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  • 1. Aghanavesi, S
    et al.
    Bergquist, F
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Memedi, M
    Motion Sensor-Based Assessment of Parkinson's Disease Motor Symptoms During Leg Agility Tests: Results From Levodopa Challenge2020In: IEEE journal of biomedical and health informatics, ISSN 2168-2194, E-ISSN 2168-2208, Vol. 24, no 1, p. 111-119Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is a degenerative, progressive disorder of the central nervous system that mainly affects motor control. The aim of this study was to develop data-driven methods and test their clinimetric properties to detect and quantify PD motor states using motion sensor data from leg agility tests. Nineteen PD patients were recruited in a levodopa single dose challenge study. PD patients performed leg agility tasks while wearing motion sensors on their lower extremities. Clinical evaluation of video recordings was performed by three movement disorder specialists who used four items from the motor section of the unified PD rating scale (UPDRS), the treatment response scale (TRS) and a dyskinesia score. Using the sensor data, spatiotemporal features were calculated and relevant features were selected by feature selection. Machine learning methods like support vector machines (SVM), decision trees, and linear regression, using ten-fold cross validation were trained to predict motor states of the patients. SVM showed the best convergence validity with correlation coefficients of 0.81 to TRS, 0.83 to UPDRS #31 (body bradykinesia and hypokinesia), 0.78 to SUMUPDRS (the sum of the UPDRS items: #26-leg agility, #27-arising from chair, and #29-gait), and 0.67 to dyskinesia. Additionally, the SVM-based scores had similar test-retest reliability in relation to clinical ratings. The SVM-based scores were less responsive to treatment effects than the clinical scores, particularly with regards to dyskinesia. In conclusion, the results from this study indicate that using motion sensors during leg agility tests may lead to valid and reliable objective measures of PD motor symptoms.

  • 2. Ahmed, Niaz
    et al.
    Audebert, Heinrich
    Turc, Guillaume
    Cordonnier, Charlotte
    Christensen, Hanne
    Sacco, Simona
    Sandset, Else Charlotte
    Ntaios, George
    Charidimou, Andreas
    Toni, Danilo
    Pristipino, Christian
    Köhrmann, Martin
    Kuramatsu, Joji B
    Thomalla, Götz
    Mikulik, Robert
    Ford, Gary A
    Martí-Fàbregas, Joan
    Fischer, Urs
    Thoren, Magnus
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Rinkel, Gabriel Je
    van der Worp, H Bart
    Matusevicius, Marius
    Tsivgoulis, Georgios
    Milionis, Haralampos
    Rubiera, Marta
    Hart, Robert
    Moreira, Tiago
    Lantz, Maria
    Sjöstrand, Christina
    Andersen, Grethe
    Schellinger, Peter
    Kostulas, Konstantinos
    Sunnerhagen, Katharina Stibrant
    Keselman, Boris
    Korompoki, Eleni
    Purrucker, Jan
    Khatri, Pooja
    Whiteley, William
    Berge, Eivind
    Mazya, Michael
    Dippel, Diederik Wj
    Mustanoja, Satu
    Rasmussen, Mads
    Söderqvist, Åsa Kuntze
    Escudero-Martínez, Irene
    Steiner, Thorsten
    Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11-13 November 2018.2019In: European Stroke Journal, ISSN 2396-9873, E-ISSN 2396-9881, Vol. 4, no 4, p. 307-317Article in journal (Refereed)
    Abstract [en]

    The purpose of the European Stroke Organisation-Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. The meeting started 22 years ago as Karolinska Stroke Update, but since 2014 it is a joint conference with European Stroke Organisation. Importantly, it provides a platform for discussion on the European Stroke Organisation guidelines process and on recommendations to the European Stroke Organisation guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guideline procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. This year's European Stroke Organisation-Karolinska Stroke Update Meeting was held in Stockholm on 11-13 November 2018. There were 11 scientific sessions discussed in the meeting including two short sessions. Each session except the short sessions produced a consensus statement (Full version with background, issues, conclusions and references are published as web-material and at www.eso-karolinska.org and http://eso-stroke.org) and recommendations which were prepared by a writing committee consisting of session chair(s), scientific secretary and speakers. These statements were presented to the 250 participants of the meeting. In the open meeting, general participants commented on the consensus statement and recommendations and the final document were adjusted based on the discussion from the general participants Recommendations (grade of evidence) were graded according to the 1998 Karolinska Stroke Update meeting with regard to the strength of evidence. Grade A Evidence: Strong support from randomised controlled trials and statistical reviews (at least one randomised controlled trial plus one statistical review). Grade B Evidence: Support from randomised controlled trials and statistical reviews (one randomised controlled trial or one statistical review). Grade C Evidence: No reasonable support from randomised controlled trials, recommendations based on small randomised and/or non-randomised controlled trials evidence.

  • 3.
    Berntsson, Shala G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Gauffin, Helena
    Univ Linköping, Med Fac, Dept Clin & Expt Med, Neurol, Linköping, Sweden.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Holtz, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology. Univ Linköping, Med Fac, Dept Clin & Expt Med, Neurol, Linköping, Sweden.
    Inherited Ataxia and Intrathecal Baclofen for the Treatment of Spasticity and Painful Spasms2019In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 97, no 1, p. 18-23Article in journal (Refereed)
    Abstract [en]

    Background: Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury.

    Objectives: The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity.

    Method: A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich's ataxia were included in this observational multicenter study. The patients were interviewed and completed outcome measures assessing pain (The Brief Pain Inventory), fatigue (Fatigue Severity Scale), and life satisfaction (LiSAT-9) before and 1 year after the treatment. Spasticity (Modified Ashworth Scale) and spasm frequency (SPFS) were measured objectively for each patient.

    Results: The mean treatment time was 1.9 years. Evaluation of established standard forms revealed symptomatic relief from spasticity, spasms, pain, and fatigue in addition to improved body posture, sleep, and life satisfaction after ITB treatment.

    Conclusions: We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/spasms in patients with hereditary ataxia.

