Peripheral neuropathy due to neuroborreliosis: Insensitivity for CXCL13 as early diagnostic marker.

The case of a 69-year-old woman with peripheral neuropathy caused by Lyme neuroborreliosis (LNB) in an endemic region in Eastern Austria is reported. The patient had noticed transient numbness of her left leg. On initial examination, she had patchy sensory disturbances of the left lower leg, but ancillary examinations of nerve conduction and cerebrospinal fluid (CSF), including the B-cell chemokine CXCL13, were normal. A re-tap performed 54 days later, following clinical progression with foot drop, widespread lower leg paresthesia, and pain, revealed an increased cell count, autochthonous IgM production, synthesis of Borrelia-specific IgM, and elevated CXCL13. Neurophysiological examinations disclosed an incomplete conduction block, mixed axonal and demyelinating sensorimotor neuropathy, and subacute neurogenic damage of muscles innervated by the peroneal nerve. This case study presents rare evidence of very early diagnostic findings in peripheral neuropathy caused by LNB. These are characterized by insensitivity of CXCL13 in CSF to aid earlier diagnosis and the development of an intrathecal immune response against Borrelia at a later stage. These findings reinforce the need for a re-tap to confirm the diagnosis and facilitate appropriate treatment in this rare manifestation of LNB.

Conserved lysine residues in decorin binding proteins of Borrelia garinii are critical in adhesion to human brain microvascular endothelial cells.

Lyme borreliosis is a tick-borne disease caused by Borrelia burgdorferi sensu lato spirochetes (Lyme borreliae). When the disease affects the central nervous system, it is referred to as neuroborreliosis. In Europe, neuroborreliosis is most often caused by Borrelia garinii. Although it is known that in the host Lyme borreliae spread from the tick bite site to distant tissues via the blood vasculature, the adherence of Lyme borreliae to human brain microvascular endothelial cells has not been studied before. Decorin binding proteins are adhesins expressed on Lyme borreliae. They mediate the adhesion of Lyme borreliae to decorin and biglycan, and the lysine residues located in the binding site of decorin binding proteins are important to the binding activity. In this study, we show that lysine residues located in the canonical binding site can also be found in decorin binding proteins of Borrelia garinii, and that these lysines contribute to biglycan and decorin binding. Most importantly, we show that the lysine residues are crucial for the binding of Lyme borreliae to decorin and biglycan expressing human brain microvascular endothelial cells, which in turn suggests that they are involved in the pathogenesis of neuroborreliosis.

Neutrophils and Neutrophil Extracellular Traps Regulate Immune Responses in Health and Disease.

Neutrophils are first responders of antimicrobial host defense and sterile inflammation, and therefore, play important roles during health and disease [...].

Neuroborreliosis ­ clinical presentation ­ Current state of knowledge

Neuroborreliosis is one of the manifestations of Lyme disease involving central and peripheral nervous system. It is caused by infection with Borrelia burgdorferi spirochete which is transmitted by tick bites. Neuroborreliosis can affect both adults and children. The clinical course in children is often different than in adults. The article discusses the most common clinical symptoms, complications, diagnostics and treatment of neuroborreliosis in children.

Incidence and characteristics of Lyme neuroborreliosis in adult patients with facial palsy in an endemic area in the Netherlands.

Making a distinction between facial palsy due to Lyme neuroborreliosis (LNB) and idiopathic facial palsy (IFP) is of importance to ensure timely and adequate treatment. The study objective was to assess incidence and patient characteristics of facial palsy due to LNB. Hospital records were reviewed of adult patients with facial palsy visiting the departments of neurology and/or otorhinolaryngology of Gelre hospitals between June 2007 and December 2017. Gelre hospitals are located in an area endemic for Lyme borreliosis. Patients with LNB had pleocytosis and intrathecal antibody production or pleocytosis with positive IgG serology. Patients with IFP had negative serology. Clinical characteristics were compared between patients with LNB and patients with IFP. Five hundred and fifty-nine patients presented with facial palsy, 4.7% (26) had LNB and 39.4% (220) IFP. The incidence of facial palsy due to LNB was 0.9/100 000 inhabitants/year. Over 70% of patients with facial palsy due to LNB did not report a recent tick bite and/or erythema migrans (EM). Patients with facial palsy due to LNB presented more often in July to September (69.2% vs. 21.9%, P < 0.001), and had more often headache (42.3% vs. 15.5%, P < 0.01). To reduce the risk of underdiagnosing LNB in an endemic area, we recommend testing for LNB in patients with facial palsy in summer months especially when presenting with headache, irrespective of a recent tick bite and/or EM.

