European neuroborreliosis: Long term follow-up

Lyme disease is the most common human tick borne disease in the northern hemisphere, and the southern coastline of Norway is a high endemic region regarding Lyme disease. European Lyme neuroborreliosis (LNB) often presents with a sub acute painful lymphocytic meningoradiculitis (Bannwarth syndrome) with or without paresis in the abdominal wall, the limbs or muscles innervated by cranial nerves. Central nervous system involvement as encephalitis, myelitis and vasculitis is rare. Most LNB patients experience marked improvement in neurological symptoms within weeks to a few months after antibiotic treatment, but years after treatment 10 – 50% report persisting or new symptoms including fatigue, concentration difficulties and musculoskeletal problems. Remaining complaints after adequately treated Bb infections are often named Post Lyme Disease Syndrome (PLDS). The prevalence and impact of PLDS is debated since similar symptoms are common in the general population, and there are few European controlled studies on the issue. Most studies on outcome after LNB are conducted in the US, and as Borrelia genotype and the clinical picture of Lyme disease in the US differ somewhat from what we find in Europe, the study results are not necessarily transferable to European patients. Aims Our aim was to assess the long-term impact of LNB on Health Related Quality of Life (HRQoL) in a controlled study of well-characterized adult European LNB patients. We also wanted to compare the neuropsychological (NP) functioning by assessing executive/attention functions, processing speed and memory in a group of adult LNB patients 30 months after treatment to a matched control group. Finally, we wanted to identify clinical, demographical or laboratory factors associated with a reduced HRQoL and fatigue after treatment of LNB. Patients and methods A cohort of 50 patients was followed for 30 months after treatment for LNB. The patients were recruited from a treatment study conducted in southern Norway comparing per oral doxycycline to intravenous ceftriaxone. All patients were living in the geographical region of Agder Counties, and received treatment between May 2004 and December 2007. The LNB patients brought a control person from the same geographical area, matched for age, gender and education level. Exclusion criterion for the controls was a history of acknowledged LNB. At basis pre-treatment and at 4, 12 and 30 months we did a semi structured interview, a clinical score, and spinal and blood tap. At 30 months NP functioning was assessed, and all participants completed the following questionnaires: the Fatigue Severity Scale (FSS), the Montgomery-Åsberg-Depression Rating Scale (MADRS), and the Short Form-36 (SF-36: A HRQoL questionnaire including the sum scores Mental Component Summary (MCS) and Physical Component Summary (PCS)). They were asked about previous and current coexisting diseases, psychological distress and subjective complaints. A composite clinical score made for the treatment study, summarizing subjective complaints and objective findings, was used to assess clinical status. Non-complete recovery was defined as more than 1 point score on the composite clinical score. The four NP tests in our test panel consisted of 23 subtasks, and we calculated a sumscore expressing the number of NP subtasks with the scores ≤-1 SD from the mean in the control group (range 0-23). The sumscores were then categorized into three groups: Normal: 1-5(≤-1 SD from the mean sumscore in the control group), deficit: 6-8 (>-1≤2 SD from the mean sumscore in the control group) and impairment: 9-23 (>-2 SD from the mean sumscore in the control group). In the study regarding risk factors we did a univariate analysis comparing independent demographical, clinical and laboratory data to the PCS, MCS and FSS scores to look for associations. The variables which were associated with the outcome in the univariate analyses were analyzed further in a multiple regression model. Before treatment 80 % of the patients had a complete or partial Bannwart syndrome, and 8 % had symptoms suggesting involvement of the central nervous system (myelitis, ataxia and confusion). Fifty percent were treated with oral doxycycline and 50 % with IV ceftriaxone. Sixty-eight percent were classified as definite LNB according to the criteria of the European Foundation of Neurological Society, and 32 % as possible LNB. Mean age at follow up was 55, and 58 % were male. Results Paper I: LNB treated patients had reduced HRQoL compared to controls as assessed with the SF-36 summary components PCS (P<0.001) and MCS ( p=0.010) 30 months after treatment. The patients scored lower on all the eight subscales of the SF-36, except for bodily pain. The LNB patients who reported complete recovery (56%) had similar HRQoL scores as the controls. Paper II: LNB treated patients scored lower on four NP subtasks assessing executive/attention functions, processing speed, visual and verbal memory, as compared to matched controls: Stroop test 4 (P=0.015), TMT 5 (P=0.004) Digit Symbol recall (P=0.038) and CVLT list B (P=0.003). The distribution of global NP function indicates that most of the LNB treated patients perform comparable to controls, while a small subgroup have a debilitating long-term course with cognitive impairment. Fatigue, depression, neurological deficits or HRQoL at 30 months after treatment were not associated with the global NP sum score. Eighteen out of 50 patients (36%) had objective findings in terms of neurological deficits and/or cognitive impairment. Paper III: Delayed start of treatment and remaining complaints 4 and 12 months after treatment seem to predict a worse outcome with respect to HRQoL. Delayed start f treatment, a more severe disease pre-treatment and remaining complains at 4 and 12 months after treatment seem to predict more fatigue at 30 months. Age, gender, educational level, diagnostic accuracy, treatment option, signs of infection in the central nervous pre-treatment or coexisting somatic diseases or psychological distress were not associated with HRQoL outcome 30 months after treatment in our cohort, neither were any of the assessed CSF findings before treatment or during follow-up . Conclusions 1. HRQoL was reduced in well-characterized European patients treated for LNB with a current recommended antibiotic regimen 30 months earlier, as compared to matched controls. The LNB treated patients were not more depressed and did not report more pain than the controls. Fatigue was the most disturbing persisting complaint, and was negatively associated with HRQoL. Mild neurological deficits were found in 28 % of the patients, and seemed to influence negative on the physical HRQoL and fatigue scores. The patients who reported subjective recovery had the same HRQoL as the controls. 2. Most of the patients who were treated for European LNB 30 months earlier had comparable NP functioning to matched controls, but a small subgroup had cognitive impairments regarding attention/ excecutive function, processing speed and memory that could affect their daily life. The LNB treated patients with complete recovery had similar NP functioning as the controls. We did not find any association between NP test results and HRQoL or fatigue. 3. It seems as a more serious LNB disease and a longer duration of symptoms before treatment can reduce HRQoL, and as symptom duration more than 6 weeks before treatment, a more severe disease and non-complete recovery at four and 12 months predict a higher burden of fatigue 30 months after treatment. We did not find that any laboratory data predicted outcome after treated LNB, or that any CSF finding indicated an active Bb infection 30 months after treatment. Gender, age, comorbidity, signs of pre-treatment infection of the central nervous system or CSF findings before and during follow-up were not associated with HRQoL or fatigue at 30 months. 4. Thirty months after treatment of LNB 18 out of 50 patients (36%) had objective findings in terms of neurological deficits and/or cognitive impairment