  • 4. Bolin, Kristian
    et al.
    Niska, Per-Åke
    Pirhonen, Laura
    Wasling, Pontus
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    The cost-utility of pitolisant as narcolepsy treatment.2019In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The cost-effectiveness of available pharmacological treatments for narcolepsy is largely unknown. Available pharmacological treatments are associated with tolerability, abuse and adherence issues. Pitolisant is the first inverse agonist of the histamine H3 receptor to be prescribed for the treatment of narcolepsy with and without cataplexy. Studies suggest that pitolisant is both as effective as previously introduced drugs and is associated with fewer adverse effects. The objective in this study was to estimate the cost-effectiveness of pitolisant as monotherapy, and pitolisant as an adjunctive treatment to modafinil, compared to standard treatment.

    MATERIALS & METHODS: Calculations were performed using a Markov model with a 50-year time horizon. Healthcare utilisation and quality-adjusted life years (QALYs) for each treatment alternative were calculated assuming no treatment effect on survival. Probabilistic sensitivity analyses were performed for treatment effectiveness and healthcare cost parameters.

    RESULTS: The cost per additional quality-adjusted life year was estimated at SEK 356 337 (10 SEK ≈1 Euro) for pitolisant monotherapy, and at SEK 491 128 for pitolisant as an adjunctive treatment, as compared to standard treatment. The cost-effectiveness measure was demonstrated to be particularly sensitive to the assumptions made concerning indirect effects on total healthcare utilization and the pitolisant treatment cost.

    CONCLUSIONS: The incremental cost-effectiveness ratios were below the unofficial willingness-to-pay threshold at SEK 500 000. The estimated costs per additional QALY obtained here are likely to overestimate the true cost-effectiveness ratio since significant potential indirect effects - pertaining both to labour-market and household-related productivity - of treatment are not taken into account.

  • 5.
    Bridel, Claire
    et al.
    Vrije Univ Amsterdam Med Ctr, Neurochem Lab, Dept Clin Chem, Neurosci Campus Amsterdam, NL-1081 HV Amsterdam, Netherlands.
    van Wieringen, Wessel N.
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands;Vrije Univ Amsterdam, Dept Math, Amsterdam, Netherlands.
    Zetterberg, Henrik
    Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden;Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden;UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England;UCL, Dementia Res Inst, London, England.
    Tijms, Betty M.
    Vrije Univ Amsterdam Med Ctr, Dept Neurol, Neurosci Campus Amsterdam, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Neurosci Campus Amsterdam, Amsterdam, Netherlands.
    Teunissen, Charlotte E.
    Vrije Univ Amsterdam Med Ctr, Neurochem Lab, Dept Clin Chem, Neurosci Campus Amsterdam, NL-1081 HV Amsterdam, Netherlands.
    Alvarez-Cermeno, Jose C.
    Ramon y Cajal Univ Hosp, Multiple Sclerosis Unit, Madrid, Spain.
    Andreasson, Ulf
    Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.
    Axelsson, Markus
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Backstrom, David C.
    Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden.
    Bartos, Ales
    Charles Univ Prague, Dept Neurol, Fac Med 3, Prague, Czech Republic;Gen Univ Hosp, Prague, Czech Republic;Natl Inst Mental Hlth, Klecany, Czech Republic.
    Bjerke, Maria
    Univ Antwerp, Dept Biomed Sci, Reference Ctr Biol Markers Dementia BIODEM, Inst Born Bunge, Antwerp, Belgium.
    Blennow, Kaj
    Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden;Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Boxer, Adam
    Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA.
    Brundin, Lou
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Christensen, Tove
    Aarhus Univ, Dept Biomed, Aarhus, Denmark;Rigshosp, Dept Neurol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Fialova, Lenka
    Gen Univ Hosp, Prague, Czech Republic;First Fac Med, Inst Med Biochem, Prague, Czech Republic;Charles Univ Prague, Diagnost Lab, Prague, Czech Republic.
    Forsgren, Lars
    Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden.
    Frederiksen, Jette L.
    Rigshosp, Dept Neurol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Gisslen, Magnus
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Gray, Elizabeth
    Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England.
    Gunnarsson, Martin
    Orebro Univ Hosp, Dept Neurol, Fac Med & Hlth, Orebro, Sweden.
    Hall, Sara
    Lund Univ, Clin Memory Res Unit, Dept Clin Sci, Fac Med, Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden.
    Hansson, Oskar
    Lund Univ, Clin Memory Res Unit, Dept Clin Sci, Fac Med, Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden.
    Herbert, Megan K.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Inst Med, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden.
    Jakobsson, Joel
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Jessen-Krut, Jan
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Janelidze, Shorena
    Lund Univ, Clin Memory Res Unit, Dept Clin Sci, Fac Med, Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden.
    Johannsson, Gudmundur
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Inst Med, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden.
    Jonsson, Michael
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Kappos, Ludwig
    Univ Hosp, Dept Med, Basel, Switzerland;Univ Basel, Basel, Switzerland.
    Khademi, Mohsen
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden.
    Khalil, Michael
    Med Univ Graz, Dept Neurol, Graz, Austria.
    Kuhle, Jens
    Univ Hosp, Dept Med, Basel, Switzerland;Univ Basel, Basel, Switzerland.
    Landen, Mikael
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Leinonen, Ville
    Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland;Kuopio Univ Hosp, Dept Neurosurg, Kuopio, Finland.
    Logroscino, Giancarlo
    Univ Bari, Unit Neurodegenerat Dis, Dept Clin Res Neurol, Bari, Italy.
    Lu, Ching-Hua
    Blizard, North East London & Essex MND Care Ctr, Neurosci & Trauma Ctr, London, England;China Med Univ Hosp, Dept Neurol, Taichung, Taiwan.
    Lycke, Jan
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Magdalinou, Nadia K.
    UCL Inst Neurol, Reta Lila Weston Inst Neurol Studies, Queen Sq, London, England.
    Malaspina, Andrea
    Blizard, North East London & Essex MND Care Ctr, Neurosci & Trauma Ctr, London, England;Barts, Inst Cell & Mol Med, London, England;Barts, London Sch Med & Dent, London, England;Barts, Barts Hlth NHS Trust, London, England.
    Mattsson, Niklas
    Lund Univ, Clin Memory Res Unit, Dept Clin Sci, Fac Med, Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden.
    Meeter, Lieke H.
    Erasmus MC, Alzheimer Ctr, Rotterdam, Netherlands;Erasmus MC, Dept Neurol, Rotterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands.
    Mehta, Sanjay R.
    Univ Calif San Diego, Div Infect Dis, La Jolla, CA 92093 USA.
    Modvig, Signe
    Rigshosp, Dept Clin Immunol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Olsson, Tomas
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden.
    Paterson, Ross W.
    UCL Inst Neurol, Dementia Res Ctr, Queen Sq, London, England.
    Perez-Santiago, Josue
    Univ Puerto Rico, Puerto Rico OMICS Ctr, Ctr Comprehens Canc, San Juan, PR 00936 USA.
    Piehl, Fredrik
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden.
    Pijnenburg, Yolande A. L.
    Vrije Univ Amsterdam Med Ctr, Dept Neurol, Neurosci Campus Amsterdam, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Neurosci Campus Amsterdam, Amsterdam, Netherlands.
    Pyykko, Okko T.
    Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland;Kuopio Univ Hosp, Dept Neurosurg, Kuopio, Finland.
    Ragnarsson, Oskar
    Orebro Univ Hosp, Dept Neurol, Fac Med & Hlth, Orebro, Sweden.
    Rojas, Julio C.
    Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA.
    Christensen, Jeppe Romme
    Aarhus Univ, Dept Biomed, Aarhus, Denmark;Rigshosp, Dept Neurol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Sandberg, Linda
    Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden.
    Scherling, Carole S.
    Belmont Univ, Dept Psychol Sci, Nashville, TN USA;Belmont Univ, Neurosci Program, Nashville, TN USA.
    Schott, Jonathan M.
    UCL Inst Neurol, Dementia Res Ctr, Queen Sq, London, England.
    Sellebjerg, Finn T.
    Rigshosp, Dept Neurol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Simone, Isabella L.
    Univ Bari, Dept Basic Med Sci Neurosci & Sense Organs, Bari, Italy;San Camillo Forlanini Hosp, Rome, Italy.
    Skillback, Tobias
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Stilund, Morten
    Aarhus Univ, Dept Biomed, Aarhus, Denmark.
    Sundstrom, Peter
    Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden.
    Svenningsson, Anders
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Tortelli, Rosanna
    Univ Bari, Unit Neurodegenerat Dis, Dept Clin Res Neurol, Bari, Italy;Pia Fdn Cardinale G Panico, Lecce, Italy.
    Tortorella, Carla
    Univ Bari, Dept Basic Med Sci Neurosci & Sense Organs, Bari, Italy.
    Trentini, Alessandro
    Univ Ferrara, Dept Biomed & Specialist Surg Sci, Ferrara, Italy.
    Troiano, Maria
    Univ Bari, Dept Basic Med Sci Neurosci & Sense Organs, Bari, Italy.
    Turner, Martin R.
    Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England.
    van Swieten, John C.
    Erasmus MC, Alzheimer Ctr, Rotterdam, Netherlands;Erasmus MC, Dept Neurol, Rotterdam, Netherlands.
    Vagberg, Mattias
    Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden.
    Verbeek, Marcel M.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands;Radboud Alzheimer Ctr, Dept Lab Med, Nijmegen, Netherlands.
    Villar, Luisa M.
    Ramon y Cajal Univ Hosp, Dept Immunol, Madrid, Spain.
    Visser, Pieter Jelle
    Vrije Univ Amsterdam Med Ctr, Dept Neurol, Neurosci Campus Amsterdam, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Neurosci Campus Amsterdam, Amsterdam, Netherlands;Maastricht Univ, Dept Psychiat & Neuropsychol, Sch Mental Hlth & Neurosci, Alzheimer Ctr Limburg, Maastricht, Netherlands.
    Wallin, Anders
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Weiss, Andreas
    Evotec AG, Manfred Eigen Campus, Hamburg, Germany.
    Wikkelso, Carsten
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden.
    Wild, Edward J.
    UCL Inst Neurol, Queen Sq, London, England.
    Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis2019In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 76, no 9, p. 1035-1048Article, review/survey (Refereed)
    Abstract [en]