Extensive meningeal enhancement in acute central nervous system Lyme: Case series and review of literature.

INTRODUCTION: Clinical presentation of the central nervous system Lyme disease is nonspecific and therefore brain imaging and disease-specific serological testing is generally pursued to assist with diagnosis. Brain imaging findings are, however, rare and often unspecific. CASE DESCRIPTION: In the current report, we are presenting a rare magnetic resonance imaging (MRI) finding of extensive meningeal enhancement in two patients with acute Lyme disease. DISCUSSION: We discussed clinical implications and reviewed the relevant literature.

Lyme neuroborreliosis.

PURPOSE OF REVIEW: To review the recent evidence clarifying the symptomatology and diagnosis of nervous system Lyme disease. RECENT FINDINGS: Two-tier testing combining pairs of ELISAs, using C6 or VlsE assays to replace second tier Western blots, may eliminate confusion about test interpretation. Cerebrospinal fluid (CSF) can be informative in diagnosing central nervous system (CNS) Lyme disease, not peripheral nervous system (PNS) disorders. CSF CXCL13 may provide useful adjunctive information in CNS infection; its specificity remains to be defined. Lyme encephalopathy is not indicative of CNS infection. Post treatment Lyme disease symptoms do not occur in patients who have had definite CNS Lyme infection. Whether post treatment Lyme disease symptom (PTLDS) is an actual entity, or reflects anchoring bias when commonly occurring symptoms arise in patients previously treated for Lyme disease, remains to be determined. Regardless, these symptoms do not reflect CNS infection and do not respond to additional antimicrobial therapy. SUMMARY: Serologic testing is robust in individuals with a priori likelihood of infection of greater than 2-6 weeks duration. Western blots provide useful confirmation of screening ELISAs, but may be replaced by second ELISAs. CSF testing, including CXCL13, may be informative in CNS Lyme, not PNS, and is generally normal in Lyme encephalopathy. PTLDS does not occur following CNS infection, and may not be a distinct entity.

Lyme Neuroborreliosis is a Severe and Frequent Neurological Disease in Mexico.

OBJECTIVE: To describe clinical cases with neurological manifestations associated with Borrelia burgdorferi infection in a large cohort of children and adults from Mexico. MATERIAL AND METHODS: Patients with neurological manifestation (cranial neuritis, radiculoneuritis, meningitis and encephalomyelitis) were recruited in one pediatric and two general hospitals, during January 2006-December 2015. Blood and cerebrospinal fluid (CSF) samples were drawn from each patient at inclusion. IgM and IgG antibodies against B. burgdorferi were detected using a commercial ELISA test, and confirmed by Western-Blot test (WB) using three different antigens from Borrelia burgdorferi complex. Following CDC criteria were considered true cases with both positive tests. RESULTS: Of 606 patients recruited, 403 (66.5%) were adults and 203 (33.4%) children, 50.5% were male. B. burgdorferi infection was diagnosed in 168 patients (27.7%), 97 adults, mean age 42 ± 14.7 years and 71 children, mean age 9.6 ± 5 years; early disseminated disease occurred in 130 cases (77.4 %) and chronic stage in 38 (22.6 %). A previous tick bite was reported by 21% cases, and 5% recalled an erythema migrans lesion. Polyradiculoneuropathy and encephalomyelitis were the most common manifestations, whereas 14.8% presented an initial Guillain-Barré Syndrome. B. burgdorferi sensu stricto was identified in 142 (84%) cases, B. garinii in 14 (8%), B. afzelii in three, and nine cases presented coinfection with two species. CONCLUSION: Lyme neuroborreliosis is a frequent condition in patients with neurological diseases in Mexico.

Enzootic origins for clinical manifestations of Lyme borreliosis.

