Attenuation of relapsing fever neuroborreliosis in mice by IL-17A blockade.

Relapsing fever due to Borrelia hermsii is characterized by recurrent bacteremia episodes. However, infection of B. hermsii, if not treated early, can spread to various organs including the central nervous system (CNS). CNS disease manifestations are commonly referred to as relapsing fever neuroborreliosis (RFNB). In the mouse model of B. hermsii infection, we have previously shown that the development of RFNB requires innate immune cells as well as T cells. Here, we found that prior to the onset of RFNB, an increase in the systemic proinflammatory cytokine response followed by sustained levels of IP-10 concurrent with the CNS disease phase. RNA sequencing analysis of the spinal cord tissue during the disease phase revealed an association of the interleukin (IL)-17 signaling pathway in RFNB. To test a possible role for IL-17 in RFNB, we compared B. hermsii infection in wild-type and IL-17A-/- mice. Although the onset of bacteremia and protective anti-B. hermsii antibody responses occurred similarly, the blood-brain barrier permeability, proinflammatory cytokine levels, immune cell infiltration in the spinal cord, and RFNB manifestations were significantly diminished in IL-17A-/- mice compared to wild-type mice. Treatment of B. hermsii-infected wild-type mice with anti-IL-17A antibody ameliorated the severity of spinal cord inflammation, microglial cell activation, and RFNB. These data suggest that the IL-17 signaling pathway plays a major role in the pathogenesis of RFNB, and IL-17A blockade may be a therapeutic modality for controlling neuroborreliosis.

Genome-wide DNA Methylation Profiling in Lyme Neuroborreliosis Reveals Altered Methylation Patterns of HLA Genes.

Lyme neuroborreliosis (LNB) is a complex neuroinflammatory disorder caused by Borrelia burgdorferi, which is transmitted through tick bites. Epigenetic alterations, specifically DNA methylation (DNAm), could play a role in the host immune response during infection. In this study, we present the first genome-wide analysis of DNAm in peripheral blood mononuclear cells from patients with LNB and those without LNB. Using a network-based approach, we highlighted HLA genes at the core of these DNAm changes, which were found to be enriched in immune-related pathways. These findings shed light on the role of epigenetic modifications in the LNB pathogenesis that should be confirmed and further expanded upon in future studies.

Changes in the serum proteome profile of patients with neuroborreliosis, foresters, and patients treated according to ILADS method.

OBJECTIVES: The aim of study was to evaluate the changes in proteomic profile of human serum induced by the development of tick-borne neuroborreliosis (NB), before/after therapy, patients treated with prolonged multidrug therapy according to ILADS (International Lyme and Associated Diseases Society), and foresters frequently exposed to tick bites. METHODS: A proteomics approach was used to analyze the expression of proteins in serum of patients and sex/age-matched healthy donors. The analysis was performed using SDS-PAGE/LC-MS/MS (Q-Exactive OrbiTrap mass spectrometer). RESULTS: Obtained results indicated changes in the serum proteome of patients with NB putting attention to the proteins involved mainly in calcium transport/metabolism and signaling molecules that differ patients before and after classic therapy. Moreover, ILADS treated patients have different protein distribution than patients from other groups, what is the consequence of prolonged antibiotic therapy. In the case of foresters, the most important result is the increased ß-secretase level. CONCLUSIONS: Obtained results may contribute to a better understanding of the mechanism of the development of tick-borne diseases, as well as will allow create new opportunities for its rapid and more effective therapy. However, further studies, on larger patients groups, are needed to apply them in clinical practice.

Antibody responses to immunoevasion proteins BBK32 and OspE constitute part of the serological footprint in neuroborreliosis but are insufficient to prevent the disease.

