Serum neurofilament light chain associates with symptom burden in Lyme neuroborreliosis patients: a longitudinal cohort study from Norway.

OBJECTIVES: Serum neurofilament light chain (sNfL), an indicator of neuronal damage, is increasingly recognized as a potential biomarker for disease activity in neurodegenerative disorders. In this study, we wanted to investigate sNfL as a prognostic marker in a large, well-defined population of 90 patients with Lyme neuroborreliosis (LNB). In addition, we sought to explore associations between symptoms and sNfL levels during the acute phase of LNB. MATERIALS AND METHODS: Patients diagnosed with definite or possible LNB were recruited from a double-blinded, placebo-controlled, multi-center trial, in which the participants were randomly assigned to 2 or 6 weeks of oral doxycycline treatment. The sNfL levels were measured using a single molecule array assay at both diagnosis and 6-month follow-up, and analysed against clinical parameters, variations in symptom burden and long-term complaints as assessed by a composite clinical score. RESULTS: At the time of diagnosis, approximately 60% of the patients had elevated sNfL levels adjusted for age. Notably, mean sNfL levels were significantly higher at diagnosis (52 pg/ml) compared to 6 months after treatment (12 pg/ml, p < 0.001), when sNfL levels had normalized in the majority of patients. Patients with objective signs of spinal radiculitis had significantly higher baseline sNfL levels compared to patients without spinal radiculitis (p = 0.033). CONCLUSION: Our findings suggest that sNfL can serve as a biomarker for peripheral nerve tissue involvement in the acute phase of LNB. As found in an earlier study, we confirm normalization of sNfL levels in blood after treatment. We found no prognostic value of acute-phase sNfL levels on patient outcome.

Tick-borne diseases in the North Sea region-A comprehensive overview and recommendations for diagnostics and treatment.

As part of the NorthTick project, co-funded by the European Union through the European Regional Development Fund and the North Sea Region Programme, specialists in the field of tick-borne diseases from seven North Sea countries co-operated with patient organisations and governmental health care institutions to provide this comprehensive overview of diagnostics and treatment recommendations in the region for Lyme borreliosis, Borrelia miyamotoi infection, tick-borne encephalitis, human granulocytic anaplasmosis, rickettsiosis, neoehrlichiosis and babesiosis. The main conclusion is that the recommendations in these northern countries are essentially the same, with very few differences. This overview presents the current diagnostics and provides useful clinical guidance.

Risk factors for SARS-CoV-2 infection: a test-negative case-control study with additional population controls in Norway.

OBJECTIVES: This study aims to assess risk factors for SARS-CoV-2 infection by combined design; first comparing positive cases to negative controls as determined by PCR testing and then comparing these two groups to an additional prepandemic population control group. DESIGN AND SETTING: Test-negative design (TND), multicentre case-control study with additional population controls in South-Eastern Norway. PARTICIPANTS: Adults who underwent SARS-CoV-2 PCR testing between February and December 2020. PCR-positive cases, PCR-negative controls and additional age-matched population controls. PRIMARY OUTCOME MEASURES: The associations between various risk factors based on self- reported questionnaire and SARS-CoV-2 infection comparing PCR-positive cases and PCR-negative controls. Using subgroup analysis, the risk factors for both PCR-positive and PCR-negative participants were compared with a population control group. RESULTS: In total, 400 PCR-positive cases, 719 PCR-negative controls and 14 509 population controls were included. Male sex was associated with the risk of SARS-CoV-2 infection only in the TND study (OR 1.9, 95% CI 1.4 to 2.6), but not when PCR-positive cases were compared with population controls (OR 1.2, 95% CI 0.9. to 1.5). Some factors were positively (asthma, wood heating) or negatively (hypertension) associated with SARS-CoV-2 infection when PCR-positive cases were compared with population controls, but lacked convincing association in the TND study. Smoking was negatively associated with the risk of SARS-CoV-2 infection in both analyses (OR 0.5, 95% CI 0.3 to 0.8 and OR 0.6, 95% CI 0.4 to 0.8). CONCLUSIONS: Male sex was a possible risk factor for SARS-CoV-2 infection only in the TND study, whereas smoking was negatively associated with SARS-CoV-2 infection in both the TND study and when using population controls. Several factors were associated with SARS-CoV-2 infection when PCR-positive cases were compared with population controls, but not in the TND study, highlighting the strength of combining case-control study designs during the pandemic.