Both early localized and late disseminated forms of Lyme borreliosis are caused by Borrelia burgdorferi senso lato. Differentiating between the spirochetes that only cause localized skin infection from those that cause disseminated infection, and tracing the group of medically-important spirochetes to a specific vertebrate host species, are two critical issues in disease risk assessment and management. Borrelia burgdorferi senso lato isolates from Lyme borreliosis cases with distinct clinical manifestations (erythema migrans, neuroborreliosis, acrodermatitis chronica atrophicans, and Lyme arthritis) and isolates from Ixodes ricinus ticks feeding on rodents, birds and hedgehogs were typed to the genospecies level by sequencing part of the intergenic spacer region. In-depth molecular typing was performed by sequencing eight additional loci with different characteristics (plasmid-bound, regulatory, and housekeeping genes). The most abundant genospecies and genotypes in the clinical isolates were identified by using odds ratio as a measure of dominance. Borrelia afzelii was the most common genospecies in acrodermatitis patients and engorged ticks from rodents. Borrelia burgdorferi senso stricto was widespread in erythema migrans patients. Borrelia bavariensis was widespread in neuroborreliosis patients and in ticks from hedgehogs, but rare in erythema migrans patients. Borrelia garinii was the dominant genospecies in ticks feeding on birds. Spirochetes in ticks feeding on hedgehogs were overrepresented in genotypes of the plasmid gene ospC from spirochetes in erythema migrans patients. Spirochetes in ticks feeding on hedgehogs were overrepresented in genotypes of ospA from spirochetes in acrodermatitis patients. Spirochetes from ticks feeding on birds were overrepresented in genotypes of the plasmid and regulatory genes dbpA, rpoN and rpoS from spirochetes in neuroborreliosis patients. Overall, the analyses of our datasets support the existence of at least three transmission pathways from an enzootic cycle to a clinical manifestation of Lyme borreliosis. Based on the observations with these nine loci, it seems to be justified to consider the population structure of B. burgdorferi senso lato as being predominantly clonal.

A critical appraisal of the mild axonal peripheral neuropathy of late neurologic Lyme disease.

In older studies, a chronic distal symmetric sensory neuropathy was reported as a relatively common manifestation of late Lyme disease in the United States. However, the original papers describing this entity had notable inconsistencies and certain inexplicable findings, such as reports that this condition developed in patients despite prior antibiotic treatment known to be highly effective for other manifestations of Lyme disease. More recent literature suggests that this entity is seen rarely, if at all. A chronic distal symmetric sensory neuropathy as a manifestation of late Lyme disease in North America should be regarded as controversial and in need of rigorous validation studies before acceptance as a documented clinical entity.

Retrospective Evaluation of Horses Diagnosed with Neuroborreliosis on Postmortem Examination: 16 Cases (2004-2015).

BACKGROUND: Equine neuroborreliosis (NB), Lyme disease, is difficult to diagnose and has limited description in the literature. OBJECTIVE: Provide a detailed description of clinical signs, diagnostic, and pathologic findings of horses with NB. ANIMALS: Sixteen horses with histologically confirmed NB. METHODS: Retrospective review of medical records at the University of Pennsylvania and via an ACVIM listserv query with inclusion criteria requiring possible exposure to Borrelia burgdorferi and histologic findings consistent with previous reports of NB without evidence of other disease. RESULTS: Sixteen horses were identified, 12 of which had additional evidence of NB. Clinical signs were variable including muscle atrophy or weight loss (12), cranial nerve deficits (11), ataxia (10), changes in behavior (9), dysphagia (7), fasciculations (6), neck stiffness (6), episodic respiratory distress (5), uveitis (5), fever (2), joint effusion (2), and cardiac arrhythmias (1). Serologic analysis was positive for B. burgdorferi infection in 6/13 cases tested. CSF abnormalities were present in 8/13 cases tested, including xanthochromia (4/13), increased total protein (5/13; median: 91 mg/dL, range: 25-219 mg/dL), and a neutrophilic (6/13) or lymphocytic (2/13) pleocytosis (median: 25 nucleated cells/µL, range: 0-922 nucleated cells/µL). PCR on CSF for B. burgdorferi was negative in the 7 cases that were tested. CONCLUSION AND CLINICAL IMPORTANCE: Diagnosis of equine NB is challenging due to variable clinical presentation and lack of sensitive and specific diagnostic tests. Negative serology and normal CSF analysis do not exclude the diagnosis of NB.

Antagonist of the neurokinin-1 receptor curbs neuroinflammation in ex vivo and in vitro models of Lyme neuroborreliosis.