Lyme borreliosis, caused by Borrelia burgdorferi sensu lato, is the most common tickborne disease. Its neuronal form, neuroborreliosis, comprises 3 to 38% of borreliosis cases in Europe. Borrelia outer surface proteins and virulence factors, OspE and BBK32, have been previously reported to help cause infection by promoting attachment to human host epithelial cells and evading complement attack. We assessed the serological responses to BBK32 and OspE in 19 individuals diagnosed with neuroborreliosis to see whether antibodies that could both target the bacteria and neutralize the virulence mechanisms on the microbial surface emerge. Results evaluate levels of total protein, IgG and the chemokine CXCL13, a determinant for B-cell recruitment during neuroinflammation, in patients' cerebrospinal fluid samples. Antibody levels against BBK32 and OspE correlated with those against VlsE, a well-characterized diagnostic serological marker of the disease. A dual serological profile of the patients was observed. K-means clustering split the cohort into two discrete groups presenting distinct serological and CNS responses. One group contained young patients with low levels of anti-BBK32 and OspE antibodies. The other group showed stronger responses, possibly following prolonged infections or reinfections. Additionally, we assessed anti-ganglioside antibodies that could cause autoimmunity or complement dysregulation but observed that they did not correlate with neuroborreliosis in our patient cohort. The dual nature of antibody responses against the virulence factors BBK32 and OspE in neuroborreliosis patients may suggest the necessity of repeated exposures for efficient immune responses. Better protection could be achieved if the virulence factors were formulated into vaccines.

Clinical and laboratory characteristics during a 1-year follow-up in European Lyme neuroborreliosis: A prospective cohort study.

BACKGROUND AND PURPOSE: We need more knowledge on clinical presentations, time course, biomarkers, and prognosis in European Lyme neuroborreliosis (LNB). METHODS: A prospective 12-month follow-up of predetermined clinical and laboratory parameters was undertaken in 105 patients with LNB. RESULTS: At presentation, 79% had radiculopathy, 49% had facial palsy, and 13% had solely subjective symptoms (predominately pain). Intrathecally produced Borrelia burgdorferi (Bb) antibodies were demonstrated and cerebrospinal fluid (CSF) CXCL13 was positive in 85% and 82% pretreatment, in 73% and 10% at 6 months, and in 58% and 14% at 12 months, respectively. CSF Bb polymerase chain reaction (PCR) was positive in 40% pretreatment. In four patients who tested negative for Bb antibodies in both serum and CSF, the diagnosis was supported by typical clinical features, pleocytosis, CSF Bb-PCR (n = 1), or CSF CXCL13 (n = 2). The proportion with symptoms influencing daily life was 91% pretreatment, 25% at 10 weeks, 20% at 6 months, and 15% at 12 months. Fatigue was the most common complaint at 12 months. A high burden of symptoms before and after treatment was associated with residual complaints at 12 months, whereas background data, other clinical features, and laboratory features were not. CONCLUSIONS: LNB can present with solely subjective symptoms, especially pain. Many LNB patients have persistent Bb antibodies in serum and CSF. In seronegative LNB, CSF Bb-PCR and CXCL13 may give diagnostic support. CXCL13 may be persistently positive after treatment in some patients. Most of the clinical improvement occurs during the first 10 weeks. High initial clinical score is associated with poorer outcome.

Treatment of post-treatment Lyme disease symptoms-a systematic review.

BACKGROUND AND PURPOSE: Residual symptoms after treatment of Lyme disease, sometimes called post-treatment Lyme disease symptoms (PTLDs), are a matter of ongoing controversy. To guide treatment recommendations, a systematic review was performed of the available literature on specific treatment for PTLDs. METHODS: A systematic literature search of MEDLINE and CENTRAL was performed. No restrictions on case definitions, study types or specific interventions were applied to enable a comprehensive overview of the available literature. Risk of bias was assessed using the Cochrane risk of bias tools for randomized controlled trials. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Outcomes of interest were quality of life, fatigue, depression and cognition as well as adverse events. RESULTS: After screening 1274 records, eight eligible randomized controlled trials were included. Heterogeneity was observed regarding inclusion criteria, intervention, length of treatment and outcome measures. For efficacy outcomes, results are presented narratively due to heterogeneity. Eligible studies show no statistically significant difference between antibiotics and placebo regarding quality of life, cognition and depression. Results for fatigue were inconsistent whilst studies with low risk of bias showed no statistically significant difference between antibiotics and placebo. Meta-analysis of safety outcomes showed statistically significantly more adverse events for antibiotics compared to placebo. CONCLUSIONS: Available literature on treatment of PTLDs is heterogeneous, but overall shows evidence of no effect of antibiotics regarding quality of life, depression, cognition and fatigue whilst showing more adverse events. Patients with suspected PTLDs should not be treated with antibiotics.