    Importance  Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

    Objectives  To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

    Data Sources  PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.

    Study Selection  Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.

    Data Extraction and Synthesis  Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.

    Main Outcome and Measure  The cNfL levels adjusted for age and sex across diagnoses.

    Results  Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.

    Conclusions and Relevance  These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

  • 6.
    Bådagård, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Braun, Madelene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Nilsson, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Stridh, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Negative predictors of shunt surgery outcome in normal pressure hydrocephalusIn: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404Article in journal (Refereed)
    Abstract [en]

    Objectives

    The prevalence of idiopathic normal pressure hydrocephalus (iNPH) and vascular comorbidity increases with age. It has not been clarified if high age and vascular disease are negative predictors of shunt surgery outcome in patients with iNPH. The aim of this study was to investigate the impact of high age and vascular comorbidity on outcome after shunt surgery in patients with iNPH.

    Methods

    All 332 patients with iNPH who were treated with shunts between 2011 and 2015 at a single centre were consecutively included. Hellström iNPH scale, without the neuropsychological tests, was calculated preoperatively and at follow‐up 12 months after shunt surgery. Outcome was defined as the difference between the post‐operative and preoperative iNPH scale scores. A multivariable model was used to investigate the predictive effects of age and vascular comorbidity on shunt surgery outcome.

    Results

    In a multivariable analysis of covariance (ANCOVA) with post‐operative outcome as the dependent variable, increasing age (years, B = −0.63, P < .001) and history of ischaemic stroke (B = −10.06, P = .0038) were negative predictors of shunt surgery outcome after controlling for waiting time for surgery, symptom severity at preoperative control, presence of diabetes mellitus, hypertension, hyperlipidaemia, history of myocardial infarction, duration of symptoms and shunt complications.

    Conclusions

    High age and established cerebrovascular disease are associated with less favourable outcome after shunt surgery in patients with iNPH.

