Neuroborreliosis in patients hospitalised for Lyme borreliosis in the Czech Republic in 2003 – 2013

Overview

Study objective:
The objective was to analyse and evaluate a cohort of Lyme borreliosis (LB) patients with neuroborreliosis (LNB) hospitalised in the Czech Republic in 2003–2013.

Material and methods:
Data analysed in this study were obtained from the National Register of Hospitalised Patients, which is a nationwide population register maintained at the Institute of Health Information and Statistics of the Czech Republic. Data collection from all departments of bed care establishments are regularly processed every year. Registration of basic hospitalisation diagnoses is performed in accordance with the 10th revision of the International Classification of Diseases (ICD-10). The study cohort consisted of 23,631 patients with clinically and laboratory confirmed LB hospitalised between 2003 and 2013.

Results:
Nervous system involvement, i. e. LNB (ICD-10 codes G00-G99) was recorded in 27.1% (6,392) of LB patients. Hospital admissions for LB exhibited a slight downward trend with year-on-year fluctuations over the study period. In contrast, LNB showed an upward trend with slight year-on-year fluctuations (345–779 cases) (p = 0.003). Overall, 6,392 persons, 3,220 males and 3,172 females, were diagnosed with LNB over the 11-year study period. Some patients presented with multiple concomitant neurological symptoms. Overall, 6,392 hospitalised patients were diagnosed with 8,168 diseases of the nervous system. The most common diagnoses were facial nerve disorders (21.1%), meningitis (18.3%), polyneuropathies (13.6%), encephalitis, myelitis, and encephalomyelitis (11.3%), and nerve root and plexus disorders (4.9%). The average age of male and female patients hospitalised with LNB was 44.4 and 44.7 years, respectively. It varied significantly between the ICD-10 code groups (p < 0.001) from 38.0 to 63.0 years. The relative incidence of LB by five-year age group showed the first peak at the age of 5–9, followed by a considerable drop at the age of 20–24 and then by another higher peak at the age of 55–59 (the hospitalisation rate ratio comparing the peaks in the adults and children was 1.78). For LNB, the second peak shifted to the age of 65 to 74 years and was similar to the peak in children age groups (hospitalisation rate ratio of 0.95). The distribution of hospital admissions for LNB by month of admission showed the highest numbers of admissions in July and September and the lowest numbers of admissions in December and April. The length of hospital stay was significantly higher (mean of 12.4 days and median of 13 days) in LNB patients (p < 0.001) than in other LB patients (mean of 10.3 days and median of 10 days).

Conclusion:
The basic prerequisite for reliable diagnosis of LNB is a multidisciplinary collaboration of highly experienced neurologists, infection disease specialists, and microbiologists. The cohort of 6,392 patients hospitalised for LNB was analysed by gender, length of hospital stay, and month of hospital admission. The study found LNB cases to occur in all age groups. LNB diagnosis performed in accordance with the ICD-10 enables valid comparison between neurological outcomes of LB patients at both the national and international levels.

KEYWORDS:
Lyme borreliosis – neuroborreliosis – nervous system involvement – National Register of Hospitalised Patients – International Classification of Diseases and Related Problems – ICD-10 – medical importance

INTRODUCTION

Lyme borreliosis (LB) is a disease caused by gram-negative spirochetes from the Borrelia burgdorferi sensu lato complex. The following spirochetes have been detected in the Czech Republic (CZ): Borrelia burgdorferi sensu lato (s.l.)/(BBSL), Borrelia afzelii, B. garinii, B. burgdorferi sensu stricto (s.s.), B. bavariense, B. bissettii, B. valaisiana, B. spielmanii, and B. lusitaniae [6].The tick Ixodes ricinus is the most important vector of LB in the Czech Republic.