Dynamic contrast-enhanced MRI shows altered blood-brain barrier function of deep gray matter structures in neuroborreliosis: a case-control study.

BACKGROUND: Main aim was assessment of regional blood-brain barrier (BBB) function by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with neuroborreliosis. Secondary aim was to study the correlation of BBB function with biochemical, clinical, and cognitive parameters. METHODS: Regional ethical committee approved this prospective single-center case-control study. Within 1 month after diagnosis of neuroborreliosis, 55 patients underwent DCE-MRI. The patient group consisted of 25 males and 30 females with mean age 58 years, and the controls were 8 males and 7 females with mean age 57 years. Pharmacokinetic compartment modelling with Patlak fit was applied, providing estimates for capillary leakage rate and blood volume fraction. Nine anatomical brain regions were sampled with auto-generated binary masks. Fatigue, severity of clinical symptoms and findings, and cognitive function were assessed in the acute phase and 6 months after treatment. RESULTS: Leakage rates and blood volume fractions were lower in patients compared to controls in the thalamus (p = 0.027 and p = 0.018, respectively), caudate nucleus (p = 0.009 for both), and hippocampus (p = 0.054 and p = 0.009). No correlation of leakage rates with fatigue, clinical disease severity or cognitive function was found. CONCLUSIONS: In neuroborreliosis, leakage rate and blood volume fraction in the thalamus, caudate nucleus, and hippocampus were lower in patients compared to controls. DCE-MRI provided new insight to pathophysiology of neuroborreliosis, and can serve as biomarker of BBB function and regulatory mechanisms of the neurovascular unit in infection and inflammation. RELEVANCE STATEMENT: DCE-MRI provided new insight to pathophysiology of neuroborreliosis, and can serve as biomarker of blood-brain barrier function and regulatory mechanisms of the neurovascular unit in infection and inflammation. KEY POINTS: • Neuroborreliosis is an infection with disturbed BBB function. • Microvessel leakage can be studied with DCE-MRI. • Prospective case-control study showed altered microvessel properties in thalamus, caudate, and hippocampus.

Assessment of cognitive function, structural brain changes and fatigue 6 months after treatment of neuroborreliosis.

BACKGROUND: Complete recovery after adequately treated neuroborreliosis is common, but studies report that some patients experience persistent symptoms like self-reported cognitive problems and fatigue. Persisting symptoms are often termed post-Lyme disease syndrome, of which etiology is not clearly understood. The aim of this study was to investigate cognitive function, possible structural changes in brain regions and level of fatigue. We have not found previous studies on neuroborreliosis that use standardized neuropsychological tests and MRI with advanced image processing to investigate if there are subtle regional changes in cortical thickness and brain volumes after treatment. METHODS: We examined 68 patients treated for neuroborreliosis 6 months earlier and 66 healthy controls, with a comprehensive neuropsychological test protocol, quantitative structural MRI analysis of the brain and Fatigue Severity Scale. RESULTS: We found no differences between the groups in either cognitive function, cortical thickness or brain volumes. The patients had higher score on Fatigue Severity Scale 3.8 vs. 2.9 (p = 0.001), and more patients (25.4%) than controls (5%) had severe fatigue (p = 0.002), but neither mean score nor proportion of patients with severe fatigue differed from findings in the general Norwegian population. CONCLUSION: The prognosis regarding cognitive function, brain MRI findings and fatigue after adequately treated neuroborreliosis is favorable.

SARS-CoV-2 antibody persistence after five and twelve months: A cohort study from South-Eastern Norway.

