Lyme neuroborreliosis with encephalitis; a systematic literature review and a Scandinavian cohort study

Background Lyme neuroborreliosis (LNB) presenting with encephalitis is rare and scarcely described. Objectives To describe the available literature on LNB encephalitis and to characterize this patient group through a Scandinavian retrospective cohort study. Data sources Medline, Embase, Scopus, Cochrane library. Study eligibility criteria There was no discrimination on study type, time of publication or language. Participants Review: All articles with definite LNB and confirmed/possible encephalitis. Cohort: LNB cohorts from Denmark, Sweden and Norway 1990–2019 were screened for patients with encephalitis. Methods Review: Adhering to PRISMA guidelines; two authors extracted reviews and assessed quality of studies. Cohort: Data on demography, symptoms, cerebrospinal fluid findings, differential diagnostic examinations, treatment, residual symptoms, 1-year mortality were registered. Results Review: 2330 articles screened on title/abstract, 281 full texts, yielding 42 articles (case reports/series or cohort studies), including 45 patients from 18 countries spanning 35 years. Altered mental status ranged from personality changes and confusion to unconsciousness. Common focal symptoms were hemiparesis, ataxia and dysarthria; seven patients had seizures. Median time from symptom onset to hospital was 2 weeks (IQR 2–90 days). Of 38 patients with available follow-up after median 12 months (IQR 5–13), 32 had fully or partially recovered, two had died. Cohort: Thirty-five patients (median age 67 years, IQR 48–76) were included. The encephalitis prevalence was 3.3% (95% CI 2.2–4.4%) among 1019 screened LNB patients. Frequent encephalitis symptoms were confusion, personality changes, aphasia, ataxia. EEGs and neuroimaging showed encephalitis in 93.8% and 20.6%, respectively. Median delay from symptom onset to hospital was 14 days (IQR 7–34), with further 7 days (IQR 3–34) delay until targeted therapy. At follow-up (median 298 days post-treatment; IQR 113–389), 65.6% had residual symptoms. None had died. Conclusions This study shows that encephalitis is an uncommon, but likely overlooked clinical manifestation of LNB. As the high frequency of residual symptoms may be related to prolonged treatment delay, prompt LNB testing of patients with encephalitis in Borrelia burgdorferi-endemic areas should be considered.publishedVersio

Serum and cerebrospinal fluid brain damage markers neurofilament light and glial fibrillary acidic protein correlate with tick-borne encephalitis disease severity—a multicentre study on Lithuanian and Swedish patients

Background and purpose: Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis.// Methods: One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and cerebrospinal fluid (CSF) and serum samples were obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate or severe tick-borne encephalitis. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of the brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL-40, S100B, neurogranin, neurofilament light (NfL) and tau were analysed in CSF and, in addition, NfL, GFAP and S100B levels were measured in serum. The Jonckheere-Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test was used to adjust for age.// Results: Cerebrospinal fluid and serum concentrations of GFAP and NfL correlated with disease severity, independent of age, and with the presence of nerve paralysis. The markers neurogranin, YKL-40, tau and S100B in CSF and S100B in serum were detected, but their concentrations did not correlate with disease severity.// Conclusions: Neuronal cell damage and astroglial cell activation with increased NfL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NfL concentrations in CSF and NfL in serum were also indicative of spinal and/or cranial nerve damage. NfL and GFAP are promising prognostic biomarkers in tick-borne encephalitis, and future studies should focus on determining the association between these biomarkers and long-term sequelae

Antibiotic therapy of neuroborreliosis:A survey among infectious disease specialists and neurologists in Norway, Sweden, and Denmark