Borrelia genomospecies have diverse reservoirs and vectors, differ in organotrophy, and cause various clinical symptoms. Their prevalence varies between ecosystems and geographical regions [11, 14]. Serotyping studies of Borrelia isolates from Europe revealed a striking correlation between infection caused by B. garinii and neuroborreliosis. B. garinii is the most common causative agent of neuroborreliosis in Europe [31, 37]. Neurotropism of B. garinii was detected in a study conducted in an LB endemic area in Norway [41]. Birds are the core reservoir of B. garinii and B. valaisiana in the CZ and Slovakia [9, 39]. In Slovenia, B. garinii causes a more severe clinical disease than B. afzelii [38].

In the Czech Republic, the geographical distribution pattern of LB cases does not overlap with those of other tick-borne infections. The differences result from the fact that the animal reservoirs of various infections are diversely distributed in nature. Rodents, birds, and small animals, all contribute to the spread of LB infection [4]. Compared to other infections, e.g. tick-borne encephalitis, active LB focal points occur more often in parks and gardens of urban agglomerations [1, 30, 45]. LB risk in periurban forest areas and the importance of its mapping for public health in France has been pointed out by [42].

The disease involves several phases and variable symptoms. It can be symptom-free or can have severe symptoms culminating in Lyme neuroborreliosis (LNB). Most infections begin with a dermal manifestation, erythema migrans [11, 14, 35]. It is typically a red spot, with a diameter greater than 5 cm, that is paler in the centre. The incubation period is from three to 32 days (exceptionally longer), but it averages 7–10 days. In later stages of the disease, the joints, nerves, heart, brain, and other organs can be affected. The disease can be treated by antibiotics, but symptoms may persist, such as joint pain.

LB can be considered as one of the most common vector-borne diseases. In Europe, approximately 85,000 cases of LB were diagnosed in 2011. The annual total of LB cases in the world might be as many as 255,000 [31]. However, LB incidence varies widely across European countries. In the CZ, it ranged from 27.6/100,000 to 46.1/100,000 population between 2006 and 2015.

The surveillance of LB in the CZ is comprehensive: LB has been a mandatory reportable disease since 1988. The case definition is provided in Ministerial Decree 275 [8]. Reports received from paediatricians, GPs, and hospital physicians at the district level are sent to the regional authorities and to the National Institute of Public Health (NIPH). Reliable LB disease data have been available since the beginning of the nineties of the last century. Data of hospitalised persons are reported additionally by hospital administrations to a separate register.

MATERIAL AND METHODS

Data used in this study were obtained from the National Register of Hospitalised Patients (NRHOSP), which is a nationwide population register that builds on the information system Hospitalisation maintained in the CZ since 1960 by the Institute of Health Information and Statistics founded by the Ministry of Health of the Czech Republic. Data collection from all bed departments of bed care establishments have been regularly processed every year since 1992. Since 1994, registration of basic hospitalisation diagnoses is performed according to the 10^th revision of the International Classification of Diseases and Related Health Problems (ICD-10) [www.who.int/classifications/icd/en/].

The basic diagnosis is recorded and possibly added with up to four other health problems as additional diagnoses [http://www.uzis.cz/en/registers/national-health-registers/nr-hospitalised-patients]. The mid-period population data were obtained from the Czech Statistical Office [https://www.czso.cz/].

The hospitalisation records studied were those of patients diagnosed with LB and classified into the basic diagnosis (A 69.2 Lyme disease, ICD-10). The study patients were those with manifestations involving the nervous system (LNB) with at least one of four additional diagnoses from ICD-10 group G. The remaining patients were classified into the respective ICD-10 groups based on their additional diagnoses.

Laboratory diagnosis consists in the detection of IgM and IgG antibodies against Borrelia in the serum or cerebrospinal fluid and synovial fluid by the enzyme-linked immunosorbent assay (ELISA). In clinically ambiguous cases, the result is confirmed by immunoblot (Western blot) or possibly by culture detection of Borrelia burgdorferi sensu lato from clinical specimens. Another option is non-culture detection of the antigen or borrelial genomic and plasmid nucleic acid (DNA).