  • 7.
    Carlsson, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Abujrais, Sandy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Herman, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Svenningsson, Anders
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Targeted metabolomics of CSF in healthy individuals and patients with secondary progressive multiple sclerosis using high-resolution mass spectrometry2020In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 16, no 2, article id 26Article in journal (Refereed)
    Abstract [en]

    Introduction: Standardized commercial kits enable targeted metabolomics analysis and may thus provide an attractive complement to the more explorative approaches. The kits are typically developed for triple quadrupole mass spectrometers using serum and plasma.

    Objectives: Here we measure the concentrations of preselected metabolites in cerebrospinal fluid (CSF) using a kit developed for high-resolution mass spectrometry (HRMS). Secondarily, the study aimed to investigate metabolite alterations in patients with secondary progressive multiple sclerosis (SPMS) compared to controls.

    Methods: We performed targeted metabolomics in human CSF on twelve SPMS patients and twelve age and sex-matched healthy controls using the Absolute IDQ-p400 kit (Biocrates Life Sciences AG) developed for HRMS. The extracts were analysed using two methods; liquid chromatography-mass spectrometry (LC-HRMS) and flow injection analysis-MS (FIA-HRMS).

    Results: Out of 408 targeted metabolites, 196 (48%) were detected above limit of detection and 35 were absolutely quantified. Metabolites analyzed using LC-HRMS had a median coefficient of variation (CV) of 3% and 2.5% between reinjections the same day and after prolonged storage, respectively. The corresponding results for the FIA-HRMS were a median CV of 27% and 21%, respectively. We found significantly (p < 0.05) elevated levels of glycine, asymmetric dimethylarginine (ADMA), glycerophospholipid PC-O (34:0) and sum of hexoses in SPMS patients compared to controls.

    Conclusion: The Absolute IDQ-p400 kit could successfully be used for quantifying targeted metabolites in the CSF. Metabolites quantified using LC-HRMS showed superior reproducibility compared to FIA-HRMS.

  • 8. Carstam, Louise
    et al.
    Rydén, Isabelle
    Gulati, Sasha
    Rydenhag, Bertil
    Henriksson, Roger
    Salvesen, Øyvind
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Jakola, Asgeir Store
    Socioeconomic factors affect treatment delivery for patients with low grade glioma: a Swedish population-based study.2019In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite aspirations to achieve equality in healthcare we know that socioeconomic differences exist and may affect treatment and patient outcome, also in serious diseases such as cancer. We investigated disparities in neurosurgical care and outcome for patients with low-grade glioma (LGG).

    METHODS: In this nationwide registry-based study, patients who had undergone surgery for LGG during 2005-2015 were identified (n = 547) through the Swedish Brain Tumor Registry. We linked data to multiple national registries with individual level data on income, education and comorbidity and analyzed the association of disease characteristics, surgical management and outcome, with levels of income, education and sex.

    RESULTS: Patients with either low income, low education or female gender showed worse pre-operative performance status. Patients with low income or education also had more comorbidities and those with low education endured longer waiting times for surgery. Median time from radiological imaging to surgery was 51 days (Q1-3 27-191) for patients with low education, compared to 32 days (Q1-3 20-80) for patients with high education (p = 0.006). Differences in waiting time over educational levels remained significant after stratification for age, comorbidity, preoperative performance status, and tumor size. Overall survival was better for patients with high income or high education, but income- and education-related survival differences were not significant after adjustment for age and comorbidity. The type of surgical procedure or complications did not differ over socioeconomic groups or sex.

    CONCLUSION: The neurosurgical care for LGG in Sweden, a society with universal healthcare, displays differences that can be related to socioeconomic factors.

  • 9. Drissi, Natasha Morales
    et al.
    Warntjes, Marcel
    Wessén, Alexander
    Szakacs, Attila
    Darin, Niklas
    Hallböök, Tove
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Gauffin, Helena
    Engström, Maria
    Structural anomaly in the reticular formation in narcolepsy type 1, suggesting lower levels of neuromelanin2019In: NeuroImage: Clinical, ISSN 0353-8842, E-ISSN 2213-1582, Vol. 23, article id 101875Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate structural changes in the brain stem of adolescents with narcolepsy, a disorder characterized by excessive daytime sleepiness, fragmented night-time sleep, and cataplexy. For this purpose, we used quantitative magnetic resonance imaging to obtain R1 and R2 relaxation rates, proton density, and myelin maps in adolescents with narcolepsy (n = 14) and healthy controls (n = 14). We also acquired resting state functional magnetic resonance imaging (fMRI) for brainstem connectivity analysis. We found a significantly lower R2 in the rostral reticular formation near the superior cerebellar peduncle in narcolepsy patients, family wise error corrected p = .010. Narcolepsy patients had a mean R2 value of 1.17 s-1 whereas healthy controls had a mean R2 of 1.31 s-1, which was a large effect size with Cohen d = 4.14. We did not observe any significant differences in R1 relaxation, proton density, or myelin content. The sensitivity of R2 to metal ions in tissue and the transition metal ion chelating property of neuromelanin indicate that the R2 deviant area is one of the neuromelanin containing nuclei of the brain stem. The close proximity and its demonstrated involvement in sleep-maintenance, specifically through orexin projections from the hypothalamus regulating sleep stability, as well as the results from the connectivity analysis, suggest that the observed deviant area could be the locus coeruleus or other neuromelanin containing nuclei in the proximity of the superior cerebellar peduncle. Hypothetically, the R2 differences described in this paper could be due to lower levels of neuromelanin in this area of narcolepsy patients.