Assessment of three criteria to establish borrelial infection in suspected lyme neuroborreliosis.

PURPOSE: Diagnosis of (European) Lyme neuroborreliosis has been based on clinical presentation, cerebrospinal fluid (CSF) pleocytosis and demonstration of intrathecal borrelial antibody synthesis (ITBAS) to document Borrelia burgdorferi s. l. INFECTION: It is not known if other criteria to document Borrelia infection may contribute to the diagnosis. METHODS: We compared the sensitivity of three individual criteria (ITBAS, CSF Borrelia culture, and the presence of erythema migrans [EM]) to confirm the diagnosis of early Lyme neuroborreliosis in 280 patients ≥ 15 years of age evaluated at a Lyme borreliosis outpatient clinic in Slovenia. The patients had either radicular pain of new onset or involvement of a cranial nerve but without radicular pain, each in conjunction with CSF pleocytosis. Evaluation was of patients who had each of the three confirmatory criteria assessed, and for whom at least one criterion was positive. RESULTS: Analysis of 280 patients, 120 women and 160 men, median age 57 (range 15-84) years, revealed that ITBAS was the most frequently observed positive criterion (85.4%), followed by EM (52.9%), and by a positive CSF Borrelia culture (9.6%). Of the 280 patients, 154 (55%) met only one criterion (43.2% ITBAS only, 10.7% EM only, and 1.1% positive CSF culture only), whereas 42.1% met two criteria. Only 2.9% of patients were positive by all three criteria. CONCLUSION: Although ITBAS was the most frequent criterion for confirmation for Borrelia infection, the presence of EM alone confirmed an additional 10.7% of patients and a positive CSF Borrelia culture alone added another 1.1%.

Are white matter hyperintensities associated with neuroborreliosis? The answer is twofold.

PURPOSE: Many consider white matter hyperintensities (WMHs) to be important imaging findings in neuroborreliosis. However, evidence regarding association with WMHs is of low quality. The objective was to investigate WMHs in neuroborreliosis visually and quantitatively. MATERIALS AND METHODS: Patients underwent brain MRI within one month of diagnosis and six months after treatment. Healthy controls were recruited. WMHs were counted by visual rating and the volume was calculated from automatic segmentation. Biochemical markers and scores for clinical symptoms and findings were used to explore association with longitudinal volume change of WMHs. RESULTS: The study included 74 patients (37 males) with early neuroborreliosis and 65 controls (30 males). Mean age (standard deviation) was 57.4 (13.5) and 57.7 (12.9) years, respectively. Baseline WMH lesion count was zero in 14 patients/16 controls, < 10 in 36/31, 10-20 in 9/7 and > 20 in 13/11, with no difference between groups (p = 0.90). However, from baseline to follow-up the patients had a small reduction in WMH volume and the controls a small increase, median difference 0.136 (95% confidence interval 0.051-0.251) ml. In patients, volume change was not associated with biochemical or clinical markers, but with degree of WMHs (p values 0.002-0.01). CONCLUSION: WMH lesions were not more numerous in patients with neuroborreliosis compared to healthy controls. However, there was a small reduction of WMH volume from baseline to follow-up among patients, which was associated with higher baseline WMH severity, but not with disease burden or outcome. Overall, non-specific WMHs should not be considered suggestive of neuroborreliosis.

