**8. Factors influencing clinical course of acute disease and/or long‐term outcome**

## **8.1. Subtype of TBEV**

Subtype of TBEV influences the course of acute TBE as well as its long‐term outcome. The disease caused by the European TBEV subtype usually has a biphasic course, around 10% of adult patients have a severe neurologic deficit, case‐fatality rate is <2% [12, 32]. According to a prospective study the abortive form of TBE is rare—the initial phase most of the time move on to the second phase of the disease [51]. Long‐lasting sequelae are identified in up to 50% of adult patients [103]. The disease is less severe and has a better outcome in children than in adults [34, 50, 104, 105].

Symptomatic infections with Far Eastern TBEV subtype often cause an illness with a gradual onset, more severe course, higher rates of severe neurologic sequelae, and a fatality rate of 20–40%; the severity and outcome in adults and children are similar. Limited information about the clinical course of the disease is available for Siberian TBEV subtype. The case-fatality rate is 2–3%; some reports from Russia suggest an association with a chronic progressive form of TBE [1, 11].

## **8.2. Age of patients**

Published data suggest the relationship between age of patients and the severity of TBE and its outcome — the severity of acute illness and the proportion of patients with unfavorable outcome increase with age [33, 47, 50, 106].

The disease caused by European subtype of TBEV generally has a milder course and better outcome in children than in adults. The predominant form of TBE in children and adolescents is meningitis. A summary of 8 studies on 1169 children with TBE showed that meningitis was present in 802 (69%), meningoencephalitis in 356 (30%), and meningoencephalomyelitis in 11 (1%) patients. A total of 20 out of 945 patients (2.1%) had long‐term neurologic sequelae [34]. In contrary to children, in adults, and especially in elderly patients with TBE caused by European subtype of TBEV, the most frequent presentation is meningoencephalitis [33, 47].

Furthermore, fatality rate, the ratio of patients who develop pareses, and the frequency of postencephalic syndrome is also parallel with the increasing age [33, 47, 106].

#### **8.3. Other factors associated with severe acute disease**

Some clinical studies have shown that TBE with monophasic presentation is associated with a more severe course of the acute disease [42, 107–111].

Concomitant TBE and Lyme neuroborreliosis may occur with a more severe clinical course [59, 112, 113].

#### **8.4. Severity of acute illness and other risk factors for unfavorable outcome**

The outcome of TBE is associated with clinical presentation. The risk of incomplete recovery is higher for patients who have more severe clinical illness during acute phase of TBE [45, 47].

Other identified risk factors found to be associated with unfavorable outcome are CSF cell count > 300 cells/μL, impaired blood‐brain barrier (total protein >600 mg/L) and abnormal findings on MRI [46].