  • 10.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Moreno, Pablo
    Bergmann, Sven
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Capuccini, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carone, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cascante, Marta
    de Atauri, Pedro
    Foguet, Carles
    Gonzalez-Beltran, Alejandra N.
    Hankemeier, Thomas
    Haug, Kenneth
    He, Sijin
    Herman, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johnson, David
    Kale, Namrata
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Neumann, Steffen
    Peters, Kristian
    Pireddu, Luca
    Rocca-Serra, Philippe
    Roger, Pierrick
    Rueedi, Rico
    Ruttkies, Christoph
    Sadawi, Noureddin
    Salek, Reza M.
    Sansone, Susanna-Assunta
    Schober, Daniel
    Selivanov, Vitaly
    Thévenot, Etienne A.
    van Vliet, Michael
    Zanetti, Gianluigi
    Steinbeck, Christoph
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Interoperable and scalable data analysis with microservices: Applications in metabolomics2019In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, no 19, p. 3752-3760Article in journal (Refereed)
    Abstract [en]

    Motivation

    Developing a robust and performant data analysis workflow that integrates all necessary components whilst still being able to scale over multiple compute nodes is a challenging task. We introduce a generic method based on the microservice architecture, where software tools are encapsulated as Docker containers that can be connected into scientific workflows and executed using the Kubernetes container orchestrator.

    Results

    We developed a Virtual Research Environment (VRE) which facilitates rapid integration of new tools and developing scalable and interoperable workflows for performing metabolomics data analysis. The environment can be launched on-demand on cloud resources and desktop computers. IT-expertise requirements on the user side are kept to a minimum, and workflows can be re-used effortlessly by any novice user. We validate our method in the field of metabolomics on two mass spectrometry, one nuclear magnetic resonance spectroscopy and one fluxomics study. We showed that the method scales dynamically with increasing availability of computational resources. We demonstrated that the method facilitates interoperability using integration of the major software suites resulting in a turn-key workflow encompassing all steps for mass-spectrometry-based metabolomics including preprocessing, statistics and identification. Microservices is a generic methodology that can serve any scientific discipline and opens up for new types of large-scale integrative science.

  • 11.
    Fahlström, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Engström, Mathias
    GE Healthcare, Applied Science Laboratory.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Evaluation of pseudo-continuous arterial spin labeling MRI – agreement with 15O-water PET with arterial input function and use of integrated PET/MRManuscript (preprint) (Other academic)
  • 12.
    Feresiadou, Amalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Press, Rayomand
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Kmezic, Ivan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden..
    Niemelä, Valter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease2019In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 332, p. 31-36Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

    METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

    RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

    CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

  • 13. Hedlund, Fredrik
    et al.
    Leighs, Andrew
    Barber, P Alan
    Lundström, E
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Wu, Teddy Y
    Ranta, Annemarei
    Trends in stroke reperfusion treatment and outcomes in New Zealand.2019In: Internal medicine journal (Print), ISSN 1444-0903, E-ISSN 1445-5994Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) can help reverse stroke symptoms in selected patients but are both time sensitive interventions.

    AIMS: To report current stroke reperfusion rates and quality measures as well as trends over time in New Zealand.

    METHOD: Since 2015 New Zealand treatment centers have been mandated to prospectively enter all IVT and EVT patients into a low cost National Stroke Register. Data was cleaned and missing data added where possible through contact with individual hospitals. Main outcomes include treatment delays, vital status at day seven and complications.

    RESULTS: In 2018, there were 719 of 7173 (10.0%) patients with ischemic stroke or stroke unspecified treated with intravenous IVT, up from 389 of 5963 (6.5%) patients in 2015 (p < 0.001), with no change in day seven mortality (p = 0.63) or sICH rate (p = 0.22). Median (interquartile range (IQR)) door-to-needle times decreased from 65 (47-89) minutes in 2017 to 59 (40-84) minutes in 2018 (p = 0.022), and patients treated within 60 min increased from 40% to 51% (p < 0.001). In 2018, there were 243 (3.4%) patients treated with EVT up from 134/6859 (1.9%) in 2017 (p < 0.0001), with no change in seven mortality (p = 0.39) or sICH (p = 0.78). There was no significant change in onset-to-needle (p = 0.21), arrival-to-groin (p = 0.28) or onset-to-reperfusion time (p = 0.32).

    CONCLUSION: Stroke reperfusion rates in New Zealand are continuously rising with no associated increase in complications. More patients are being treated faster upon hospital arrival but there remains room for further improvement in reducing onset to treatment delays. This article is protected by copyright. All rights reserved.

  • 14.
    Isaksson, Eva
    et al.
    Karolinska Inst, Dept Clin Neurosci, Neurol, Nobels Vag 6, SE-17176 Stockholm, Sweden.
    Wester, Per
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, SE-18288 Stockholm, Sweden;Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden.
    Laska, Ann Charlotte
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, SE-18288 Stockholm, Sweden.
    Nasman, Per
    KTH Royal Inst Technol, Ctr Safety Res, SE-10044 Stockholm, Sweden.
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Identifying important barriers to recruitment of patients in randomised clinical studies using a questionnaire for study personnel2019In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 20, no 1, article id 618Article in journal (Refereed)
    Abstract [en]

    Background:

    Many randomised controlled trials (RCT) fail to meet their recruitment goals. Study personnel play a key role in recruitment. The aim of this study was to identify successful strategies that study personnel consider to be important in patient recruitment to RCT.

    Methods:

    We constructed a questionnaire based on the literature, discussions with colleagues and our own experience as trialists. The survey was named "What is Important for Making a Study Successful questionnaire" (WIMSS-q). Our target group was the study personnel in the ongoing EFFECTS study. The questionnaire was sent out electronically to all physicians and nurses (n = 148). Success factors and barriers were divided according to patient, centre and study level, respectively.

    Results:

    Responses were received from 94% of the study personnel (139/148). The five most important factors at centre level for enhancing recruitment were that the research question was important (97%), a simple procedure for providing information and gaining consent (92%), a highly engaged local principal investigator and research nurse (both 87%), and that study-related follow-ups are practically feasible and possible to coordinate with the clinical follow-up (87%). The most significant barrier at the local centre was lack of time and resources devoted to research (72%). Important patient-related barriers were fear of side effects (35%) and language problems (30%).

    Conclusions:

    For recruitment in an RCT to be successful, the research question must be relevant, and the protocol must be simple and easy to implement in the daily routine.