Optic nerve involvement in patients with Lyme neuroborreliosis: an electrophysiological study.

PURPOSE: The aim of this neurophysiological study was to retrospectively analyze visual evoked potentials (VEPs) acquired during an examination for diagnosing optic nerve involvement in patients with Lyme neuroborreliosis (LNB). Attention was focused on LNB patients with peripheral facial palsy (PFP) and optic nerve involvement. METHODS: A total of 241 Czech patients were classified as having probable/definite LNB (193/48); of these, 57 were younger than 40 years, with a median age of 26.3 years, and 184 were older than 40 years, with a median age of 58.8 years. All patients underwent pattern-reversal (PVEP) and motion-onset (MVEP) VEP examinations. RESULTS: Abnormal VEP results were observed in 150/241 patients and were noted more often in patients over 40 years (p = 0.008). Muscle/joint problems and paresthesia were observed to be significantly more common in patients older than 40 years (p = 0.002, p = 0.030), in contrast to headache and decreased visual acuity, which were seen more often in patients younger than 40 years (p = 0.001, p = 0.033). Peripheral facial palsy was diagnosed in 26/241 LNB patients. Among patients with PFP, VEP peak times above the laboratory limit was observed in 22 (84.6%) individuals. Monitoring of patients with PFP and pathological VEP showed that the adjustment of visual system function occurred in half of the patients in one to more years, in contrast to faster recovery from peripheral facial palsy within months in most patients. CONCLUSION: In LNB patients, VEP helps to increase sensitivity of an early diagnostic process.

Diagnosis and management of suspected Lyme neuroborreliosis-related facial nerve palsy in children by paediatricians and general practitioners: a French survey.

The diagnosis and management of facial nerve palsy in children in Lyme borreliosis endemic area can be complex. The objective of this study was to evaluate the diagnosis and management of children with suspected Lyme neuroborreliosis (LNB)-related facial nerve palsy by general practitioners (GP) and paediatricians. We conducted a prospective national survey of clinical practice between September 2018 and January 2020. The questionnaire was intended for GPs and paediatricians. It is based on two distinct clinical situations (a 10-year-old child and a 5-year-old child) and contains questions about the diagnosis and management of facial nerve palsy in children with a recent tick bite. We obtained 598 responses (350/4125 paediatricians and 245/577 GPs). For a 10-year-old child with a facial nerve palsy in the context of a tick bite, more than half of GPs (52%) required a paediatric infectious consultation and 18% an admission to the hospital for lumbar puncture before the result of Lyme serology. The most prescribed antimicrobial therapies were amoxicillin (32%) and ceftriaxone (29%). For a 5-year-old child, there is no difference in the diagnosis of LNB and treatment except for doxycycline which was less prescribed. Concerning treatment, 18% of practitioners prescribed antibiotic therapy only (14% of GPs vs 21% of paediatricians, p = 0.09), and 17% prescribed antibiotic therapy combined with corticosteroids (14% of GPs vs 19% of paediatricians, p = 0.15). Finally, 93% of GPs and 75% of paediatricians reported to be uncomfortable with the diagnosis of LNB in children. CONCLUSION: Most participants were uncomfortable with the diagnosis of LNB. There was a limited difference in the management of LNB in children between GPs and paediatricians. WHAT IS KNOWN: • Lyme neuroborreliosis (LNB) is the second cause of facial nerve palsy in Europe, and its diagnosis is based on neurological symptoms and a lumbar puncture. However, no clinical criteria could be used to differentiate Bell's palsy and LNB. Moreover, data on the adjunctive corticosteroid treatment and outcome in patients with LNB-related facial nerve palsy are controversial. WHAT IS NEW: • Most participants were uncomfortable with the diagnosis of LNB. Its management was heterogeneous and most often not consistent with guidelines. Only 28% of participants requested a lumbar puncture in cases of suspected LNB, and 17% prescribed antibiotics with corticosteroids. • This study highlights the need for new specific guidelines in management (need for lumbar puncture and/or LB serology) and treatment (time to antibiotic initiation, probabilistic therapy, role of corticosteroids, doxycycline in children younger than 8 years) of LNB in children.