OBJECTIVES: To assess total antibody levels against Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS CoV-2) spike protein up to 12 months after Coronavirus Disease (COVID-19) infection in non-vaccinated individuals and the possible predictors of antibody persistence. METHODS: This is the first part of a prospective multi-centre cohort study. PARTICIPANTS: The study included SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) positive and negative participants in South-Eastern Norway from February to December 2020. Possible predictors of SARS-CoV-2 total antibody persistence was assessed. The SARS-CoV-2 total antibody levels against spike protein were measured three to five months after PCR in 391 PCR-positive and 703 PCR-negative participants; 212 PCR-positive participants were included in follow-up measurements at 10 to 12 months. The participants completed a questionnaire including information about symptoms, comorbidities, allergies, body mass index (BMI), and hospitalisation. PRIMARY OUTCOME: The SARS-CoV-2 total antibody levels against spike protein three to five and 10 to 12 months after PCR positive tests. RESULTS: SARS-CoV-2 total antibodies against spike protein were present in 366 (94%) non-vaccinated PCR-positive participants after three to five months, compared with nine (1%) PCR-negative participants. After 10 to 12 months, antibodies were present in 204 (96%) non-vaccinated PCR-positive participants. Of the PCR-positive participants, 369 (94%) were not hospitalised. The mean age of the PCR-positive participants was 48 years (SD 15, range 20-85) and 50% of them were male. BMI ≥ 25 kg/m2 was positively associated with decreased antibody levels (OR 2.34, 95% CI 1.06 to 5.42). Participants with higher age and self-reported initial fever with chills or sweating were less likely to have decreased antibody levels (age: OR 0.97, 95% CI 0.94 to 0.99; fever: OR 0.33, 95% CI 0.13 to 0.75). CONCLUSION: Our results indicate that the level of SARS-CoV-2 total antibodies against spike protein persists for the vast majority of non-vaccinated PCR-positive persons at least 10 to 12 months after mild COVID-19.

Six versus 2 weeks treatment with doxycycline in European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blinded, randomised and placebo-controlled trial.

BACKGROUND: There is limited evidence regarding optimal duration of antibiotic treatment in neuroborreliosis. We aimed to compare efficacy and safety of oral doxycycline for 2 and 6 weeks in European Lyme neuroborreliosis (LNB). METHODS: The trial had a randomised, double-blinded, placebo-controlled, non-inferiority design. Patients with LNB were recruited from eight Norwegian hospitals and randomised to doxycycline 200 mg once daily for 2 weeks, followed by 4 weeks of placebo, or doxycycline 200 mg once daily for 6 weeks. The primary endpoint was clinical improvement as measured by difference in a Composite Clinical Score (0-64 points) from baseline to 6 months. The non-inferiority margin was predetermined to 0.5 points. RESULTS: One hundred and twenty-one patients were included. Fifty-two treated for 2 weeks and 53 for 6 weeks were included in the intention-to-treat analyses, and 52 and 51 in per-protocol analysis. Mean difference in clinical improvement between the groups was 0.06, 95% CI -1.2 to 1.2, p=0.99 in the intention-to-treat population, and -0.4, 95% CI -1.4 to 0.7, p=0.51 in the per-protocol population and non-inferiority could not be established. There were no treatment failures and no serious adverse events. The groups did not differ in secondary outcomes including clinical scores at 10 weeks and 12 months, cerebrospinal fluid data and patient-reported outcome measures. Patients receiving 6 weeks doxycycline reported slightly more side effects in week 5. CONCLUSION: Our results strongly indicate that there are no benefits of doxycycline treatment beyond 2 weeks in European LNB. TRIAL REGISTRATION NUMBER: 2015-001481-25.

Enhancement of cranial nerves in Lyme neuroborreliosis: incidence and correlation with clinical symptoms and prognosis.

PURPOSE: Symptoms of cranial neuritis are a common presentation of Lyme neuroborreliosis (LNB). Imaging studies are scarce and report contradictory low prevalence of enhancement compared to clinical studies of cranial neuropathy. We hypothesized that MRI enhancement of cranial nerves in LNB is underreported, and aimed to assess the prevalence and clinical impact of cranial nerve enhancement in early LNB. METHODS: In this prospective, longitudinal cohort study, 69 patients with acute LNB were examined with MRI of the brain. Enhancement of cranial nerves III-XII was rated. MRI enhancement was correlated to clinical findings of neuropathy in the acute phase and after 6 months. RESULTS: Thirty-nine of 69 patients (57%) had pathological cranial nerve enhancement. Facial and oculomotor nerves were most frequently affected. There was a strong correlation between enhancement in the distal internal auditory canal and parotid segments of the facial nerve and degree of facial palsy (gamma = 0.95, p < .01, and gamma = 0.93, p < .01), despite that 19/37 nerves with mild-moderate enhancement in the distal internal auditory canal segment showed no clinically evident palsy. Oculomotor and abducens nerve enhancement did not correlate with eye movement palsy (gamma = 1.00 and 0.97, p = .31 for both). Sixteen of 17 patients with oculomotor and/or abducens nerve enhancement had no evident eye movement palsy. CONCLUSIONS: MRI cranial nerve enhancement is common in LNB patients, but it can be clinically occult. Facial and oculomotor nerves are most often affected. Enhancement of the facial nerve distal internal auditory canal and parotid segments correlate with degree of facial palsy.

