Antibiotics for the neurological complications of Lyme disease.

BACKGROUND: Various central nervous system-penetrant antibiotics are bactericidal in vitro and in vivo against the causative agent of Lyme neuroborreliosis (LNB), Borrelia burgdorferi. These antibiotics are routinely used clinically to treat LNB, but their relative efficacy is not clear. OBJECTIVES: To assess the effects of antibiotics for the treatment of LNB. SEARCH METHODS: On 25 October 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched clinical trial registers on 26 October 2016. We reviewed the bibliographies of the randomized trials identified and contacted the authors and known experts in the field to identify additional published or unpublished data. There were no language restrictions when searching for studies. SELECTION CRITERIA: Randomized clinical trials of antibiotic treatment of LNB in adults and children that compared any antibiotic treatment, including combinations of treatments, versus any other treatment, placebo, or no treatment. We excluded studies of entities considered as post-Lyme syndrome. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified seven randomized studies involving 450 European participants with LNB for inclusion in this systematic review. We found no trials conducted in the United States. Marked heterogeneity among these studies prevented meta-analysis. None of the studies included a placebo control on the initial antibiotic treatment, and only one was blinded. None were delayed-start studies. All were active comparator studies, and most were not adequately powered for non-inferiority comparison. The trials investigated four antibiotics: penicillin G and ceftriaxone in four studies, doxycycline in three studies, and cefotaxime in two studies. One study tested a three-month course of oral amoxicillin versus placebo following initial treatment with intravenous ceftriaxone. One study was limited to children. The trials measured efficacy using heterogeneous physician- or patient-reported outcomes, or both. In some cases cerebrospinal fluid analysis was included as an indirect biomarker of disease and outcome. None of the studies reported on our proposed primary outcome, 'Improvement in a measure of overall disability in the long term (three or more months).' None of the trials revealed any between-group differences in symptom resolution in response to active treatment. In general, treatment was tolerated well. The quality of adverse event reporting, however, was low. AUTHORS' CONCLUSIONS: There is mostly low- to very low-quality clinical evidence from a limited number of mostly small, heterogeneous trials with diverse outcome measures, comparing the relative efficacy of central nervous system-penetrant antibiotics for the treatment of LNB. The few existing randomized studies have limited power and lack consistent and well-defined entry criteria and efficacy endpoints. It is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of LNB. The majority of people are reported to have good outcomes, and symptoms resolve by 12 months regardless of the antibiotic used. A minority of participants did not improve sufficiently, and some were retreated. These randomized studies provide some evidence that doxycycline, penicillin G, ceftriaxone, and cefotaxime are efficacious in the treatment of European LNB. No evidence of additional efficacy was observed when, in one study, an initial antibiotic treatment with intravenous ceftriaxone was followed by additional longer treatment with oral amoxicillin. There is a lack of evidence identified through our high-quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.

High production of CXCL13 in blood and brain during persistent infection with the relapsing fever spirochete Borrelia turicatae.

Relapsing fever (RF) is a multisystemic borrelial infection with frequent neurologic involvement referred to as neuroborreliosis. The absence of an effective antibody response results in persistent infection. To study the consequences to the brain of persistent infection with the RF spirochete Borrelia turicatae, we studied B cell (Igh6-/-) and B and T (Rag1-/-) cell-deficient mice inoculated with isogenic serotypes 1 (Bt1) or 2 (Bt2). We found that Bt1 was more tissue tropic than Bt2, not only for brain but also for heart. Igh6-/- mice developed more severe clinical disease than Rag1-/- mice. Bt1-infected brains had widespread microgliosis/brain macrophage activation despite localization of spirochetes in the leptomeninges rather than the brain parenchyma itself. Oligoarray analysis revealed that CXCL13 was the most upregulated gene in the brain of Bt1-infected Igh6-/- mice. CXCL13 was also the most abundant of the chemokines we measured in infected blood. Persistent infection did not result in injury to the brain. Treatment with exogenous interleukin-10 reduced microgliosis in the brain and production of CXCL13 in the blood. We concluded that brain involvement in B cell-deficient mice persistently infected with B. turicatae is characterized by prominent microgliosis and production of CXCL13 without detectable injury.

Bupropion for the treatment of apathy in Huntington's disease: A multicenter, randomised, double-blind, placebo-controlled, prospective crossover trial.