Central nervous system manifestations in rheumatic diseases.

As the role of neurologists in managing patients with rheumatic diseases expands, collaboration between rheumatologists and neurologists becomes increasingly vital. This literature review provides an overview of the central nervous system (CNS) manifestations of major autoimmune rheumatic disorders, which may include parenchymal brain and meningeal disease (stroke, meningoencephalitis, meningitis), myelopathies, psychosis, chorea, seizure disorders, and various forms of cephalea. Novel findings linking specific autoimmune markers to CNS damage reveal a direct, previously underestimated link between systemic inflammation and neural injury. Besides, with the increasing use of biological therapies, it is crucial to recognize when neurological manifestations are related to adverse events of therapy, as this may significantly influence treatment decisions. Neurologists play a key role in this assessment, working closely with rheumatologists. Overall, addressing CNS involvement in rheumatic diseases is important for improving patient outcomes and advancing medical knowledge in this complex field. A thorough understanding of the neurologic aspects of rheumatic diseases is essential for optimal patient care, necessitating a multidisciplinary approach to management.

Peripheral facial palsy in children: Serum Borrelia antibodies may reduce the need for lumbar puncture.

AIM: We aimed to investigate the causes of acute peripheral facial palsy (PFP) in Danish children and to explore whether neuroborreliosis-related PFP could be diagnosed without lumbar puncture using clinical symptoms and serum Borrelia burgdorferi (Bb) antibodies. METHODS: This retrospective population-based cohort study included children undergoing lumbar puncture for PFP between 2019 and 2023 in Denmark's Capital Region. Diagnostic performance measures for neuroborreliosis-related PFP were compared between serum Bb IgG alone and clinical risk scores combining Bb IgG with clinical parameters. RESULTS: Of the 326 patients with PFP, 137 (42%) were diagnosed with neuroborreliosis and 151 (46%) had Bell's palsy. Positive predictive value for serum Bb IgG alone was 88% (95% CI 79-93) and negative predictive value was 83% (95% CI 75-88). The positive predictive value of a risk score with seven additional parameters was 90% (95% CI 81-95) and negative predictive value 87% (95% CI 80-92). CONCLUSION: The positive predictive value of serum Bb IgG alone was high in our setting, where nearly half of children with PFP had neuroborreliosis. In high endemic settings, lumbar punctures may be reduced by (i) treating all children with PFP with doxycycline or (ii) treating Bb IgG positive children and performing lumbar puncture in seronegative children.

Clinical characteristics of children with Borrelia-related peripheral facial palsy and utility of cerebrospinal fluid testing.

AIM: To describe the aetiology and clinical characteristics of acute peripheral facial palsy (PFP) in children and investigate the utility of the European Federation of Neurological Societies (EFNS) criteria for diagnosing Borrelia-related PFP (BPFP) based on cerebrospinal fluid (CSF) testing and the Centers for Disease Control and Prevention (CDC) criteria based on serology. METHODS: We retrospectively identified children aged <18 years diagnosed with acute PFP between 2014 and 2020. We used the EFNS criteria as the gold standard and the CDC criteria for diagnosing BPFP. RESULTS: Out of 257 children with PFP, 93 (36%) fulfilled the EFNS or CDC criteria for BPFP. We found a discrepancy between the EFNS criteria with CSF testing and the CDC without CSF testing in 27 (14%) of the 190 children with available data. Of the 37 children with PFP and ≥2 symptoms of fever, fatigue, nausea/vomiting or meningeal symptoms, 31 (84%) fulfilled the EFNS criteria for BPFP. CONCLUSION: Borrelia is a common cause of PFF in children, and its prevalence is higher in children with systemic symptoms. Also, CSF testing did not have decisive management implications in most cases. Therefore, clinical evaluation and Borrelia serology could be the initial steps in the diagnosis of PFP in children.

