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

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Acute Encephalitis and Aseptic Meningitis: Clinical characteristics, immune activation and outcome

The aims of this prospective observational study were to evaluate the etiology, clinical presentations, immune activation, and short- and long-term outcomes in patients with acute encephalitis and aseptic meningitis (ASM). Between 2014-2018, patients admitted to Oslo University Hospital Ullevål with suspected or proven acute CNS-infection were included in the study. Encephalitis was classified according to a consortium definition. A diagnostic algorithm used for assessment of patients included a broad panel of analyses in both cerebrospinal fluid (CSF) and serum. Inflammatory markers and metabolites of the kynurenine pathway were measured in CSF and serum. Short- and long-term outcomes of the patients were assessed through semi-structured interviews, self-report questionnaires and neuropsychological testing. In patients with encephalitis, an etiological cause was found in 53%. Compared to other patients with encephalopathy, the combination of a low level of systemic inflammatory markers, fever and nausea was associated with encephalitis. For both encephalitis and ASM, increased cytokine levels and kynurenine metabolites were revealed in the CSF, and for patients with encephalitis, a net neurotoxic ratio of kynurenine metabolites was found. At follow-up after two months, 97% of the patients with encephalitis and 63% with ASM reported persisting complaints. In encephalitis, immune activation and activation of the kynurenine pathway during the acute phase were associated with a lower Health Related Quality of Life at follow-up. After 1 year, patients with encephalitis had lower scores than ASM patients on fine motor and psychomotor skills, learning, and memory. Overall, the etiologic range is wide for patients with encephalitis, and the diagnostic challenges are substantial. Both encephalitis and ASM are associated with a generalized immune activation in the CNS during the acute stage, and the burden of both conditions is high, at least on the short term

The first tigecycline resistant Enterococcus faecium in Norway was related to tigecycline exposure

Objectives - We describe the first tigecycline resistant enterococcal isolate in Norway and the mechanisms involved. Material and methods - The Norwegian National Advisory Unit on Detection of Antimicrobial Resistance (K-res). received in 2022 an Enterococcus faecium blood culture isolate with decreased susceptibility to tigecycline from a hospitalized patient in the South-Eastern Norway Health region for confirmatory testing. K-res verified a tigecycline-resistant E. faecium (TigR) with broth microdilution MIC of 0.5 mg/L. The patient had received treatment with tigecycline because of an infection with a linezolid- and vancomycin-resistant but tigecycline susceptible E. faecium (TigS) 47 days prior to the detection of the corresponding tigecycline-resistant isolate. Whole-genome comparisons, cgMLST and SNP analyses revealed that the two ST117 strains were closely related. Results - The TigR isolate showed a novel deletion of 2 amino acids (K57Y58) in a polymorphic region of ribosomal protein S10 previously associated with tigecycline resistance and a deletion of the tet(M) leader peptide previously related to increased expression of tet(M) and tigecycline resistance in enterococci. Conclusions - Genomic and epidemiological analyses confirm that the two E. faecium (TigR and TigS) are closely related isolates of the same strain and that the two deletions (in rpsJ and of tet(M) leader peptide) account for the tigecycline resistance in TigR

The burden of herpes zoster disease in Norway

Background No national vaccination program against herpes zoster (HZ) is currently in place in Norway. We aimed to quantify the burden of medically attended HZ to assess the need for a vaccination program. Methods We linked data from several health registries to identify medically attended HZ cases during 2008–2014 and HZ-associated deaths during1996–2012 in the entire population of Norway. We calculated HZ incidences for primary and hospital care by age, sex, type of health encounter, vaccination status, and co-morbidities among hospital patients. We also estimated HZ-associated mortality and case-fatality. Results The study included 82,064 HZ patients, of whom none were reported as vaccinated against HZ. The crude annual incidence of HZ was 227.1 cases per 100,000 in primary healthcare and 24.8 cases per 100,000 in hospitals. Incidence rates were higher in adults aged ≥50 years (461 per 100,000 in primary care and 57 per 100,000 in hospitals), and women than in men both in primary healthcare (267 vs 188 per 100,000), and hospitals (28 vs 22 per 100,000). Among hospital patients, 47% had complicated zoster and 25% had comorbidities, according to the Charlson comorbidity index. The duration of hospital stay (median 4 days) increased with the severity of comorbidities. The estimated mortality rate was 0.18 per 100,000; and in-hospital case-fatality rate was 1.04%. Conclusions Medically attended HZ poses a substantial burden in the Norwegian healthcare sector. The majority of the zoster cases occurred among adults aged ≥50 years – the group eligible for zoster vaccination – and increased use of zoster vaccination may be warranted, especially among persons with co-morbidities