The data presented are expressed as absolute frequencies and percentages. Tests for trend were based on Poisson regression model and on linear regression applied to transformed data. The comparison of continuous data between groups was performed using the Mann-Whitney test. To compare percentages of categorical data, the Pearson χ2 test was used. All statistical tests were evaluated as two-sided at a significance level of 0.05. Statistical analysis was performed by the statistical software Stata, release 9.2 (Stata Corp LP, College Station, TX).

RESULTS

In 2003–2013, a total of 23,631 patients diagnosed with LB were recorded in the hospitalisation database of the CZ (Table 1).

In more than a quarter of patients hospitalised with LB (27.5%), LB was reported as the basic disease without additional diagnoses. Additional diagnoses were most often diseases of the nervous system – detected in 27.1% of LB patients. Musculoskeletal and circulatory system disorders were recorded in 12.9% and 10.2% of LB patients, respectively (Table 2). The number of hospital admissions for LB had a slight downward trend in the first years of the monitoring, peaking in 2003 (2385 cases) and being the lowest in 2006 (1943 cases), followed by year-on-year fluctuations approximately at the same level (Figure 1). In general, the trend is non-significant (p = 0.415). However, LNB showed an upward trend (p = 0.003), with the lowest number of cases in 2003 (345 cases) and a peak in 2010 (779 cases). Consequently, the percentage of hospital admissions for LNB was also on the rise (p = 0.001).

Table 3 summarizes LB cases with an additional neurological diagnosis listed under ICD-10 codes G00-G99 by gender. The highest proportion of admissions for LNB was due to inflammatory diseases of the central nervous system, particularly meningitis and encephalitis (35.0 %). Nerve, nerve root, and plexus disorders and polyneuropathies and other disorders were reported in 27.1% and 14.1% of cases, respectively. Over 11 years of the monitoring, LNB occurred in 3,220 males and 3,172 females. Females were less often affected by disorders under ICD-10 codes G50-G59 and G60-G64 and more often diagnosed with those under ICD-10 codes G40-G47 and G35-G37 than males.

Some patients presented with multiple concomitant neurological diagnoses (symptoms). Overall, 6392 hospitalised patients were diagnosed with 8168 diseases of the nervous system (codes G00-G99). Selected diagnoses that accounted for more than 1% of the total of these 8168 diseases are listed in Table 4. The most common diagno-ses were facial nerve disorders (21.1%), meningitis (18.3%), mononeuropathies and polyneuropathies (16.2%), and encephalitis, myelitis, and encephalomyelitis (11.3%).

The average age of male and female patients hospitalised with LNB was 44.4 and 44.7 years, respectively. It varied significantly between ICD-10 code groups (p < 0.001) from 38.0 to 63.0 years (Table 5).

The age distribution of hospital admissions for LB and LNB calculated per 100,000 population and year within 5-year age groups and gender is shown in Table 6.

The highest total rates of hospital admissions for LB and LNB were found in children aged 5–9 (24.3/100,000 and 9.9/100,000, respectively). In adults, LB was most prevalent in age group 55–59 (33.7/100,000), and LNB in 65–74 (9.3/100,000).

The trends of LB curves by age and gender typically have two peaks, with the first peak in both males and females at the age of 5–9 years (24.7/100,000 and 23.9/100,000, respectively), followed by a drop to the lowest incidence in the age group 20–24 years (9.4/100,000 and 11.1/100,000, respectively) and another peak in males of the age group 55–59 years (35.2/100,000) and in females of the age group 50–54 years (36.8/100,000). Nevertheless, high morbidity levels are recorded in a wider age range from 55 to 74 years in males and from 50 to 69 years in females.