The Rrp2-RpoN-RpoS pathway plays an important role in the blood-brain barrier transmigration of the Lyme disease pathogen.

Lyme disease, caused by Borrelia (or Borreliella) burgdorferi, is a complex multisystemic disorder that includes Lyme neuroborreliosis resulting from the invasion of both the central and peripheral nervous systems. However, factors that enable the pathogen to cross the blood-brain barrier (BBB) and invade the central nervous system (CNS) are still not well understood. The objective of this study was to identify the B. burgdorferi factors required for BBB transmigration. We utilized a transwell BBB model based on human brain-microvascular endothelial cells and focused on investigating the Rrp2-RpoN-RpoS pathway, a central regulatory pathway that is essential for mammalian infection by B. burgdorferi. Our results demonstrated that the Rrp2-RpoN-RpoS pathway is crucial for BBB transmigration. Furthermore, we identified OspC, a major surface lipoprotein controlled by the Rrp2-RpoN-RpoS pathway, as a significant contributor to BBB transmigration. Constitutive production of OspC in a mutant defective in the Rrp2-RpoN-RpoS pathway did not rescue the impairment in BBB transmigration, indicating that this pathway controls additional factors for this process. Two other major surface lipoproteins controlled by this pathway, DbpA/B and BBK32, appeared to be dispensable for BBB transmigration. In addition, both the surface lipoprotein OspA and the Rrp1 pathway, which are required B. burgdorferi colonization in the tick vector, were found not required for BBB transmigration. Collectively, our findings using in vitro transwell assays uncover another potential role of the Rrp2-RpoN-RpoS pathway in BBB transmigration of B. burgdorferi and invasion into the CNS.

Borrelia bavariensis in Questing Ixodes ricinus Ticks, United Kingdom.

We detected Borrelia bavariensis in Ixodes ricinus ticks collected near 2 towns in the United Kingdom. Human B. bavariensis infections have not been reported previously in the country, underscoring the value of tick surveillance to warn of emerging human disease. B. bavariensis should be considered in patients with suspected neuroborreliosis.

Association of Persistent Symptoms after Lyme Neuroborreliosis and Increased Levels of Interferon-α in Blood.

Patients who have Lyme neuroborreliosis (LNB) might experience lingering symptoms that persist despite antibiotic drug therapy. We tested whether those symptoms are caused by maladaptive immune responses by measuring 20 immune mediators in serum and cerebrospinal fluid (CSF) in 79 LNB patients followed for 1 year. At study entry, most mediators were highly concentrated in CSF, the site of the infection. Those responses resolved with antibiotic therapy, and associations between CSF cytokines and signs and symptoms of LNB were no longer observed. In contrast, subjective symptoms that persisted after use of antibiotics were associated with increased levels of serum interferon-α (IFN-α), which were already observed at study entry, and remained increased at each subsequent timepoint. Highest IFN-α levels corresponded with severe disease. Although the infection serves as the initial trigger, sequelae after antibiotic therapy are associated with unremitting systemic IFN-α levels, consistent with the pathogenic role of this cytokine in interferonopathies in other conditions.

The FGF/FGFR system in the microglial neuroinflammation with Borrelia burgdorferi: likely intersectionality with other neurological conditions.