  • 15.
    Johansson, Dongni
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden.
    Thomas, Ilias
    Dalarna Univ, Dept Microdata Anal, Falun, Sweden.
    Ericsson, Anders
    RISE Acreo, Gothenburg, Sweden;Karolinska Inst, Dept Clin Neurosci, Neurol, Stockholm, Sweden.
    Johansson, Anders
    Medvedev, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control.
    Memedi, Mevludin
    Orebro Univ, Sch Business, Informat, Orebro, Sweden.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Ohlsson, Fredrik
    RISE Acreo, Gothenburg, Sweden.
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Spira, Jack
    Sensidose AB, Sollentuna, Sweden.
    Westin, Jerker
    Dalarna Univ, Dept Microdata Anal, Falun, Sweden.
    Bergquist, Filip
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Pharmacol, Gothenburg, Sweden.
    Evaluation of a sensor algorithm for motor state rating in Parkinson's disease2019In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 64, p. 112-117Article in journal (Refereed)
    Abstract [en]

    Introduction: A treatment response objective index (TRIS) was previously developed based on sensor data from pronation-supination tests. This study aimed to examine the performance of TRIS for medication effects in a new population sample with Parkinson's disease (PD) and its usefulness for constructing individual dose-response models.

    Methods: Twenty-five patients with PD performed a series of tasks throughout a levodopa challenge while wearing sensors. TRIS was used to determine motor changes in pronation-supination tests following a single levodopa dose, and was compared to clinical ratings including the Treatment Response Scale (TRS) and six sub-items of the UPDRS part III.

    Results: As expected, correlations between TRIS and clinical ratings were lower in the new population than in the initial study. TRIS was still significantly correlated to TRS (r(s) = 0.23, P < 0.001) with a root mean square error (RMSE) of 1.33. For the patients (n = 17) with a good levodopa response and clear motor fluctuations, a stronger correlation was found (r(s) = 0.38, RMSE = 1.29, P < 0.001). The mean TRIS increased significantly when patients went from the practically defined off to their best on state (P = 0.024). Individual dose-response models could be fitted for more participants when TRIS was used for modelling than when TRS ratings were used.

    Conclusion: The objective sensor index shows promise for constructing individual dose-response models, but further evaluations and retraining of the TRIS algorithm are desirable to improve its performance and to ensure its clinical effectiveness.

  • 16.
    Juran, Stephanie A.
    et al.
    Karolinska Inst, Dept Clin Neurosci, Div Psychol, Stockholm, Sweden;Karolinska Inst, Inst Environm Med, Unit Work Environm Toxicol, Stockholm, Sweden.
    Lundstrom, Johan N.
    Karolinska Inst, Dept Clin Neurosci, Div Psychol, Stockholm, Sweden;Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA;Univ Penn, Dept Psychol, 3815 Walnut St, Philadelphia, PA 19104 USA.
    Geigant, Michael
    Stockholm Cty Council, Mental Hlth Care, Stockholm, Sweden.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Div Psychol, Stockholm, Sweden.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Div Psychol, Stockholm, Sweden.
    Olsson, Mats J.
    Karolinska Inst, Dept Clin Neurosci, Div Psychol, Stockholm, Sweden.
    Unilateral Resection of the Anterior Medial Temporal Lobe Impairs Odor Identification and Valence Perception2016In: Frontiers in Psychology, ISSN 1664-1078, E-ISSN 1664-1078, Vol. 6, article id 2015Article in journal (Refereed)
    Abstract [en]

    The anterior medial temporal lobe (TL), including the amygdala, has been implicated in olfactory processing, e.g., coding for intensity and valence, and seems also involved in memory. With this background, the present study evaluated whether anterior medial TL-resections in TL epilepsy affected intensity and valence ratings, as well as free and cued identification of odors. These aspects of odor perception were assessed in 31 patients with unilateral anterior medial TL-resections (17 left, 14 right) and 16 healthy controls. Results suggest that the anterior medial TL is in particular necessary for free, but also cued, odor identification. TL resection was also found to impair odor valence, but not intensity ratings. Left resected patients rated nominally pleasant and unpleasant odors as more neutral suggesting a special role for the left anterior TL in coding for emotional saliency in response to odors.

  • 17.
    Kockum, Karin
    et al.
    Umea Univ, Dept Pharmacol & Clin Neurosci Neurol Ostersund, SE-90187 Umea, Sweden.
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Riklund, Katrine
    Umea Univ, Dept Radiat Sci Diagnost Radiol, SE-90187 Umea, Sweden.
    Soderstrom, Lars
    Ostersund Hosp, Unit Res Educ & Dev, SE-83131 Ostersund, Sweden.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Laurell, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology. Umea Univ, Dept Pharmacol & Clin Neurosci Neurol Ostersund, SE-90187 Umea, Sweden.
    Standardized image evaluation in patients with idiopathic normal pressure hydrocephalus: consistency and reproducibility2019In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 61, no 12, p. 1397-1406Article in journal (Refereed)
    Abstract [en]

    Purpose

    Assess the agreement for two investigators between computed tomography (CT) and magnetic resonance imaging (MRI) for seven imaging features included in the iNPH Radscale, a radiological screening tool.

    Methods

    The study included 35 patients with idiopathic normal pressure hydrocephalus (iNPH) who were treated surgically from 2011 to 2015 at Uppsala University Hospital with preoperative CT and MRI performed with maximum 3 months between scans. Seven features were assessed: Evans’ index, temporal horn size, callosal angle, periventricular white matter changes, narrow high convexity sulci, focally enlarged sulci, and enlarged Sylvian fissures. All scans were assessed by two investigators who were blinded to each other’s results and to clinical data.

    Results

    The agreement between CT and MRI was almost perfect for Evans’ index, temporal horns, narrow sulci, and Sylvian fissures (kappa and intraclass correlation, 0.84–0.91, p ≤ 0.001). There was substantial to almost perfect agreement for callosal angle and focally enlarged sulci. The concordance between modalities was fair for changes in periventricular white matter.

    Conclusion

    CT and MRI are equally good for assessing radiological signs associated with iNPH except for periventricular white matter changes, as MRI has superior soft tissue contrast. The other imaging features can be evaluated consistently, and assessments are reproducible independent of modality. Therefore, the iNPH Radscale is applicable to both CT and MRI and may become an important tool for standardized evaluation in the workup in patients with suspected iNPH.

