Sunday, May 28, 2023
| Characteristic | MR, n = 19 | PFP/meningitis, n = 42 | Suspected LNB, n = 59 | p value† | ||
|---|---|---|---|---|---|---|
| MR vs. PFP‡ | MR vs. sLNB | PFP‡ vs. sLNB | ||||
| Demographics | ||||||
| Age, y | 51 (21–73) | 52 (15–81) | 51 (25–83) | 0.4 | 0.8 | 0.4 |
| Sex | ||||||
| F | 9 (47) | 17 (40) | 45 (76) | 0.8 | 0.02 | 0.0004 |
| M | 10 (53) | 25 (60) | 14 (24) | |||
| No. tick bites/y | 1 (0–17) | 2 (0–20) | 2 (0–30) | 0.9 | 0.7 | 0.5 |
| Clinical characteristics | ||||||
| Current or recent EM | 13 (68) | 10 (24) | 59 (100)§ | 0.004 | 0.0001 | <0.0001 |
| Solitary EM | 12 (63) | 6 (14) | 53 (90) | 0.0007 | 0.01 | <0.0001 |
| Multiple EM | 1 (5) | 4 (10) | 6 (10) | 1 | 1 | 1 |
| EM duration, d | 35 (6–128) | 11 (3–60) | 21 (1–240) | 0.2 | 0.9 | 0.01 |
| No. symptoms/patient | 6 (1–12) | 3 (1–10) | 4 (1–13) | <0.0001 | 0.01 | 0.001 |
| Duration of symptoms, d | 30 (7–75) | 10 (3–365) | 16 (2–270) | 0.001 | 0.2 | 0.03 |
| Radicular pain | 19 (100%) | 0 (0%) | 9 (15%) | <0.0001 | <0.0001 | 0.01 |
| Peripheral facial palsy | 9 (47%) | 35 (83%) | 0 (0%) | 0.01 | <0.0001 | <0.0001 |
| CSF findings | ||||||
| Pleocytosis | 19 (100) | 42 (100) | 0 | 1.0 | <0.0001 | <0.0001 |
| Leukocyte count, × 106 cells/L | 160 (15–886) | 56 (6–1579) | 1 (0–4) | 0.005 | <0.0001 | <0.0001 |
| Lymphocyte count no. × 106 cells/L | 144 (15–811) | 47 (4–1477) | 1 (0–4) | 0.005 | <0.0001 | <0.0001 |
| Borrelia culture positivity¶ | 4 (21) | 3 (7) | 0 | 0.2 | 0.002 | 0.06 |
Table 1. Clinical characteristics of patients with confirmed or suspected Lyme neuroborreliosis, Ljubljana, Slovenia, 2006–2013*
*Values are no. (%) or median (range). CSF, cerebrospinal fluid; EM, erythema migrans; LNB, Lyme neuroborreliosis; MR, meningoradiculoneuritis; PFP, peripheral facial palsy; sLNB, suspected Lyme neuroborreliosis. †Statistical analyses were performed using Mann-Whitney nonparametric rank sum test. Median values are shown. Bold type indicates statistically significant p values after Benjamini-Hochberg correction for multiple comparisons (false discovery rate = 0.05). ‡PFP group includes 42 LNB patients without radicular pain (35 patients with PFP and 7 with lymphocytic meningitis). §Presence of EM was a criterion for suspected LNB. ¶Borrelia burgdorferi sensu lato positive culture result in CSF.
| Cytokine or chemokine | CSF, pg/mL | Serum, pg/mL | p value† |
|---|---|---|---|
| Innate | |||
| IL-8 | 39 (8–289) | 8 (0–473) | <0.0001 |
| IL-10 | 0.3 (0–54) | 0.3 (0–28) | 0.0001 |
| TNF | 5 (1–54) | 7 (0–170) | 0.3 |
| IFN-α | 88 (0–406) | 22 (0–205) | <0.0001 |
| CCL2 | 343 (71–10,000) | 213 (7–516) | <0.0001 |
| CCL3 | 5 (0.3–16) | 1 (0.3–227) | 0.07 |
| CCL4 | 5 (0.3–139) | 20 (0.3–221) | <0.0001 |
| T-cell adaptive | |||
| IFNγ | 2 (0–77) | 1 (0–25) | 0.3 |
| CXCL9 | 347 (4–6833) | 170 (2–3,508) | 0.02 |
| CXCL10 | 4,139 (156–46,025) | 143 (3–932) | <0.0001 |
| IL-17 | 3 (0–8) | 2 (0–25) | 0.02 |
| IL-23 | 2 (2–33) | 2 (2–4,949) | 0.01 |
| GM-CSF | 5 (0–22) | 3 (0–22) | <0.0001 |
| CCL19 | 84 (19–768) | 28 (2–143) | <0.0001 |
| CCL21 | 17 (17–241) | 17 (17–541) | 0.7 |
| B-cell adaptive | |||
| CXCL12 | 1,541 (89–5,518) | 820 (89–4184) | <0.0001 |
| CXCL13 | 352 (1–76,869) | 9 (1–66) | <0.0001 |
Table 2. Immune mediators in cerebrospinal fluid and serum in 61 confirmed patients with Lyme neuroborreliosis, Ljubljana, Slovenia, 2006–2013*
*Values are median (range). CCL, CC motif chemokine ligand; CSF, cerebrospinal fluid; CXCL, CXC motif chemokine ligand; IL, interleukin; IFN, interferon; TNF, tumor necrosis factor. †Statistical analyses were performed using Mann-Whitney non-parametric rank sum test. Bold type indicates statistically significant p values after Benjamini-Hochberg correction for multiple comparisons (false discovery rate FDR = 0.05).