BACKGROUND: Lyme neuroborreliosis, caused by the bacterium Borrelia burgdorferi affects both the central and peripheral nervous systems (CNS, PNS). The CNS manifestations, especially at later stages, can mimic/cause many other neurological conditions including psychiatric disorders, dementia, and others, with a likely neuroinflammatory basis. The pathogenic mechanisms associated with Lyme neuroborreliosis, however, are not fully understood. METHODS: In this study, using cultures of primary rhesus microglia, we explored the roles of several fibroblast growth factor receptors (FGFRs) and fibroblast growth factors (FGFs) in neuroinflammation associated with live B. burgdorferi exposure. FGFR specific siRNA and inhibitors, custom antibody arrays, ELISAs, immunofluorescence and microscopy were used to comprehensively analyze the roles of these molecules in microglial neuroinflammation due to B. burgdorferi. RESULTS: FGFR1-3 expressions were upregulated in microglia in response to B. burgdorferi. Inhibition of FGFR 1, 2 and 3 signaling using siRNA and three different inhibitors showed that FGFR signaling is proinflammatory in response to the Lyme disease bacterium. FGFR1 activation also contributed to non-viable B. burgdorferi mediated neuroinflammation. Analysis of the B. burgdorferi conditioned microglial medium by a custom antibody array showed that several FGFs are induced by the live bacterium including FGF6, FGF10 and FGF12, which in turn induce IL-6 and/or CXCL8, indicating a proinflammatory nature. To our knowledge, this is also the first-ever described role for FGF6 and FGF12 in CNS neuroinflammation. FGF23 upregulation, in addition, was observed in response to the Lyme disease bacterium. B. burgdorferi exposure also downregulated many FGFs including FGF 5, 7, 9, 11, 13, 16, 20 and 21. Some of the upregulated FGFs have been implicated in major depressive disorder (MDD) or dementia development, while the downregulated ones have been demonstrated to have protective roles in epilepsy, Parkinson's disease, Alzheimer's disease, spinal cord injury, blood-brain barrier stability, and others. CONCLUSIONS: In this study we show that FGFRs and FGFs are novel inducers of inflammatory mediators in Lyme neuroborreliosis. It is likely that an unresolved, long-term (neuro)-Lyme infection can contribute to the development of other neurologic conditions in susceptible individuals either by augmenting pathogenic FGFs or by suppressing ameliorative FGFs or both.

Primary perineuritis, a rare but treatable neuropathy: Review of perineurial anatomy, clinicopathological features, and differential diagnosis.

The perineurium surrounds each fascicle in peripheral nerves, forming part of the blood-nerve barrier. We describe its normal anatomy and function. "Perineuritis" refers to both a nonspecific histopathological finding and more specific clinicopathological entity, primary perineuritis (PP). Patients with PP are often assumed to have nonsystemic vasculitic neuropathy until nerve biopsy is performed. We systematically reviewed the literature on PP and developed a differential diagnosis for histopathologically defined perineuritis. We searched PubMed, Embase, Scopus, and Web of Science for "perineuritis." We identified 20 cases (11 M/9F) of PP: progressive, unexplained neuropathy with biopsy showing perineuritis without vasculitis or other known predisposing condition. Patients ranged in age from 18 to 75 (mean 53.7) y and had symptoms 2-24 (median 4.5) mo before diagnosis. Neuropathy was usually sensory-motor (15/20), painful (18/19), multifocal (16/20), and distal-predominant (16/17) with legs more affected than arms. Truncal numbness occurred in 6/17; 10/18 had elevated cerebrospinal fluid (CSF) protein. Electromyography (EMG) and nerve conduction studies (NCS) demonstrated primarily axonal changes. Nerve biopsies showed T-cell-predominant inflammation, widening, and fibrosis of perineurium; infiltrates in epineurium in 10/20 and endoneurium in 7/20; and non-uniform axonal degeneration. Six had epithelioid cells. 19/20 received corticosteroids, 8 with additional immunomodulators; 18/19 improved. Two patients did not respond to intravenous immunoglobulin (IVIg). At final follow-up, 13/16 patients had mild and 2/16 moderate disability; 1/16 died. Secondary causes of perineuritis include leprosy, vasculitis, neurosarcoidosis, neuroborreliosis, neurolymphomatosis, toxic oil syndrome, eosinophilia-myalgia syndrome, and rarer conditions. PP appears to be an immune-mediated, corticosteroid-responsive disorder. It mimics nonsystemic vasculitic neuropathy. Cases with epithelioid cells might represent peripheral nervous system (PNS)-restricted forms of sarcoidosis.