  • 18.
    Landtblom, A-M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Kristoffersson, A
    Boström, I
    Organic solvent exposure as a risk factor for multiple sclerosis: An updated review.2019In: Revue neurologique (Paris), ISSN 0035-3787, E-ISSN 2213-0004, Vol. 175, no 10, p. 625-630, article id S0035-3787(19)30597-1Article in journal (Refereed)
    Abstract [en]

    Organic solvents exposure has for a long time been suspected as a risk factor for developing multiple sclerosis. The evidence, containing case reports, case-control studies and cohort studies has been contradictory. An early meta-analysis, however, pointed to a doubled risk for MS. Recent major case-control studies confirm this, but also have elucidated the risk pattern, being dependent on another risk factor, i.e. smoking.

  • 19.
    Landtblom, Anne-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Guala, Dimitri
    Merck AB, Stockholm, Sweden; Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
    Martin, Claes
    Karolinska Inst, Danderyd Hosp, Div Internal Med, Neurol Unit, Stockholm, Sweden.
    Olsson-Hau, Stefan
    Skåne Univ Hosp, Dept Neurol, Malmö, Sweden.
    Haghighi, Sara
    Motala Hosp, Dept Neurol, Motala, Sweden.
    Jansson, Lillemor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology. Acad Hosp, Dept Neurol, Uppsala, Sweden.
    Fredrikson, Sten
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    RebiQoL: A randomized trial of telemedicine patient support program for health-related quality of life and adherence in people with MS treated with Rebif2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 7, article id e0218453Article in journal (Refereed)
    Abstract [en]

    RebiQoL was a phase IV multicenter randomized study to assess the impact of a telemedicine patient support program (MSP) on health-related quality of life (HRQoL) in patients with relapsing-remitting MS (RRMS) being administered with Rebif with the RebiSmart device. The primary endpoint was to assess the impact of MSP compared to patients only receiving technical support for RebiSmart on HRQoL at 12 months, using the psychological part of Multiple Sclerosis Impact Scale (MSIS-29), in patients administered with Rebif. A total of 97 patients diagnosed with RRMS were screened for participation in the study of which 3 patients did not fulfill the eligibility criteria and 1 patient withdrew consent. Of the 93 randomized patients, 46 were randomized to MSP and 47 to Technical support only. The demographic characteristics of the patients were well-balanced in the two arms. There were no statistical differences (linear mixed model) in any of the primary (difference of 0.48, 95% CI: -8.30-9.25, p = 0.91) or secondary outcomes (p>0.05). Although the study was slightly underpowered, there was a trend towards better adherence in the MSP group (OR 3.5, 95% CI 0.85-14.40, p = 0.08) although not statistically significant. No unexpected adverse events occurred. This study did not show a statistically significant effect of the particular form of teleintervention used in this study on HRQoL as compared to pure technical support, for MS patients already receiving Rebif with the RebiSmart device.

    Trial Registration: ClinicalTrials.gov: NCT01791244.

  • 20. Legg, Lynn A
    et al.
    Tilney, Russel
    Hsieh, Cheng-Fang
    Wu, Simiao
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Rudberg, Ann-Sofie
    Kutlubaev, Mansur A
    Dennis, Martin
    Soleimani, Babak
    Barugh, Amanda
    Hackett, Maree L
    Hankey, Graeme J
    Mead, Gillian E
    Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery2019In: Cochrane Database of Systematic Reviews, ISSN 1469-493X, E-ISSN 1469-493X, Vol. 2019, no 11, article id CD009286Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Stroke is a major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression and other mood disorders after stroke. The 2012 Cochrane Review of SSRIs for stroke recovery demonstrated positive effects on recovery, even in people who were not depressed at randomisation. A large trial of fluoxetine for stroke recovery (fluoxetine versus placebo under supervision) has recently been published, and it is now appropriate to update the evidence.

    OBJECTIVES: To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post-stroke, and to determine whether treatment with SSRIs is associated with adverse effects.

    SEARCH METHODS: For this update, we searched the Cochrane Stroke Group Trials Register (last searched 16 July 2018), the Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, July 2018), MEDLINE (1946 to July 2018), Embase (1974 to July 2018), CINAHL (1982 July 2018), PsycINFO (1985 to July 2018), AMED (1985 to July 2018), and PsycBITE March 2012 to July 2018). We also searched grey literature and clinical trials registers.

    SELECTION CRITERIA: We included randomised controlled trials (RCTs) that recruited ischaemic or haemorrhagic stroke survivors at any time within the first year. The intervention was any SSRI, given at any dose, for any period, and for any indication. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. To be included, trials had to collect data on at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early).

    DATA COLLECTION AND ANALYSIS: We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. Two review authors independently extracted data from each trial. We used standardised mean differences (SMDs) to estimate treatment effects for continuous variables, and risk ratios (RRs) for dichotomous effects, with their 95% confidence intervals (CIs). We assessed risks of bias and applied GRADE criteria.

    MAIN RESULTS: We identified a total of 63 eligible trials recruiting 9168 participants, most of which provided data only at end of treatment and not at follow-up. There was a wide age range. About half the trials required participants to have depression to enter the trial. The duration, drug, and dose varied between trials. Only three of the included trials were at low risk of bias across the key 'Risk of bias' domains. A meta-analysis of these three trials found little or no effect of SSRI on either disability score: SMD -0.01 (95% CI -0.09 to 0.06; P = 0.75; 2 studies, 2829 participants; moderate-quality evidence) or independence: RR 1.00 (95% CI 0.91 to 1.09; P = 0.99; 3 studies, 3249 participants; moderate-quality evidence). We downgraded both these outcomes for imprecision. SSRIs reduced the average depression score (SMD 0.11 lower, 0.19 lower to 0.04 lower; 2 trials, 2861 participants; moderate-quality evidence), but there was a higher observed number of gastrointestinal side effects among participants treated with SSRIs compared to placebo (RR 2.19, 95% CI 1.00 to 4.76; P = 0.05; 2 studies, 148 participants; moderate-quality evidence), with no evidence of heterogeneity (I2 = 0%). For seizures there was no evidence of a substantial difference. When we included all trials in a sensitivity analysis, irrespective of risk of bias, SSRIs appeared to reduce disability scores but not dependence. One large trial (FOCUS) dominated the results. We identified several ongoing trials, including two large trials that together will recruit more than 3000 participants.

