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

Eutrofiering av norske innsjøer. Tilstand og trender.

Prosjektleder/Hovedforfatter Anne Lyche SolheimDatasett for eutrofieringsrelevante parametere er tilgjengelig i Vannmiljø for 366 innsjøer, som har total fosfor i god eller dårligere tilstand og minst én biologisk parameter for minst ett år i perioden 2009-2020. Den økologiske tilstanden er moderat, dårlig eller svært dårlig i ca. halvparten av disse. Oppblomstringer av giftige cyanobakterier eller andre problemalger er vanlige i flere av disse innsjøene. Utviklingstrender er analysert for klorofyll og total fosfor i 125 innsjøer som har minst fire års data etter 2008. De fleste av disse innsjøene viser ingen trender. 24 innsjøer har stigende trend for én eller begge parameterne, det vil si forverring, mens 36 har avtagende trend, det vil si forbedring for én eller begge parameterne. De fleste av innsjøene med forbedring for klorofyll er i Vannområdene Morsa, Haldenvassdraget og Jæren, der avløps- og jordbrukstiltak har vært gjennomført over lang tid. Klimaendringer kan forverre situasjonen og kreve mer omfattende tiltak for å nå miljømålet.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

publishedVersionPaid Open Acces

A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland

Background: The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population. Methods: Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact. Findings: We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = −232 pmol/L, βSD = −0.695, P = 4.43 × 10−4) and higher 30-min glucose (β = 1.20 mmol/L, βSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10−6) and HbA1c (β = 0.113 HbA1c%, βSD = 0.205, P = 7.84 × 10−3). The variant explained 2.5% of diabetes variance in Greenland. Interpretation: The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1–3% in large populations.publishedVersio

OPPFØLGING OG BEHANDLING AV PASIENTER MED MS VED ULLEVÅL UNIVERSITETSSYKEHUS

Bakgrunn: Tall fra Reseptregisteret har vist lav bruk av immunmodulerende behandling ved multippel sklerose (MS) i Oslo. Målet med denne studien er å undersøke om Ullevål Universitetssykehus gir adekvat oppfølging og behandling til pasienter med MS. Metode: Journalene til alle som fikk diagnostisert MS i perioden 1998 2002 ble gjennomgått med tanke på oppfølging og bruk av immunmodulerende behandling fram til juni 2007. Resultater. 193 personer fikk diagnostisert MS etter Poser-kriteriene. Pr. juni 2007 hadde 68% av disse relapsing remitting, 14% sekundær progressiv og 18% primær progressiv MS. Totalt 47 pasienter (26%) startet immunmodulerende behandling. Av disse fikk 29 (61%) glatiramer acetat, 16 (34%) betainterferon-1a subkutant, en (2%) betainterferon-1a intramuskulært, syv (15%) betainterferon-1b, tre (6%) natalizumab, to (4%) mitoxantrone, og (4%) deltok i utprøving av teriflunomid. Behandlingen ble startet innen ett år etter diagnosetidspunktet hos 25 (53%), mellom to og fire år hos 12 (26%), og mellom fem og syv år hos 9 (19%). 8 pasienter (17%) hadde hatt ett, 24 (51%) to eller tre, og 12 (26%) flere enn fire schub før behandlingen ble startet. 18 (75%) av de som fikk betainterferon og 10 (34%) av de som fikk glatiramer acetat avsluttet behandlingen, oftest på grunn av bivirkninger. Av pasientene som ikke startet immunmodulerende behandling hadde 22 (22%) ingen, 58 (57%) ett, og 21 (21%) to eller flere registrerte schub de to første årene etter diagnosetidspunktet. Totalt hadde 28 (28%) pasienter to eller flere schub i løpet av en toårsperiode uten at det ble startet immunmodulerende behandling. 107 pasienter (59%) ble fulgt regelmessig ved avdelingen hele studieperioden. 13 (7%) ble etter eget ønske ikke kalt inn regelmessig, 21 (12%) hadde flyttet og 16 (9%) falt ut av oppfølgingen. Konklusjon. De fleste som fikk påvist MS i perioden 1998-2002 benyttet tilbud om regelmessig oppfølging ved avdelingen. Gjeldende retningslinjer for behandling ble oftest fulgt, selv om det forekom enkelte avvik. Flere pasienter startet immunmodulerende behandling enn det som tidligere er utledet fra Reseptregisteret. Forskjellen kan skyldes at vi har registrert bruk av immunmodulerende behandling gjennom flere år, og at en stor andel av de behandlede pasientene avbrøt denne