OBJECTIVE: To evaluate the efficacy and safety of bupropion in the treatment of apathy in Huntington's disease (HD). METHODS: In this phase 2b multicentre, double-blind, placebo-controlled crossover trial, individuals with HD and clinical signs of apathy according to the Structured Clinical Interview for Apathy-Dementia (SCIA-D), but not depression (n = 40) were randomized to receive either bupropion 150/300mg or placebo daily for 10 weeks. The primary outcome parameter was a significant change of the Apathy Evaluation Scale (AES) score after ten weeks of treatment as judged by an informant (AES-I) living in close proximity with the study participant. The secondary outcome parameters included changes of 1. AES scores determined by the patient (AES-S) or the clinical investigator (AES-C), 2. psychiatric symptoms (NPI, HADS-SIS, UHDRS-Behavior), 3. cognitive performance (SDMT, Stroop, VFT, MMSE), 4. motor symptoms (UHDRS-Motor), 5. activities of daily function (TFC, UHDRS-Function), and 6. caregiver distress (NPI-D). In addition, we investigated the effect of bupropion on brain structure as well as brain responses and functional connectivity during reward processing in a gambling task using magnetic resonance imaging (MRI). RESULTS: At baseline, there were no significant treatment group differences in the clinical primary and secondary outcome parameters. At endpoint, there was no statistically significant difference between treatment groups for all clinical primary and secondary outcome variables. Study participation, irrespective of the intervention, lessened symptoms of apathy according to the informant and the clinical investigator. CONCLUSION: Bupropion does not alleviate apathy in HD. However, study participation/placebo effects were observed, which document the need for carefully controlled trials when investigating therapeutic interventions for the neuropsychiatric symptoms of HD. TRIAL REGISTRATION: ClinicalTrials.gov 01914965.

Borrelia burgdorferi Induces TLR1 and TLR2 in human microglia and peripheral blood monocytes but differentially regulates HLA-class II expression.

The spirochete Borrelia burgdorferi is the agent of Lyme disease, which causes central nervous system manifestations in up to 20% of patients. We investigated the response of human brain microglial cells, glial progenitors, neurons, astrocytes, as well as peripheral blood monocytes to stimulation with B. burgdorferi. We used oligoarrays to detect changes in the expression of genes important for shaping adaptive and innate immune responses. We found that stimulation with B. burgdorferi lysate increased the expression of Toll-like receptors (TLRs) 1 and 2 in all cell types except neurons. However, despite similarities in global gene profiles of monocytes and microglia, only microglial cells responded to the stimulation with a robust increase in HLA-DR, HLA-DQ, and also coexpressed CD11-c, a dendritic cell marker. In contrast, a large number of HLA-related molecules were repressed at both the RNA and the protein levels in stimulated monocytes, whereas secretion of IL-10 and TNF-alpha was strongly induced. These results show that signaling through TLR1/2 in response to B. burgdorferi can elicit opposite immunoregulatory effects in blood and in brain immune cells, which could play a role in the different susceptibility of these compartments to infection.

Peptidic complex mixtures as therapeutic agents in CNS autoimmunity.

Limited success with antigen-specific immunotherapies has led to the identification of novel approaches which consider the degeneracy of the T cell response, i.e. their ability to respond to multiple antigenic peptides. Random complex mixtures of polypeptides such as glatiramer acetate (GA) were among the first to be applied as immunodulators that take into account T cell degeneracy. While the mechanisms of action are not completely understood, the immunogenicity of GA, its strong major histocompatability complex (MHC) binding, immune deviation and bystander suppression all appear to be important. In the present study we have designed peptidic complex mixtures (CM) of varied lengths and compositions to test their potential as immunomodulating agents. CM were synthesized that had defined lengths and contained aa corresponding to binding motifs of MHC class II molecules relevant in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), specifically HLA-DRB1*1501 and HLA-DRB5*0101, which are related to MS, and H2-IA(s) associated with EAE in SJL mice. Additional CM were designed based on specificity profiles derived from positional scanning synthetic combinatorial library (PS-SCL) testing of a GA-specific T cell clone (TCC). Several mixtures were strongly stimulatory for peripheral blood mononuclear cells (PBMC) from MS patients and healthy donors suggesting a high degree of cross-reactivity with other peptide antigens. A subset of these mixtures exhibited cross-reactivity to myelin antigens and prophylactic efficacy in reducing the severity of EAE. Based on these observations we envision mixture-based peptidic compounds can be developed not only for immunotherapeutic purposes in autoimmune diseases and cancer, but also in vaccine development.