BACKGROUND: Lyme neuroborreliosis (LNB) can affect both the peripheral (PNS) and the central nervous systems (CNS); it is caused by the spirochete Borrelia burgdorferi. The neuropeptide substance P (SP) is an important mediator of both neuroinflammation and blood-brain barrier dysfunction, through its NK1 receptor. Increased levels of SP have been shown to correlate with cell death. The present study used both ex vivo and in vitro models of experimentation to determine if the inflammatory mediator production and concomitant cell death caused by exposure of neural tissues and cells to B. burgdorferi could be attenuated by treatment with a NK1 receptor antagonist. METHODS: We incubated normal rhesus frontal cortex tissue explants (CNS) and primary cultures of rhesus dorsal root ganglia cells (PNS) with live B. burgdorferi and tested the effectiveness of the NK1 receptor antagonist L703,606 in attenuating inflammatory immune responses and neuronal and glial damage. Culture supernatants and tissue lysates were subjected to multiplex ELISA to quantify immune mediators, while the cells were evaluated for apoptosis by the in situ TUNEL assay. In addition, we identified immune mediators and producer cells in tissue sections by immunofluorescence staining and confocal microscopy. RESULTS: Co-incubation of both CNS tissues and PNS cells with the NK1 receptor antagonist attenuated bacterially induced increases in inflammatory cytokine and chemokine production, particularly, IL-6, CXCL8, and CCL2, and reduced apoptosis levels. Confocal microscopy confirmed that neurons and glial cells are sources of these immune mediators. These results suggest that NK1R antagonist treatment is able to reduce downstream pro-inflammatory signaling, thereby indicating that its systemic administration may slow disease progression. CONCLUSIONS: We propose that SP contributes to neurogenic inflammation in LNB, and provide data to suggest that an NK1 receptor antagonist may represent a novel neuroprotective therapy.

Cerebrospinal Fluid Cytology of Lyme Neuroborreliosis: A Report of 3 Cases with Literature Review.

Lyme disease can affect the central nervous system causing a B-cell-predominant lymphocytic pleocytosis. Since most reactions to infection in the cerebrospinal fluid (CSF) are typically T-cell predominant, a B-cell-predominant lymphocytosis raises concern for lymphoma. We present 3 Lyme neuroborreliosis cases in order to illustrate the challenging cytomorphological and immunophenotypic features of their CSF specimens. Three male patients who presented with central nervous system manifestations were diagnosed with Lyme disease. The clinical presentation, laboratory tests, CSF cytological examination and flow-cytometric studies were described for each case. CSF cytology showed lymphocytic pleocytosis with increased plasmacytoid cells and/or plasma cells. Flow cytometry showed the presence of polytypic B lymphocytes with evidence of plasmacytic differentiation in 2 cases. In all cases, Lyme disease was confirmed by the Lyme screening test and Western blotting. In such cases of Lyme neuroborreliosis, flow cytometry of CSF samples employing plasmacytic markers and cytoplasmic light-chain analysis is diagnostically helpful to exclude lymphoma.

Lyme neuroborreliosis in a patient treated with TNF-alpha inhibitor.

A 57-year-old woman, receiving TNF-alpha inhibitor adalimumab for psoriasis, presented with early Lyme neuroborreliosis (Bannwarth's syndrome). Discontinuation of adalimumab and 14-day therapy with ceftriaxone resulted in a smooth course and favorable outcome of Lyme borreliosis. This is the first report on Lyme neuroborreliosis in a patient treated with TNF-alpha inhibitor.

Inflammation in the pathogenesis of lyme neuroborreliosis.