Similarly to the incidence of LB, the hospitalisation curves for LNB by age group show the first peak in the age group 5–9 years, but with lower levels (males 10.0/100,000 and females 9.7/100,000). In the following adolescent age groups, the proportion of LNB among LB cases declines rapidly. In the working-age population aged between 20 and 69 years, LNB exhibits an upward trend with age. The percentage increase between neighbouring age categories shows similar patterns in both the LNB group and the LB group without LNB up to the age of 54 years. LNB continues to be on the rise up to the age of 69 years, but the total of LB cases is declining (p = 0.013). The second peak of LNB is thus shifted to higher age groups, to the age of 70–74 years in males (11.1/100,000) and 65–69 years in females (8.7/100 000) .The second LNB peak is less pronounced than that in the total LB cases, particularly in females. While the hospitalisation rate ratio between second and first peak is 1.78 for the total of LB cases, it equals to 0.95 for LNB, which means that the hospitalisation rates for LNB are practically equal for both peaks, while second peak is markedly higher for the total of LB cases (p < 0.001) (Figures 2 and 3).

The age distribution of selected neurological disorders (LNB) in hospitalised LB patients in 2003–2013 is shown in Figure 4. In children, facial nerve disorders and meningitis were most often diagnosed at the age of 5–9 years (4.8/100,000 and 3.0/100,000, respectively). The same holds for encephalitis and myelitis but in less extend (0.8/100,000). Polyneuropathies and nerve root and plexus disorders were almost never reported in child-hood. In adults, the most common conditions were encephalitis and myelitis at the age of 50–59 (1.6/100,000), meningitis at the age of 65–69 years (2.3/100,000), nerve root and plexus disorders at the age of 70–74 years (0.6/100,000), and polyneuropathies at the age 70–74 years (2.9/100,000).

Figure 5 shows the distribution of hospital admissions for LNB by calendar month of admission. A seasonal trend is evident in LNB cases, with a peak in August and September and the lowest incidence in the winter and spring months.

The length of hospital stay for LNB showed a slight downward trend during the study period from 2003 (mean of 14.1 days and median of 14 days) to 2013 (mean of 12.2 days and median of 13 days). Shortening took place mainly in 2008–2010. No marked difference was seen between years in 2003–2007 and then in 2010–2013, except for 2012 with the shortest hospital stays. The 25th percentile dropped from nine to six days, which means that in one of four patients, the length of hospital stay is now under one week.

Table 7 (see p. 121) summarizes the length of hospital stay data for the entire study period 2003–2013 by G code group (LNB). The longest median hospital stays were recorded for conditions from code groups G00–G09, G10–G13 and G50–G59 while the shortest ones for conditions from code groups G40–G47 and G90–G99. The length of hospital stay was significantly higher (mean of 12.4 days and median of 13 days) in LNB patients (p < 0.001) than in other LB patients (mean of 10.3 days and median of 10 days).

DISCUSSION

The present study analysed LNB cases reported in 27.5% of hospitalised LB patients in the study period 2003–2013. The curve of annual hospital admissions for LB exhibited a slight downward trend (nonsignificant) with year-on-year fluctuations. In contrast, LNB showed an upward trend (p = 0.003). Interestingly, the length of hospital stay of LNB patients became significantly shorter during the study period. In this context, a question arises of how to interpret the reduced length of hospital stay. On the one hand, it might be a result of new therapeutic options that became available, but, on the other hand, it cannot be excluded either that administrative pressure to reduce the length of hospital stay, particularly in acute care beds, might have contributed to this reduction. In any case, it means lower hospital costs for LNB patients. The case definition of LB, including the principles of diagnosis, is specified in the annex Surveillance of L. borreliosis in the CR within the Ministerial Decree No 275/2010 Coll. [8].