Severe cognitive impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis.

IMPORTANCE: Some patients with multiple sclerosis (MS) can either present with or develop severe cognitive impairment during the course of their disease. However, the mechanisms underlying severe cognitive dysfunction in MS are not well understood. OBSERVATIONS: We report on a woman who was diagnosed as having MS at age 33 years and who after giving birth at age 37 years developed cognitive impairment with severe memory dysfunction as the leading symptom. Treatment with different immunotherapies, including cyclophosphamide and natalizumab, did not improve her cognitive deficits, necessitating admission to a nursing home at age 39 years. During a thorough reevaluation at age 43 years, analysis of current and stored cerebrospinal fluid and serum samples demonstrated an intrathecal synthesis of IgG antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor, that is, the characteristic laboratory finding of anti-N-methyl-D-aspartate receptor encephalitis. Although the patient initially stabilized under therapy with corticosteroids, plasma exchange, and mitoxantrone, severe cognitive impairment persisted and she eventually died from the sequelae of her disease. CONCLUSIONS AND RELEVANCE: This report suggests that the occasional occurrence of severe cognitive impairment in patients with MS may, in some cases, be related to a superimposed antibody-mediated autoimmune encephalitis.

Research opportunities on human neuroborreliosis.

A workshop, sponsored by the National Institutes of Health, was convened in September 2001 to evaluate the current knowledge in neurological Lyme disease. The meeting was centered into discussion of both clinical and basic aspects of the disease. Participants included researchers from the fields of infectious diseases, neurology, rheumatology, autoimmunity and basic immunology, largely but not exclusively focused on Lyme disease. This report summarizes the presentations made at the meeting.

Coinfection with Borrelia turicatae serotype 2 prevents the severe vestibular dysfunction and earlier mortality caused by serotype 1.

BACKGROUND: Relapsing fever (RF) is a multisystemic spirochetal infection caused by different Borrelia species. Studies in our laboratory have shown that disease severity varies depending on the infecting serotype. However, the relative contribution of each serotype to pathogenesis during mixed infections is not known. To investigate this, we compared the outcome of infection with isogenic serotypes 1 (Bt1) or 2 (Bt2) of the RF agent B. turicatae alone or in combination. METHODS: B cell-deficient mice were used for these experiments, to avoid serotype clearance by the host's variable membrane protein-specific antibodies. Observers masked to infection status examined infected and uninfected control mice for clinical disease and functional impairment for up to 65 days. RESULTS: All mice developed persistent infection with the serotypes with which they were originally inoculated. Severe vestibular dysfunction developed in mice infected with Bt1 alone and was associated with increased morbidity and mortality. However, coinfection with Bt2 significantly reduced the severity of vestibular dysfunction and prevented earlier mortality. In contrast, coinfection with Bt1 had little effect on the severe arthritis caused by Bt2 infection. CONCLUSIONS: The manifestations of infection with B. turicatae are significantly influenced by the combination of serotypes present during mixed infection.

Cerebrospinal fluid-infiltrating CD4+ T cells recognize Borrelia burgdorferi lysine-enriched protein domains and central nervous system autoantigens in early lyme encephalitis.

Neurological manifestations of Lyme disease are usually accompanied by inflammatory changes in the cerebrospinal fluid (CSF) and the recruitment of activated T cells into the CSF compartment. In order to characterize the phenotype and identify target antigens of CSF-infiltrating T cells in early neuroborreliosis with central nervous system (CNS) involvement, we combined T-cell cloning, functional testing of T-cell responses with positional scanning synthetic combinatorial peptide libraries, and biometric data analysis. We demonstrate that CD4+ gamma interferon-producing T cells specifically responding to Borrelia burgdorferi lysate were present in the CSF of a patient with acute Lyme encephalitis. Some T-cell clones recognized previously uncharacterized B. burgdorferi epitopes which show a specific enrichment for lysine, such as the heat shock-induced chaperone HSP90. Degenerate T-cell recognition that included T-cell responses to borrelia-specific and CNS-specific autoantigens derived from the myelin protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) could be demonstrated for one representative clone. Our results show that spirochetal antigen-specific and Th1-polarized CD4+ lymphocytes infiltrate the CSF during monophasic CNS symptoms of Lyme disease and demonstrate that cross-recognition of CNS antigens by B. burgdorferi-specific T cells is not restricted to chronic and treatment-resistant manifestations.

