Barbro Hedin Skogman

Lyme Neuroborreliosis in Children - a Prospective Study of Clinical features, Prognosis, and Outcome

Background: Evaluation of children with clinically suspected neuroborreliosis (NB) is difficult. With a prospective study design we wanted to characterize children with signs and symptoms indicative for NB, investigate clinical outcome and, if possible, identify factors of importance for recovery. Material/Methods: Children being evaluated for NB (n = 177) in southeast Sweden were categorized into 3 groups: “confirmed neuroborreliosis” (41%) with Borrelia antibodies in the cerebrospinal fluid, “possible neuroborreliosis” (26%) with pleocytosis but no Borrelia antibodies in the cerebrospinal fluid, and “not determined” (33%) with no pleocytosis and no Borrelia antibodies in the cerebrospinal fluid. Antibiotic treatment was given to 69% of children. Patients were followed during 6 months and compared with a matched control group (n = 174). Results: Clinical recovery at the 6-month follow-up (n = 177) was generally good and no patient was found to have recurrent or progressive neurologic symptoms. However, persistent facial nerve palsy caused dysfunctional and cosmetic problems in 11% of patients. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls. Influence on daily life was reported to the same extent in patients and controls. Consequently, persistent headache and fatigue at follow-up should not be considered as attributable to NB. No prognostic factors could be identified. Conclusions: Clinical recovery was satisfactory in children being evaluated for NB although persistent symptoms from facial nerve palsy occurred. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls.

Long-term Clinical Outcome After Lyme Neuroborreliosis in Childhood

OBJECTIVES: To determine long-term clinical outcome in children with confirmed Lyme neuroborreliosis (LNB) and to evaluate persistent subjective symptoms compared with a control group. METHODS: After a median of 5 years, 84 children with confirmed LNB underwent a neurologic re-examination, including a questionnaire. Medical records were analyzed, and a control group (n = 84) was included. RESULTS: The total recovery rate was 73% (n = 61). Objective neurologic findings, defined as “definite sequelae,” were found in 16 patients (19%). The majority of these children had persistent facial nerve palsy (n = 11), but other motor or sensory deficits occurred (n = 5). Neurologic signs and/or symptoms defined as “possible sequelae” were found in another 7 patients (8%), mainly of sensory character. Nonspecific subjective symptoms were reported by 35 patients (42%) and 32 controls (38%) (nonsignificant). Affected daily activities or school performance were reported to the same extent in both groups (23% vs 20%, nonsignificant). CONCLUSIONS: The long-term clinical recovery rate was 73% in children with confirmed LNB. Persistent facial nerve palsy occurred in 13%, whereas other motor or sensory deficits were found in another 14%. Neurologic deficits did not affect daily activities or school performance more often among patients than controls and should be considered as mild. Furthermore, nonspecific subjective symptoms such as headache, fatigue, or memory or concentration problems were reported as often among patients as controls and should not be considered as sequelae after LNB.

Seroprevalence of Borrelia IgG antibodies among young Swedish children in relation to reported tick bites, symptoms and previous treatment for Lyme borreliosis: a population-based survey

Background Lyme borreliosis (LB) is the most common tickborne infection in Sweden and the seroprevalence of Borrelia immunoglobulin G (IgG) antibodies varies between 2% and 26%. The seroprevalence in young Swedish children is unknown and the relation to clinical data has not been previously studied. Objective To determine the seroprevalence of Borrelia IgG antibodies in serum of young Swedish children and to relate it to gender, geographical location, reported tick bites, symptoms and previous treatment for LB. Methods 2000 healthy 5-year-old children (n=2000) were randomly selected from among participants of a larger prospective population-based study, the ABIS (All Babies in Southeast Sweden) study. Serum samples were collected and a Borrelia specific ELISA test (Dako) were performed for IgG antibody detection. Clinical data were collected from questionnaires completed by the parents. Results The seroprevalence of Borrelia IgG antibodies was 3.2% (64/2000). Previous tick bite had been noted in 66% of these seropositive children but the majority (94%) had not previously been treated for LB. In addition, another 55 children reported a history of LB but were negative to Borrelia IgG antibodies in serum. Many of these seronegative children had received treatment for erythema migrans (n=24), which is a clinical diagnosis. Whether children were correctly treated or overtreated for LB is however unknown. No differences in gender, geographical location or reported tick bites were found when comparing Borrelia-seropositive children (n=64) and seronegative children with previous LB (n=55). Conclusion This population-based study demonstrates a Borrelia IgG antibody seroprevalence of 3.2% in young Swedish children. Very few of these seropositive children report previous symptoms or treatment for LB. Thus the findings suggest that exposure to the Borrelia spirochaete (with subsequent antibody response in serum) does occur in young children, mostly without giving rise to clinical LB. Future studies on cell-mediated immune responses are needed to investigate explanatory immunological mechanisms.