Translation and psychometric testing of the Norwegian version of the “Patients’ Perspectives of Surgical Safety Questionnaire”

Purpose To translate the Patients’ Perspectives of Surgical Safety (PPSS) questionnaire into Norwegian and to test it for structural validity and internal consistency. Design This is a methodological study. Methods The original 20-item PPSS questionnaire was translated into Norwegian using a model of translation-back translation. We assessed content validity via a pretest with 20 surgical patients. A sample of 218 surgical patients in a university hospital in Norway completed the PPSS questionnaire. Psychometric analysis included item characteristics, and structural validity was evaluated by an exploratory factor analysis. Internal consistency was calculated using Cronbach's alpha. Findings We successfully translated and adapted the Norwegian PPSS questionnaire. Completion rate was 74%. Missing values were less than 5% and all 20 items had a high skewness (≥15 %) ranging from 52.8% to 95.9%. The exploratory factor analysis yielded two significant factors that explained 45.15% of variance. The Cronbach's alpha for Factor 1 “Team interaction safety” was 0.88 and for Factor 2 “Patient's ID safety”, 0.82. Overall, most patients reported a high sense of surgical safety. Conclusions The first Norwegian version of the PPSS measuring surgical patients’ perception shows promising psychometric properties regarding structural validity and internal consistency. However, future research on PPSS should provide an examination of construct validity, validation and testing in other populations of surgical patients. To improve safety of the surgical trajectory, it is necessary to pay more attention to patients’ perceptions of surgical safety.publishedVersio

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

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

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 fndings 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 afected. 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 afected. Enhancement of the facial nerve distal internal auditory canal and parotid segments correlate with degree of facial palsy.publishedVersio

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.publishedVersio

Six versus 2 weeks treatment with doxycycline in European Lyme neuroborreliosis: a multicentre, noninferiority, double-blinded, randomised and placebocontrolled 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.publishedVersio

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

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The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis

The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS).publishedVersio

Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study

Background The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. Objective Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. Methods 85 patients, originally enrolled in a multicentre, randomised trial of ω−3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. Results Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (β=−0.399, p=0.040) and deep (β=−0.556, p=0.010) GM volume, lower mean cortical thickness (β=−0.581, p=0.010) and higher T2 lesion count (β=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (β=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. Conclusion Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.publishedVersio