7]. These symptoms/signs decline over time and their frequency stabilizes 12 months after the acute illness [ [7] Bogovič P. Stupica D. Rojko T. Lotrič-Furlan S. Avšič-Županc T. Kastrin A. et al. The long-term outcome of tick-borne encephalitis in Central Europe. Ticks Tick Borne Dis. 2018; 9: 369-378https://doi.org/10.1016/j.ttbdis.2017.12.001 Crossref PubMed Scopus (38) Google Scholar ].