Lyme neuroborreliosis, caused by the spirochete Borrelia burgdorferi, affects both peripheral and central nervous systems. We assessed a causal role for inflammation in Lyme neuroborreliosis pathogenesis by evaluating the induced inflammatory changes in the central nervous system, spinal nerves, and dorsal root ganglia (DRG) of rhesus macaques that were inoculated intrathecally with live B. burgdorferi and either treated with dexamethasone or meloxicam (anti-inflammatory drugs) or left untreated. ELISA of cerebrospinal fluid showed significantly elevated levels of IL-6, IL-8, chemokine ligand 2, and CXCL13 and pleocytosis in all infected animals, except dexamethasone-treated animals. Cerebrospinal fluid and central nervous system tissues of infected animals were culture positive for B. burgdorferi regardless of treatment. B. burgdorferi antigen was detected in the DRG and dorsal roots by immunofluorescence staining and confocal microscopy. Histopathology revealed leptomeningitis, vasculitis, and focal inflammation in the central nervous system; necrotizing focal myelitis in the cervical spinal cord; radiculitis; neuritis and demyelination in the spinal roots; and inflammation with neurodegeneration in the DRG that was concomitant with significant neuronal and satellite glial cell apoptosis. These changes were absent in the dexamethasone-treated animals. Electromyography revealed persistent abnormalities in F-wave chronodispersion in nerve roots of a few infected animals; which were absent in dexamethasone-treated animals. These results suggest that inflammation has a causal role in the pathogenesis of acute Lyme neuroborreliosis.

Chemokine CXCL13 concentration in cerebrospinal fluid in patients with neuroborreliosis--own observations.

THE AIM: of the study was to evaluate the usefulness of cerebrospinal fluid chemokine CXCL13 concentration assay in diagnostics of neuroborreliosis in adults. MATERIAL AND METHODS: Investigations were carried out in 22 patients treated for neuroborreliosis , manifested as lymphocytic meningitis, at the Department of Infectious Diseases, Medical University of Silesia, in Bytom between 2011-2013. Based on the presence or absence of anti-borrelial antibodies in the cerebrospinal fluid, the examined individuals were divided into two groups on the day of admission: group I--patients with antiborrelial antibodies in the cerebrospinal fluid (confirmed diagnosis of neuroborreliosis), group II--patients without antiborrelial antibodies in the cerebrospinal fluid (possible diagnosis of neuroborreliosis). In all patients the cerebrospinal fluid CXCL13 level was assessed on the first day of hospitalization. Control tests were performed in both groups after 14 days of therapy with antibiotics. RESULTS: Mean cerebrospinal fluid CXCL13 concentration in group I on the 1st day was 4123 pg/mL, and in group II--3422 pg/mL. Differences in mean concentrations of this chemokine were statistically insignificant. No correlations between examined mean CXCL13 concentrations and other cerebrospinal fluid inflammatory parameters were revealed. The control tests showed the evident decrease of CXCL13 level in cerebrospinal fluid in both groups. Besides, in individuals of group II anti-Borrelia burgdorferi antibodies appeared in cerebrospinal fluid, whereas in group I, the control results of this parameter were similar to preliminary values. CONCLUSION: The obtained results indicate a kind of usefulness of estimation of cerebrospinal fluid chemokine CXCL13 concentration in diagnostics of early, acute neuroborreliosis, manifested as lymphocytic meningitis, especially in case of anti-borrelia antibodies absence in cerebrospinal fluid. Changes in this chemokine concentrations, opposite to cerebrospinal fluid levels of anti-borrelia antibodies, may be prognostic in acute, early neuroborreliosis.

A unique case of adolescent neuroborreliosis presenting with multiple cranial neuritis and cochlear inflammation on magnetic resonance imaging.

BACKGROUND: Lyme disease is the most common vector-borne disease in the United States and is caused by infection with the spirochete Borrelia burgdorferi. In children, neuroborreliosis usually presents as peripheral facial nerve palsy and lymphocytic meningitis and only rarely is associated with cranial polyneuritis. PATIENT DESCRIPTION: We present a 15-year-old with tinnitus, hearing loss, and facial nerve palsy in the setting of acute, severe right arm pain and a several week history of malaise and headache. Lumbar puncture was notable for lymphocytic pleocytosis. Serologic testing demonstrated positive Lyme antibody and a positive immunoglobulin M Western blot. Immunofluorescent assay of cerebrospinal fluid was also positive for anti-Lyme immunoglobulin M. Audiologic testing revealed mixed, right-sided hearing loss. Neuroimaging demonstrated cranial polyneuritis and right-sided cochlear inflammation. The patient was treated with parenteral ceftriaxone with resolution of his symptoms at close follow-up. DISCUSSION: Neuroborreliosis with radiculopathy, lymphocytic meningitis, and cranial polyneuritis is a rare presentation of pediatric Lyme disease. Additionally, cochlear inflammation along with cranial nerve VIII inflammation may contribute to hearing loss in patients with neuroborreliosis.