This activity is intended for infectious disease clinicians, internists, neurologists and other clinicians who treat and manage patients with Lyme neuroborreliosis.
The goal of this activity is to describe the role of innate and adaptive immune responses and the TLR1-1805GG single nucleotide polymorphism in specific clinical presentations of Lyme neuroborreliosis, including painful meningoradiculoneuritis or lymphocytic meningitis with or without cranial neuritis (peripheral facial palsy), based on a clinical and genetic study.
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Lyme neuroborreliosis (LNB) in Europe may manifest with painful meningoradiculoneuritis (also known as Bannwarth syndrome) or lymphocytic meningitis with or without cranial neuritis (peripheral facial palsy). We assessed host immune responses and the prevalence of TLR1 (toll-like receptor 1)–1805GG polymorphism to gain insights into the pathophysiology of these conditions. Regardless of LNB manifestation, most mediators associated with innate and adaptive immune responses were concentrated in cerebrospinal fluid; serum levels were unremarkable. When stratified by specific clinical manifestation, patients with meningoradiculoneuritis had higher levels of B-cell chemoattractants CXC motif chemokine ligand (CXCL) 12 and CXCL13 and T-cell–associated mediators CXCL9, CXCL10, and interleukin 17, compared with those without radicular pain. Moreover, these patients had a higher frequency of TLR1–1805GG polymorphism and more constitutional symptoms. These findings demonstrate that meningoradiculoneuritis is a distinct clinical entity with unique immune and genetic pathophysiology, providing new considerations for the study of LNB and borrelial meningoradiculitis.
Lyme borreliosis, which is caused by several species of the Borrelia burgdorferi sensu lato complex, is the most common vectorborne disease in the Northern Hemisphere. The first sign of infection is usually an expanding skin lesion, erythema migrans (EM), that appears within days or weeks at the site of the tick bite. If untreated, the infection may disseminate to involve other organ systems, including the central nervous system (CNS), heart, or joints[1,2].
Lyme neuroborreliosis (LNB) is the most common extracutaneous manifestation of Lyme borreliosis in Europe and the second most common such manifestation in North America[1,2]. In Europe, LNB in adult patients typically begins as painful meningoradiculoneuritis (also known as Garin-Bujadoux-Bannwarth syndrome or Bannwarth syndrome), which is rare in the United States, or with cranial neuritis characterized by peripheral facial palsy (PFP) or lymphocytic meningitis[1–4]. In addition, a subset of patients experience EM and symptoms indicative of LNB (e.g., headache, vertigo, concentration disturbance), but do not fulfill the European diagnostic criteria for LNB, namely cerebrospinal fluid (CSF) pleocytosis and intrathecal borrelial antibody production[5,6]. This subset poses a particular diagnostic and clinical challenge because the etiology of illness is often unclear.
Pathogenic mechanisms that account for different clinical manifestations of LNB are not well understood. Clinical heterogeneity in Lyme borreliosis has been largely attributed to differences in the infecting B. burgdorferi s.l. species[1,2]. In Europe, LNB is caused predominantly by B. garinii (and closely related B. bavariensis) but only rarely by B. afzelii, which is associated with skin manifestations, or B. burgdorferi sensu stricto, which is highly arthritogenic, implying a strong species-specific imprinting of clinically evidenced disease[1,2,7,8]. However, although B. garinii has particular proclivity for the central nervous system (CNS) and undoubtedly serves as the initial trigger of LNB, Lyme borreliae do not express any known toxins that cause disease. Rather, the host immune response, which is shaped by various Borrelia species[9–13], is thought to be a key determinant of the clinical signs and symptoms of Lyme borreliosis, including LNB.
In addition to infection with a particular Borrelia species or strain, the immune responses are further augmented by alterations in the human genome. We have previously demonstrated that a single-nucleotide polymorphism (SNP; 1805GG) in the host toll-like receptor 1 (TLR1), a key pathogen sensing receptor for borrelia, is associated with more symptomatic early Lyme borreliosis and a greater frequency of postantibiotic, chronic inflammatory Lyme arthritis[12,14]. This TLR1–1805GG SNP is associated with severe disease presumably because it enables maladaptive immune responses; EM patients with the TLR1–1805GG SNP had substantially higher levels of pro-inflammatory cytokines and chemokines in blood compared with those without the SNP. Moreover, in patients with Lyme arthritis, this SNP was associated with exceptionally high levels of the interferon (IFN) γ and IFN-γ–associated mediators CXC motif chemokine ligand (CXCL) 9 and CXCL10 in synovial fluid, supporting the predominant cellular and inflammatory T-helper 1 (Th1) responses in joints in these patients. Thus, host immune response, which is shaped by both microbial and host genetics, is a key driver of the clinical heterogeneity in Lyme borreliosis in general and probably in LNB, although this has not been tested directly.
Several studies in Europe and the United States have characterized host immune responses in patients with LNB in an effort to gain insights into pathogenesis and to identify biomarkers to aid in diagnosis[15–18]. These studies demonstrated the activation of a broad-ranging innate and adaptive immune response in patients with LNB. In particular, LNB patients have marked CSF levels of CXCL13, a B-cell chemoattractant, compared with patients with other neurologic conditions[15–19], prompting the use of CXCL13 as an adjunct diagnostic biomarker of LNB[19–26]. However, the role of host immunity in the pathogenesis of clinically distinct LNB manifestations and the possibility that these outcomes are associated with specific host genetic predisposition has not been explored.
We investigated the role of innate and adaptive immune responses and the TLR1–1805GG SNP in specific clinical manifestations of LNB. Our findings demonstrate that borrelial meningoradiculoneuritis is a distinct clinical entity with unique immune and genetic pathophysiology and offer new insights into the pathogenesis and diagnosis of this condition.