LB was discovered in the last quarter of the last century. Clinical and laboratory diagnosis of the disease is constantly evolving. The implementation of novel diagnostic methods led to improved diagnosis of the disease in many European countries. Unfortunately, it cannot be stated that consensus has been reached on laboratory diagnosis of diverse manifestations of this vector-borne disease [19, 20]. A considerably improved precision in the diagnosis was achieved through the specific antibody index (AI) in the cerebrospinal fluid (CSF)/serum [15]. The standard diagnostic protocol is based on the demonstration of synthesis of intrathecal antibodies to Lyme borrelia, serological testing and clinical manifestation. Detection of Borrelia burgdorferi s. l. by culture or PCR could be used as additional methods. Important are previous well defined LB manifestations [10].

However, clinically manifest LNB cases can occur exceptionally in the absence of detectable antibodies in the CSF. The potential for use of PCR in the detection of Borrelia and monitoring of therapy response in LNB was tested in 57 clinically manifest cases of LNB with antibodies detected in the CSF. In comparison with the method of CSF antibody synthesis, nested PCR detected specific DNA concomitantly in the plasma, CSF, and urine in 63.1% of cases [27]. During a long-term follow-up of 57 LNB patients, the presence of specific DNA was detected in 48 patients after therapy, in 29 patients after three months, and in six patients after six months [28].

A controlled study tested a novel enzyme immunoassay (EIA) using recombinant fragments of the borrelial subspecies B. garinii, B. afzelii, and B. burgdorferi s. s., e.g. the highly specific antigen VIsE for IgG. In children diagnosed with LNB, elevated sensitivity of IgG antibodies was revealed, and the assay had comparable specificity to western blot [17]. VlsE peptide ELISA showed high specificity and sensitivity in the serological diagnosis of Lyme facial paralysis [24].

Another controlled study has confirmed the clinical relevance of the detection of chemokine CXCL13 (B cell chemoattractant) and anti-C6 peptide antibodies (C6 peptide is a synthetic antigen derived from the VlsE protein of B. burgdorferi) in LNB patients. The highest concentrations of chemokine CXCL13 in the CSF were detected in early-stage LNB. The detection of CXCL13 could be used mainly in patients with acute stage LNB who had an as yet negative AI [29].

A systematic literature review evaluated 78 publications on the diagnostic accuracy of serological tests for Lyme borreliosis. The sensitivity of the EIA or immunoblot (IB) in case-control studies was 0.77 (95% CI 0.67–0.85). The specificity was around 0.95 [10]. According to the EFNS guidelines, neurological symptoms, cerebrospinal fluid (CSF) pleocytosis, and Bb-specific antibodies produced intrathecally are the basic criteria for the diagnosis of LNB [21].

In the USA, neurological involvement occurs in 10–15% of untreated LB patients [12]. The prevalence of LNB in the USA is < 10% of all LB cases, whereas in Europe, the rate is 35% [33]. In the South of England, the incidence of LB was in the mean range of 9.8/100 000 in 1992–2012. Neurological involvement has been observed in up to 25% of Czech LB patients [17]. LNB cases have been reported practically from all countries where LB occurs.

The present study found the following conditions to be the most prevalent (in descending order): facial nerve disorders (21.1%), meningitis (18.3%), polyneuropathy (13.6%), encephalitis, myelitis, and encephalomyelitis (11.3%), migraine and other headache syndromes (6.1%), nerve root and plexus disorders (4.9%), and other disorders of the brain including cerebral oedema (4.4%).