CSF sTREM2 in delirium—relation to Alzheimer’s disease CSF biomarkers Aβ42, t-tau and p-tau

Abstract Background Delirium and dementia share symptoms of cognitive dysfunctions, and mechanisms of neuroinflammation appear involved in both conditions. Triggering receptor expressed on myeloid cells 2 (TREM2) is linked to dementia and neurodegenerative disease. It encodes expression of an innate immune receptor in the brain expressed by microglia. The level of the soluble fragment of TREM2 (sTREM2) is reported to increase in the cerebrospinal fluid (CSF) already in prodromal and asymptomatic Alzheimer’s disease. Methods We analyzed the level of CSF sTREM2 in relation to delirium and dementia. The study included patients with or without pre-existing dementia who underwent acute hip fracture surgery (n = 120), and some of the patients developed delirium (n = 65). A medical delirium cohort (n = 26) was also examined. ELISA was used to determine the level of sTREM2 in CSF. Results Delirium was associated with a higher level of CSF sTREM2 only among those without pre-existing dementia (p = 0.046, n = 15, n = 44), particularly among patients developing delirium after CSF sampling (p = 0.02, n = 7, n = 44). Between patients with dementia, there was no group difference, but the CSF sTREM2 level increased with waiting time for surgery (r S = 0.39, p = 0.002, n = 60) and correlated well with the CSF Alzheimer’s disease biomarkers, Aβ42, and t-tau/p-tau (r S = 0.40, p = 0.002, r S = 0.46, p < 0.001/ r S = 0.49, p < 0.001, n = 60). Among patients with dementia, the level of Aβ38 and Aβ40 also correlated positively with sTREM2 in CSF (Aβ38MSD r S = 0.44, p = 0.001; Aβ40MSD r S = 0.48, p < 0.001; Aβ42MSD r S = 0.43, p < 0.001, n = 60). Conclusion The findings reinforce the involvement of neuroinflammation in delirium, yet with separate responses in patients with or without pre-existing dementia. Our findings support the concept of primed microglia in neurodegenerative disease and central immune activation after a peripheral trauma in such patients. A CSF biomarker panel of neuroinflammation might be valuable to prevent delirium by identifying patients at risk

To what extent can clinical characteristics be used to distinguish encephalitis from encephalopathy of other causes? Results from a prospective observational study

Background Recognizing patients with encephalitis may be challenging. The cardinal symptom, encephalopathy, has a wide array of differential diagnoses. In this prospective study we aimed to explore the etiology of encephalitis and to assess the diagnostic accuracy of symptoms and clinical findings in patients with encephalitis in an encephalopathic population. Methods Patients with acute onset of encephalopathy (n = 136) were prospectively enrolled from January 2014–December 2015 at Oslo University Hospital, Ullevaal. Clinical and biochemical characteristics of patients who met the case definition of encephalitis were compared to patients with encephalopathy of other causes. Results Among 136 patients with encephalopathy, 19 (14%) met the case-definition of encephalitis. For 117 patients other causes of encephalopathy were found, infection outside the CNS was the most common differential diagnosis. Etiology of encephalitis was confirmed in 53% (4 bacterial, 4 viral, 1 parasitic, and 1 autoimmune). Personality change, nausea, fever, focal neurology, recent travel history, and low inflammation markers were significantly more abundant in patients with encephalitis, but the diagnostic accuracy for individual parameters were low (area under the curve (AUC) < 0.7). The combination of fever (OR = 6.6, 95% CI, 1.6–28), nausea (OR = 8.9, 95% CI, 1.7–46) and a normal level of ESR (erythrocyte sedimentation rate < 17 mm/hr, OR = 6.9, 95% CI, 1.5–33) was significant in multivariate analysis with an AUC (area under the curve) of 0.85 (95% CI, 0.76–0.94). Moderately increased pleocytosis in CSF (5-100 × 106/L) further increased the diagnostic accuracy of this combination, AUC 0.90 (95% CI, 0.81–0.98). Conclusions There is a wide diversity in differential diagnoses in patients with encephalopathy, and no single symptom or finding can be used to predict encephalitis with high accuracy in this group. The combination of fever, nausea and a low ESR in an encephalopathic population, increased the diagnostic accuracy of encephalitis compared to solitary parameters. The triad could be a useful clinical tool for early diagnosis of encephalitis, and these patients should be considered for further diagnostics such as lumbar puncture (LP)

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