Introduction: Neuroborreliosis (NB) is a prevalent tick-borne neuroinfection in Europe. To delineate current practice in antimicrobial management of adults with NB and to prioritize future trials needed to optimize treatment recommendations, a questionnaire-based survey was performed. Methods: A self-administered Internet-based survey of NB treatment practices among specialists in infectious diseases and neurology based in Norway, Sweden, and Denmark was carried out between October 2021 and February 2022. The participants were also asked to prioritize four pre-defined research questions for randomized controlled trials (RCTs) on therapy for NB. Results: In total, 290 physicians (45% female) from Norway (30%), Sweden (40%), and Denmark (30%) participated in the survey. Of the responders, 230 (79%) were infectious disease specialists and 56 (19%) were neurologists. The preferred antibiotic treatment for patients with early NB was oral doxycycline (n = 225, 78%). Intravenous (IV) penicillin, ceftriaxone, or cefotaxime for the full treatment course was favored by 12%. A preferred treat- ment duration of 10–14 days for patients with NB was reported by 245 respondents (85%), most common among participants from Sweden (97%). A total of 170 (59%) responders reported having local hospital guidelines on the treatment of NB, most often with recommendation of oral doxycycline (92%) for 10–14 days (90%) as first line treatment. The prioritization score for future RCTs was highest for adjunctive prednisone therapy in NB patients with facial palsy (median 5; IQR 4–6) and for placebo versus repeated antibiotics in patients with persistent symptoms after completed antibiotic therapy for NB (median 5, IQR 3–6). Conclusion: In Sweden, all respondents preferred treating NB with oral doxycycline for 10–14 days, whereas 5% in Norway and 19% in Denmark still treat NB with IV antibiotics for the entire treatment course. RCTs to define the role of adjunctive prednisolone in NB patients with facial palsy and repeated antibiotics in patients with persistent symptoms are prioritized for future research.publishedVersio

Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms

Importance: Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF). / Objective: To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity. Design, Setting, and / Participants: This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included. / Exposure: SARS-CoV-2 infection. / Main Outcomes and Measures: Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, β2-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL]). / Results: Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on the World Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P = .03) and interferon γ (r = 0.42; P = .01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, β2-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor α compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon γ (86 [47-172] vs 21 [17-81] fg/mL; P = .03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P = .04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P = .002). No differences were seen in any CSF biomarkers in moderate compared with severe disease. / Conclusions and Relevance: In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion

Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism

<p>Abstract</p> <p>Background</p> <p>The metabolism of amyloid precursor protein (APP) and β-amyloid (Aβ) is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB).</p> <p>Methods</p> <p>The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy) and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP) isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau), phosphorylated tau (P-tau) and neurofilament protein (NFL) were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers.</p> <p>Results</p> <p>In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up.</p> <p>Conclusions</p> <p>Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.</p

Lyme neuroborreliosis in HIV-1 positive men successfully treated with oral doxycycline: a case series and literature review

Abstract Introduction Lyme neuroborreliosis is the most common bacterial central nervous system infection in the temperate parts of the northern hemisphere. Even though human immunodeficiency virus (HIV) -1 infection is common in Lyme borreliosis endemic areas, only five cases of co-infection have previously been published. Four of these cases presented with typical Lyme neuroborreliosis symptoms such as meningoradiculitis and facial palsy, while a fifth case had more severe symptoms of encephalomyelitis. All five were treated with intravenous cephalosporins and clinical outcome was good for all but the fifth case Case presentations We present four patients with concomitant presence of HIV-1 infection and Lyme neuroborreliosis diagnosed in Western Sweden. Patient 1 was a 60-year-old Caucasian man with radicular pain and cognitive impairment. Patient 2 was a 39-year-old Caucasian man with headaches, leg weakness, and pontine infarction. Patient 3 was a 62-year-old Caucasian man with headaches, tremor, vertigo, and normal-pressure hydrocephalus. Patient 4 was a 50-year-old Caucasian man with radicular pain and peripheral facial palsy. Patients one, two, and three all had subnormal levels of CD4 cells, indicating impaired immunity. All patients were treated with oral doxycycline with good clinical outcome and normalization of CSF pleocytosis. Conclusion Given the low HIV-1 prevalence and medium incidence of Lyme neuroborreliosis in Western Sweden where these four cases were diagnosed, co-infection with HIV-1 and Borrelia is probably more common than previously thought. The three patients that were the most immunocompromised suffered from more severe and rather atypical neurological symptoms than are usually described among patients with Lyme neuroborreliosis. It is therefore important for doctors treating HIV patients to consider Lyme neuroborreliosis in a patient presenting with atypical neurological symptoms. All four patients were treated with oral doxycycline with a good outcome, further proving the efficacy of this regime.</p