Improved Laboratory Diagnostics of Lyme Neuroborreliosis in Children by Detection of Antibodies to New Antigens in Cerebrospinal Fluid

Background: Laboratory diagnostics in Lyme neuroborreliosis need improvement. We hereby investigate 4 new recombinant or peptide Borrelia antigens in cerebrospinal fluid in children with neuroborreliosis to evaluate their performance as diagnostic antigens. Methods: An enzyme-linked immunosorbent assay was used to detect IgG antibodies to recombinant decorin binding protein A (DbpA), BBK32, outer surface protein C (OspC), and the invariable region 6 peptide (IR6). The recombinant antigens originated from 3 pathogenic subspecies; Borrelia afzelii, Borrelia garinii, and Borrelia burgdorferi sensu stricto. Cerebrospinal fluid and serum from children with clinical features indicative for neuroborreliosis (n = 57) were analyzed. Classification of patients was based on clinical symptoms and laboratory findings. Controls were children with other neurologic diseases (n = 20) and adult patients with no proven infection (n = 16). Results: Sensitivity for DbpA was 82%, for BBK32 70%, for OspC 58% and for IR6 70%. Specificities were 94%, 100%, 97%, and 97%, respectively. No single antigen was superior. When new antigens were combined in a panel, sensitivity was 80% and specificity 100%. The reference flagella antigen showed a sensitivity of 60% and a specificity of 100%. Over all, the B. garinii related antigens dominated. Conclusions: Recombinant DbpA and BBK32 as well as the peptide antigen IR6 perform well in laboratory diagnostics of neuroborreliosis in children. New antigens seem to improve diagnostic performance when compared with the routine flagella antigen. If different antigens are combined in a panel to cover the antigenic diversity, sensitivity improves further and a specificity of 100% can be achieve.

Adaptive and Innate Immune Responsiveness to Borrelia burgdorferi sensu lato in Exposed Asymptomatic Children and Children with Previous Clinical Lyme Borreliosis

Why some individuals develop clinical manifestations in Lyme borreliosis (LB) while others remain asymptomatic is largely unknown. Therefore, we wanted to investigate adaptive and innate immune responsiveness to Borrelia burgdorferi sensu lato in exposed Borrelia-antibody-positive asymptomatic children (n = 20), children with previous clinical LB (n = 24), and controls (n = 20). Blood samples were analyzed for Borrelia-specific interferon (IFN)-γ, interleukin (IL)-4, and IL-17 secretion by ELISPOT and Borrelia-induced IL-1β, IL-6, IL-10, IL-12(p70), and tumor necrosis factor (TNF) secretion by Luminex. We found no significant differences in cytokine secretion between groups, but a tendency towards an increased spontaneous secretion of IL-6 was found among children with previous clinical LB. In conclusion, the adaptive or innate immune responsiveness to Borrelia burgdorferi sensu lato was similar in Borrelia-exposed asymptomatic children and children with previous clinical LB. Thus, the immunological mechanisms of importance for eradicating the spirochete effectively without developing clinical manifestations of LB remain unknown.

Can ELISPOT Be Applied to A Clinical Setting as A Diagnostic Utility for Neuroborreliosis

The aim of this prospective study was to investigate the diagnostic performance of Borrelia (Bb)-induced interferon (IFN)-γ secretion detected by ELISPOT modified to be feasible for clinical laboratories as a supplementary test to the laboratory diagnosis of Lyme neuroborreliosis (LNB) in an endemic setting. Between 2002 and 2004, patients with symptoms of suspected clinical LNB were included in a study conducted on the Åland islands in the Finnish archipelago, which is a hyper-endemic area for Lyme borreliosis (LB). Fourteen patients with confirmed LNB and 103 patients with non-LNB were included, and the numbers of spontaneous and Bb-induced IFN-γ-secreting cells were assayed by the ELISPOT test. The ELISPOT assay showed a weak diagnostic performance with a sensitivity of 36% and a specificity of 82%. The findings in this study show that this ELISPOT-assay modified to be feasible in clinical routine laboratories is not useful as a supplementary diagnostic tool in the laboratory diagnosis of patients with clinically suspected LNB.

T-cell epitope mapping of the Borrelia garinii outer surface protein A in lyme neuroborreliosis.

We studied the T‐cell reactivity to overlapping peptides of B. garinii OspA, in order to locate possible immunodominant T‐cell epitopes in neuroborreliosis. Cells from cerebrospinal fluid (CSF) and blood from 39 patients with neuroborreliosis and 31 controls were stimulated with 31 overlapping peptides, and interferon‐γ secreting cells were detected by ELISPOT. The peptides OspA17–36, OspA49–68, OspA105–124, OspA137–156, OspA193–212 and OspA233–252 showed the highest frequency of positive responses, being positive in CSF from 38% to 50% of patients with neuroborreliosis. These peptides also elicited higher responses in CSF compared with controls (P = 0.004). CSF cells more often showed positive responses to these peptides than blood cells (P = 0.001), in line with a compartmentalization to the central nervous system. Thus, a set of potential T‐cell epitopes were identified in CSF cells from patients with neuroborreliosis. Further studies may reveal whether these epitopes can be used diagnostically and studies involving HLA interactions may show their possible pathogenetic importance.