Six versus two weeks treatment with doxycycline in Lyme neuroborreliosis: the protocol of a multicentre, non-inferiority, double-blinded and randomised controlled trial

Introduction: Current treatment guidelines for European Lyme neuroborreliosis (LNB) recommend cephalosporins, penicillin or doxycycline for 14–28 days but evidence for optimal treatment length is poor. Treatment lengths in clinical practice tend to exceed the recommendations. Most patients experience a rapid improvement of symptoms and neurological findings within days of treatment, but some report long-term complaints. The underlying mechanisms of remaining complaints are debated, and theories as ongoing chronic infection with Borrelia burgdorferi, dysregulated immune responses, genetic predisposition, coinfection with multiple tick-borne pathogens, structural changes in CNS and personal traits have been suggested. The main purpose of our trial is to address the hypothesis of improved outcome after long-term antibiotic treatment of LNB, by comparing efficacy of treatment with 2 and 6 weeks courses of doxycycline. Methods and analysis: The trial has a multicentre, non-inferiority, double-blinded design. One hundred and twenty patients diagnosed with LNB according to European Federation of Neurological Societies (EFNS)guidelines will be randomised to 6 or 2 weeks treatment with oral doxycycline. The patients will be followed for 12 months. The primary endpoint is improvement on a composite clinical score (CCS) from baseline to 6 months after inclusion. Secondary endpoints are improvements in the CCS 12 months after inclusion, fatigue scored on Fatigue Severity Scale, subjective symptoms on the Patient Health Questionnaire-15 scale, health-related quality of life scored on RAND 36-item short form health survey and safety as measured by side effects of the two treatment arms. Blood and cerebrospinal fluid (CSF) are collected from inclusion and throughout the follow-up and a biobank will be established. The study started including patients in November 2015 and will continue throughout December 2019. Ethics and dissemination: The study is approved by the Norwegian regional committees for medical and health research ethics and the Norwegian Medicines Agency. Data from the study will be published in peer-reviewed medical journals

Quality of multiple sclerosis out-patient health care services with focus on patient reported experiences

Abstract Background To investigate multiple sclerosis (MS) patients’ satisfaction with out-patient follow-up in a general neurological hospital department. Patients with definite MS living in Vest-Agder county, Norway were invited to answer a questionnaire comprising one question regarding overall satisfaction, and 24 questions regarding demographics, disease characteristics, and experiences with different aspects of the health care services. Results Out of 330 invited patients, 159 responded (48%). Mean overall satisfaction with health care was 3.5 (SD = 1.03) on a 1–5 Likert scale (1 = not at all, 5 = to a very large extent). The best sub scores were given on confidence in the physician’s competence (mean = 4.01), the physician speaks in an understandable way (mean = 4.07), expectation of good treatment (mean = 3.72), and perception of being submitted to wrong treatment (mean = 1.5). The worst scores were given on satisfaction with frequency of outpatient appointments (mean = 2.89) and delay of outpatient appointments (mean = 3.07). Four factors were associated with high overall satisfaction; receiving the disease modifying drug natalizumab (B = 0.549, p = 0.004), satisfaction with frequency of outpatient appointments (B = 0.242, p < 0.001), experience that the physician facilitates talking about what the patient finds important (B = 0.218, p = 0.001), and confidence with the physician’s competence (B = 0.453, p < 0.001). Conclusion The patients were rather satisfied with the content of follow-up, and less satisfied with the structure. Regular and predictable contact with a trustworthy physician that facilitates that the patient is able to talk about what is important was associated with higher overall satisfaction