Cognitive function in patients with neuroborreliosis: A prospective cohort study from the acute phase to 12 months post treatment.

BACKGROUND: Long-term cognitive problems after neuroborreliosis treatment remain a subject of debate. We have previously shown that cognitive problems are not present in the acute phase of neuroborreliosis, although fatigue is common. The aim of this study was to re-assess the same patient cohort and evaluate long-term outcomes. METHODS: In this follow-up, we re-assessed 58 patients with well-characterized neuroborreliosis 12 months after completing treatment. The same protocol with eight subtests measuring attention and processing speed and the Fatigue Severity Scale (FSS) were used to compare the results from the acute phase to 12 months post treatment. RESULTS: We found no changes in attention or processing speed but a reduction in the level of fatigue (median score on FSS: 4.9 vs. 3.9, p < .001) from the acute phase to 12 months post treatment. CONCLUSION: The patient group did not develop problems with attention or processing speed post treatment, while the level of fatigue decreased.

Cognitive function, fatigue and Fazekas score in patients with acute neuroborreliosis.

Long-term cognitive problems and fatigue after adequately treated neuroborreliosis has caused uncertainty and debate among patients and health care workers for years. Despite several studies, the prevalence, cause and severity of such complaints are still not clarified. More knowledge about cognitive function, fatigue and MRI findings in the acute phase of neuroborreliosis could possibly contribute to clarification. In the current study, we therefore aimed to address this. Patients with well-characterized acute neuroborreliosis (n = 72) and a matched control group (n = 68) were screened with eight subtests from three different neuropsychological test batteries assessing attention, working memory and processing speed, and with Fatigue Severity Scale. Fazekas score was used to grade white matter hyperintensities on MRI. We found no differences in mean scores on the neuropsychological tests between the groups. The patient group reported significantly higher level of fatigue (Fatigue Severity Scale: 4.8 vs. 2.9, p < .001). There was no significant difference in Fazekas score between the groups. Neuroborreliosis does not seem to affect cognitive functions in the acute state of the disease, while fatigue is common.

The SmartSight Project: Use of Electronic Glasses to Improve Impaired Fields of Vision.

Electronic glasses use advanced assistive technology that can improve function for persons with visual impairments. This paper presents work in progress in the SmartSight project, where existing versions of electronic glasses are adapted and tested for persons with the visual impairments; macular degeneration and retinitis pigmentosa. The project aims are to adapt and innovate electronic glasses for persons with impaired fields of vision and study the impact on the daily function and quality of life. In a pilot test of the electronic glasses, promising results were found that imply a big difference for persons with impaired vision. The outcome of the SmartSight project might change the clinical practise on treatment and rehabilitation of persons with impaired fields of vision, and on how the support services are organised.

General practitioners' use of ICPC diagnoses and their correspondence with patient record notes. / Allmennlegers bruk av ICPC-diagnoser og samsvar med journalnotatene.

