Tick-borne encephalitis (TBE) is caused by a neuro-tropic flavivirus which causes isolated meningitis or meningitis accompanied by encephalitis and/or myelitis. The western subtype of virus occurs in scattered microenvironments throughout central, northern, and eastern Europe. It is transmitted to humans by the hard tick, Ixodes ricinus during the spring, summer, and fall seasons.1,2 TBE in children is thought to be less severe than in adults.1–5 The numerous studies in adults have included few if any children.2,3,5 Two large retrospective studies in children consisted of children admitted to a regional hospital in Celje, Slovenia4 and very ill patients admitted to a referral hospital in Ljubljana, Slovenia.6 To date there has been only one population-based pediatric study; it compared the incidence of TBE in a highly endemic region of Austria with the incidence in a highly endemic country, Slovenia.7 That study did not report clinical characteristics or follow-up.
We report the incidence, epidemiologic characteristics, clinical severity, and middle-term outcome of TBE in children less than 16 years of age in Switzerland during the 5-year period of 2000–2004. This is the first prospective study encompassing all children with the diagnosis of TBE in a whole country.
MATERIALS AND METHODS
Between January 2000 and December 2004 all cases of TBE occurring in Swiss children less than 16 years of age were assessed. Cases were accrued through existing nationwide mandatory laboratory notification of positive TBE serology (detectable IgM antibodies, IgG sero-conversion or a 4-fold rise in serum IgG antibodies, name of the antibody test and manufacturer not reported). During the initial 3 years of the study cases were also simultaneously accumulated through a nationwide pediatric surveillance system. As the nationwide pediatric surveillance system missed 5, 1, and 3 cases, respectively, during these 3 years, and proved to be cumbersome, it was abandoned. Only 1 case of TBE was discovered to have been missed by the nationwide mandatory laboratory notification system during the first 3 years (it was reported by the pediatric surveillance system).
A case of TBE was defined as the presence of neurologic (eg, headache, vomiting, neck stiffness, altered state of consciousness, seizures) and/or flu-like symptoms, cerebrolspinal fluid (CSF) pleocytosis (more than 10 leukocytes per milliliter), and positive serology in blood or CSF (elevated IgM antibodies or IgG sero-conversion or at least a 4-fold increase in titer 2 or more weeks after the initial sample). Lumbar puncture was required for case inclusion. It is common practice in Switzerland to test for antibodies to TBE in serum and/or CSF when a child presents with suggestive clinical signs during the spring, summer, or fall. However, there are no national guidelines. Results of diagnostic tests for Borrelia burgdorferi were requested in the questionnaire; however testing for Borrelia was not obligatory.
All cases thus identified were further evaluated by means of a questionnaire sent to the hospital and filled out by the responsible house officer. Cases classified as having moderate or severe residual findings at hospital discharge were further assessed by means of a second questionnaire sent to the responsible family doctor or pediatrician 6–12 months after the acute illness. Case reporting was anonymous.
Population figures for each age group for the whole of Switzerland were used to calculate incidences reported in this study.
Clinical severity of the acute hospital course was evaluated on the basis of whether the patient had meningitis, meningoencephalitis (ME), or meningoencephalomyelitis (MEM). Patients were categorized as having meningitis when signs were limited to fever, stiff neck, and CSF pleocytosis; ME when in addition, an altered state of consciousness, ataxia, focal neurologic signs, or abnormal findings on electroencephalogram were present; or MEM when in addition to any of the above findings, flaccid paresis or paralysis of one or more limbs occurred.3
Residual findings at hospital discharge were categorized as minor, consisting of headache, fatigue, weakness, and/or diminished concentrating ability; moderate, consisting of ataxia, hyper-reflexia, papilledema, and/or abnormal electroencephalogram; or severe, consisting of severe cognitive impairment, intractable seizures, and/or limb paresis or paralysis.
In total, 92 notifications of patients less than 16 years of age were made to the Swiss Federal Office of Public Health. Thirty-seven patients did not fulfill the study case definition for the following reasons: lumbar puncture not performed (16), lumbar puncture not reported (2), patient not hospitalized and therefore assumed not to have had a lumbar puncture (15), lack of positive IgM and lack of 4-fold increase in IgG titer (3), ME occurred while abroad on vacation (1).