Role of interleukin 10 during persistent infection with the relapsing fever Spirochete Borrelia turicatae.

Relapsing fever is an infection characterized by peaks of spirochetemia attributable to antibody selection against variable serotypes. In the absence of B cells, serotypes cannot be cleared, resulting in persistent infection. We previously identified differences in spirochetemia and disease severity during persistent infection of severe combined immunodeficiency mice with isogenic serotypes 1 (Bt1) or 2 (Bt2) of Borrelia turicatae. To investigate this further, we studied pathogen load, clinical disease, cytokine/chemokine production, and inflammation in mice deficient in B (Igh6-/-) or B and T (Rag1-/-) cells persistently infected with Bt1 or Bt2. The results showed that Igh6-/- mice, despite lower spirochetemia, had a significantly aggravated disease course compared with Rag1-/- mice. Measurement of cytokines revealed a significant positive correlation between pathogen load and interleukin (IL)-10 in blood, brain, and heart. Bt2-infected Rag1-/- mice harbored the highest spirochetemia and, at the same time, displayed the highest IL-10 plasma levels. In the brain, Bt1, which was five times more neurotropic than Bt2, caused higher IL-10 production. Activated microglia were the main source of IL-10 in brain. IL-10 injected systemically reduced disease and spirochetemia. The results suggest IL-10 plays a protective role as a down-regulator of inflammation and pathogen load during infection with relapsing fever spirochetes.

Borrelia burgdorferi lipoprotein-mediated TLR2 stimulation causes the down-regulation of TLR5 in human monocytes.

Toll-like receptors (TLRs) trigger innate immune responses via the recognition of conserved pathogen-associated molecular patterns. Lipoproteins from Borrelia burgdorferi, the agent of Lyme disease, activate inflammatory cells through TLR2 and TLR1. We show that stimulation of human monocytes with B. burgdorferi lysate, lipidated outer surface protein A, and triacylated lipopeptide Pam3CysSerLys4 results in the up-regulation of both TLR2 and TLR1 but the down-regulation of TLR5, the receptor for bacterial flagellin, and that this effect is mediated via TLR2. TLR4 stimulation had no effect on TLR2, TLR1, and TLR5 expression. Human monocytes stimulated with TLR5 ligands (including p37 or flaA, the minor protein from B. burgdorferi flagella) up-regulated TLR5. In addition, TLR2 stimulation rendered cells hyporesponsive to a TLR5 agonist. These results indicate that diverse stimuli can cause differential TLR expression, and we hypothesize that these changes may be useful for either the pathogen and/or the host.

Cardiac apoptosis in severe relapsing fever borreliosis.

Previous studies revealed that the heart suffers significant injury during experimental Lyme and relapsing fever borreliosis when the immune response is impaired (D. Cadavid, Y. Bai, E. Hodzic, K. Narayan, S. W. Barthold, and A. R. Pachner, Lab. Investig. 84:1439-1450, 2004; D. Cadavid, T. O'Neill, H. Schaefer, and A. R. Pachner, Lab. Investig. 80:1043-1054, 2000; and D. Cadavid, D. D. Thomas, R. Crawley, and A. G. Barbour, J. Exp. Med. 179:631-642, 1994). To investigate cardiac injury in borrelia carditis, we used antibody-deficient mice persistently infected with isogenic serotypes of the relapsing fever agent Borrelia turicatae. We studied infection in hearts 1 to 2 months after inoculation by TaqMan reverse transcription-PCR and immunohistochemistry (IHC) and inflammation by hematoxylin and eosin and trichrome staining, IHC, and in situ hybridization (ISH). We studied apoptosis by terminal transferase-mediated DNA nick end labeling assay and measured expression of apoptotic molecules by RNase protection assay, immunofluorescence, and immunoblot. All antibody-deficient mice, but none of the immunocompetent controls, developed persistent infection of the heart. Antibody-deficient mice infected with serotype 2 had more severe cardiac infection and injury than serotype 1-infected mice. The injury was more severe around the base of the heart and pericardium, corresponding to sites of marked infiltration by activated macrophages and upregulation of interleukin-6 (IL-6). Infected hearts showed evidence of apoptosis of macrophages and cardiomyocytes as well as significant upregulation of caspases, most notably caspase-1. We conclude that persistent infection with relapsing fever borrelias causes significant loss of cardiomyocytes associated with prominent infiltration by activated macrophages, upregulation of IL-6, induction of caspase-1, and apoptosis.