BACKGROUND: The quality of the general practitioners' setting of diagnoses using codes from the International Classification for Primary Care (ICPC) is important, because these codes are used for purposes of quality development, research and public health statistics. It is uncertain, however, to what extent these diagnoses present a correct picture of the content of and reasons for the consultations and the prevalence of illness in the population. The objective of this study was to identify the extent to which the general practitioners' use of diagnostic codes correlates with the content of the patient record notes. MATERIAL AND METHOD: A total of 23 general practitioners from five different medical centres in Agder county participated in the study. The patient record notes from all patient contacts over two working days in 2013 were reviewed by two experienced general practitioners who assessed the degree of correspondence between the content of the patient record notes and the concomitant ICPC diagnostic codes. RESULTS: A total of 1 819 patient contact were assessed, and for 1 591 of these (87.5 %) it was possible to assess the correspondence between the patient record notes and the diagnosis. We found good correspondence for 693 (85.3 %) consultations and 321 (69.9 %) simple contacts with issuance of a prescription. For simple contacts with no issuance of a prescription there was good correspondence for 213 (83.9 %), although 144 of a total of 398 (36.2 %) could not be assessed because the patient record notes were absent, too brief or imprecise. INTERPRETATION: The diagnoses made during consultations corresponded well with the patient record notes examined in this study. The results may indicate that caution should be exercised in including simple contacts in the data on diagnoses in public statistics. The findings should be followed up in larger-scale and more representative national studies.

Symptom load and general function among patients with erythema migrans: a prospective study with a 1-year follow-up after antibiotic treatment in Norwegian general practice.

OBJECTIVE: Promptly treated erythema migrans (EM) has good prognosis. However, some patients report persistent symptoms. Do patients with EM have more symptoms than the general population? We describe individual symptoms and general function in EM-patients at time of diagnosis and one year after treatment. DESIGN: Prospective study with 1-year follow up after treatment. Questionnaires included a modified version of the Subjective Health Complaints Inventory, comprising three additional Lyme borreliosis (LB) related symptoms. General function was assessed using a five-point scale modified from the COOP/WONCA charts. SETTING: Norwegian general practice. SUBJECTS: A total of 188 patients were included in a randomized controlled trial comparing three antibiotic regimens for EM, of whom 139 had complete data for this study. MAIN OUTCOME MEASURES: Individual symptoms, symptom load and general function. RESULTS: Mild symptoms were common, reported by 84.9% at baseline and by 85.6% at follow-up. At baseline, patients reported a mean of 5.4 symptoms, compared with 6.2 after one year. Severely bothersome symptoms and severely impaired general function were rare. Tiredness was the most reported symptom both at baseline and at follow-up. Palsy (other than facial) was the least reported symptom, but the only one with a significant increase. However, this was not associated to the EM. CONCLUSION: The symptom load was comparable to that reported in the general population. We found an increase in symptom load at follow-up that did not significantly affect general function. IMPLICATION: Monitoring patients' symptom loads prior to treatment reduce the probability of attributing follow-up symptoms to LB. Key points Erythema migrans has a good prognosis.Patients treated for erythema migrans have a slight increase in symptom load one year after treatment. This increase does not affect general function. The levels of subjective health complaints in patients treated for erythema migrans are comparable to the background population.

Incidence and antibiotic treatment of erythema migrans in Norway 2005-2009.

The first stage of Lyme borreliosis (LB) is mainly the typical skin lesion, erythema migrans (EM), which is estimated to comprise 80-90% of all LB cases. However, the reporting of, and the actual incidence of LB varies throughout Europe. Studies from Sweden and Holland have found EM incidences varying from 53 to 464 EM/100,000 inhabitants/year. Under-reporting of LB is common and a coefficient of three to reach a realistic estimate is suggested. In Norway, it is mandatory to report only the second and third LB stages to the National Institute of Public Health. To find the Norwegian incidence of EM, we extracted data from the electronic medical records of regular general practitioners and out-of-hours services in the four counties with the highest rates of registered LB in the 5 years from 2005 to 2009. We found an EM incidence of 448 EM/100,000 inhabitants/year in these counties, which yields a national incidence of 148 EM/100,000 inhabitants/year. Our findings show that solitary EMs comprised almost 96% of the total LB incidence in Norway. Older females have the highest rates of EM. Phenoxymethylpenicillin is the most commonly used drug to treat EM in Norway, which complies with the national guidelines for antibiotic use. Antibody tests are performed in 15% of cases. Less than 1% of patients are referred to secondary care. The study also shows a high number of patients seeking care for tick bites without signs of infection and there is an overuse of antibiotics in these patients.