The case definition of TBE was fulfilled in 55 children (69% male, 31% female). The median age was 9 years with a range of 6 weeks to 15 years. Tick exposure occurred in the area of residence in 23 cases, while visiting another endemic area in 1 case, and possibly while visiting a foreign country in 1 case. In 8 cases a tick bite was not recalled, and in 22 cases not explicitly stated. Previous vaccination against TBE (complete immunization consists of 3 doses) had been performed in 4 cases (number of doses: 2 × 1, 2 × 2), not performed in 44 cases, and not explicitly stated in 7 cases.
The incidence of TBE in Swiss children was 0.4/105/yr in children less than 6 years old and 1.1/105/yr in children 6–15 years of age. Clinical characteristics are presented in the Table 1. Isolated meningitis occurred in 67%, ME in 29%, and MEM in 4% of children. Severe neurologic residua were present in one 9-year-old patient at follow-up at 6–12 months.
The results of serologic diagnostic tests for B. burgdorferi in serum were positive in 4 patients, negative in 29 patients, and not performed or not reported in 22 patients. CSF serology for B. burgdorferi was negative in all 4 patients with positive serum serology. The hospital course of these 4 patients was severe in 1 case (MEM), moderate in 1 case (ME), and mild in 2 cases (meningitis). Only one of these patients (MEM) had permanent neurologic residua at 12 months. This patient had been treated with intravenous ceftriaxone for 2 weeks during the initial hospitalization.
The aim of this study was to evaluate cases of TBE-virus infection with central nervous system involvement, as verified by pleocytosis in the CSF. Our results show that the incidence of TBE in Swiss children 6–15 years old is similar to the incidence in Swiss adults (1.0/105/yr).8 TBE is rare in Swiss children younger than 6 years of age. It is not clear if this is because of reduced exposure to ticks or reduced risk of developing central nervous system disease after exposure. According to rough estimates, only approximately one third of the total Swiss population lives in endemic regions (Swiss Federal Office of Public Health). True incidences for all age groups are therefore likely to be 2–4 times higher than reported in this study.
The acute phase of TBE in children is less severe than in adults as manifested by a higher percentage of the mildest form, meningitis (67%), and lower percentages of ME (29%) and MEM (4%) compared with the distribution of clinical severity reported in Swiss adults: meningitis 27%, ME 65%, MEM 8%.8 Even in our patients with moderate to severe hospital courses (16 ME, 2 MEM), moderate to severe clinical signs persisted in only 5 children at the time of hospital discharge.
Severity of the initial illness, as reflected by the relative frequency of meningitis, ME or MEM, does not seem to correlate consistently with increasing age and, especially in infants, is not necessarily predictive of later outcome. Although the 6-week-old infant in our study was severely ill during the acute illness, the patient recovered completely at 10 months of age. There have been reports of very severe acute courses in a total of 3 infants in the literature: a 3-month-old infant,9 the 6-week-old infant included in this study,10 and a 17-day-old neonate11 all had protracted convulsions and altered level of consciousness. Follow-up at 1 year of age was normal in 2 infants,9,10 but the 17-day-old neonate remained severely neurologically impaired at 1 year of age (Jones N, personal communication).
Our results are consistent with other studies, which have found no, or only exceedingly rare, permanent sequelae,3,4,6,7,12 or death13,14 in children. The presence of limb paresis/paralysis at follow-up reported in the literature is 2.3–10.5% (average 4.8%) in adults12,15–18 compared with 0–1.8% (average 0.5%) in children.3,4,6,7,12 Thus, permanent residua occur in children approximately 10 times less frequently than in adults. Although rare, permanent neurologic sequelae can be devastating, as was the case in our 9-year-old patient, who became severely mentally and physically handicapped.
As serologic tests for B. burgdorferi in serum and CSF were not consistently carried out in our collective, we consider our results concerning B. burgdorferi to be inconclusive.
Since the early 1990s there has been a steady increase of TBE in Switzerland affecting mainly adults.8 As a result, Swiss vaccination policy was amended in March 2006; the new recommendations advise vaccinating adults and children 6 years of age and older who live in or visit endemic areas.19 Previously vaccination had only been recommended for those living in endemic areas for whom an increased risk of exposure was also present (eg, foresters, mushroom gatherers, orientation runners). Children were not specifically mentioned. Currently vaccination of children less than 6 years of age living in endemic areas is not generally recommended.19 We recommend considering vaccinating children less than 6 years of age if there is an increased risk of exposure such as frequent forest excursions or frequent tick bites; in these cases the decision should be made on an individual basis taking into account the local epidemiologic situation and personal behavior. The results of our study substantiate the rational for the Swiss vaccination policy.
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