Lyme neuroborreliosis: An unusual case with extensive (peri)vasculitis of the middle cerebral artery.

Lyme disease is a tick-borne infection caused by Borrelia burgdorferi sensu latu. Neuroborreliosis is reported in approximately 10% of patients with Lyme disease. We report a patient with central nervous system (CNS) large vessel vasculitis, ischemic stroke, and tumefactive contrast-enhancing brain lesions, an unusual complication of neuroborreliosis. A 56-year-old man presented with headache and disorientation for 1 month. Magnetic resonance imaging revealed basal meningitis with rapidly progressing frontotemporoinsular edema and (peri)vasculitis. Transcranial ultrasound confirmed stenosed medial cerebral arteries. [18 F]GE-180 microglia positron emission tomography (PET) showed frontotemporoinsular signal more pronounced on the right. [18 F]FET amino acid PET demonstrated low tracer uptake, suggesting an inflammatory process. Cerebrospinal fluid (CSF) showed lymphomonocytosis (243/µl), intrathecal anti-Borrelia IgM (CSF/serum index = 15.65, normal < 1.5) and anti-Borrelia IgG (CSF/serum index = 6.5, normal < 1.5), and elevated CXCL13 (29.2 pg/ml, normal < 10 pg/ml). Main differential diagnoses of neurotuberculosis and perivascular CNS lymphoma were ruled out by biopsy and Quantiferon enzyme-linked immunosorbent assay. Ceftriaxone (28 days), cortisone, and nimodipine (3 months) led to full recovery. Neuroborreliosis is an important differential diagnosis in patients with CNS large vessel vasculitis and tumefactive contrast-enhancing brain lesions, mimicking perivascular CNS lymphoma or neurotuberculosis as main neuroradiological differential diagnoses. Vasculopathy and cerebrovascular events are rare in neuroborreliosis but should be considered, especially in endemic areas.

Plasma neurofilament light significantly decreases following treatment in Lyme neuroborreliosis and is not associated with persistent symptoms.

BACKGROUND AND PURPOSE: Currently there is an unmet need for a highly standardized blood biomarker test to monitor treatment response in Lyme neuroborreliosis (LNB). Differentiating between active or past infection is challenged by the relatively high frequency of persistent symptoms after the end of antibiotic treatment (estimated 15%-20%), the variable clinical course and the long-lasting Borrelia burgdorferi antibodies. The aim was therefore to evaluate plasma neurofilament light chain (pNfL) as a marker for disease activity in LNB. METHODS: This was a prospective cohort of definite LNB (N = 36) with blood samples and clinical evaluation including Glasgow Outcome Score at treatment initiation and 3 and 6 months' follow-up. Consecutive plasma was retrospectively analysed for the content of neurofilament light chain by Quanterix® kits (Simoa® NF-light Kit). RESULTS: Plasma neurofilament light chain significantly decreased between treatment initiation and the 3-month follow-up (median 83 pg/ml vs. median 14 pg/ml (25 pairs), p < 0.0001). No significant change was observed between 3 and 6 months' follow-up (median 14 pg/ml vs. median 12 pg/ml (21 pairs), p = 0.33). At treatment initiation 90% had pNfL above the age-defined reference compared to only 23% and 7% respectively at 3 and 6 months' follow-up. Decreases in pNfL were mirrored by increasing Glasgow Outcome Score. Reporting persistent symptoms at the 6-month follow-up was not associated with pNfL (relative change from reference or actual values) at baseline or at 6 months' follow-up. CONCLUSION: Plasma neurofilament light chain decreases following antibiotic treatment in LNB and is not associated with reporting persistent symptoms. It was therefore speculated that it may prove useful as a treatment response biomarker in LNB.