Use of snus and smoking tobacco among pregnant women in the Agder counties. / Bruk av snus og røyketobakk hos gravide i Agder.

BACKGROUND: The use of snus during pregnancy increases the risk of stillbirths, premature delivery and reduced birthweight. People have been warned against smoking during pregnancy, but less so against the use of snus. We have investigated the use of snus and smoking tobacco among pregnant women in the Agder counties. MATERIAL AND METHOD: Data on pregnant women and 10 583 births for the years 2012, 2013 and 2014 were retrieved from the electronic birth records of Sørlandet Hospital. RESULTS: In the three-year period 2012 ­ 2014, altogether 5 % used snus and 19 % used smoking tobacco before pregnancy and 2 % and 8 % respectively at the end of pregnancy. The use of snus before pregnancy increased from 3.6 % in 2012 to 6.8 % in 2014. The equivalent figures for the first trimester were 1.7 % and 3.4 %, and for the last trimester 1.2 % and 2.1 %. The use of smoking tobacco declined by 2 % over the three-year period. In the age group 16 ­ 24 years, a total of 12 % used snus before pregnancy and 5 % at the end. Of 522 women who used snus before their pregnancy, altogether 57.5 % had quit during the first trimester and 71.4 % during the third trimester. The corresponding figures for those 2 015 women who used smoking tobacco before their pregnancy were 45.2 % and 58.0 % (p < 0.001). INTERPRETATION: The use of snus before and during pregnancy doubled over the three-year period 2012 ­ 2014. The use was especially widespread in the youngest age groups. The proportion of women who quit using snus during their pregnancy was significantly higher than the proportion that quit smoking.

Antibiotic resistance patterns of bacteria causing urinary tract infections in the elderly living in nursing homes versus the elderly living at home: an observational study.

BACKGROUND: Antibiotic resistance is a problem in nursing homes. Presumed urinary tract infections (UTI) are the most common infection. This study examines urine culture results from elderly patients to see if specific guidelines based on gender or whether the patient resides in a nursing home (NH) are warranted. METHODS: This is a cross sectional observation study comparing urine cultures from NH patients with urine cultures from patients in the same age group living in the community. RESULTS: There were 232 positive urine cultures in the NH group and 3554 in the community group. Escherichia coli was isolated in 145 urines in the NH group (64%) and 2275 (64%) in the community group. There were no clinically significant differences in resistance. Combined, there were 3016 positive urine cultures from females and 770 from males. Escherichia coli was significantly more common in females 2120 (70%) than in males 303 (39%) (p < 0.05). Enterococcus faecalis was significantly less common in females 223 (7%) than males 137 (18%) (p < 0.05). For females, there were lower resistance rates to ciprofloxacin among Escherichia coli (7% vs 12%; p < 0.05) and to mecillinam among Proteus mirabilis (3% vs 12%; p < 0.05). CONCLUSIONS: Differences in resistance rates for patients in the nursing home do not warrant separate recommendations for empiric antibiotic therapy, but recommendations based on gender seem warranted.

Subjective health complaints are not associated with tick bites or antibodies to Borrelia burgdorferi sensu lato in blood donors in western Norway: a cross-sectional study.

BACKGROUND: There is controversy about chronic health consequences of tick-borne infections, especially Lyme borreliosis. This study aims to assess whether general function, physical fitness and subjective health complaints are associated with tick bites or antibodies to Borrelia burgdorferi sensu lato in blood donors. METHODS: Sera from 1,213 blood donors at four different blood banks in Sogn and Fjordane county in western Norway were obtained during January to June 2010, and analysed for specific IgG and IgM antibodies. A questionnaire including questions on tick bites, subjective health complaints, general function and physical fitness was completed. RESULTS: Tick bites had been experienced by 65.7% of the study population. 78 (6.4%) were positive for IgG (9.7% in men, 2.4% in women), and 69 (5.7%) for IgM (6.1% in men, 5.1% in women), verified by immunoblot. No association between number of experienced tick bites or seropositivity for Borrelia antibodies and subjective health complaints, reduced general function or reduced physical fitness was found. CONCLUSION: The results do not support any association between tick bites or Borrelia antibodies and subjective health complaints in blood donors in an endemic area for Lyme borreliosis.