The first symptom of LB is often erythema chronicum migrans, a red circular rash at the site of the tick bite. It may not appear or may remain unnoticed by the patient. LB patients may develop LNB, nervous system involvement, in the early, acute stage of the disease three to six weeks after infection as well as in the later, chronic stage. LNB often manifests itself as a lymphocytic meningoradiculoneuritis [13] or facial nerve palsy, aseptic meningitis, and neuroradiculitis [19]. Common manifestations are facial nerve palsy, aseptic meningitis, and neuroradiculitis [24], and radiculopathy or cranial neuropathy (of facial nerve) [26]. Acute facial nerve palsy is one of five variables considered in the diagnosis of LNB in Sweden [35]. Bannwarth’s syndrome, which consists of the triad of lymphocytic meningitis, cranial neuritis, and radiculitis, is relatively common [22], with painful meningoradiculitis, inflammation of the nerve roots, and lancinating, radicular pain [32]. Facial nerve palsy is considered as the most common neurological manifestation of LNB in children in Europe [34, 40]. The following clinical manifestations were diagnosed in 57 hospitalised LNB patients: Bannwarth’s syndrome (50.9%), acute meningoencephalitis (8.8%), subacute encephalitis (5.2%), meningitis (10.5%), multiplex neuritis (15.8%), facial palsy (8.8%) [27]. Chronic stage LNB results from long-term infection accompanied by symptoms that develop for weeks to months. It manifests itself as progressive encephalitis, myelitis, and neuropathy; however, other neurological disorders are not ruled out [18]. One of the chronic manifestations of Lyme disease is Lyme encephalopathy described as the syndrome of cognitive slowing, memory impairment that complicates daily functioning of patients [5]. Late chronic organ involvement may occur months to years after infection [25]. Late chronic neuroborreliosis may present the following neurological manifestations: chronic progressive Lyme encephalitis or encephalomyelitis, cerebral vasculitis, myositis, and chronic polyneuropathy [26]. However, not even modern medicine can explain the causes of the persisting health problems, such as chronic pain, fatigue, and other disabling symptoms. Prolonged symptoms after successful treatment are rather rare, but may occur. Long-term antibiotic therapy not only fails to control such symptoms but also is a risk to human health [23].

As it follows from our results, LNB affects both adults and children in the CR. The prevalence was higher in boys than in girls. The most affected childhood age group was 5–9 years.

The prevalence of LNB in children has also been reported by epidemiological studies from Sweden [34, 35]. Of 89 Dutch children diagnosed with LNB, 79% had one or more neurological manifestations. Most of them suffered from facial palsy, cranial nerve abnormalities, and meningeal signs [3].

In an epidemiolgical study involving 1,471 LB cases, conducted in southern Sweden, LNB occurred in 16% of patients. LNB incidence was the highest in the age groups 5–9 years and 60–74 years. Boys were affected more often than girls [2]. No difference in the total rates of LNB was found between boys and girls in a Norwegian endemic area [41]. A 10-year study of 142 children diagnosed with LNB has reported facial nerve palsy to be more common in girls (86%) than in boys (62%) [42]. Bannwarth’s syndrome occurs more often in adults than in children, with less than 5% of children with LNB being affected. The most common manifestations of childhood LNB are acute facial nerve palsy in 55% of patients and lymphocytic meningitis in 27% of patients [4].

In the present study, the highest rates of hospital admissions for LNB were recorded in the summer and autumn months (55 % in the period from June to October); however, 4.8–7.1% of LNB patients were admitted to the hospital in the winter and spring months where the questing activity of I. ricinus ticks is close to zero. This can be explained, on the one hand, by the relatively long incubation period of LB and, on the other hand, by a delay in the diagnosis in some LB patients who were admitted to the hospital with a late-stage disease when presenting with severe complications. A six-year retrospective study of LNB in an Austrian endemic area has reported 74% of cases to occur in the period from June to October and 26% of cases in the remaining months of the year [16].

The authors of the present study are aware of the fact that some of the less common conditions listed in the additional diagnosis category (e.g. G10–G13) may not be causally linked to LB. However, the fact that the main reason behind the hospital admission of the study patients was LB should be taken into account. Given the size of the study cohort, possible detection of some uncommon neurological manifestations of LB cannot be ruled out.

Acknowledgement

Supported by Ministry of Health, Czech Republic – conceptual development of research organization („the National Institute of Public Health – NIPH, 75010330“).

Do redakce došlo dne 2. 2. 2017.

Adresa pro korespondenci:

doc. MUDr. Bohumír Kříž, CSc.

Státní zdravotní ústav

Šrobárova 48

100 42 Praha 10

e-mail: bohumir.kriz@szu.cz