    AUTHORS' CONCLUSIONS: We found no reliable evidence that SSRIs should be used routinely to promote recovery after stroke. Meta-analysis of the trials at low risk of bias indicate that SSRIs do not improve recovery from stroke. We identified potential improvements in disability only in the analyses which included trials at high risk of bias. A further meta-analysis of large ongoing trials will be required to determine the generalisability of these findings.

  • 21. Leiss, Lina
    et al.
    Mega, Alessandro
    Olsson Bontell, Thomas
    Nistér, Monica
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Corvigno, Sara
    Rahman, Mohummad Aminur
    Enger, Per Øyvind
    Miletic, Hrvoje
    Östman, Arne
    Platelet-derived growth factor receptor α/glial fibrillary acidic protein expressing peritumoral astrocytes associate with shorter median overall survival in glioblastoma patients.2019In: Glia, ISSN 0894-1491, E-ISSN 1098-1136Article in journal (Refereed)
    Abstract [en]

    The microenvironment and architecture of peritumoral tissue have been suggested to affect permissiveness for infiltration of malignant cells. Astrocytes constitute a heterogeneous population of cells and have been linked to proliferation, migration, and drug sensitivity of glioblastoma (GBM) cells. Through double-immunohistochemical staining for platelet-derived growth factor receptor α (PDGFRα) and glial fibrillary acidic protein (GFAP), this study explored the intercase variability among 45 human GBM samples regarding density of GFAP+ peritumoral astrocytes and a subset of GFAP+ peritumoral astrocyte-like cells also expressing PDGFRα. Large intercase variability regarding the total peritumoral astrocyte density and the density of PDGFRα+/GFAP+ peritumoral astrocyte-like cells was detected. DNA fluorescence in situ hybridization analyses for commonly altered genetic tumor markers supported the interpretation that these cells represented a genetically unaffected host cell subset referred to as PDGFRα+/GFAP+ peritumoral astrocytes. The presence of PDGFRα+/GFAP+ peritumoral astrocytes was significantly positively correlated to older patient age and peritumoral astrocyte density, but not to other established prognostic factors. Notably, presence of PDGFRα+/GFAP+ peritumoral astrocytes, but not peritumoral astrocyte density, was associated with significantly shorter patient overall survival. The prognostic association of PDGFRα+/GFAP+ peritumoral astrocytes was confirmed in multivariable analyses. This exploratory study thus demonstrates previously unrecognized intercase variability and prognostic significance of peritumoral abundance of a novel PDGFRα+ subset of GFAP+ astrocytes. Findings suggest clinically relevant roles of the microenvironment of peritumoral GBM tissue and encourage further characterization of the novel astrocyte subset with regard to origin, function, and potential as biomarker and drug target.

  • 22.
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Återinsättning av trombocythämmare RESTART ger oss (nästan) hela svaret2019In: Neurologi i sverige, , p. 2Article in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Återinsättning av trombocythämmare efter en spontan intrakraniell blödning ökar inte risken för en ny blödning jämfört med att avstå. Tvärtom. Återinsättning verkar till och med minska risken för framtida blödningar. Det är det oväntade resultatet av RESTART-studien som pre-senterades på den europeiska strokekongressen ESOC i Milano, maj 2019. I denna artikel sammanfattas RESTART av Erik Lundström, överläkare vid Akademiska sjukhuset. Pågåen-de studier (RESTART-Fr och STATICH) kommer sannolikt att kunna ge oss ett definitivt svar på denna viktiga kliniska fråga.

  • 23.
    Matic, Teodora
    et al.
    Univ Ljubljana, Fac Comp & Informat Sci, Ljubljana, Slovenia.
    Aghanavesi, Somayeh
    Dalarna Univ, Sch Technol & Business Studies, Comp Engn, Dalarna, Sweden.
    Memedi, Mevludin
    Orebro Univ, Business Sch, Informat, Orebro, Sweden.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Bergquist, Filip
    Univ Gothenburg, Dept Pharmacol, Gothenburg, Sweden.
    Groznik, Vida
    Univ Ljubljana, Fac Comp & Informat Sci, Ljubljana, Slovenia;Univ Primorska, Fac Math Nat Sci & Informat Technol, Koper, Slovenia.
    Zabkar, Jure
    Univ Ljubljana, Fac Comp & Informat Sci, Ljubljana, Slovenia.
    Sadikov, Aleksander
    Univ Ljubljana, Fac Comp & Informat Sci, Ljubljana, Slovenia.
    Unsupervised Learning from Motion Sensor Data to Assess the Condition of Patients with Parkinson's Disease2019In: ARTIFICIAL INTELLIGENCE IN MEDICINE, AIME 2019 / [ed] Riano, D Wilk, S TenTeije, A, 2019, p. 420-424Conference paper (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is a chronic neurodegenerative disorder that predominantly affects the patient's motor system, resulting in muscle rigidity, bradykinesia, tremor, and postural instability. As the disease slowly progresses, the symptoms worsen, and regular monitoring is required to adjust the treatment accordingly. The objective evaluation of the patient's condition is sometimes rather difficult and automated systems based on various sensors could be helpful to the physicians. The data in this paper come from a clinical study of 19 advanced PD patients with motor fluctuations. The measurements used come from the motion sensors the patients wore during the study. The paper presents an unsupervised learning approach applied on this data with the aim of checking whether sensor data alone can indicate the patient's motor state. The rationale for the unsupervised approach is that there was significant inter-physician disagreement on the patient's condition (target value for supervised machine learning). The input to clustering came from sensor data alone. The resulting clusters were matched against the physicians' estimates showing relatively good agreement.

  • 24. Mead, Gillian E
    et al.
    Legg, Lynn
    Tilney, Russel
    Hsieh, Cheng Fang
    Wu, Simiao
    Lundström, E
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Rudberg, Ann Sofie
    Kutlubaev, Mansur
    Dennis, Martin S
    Soleimani, Babak
    Barugh, Amanda
    Hackett, Maree L
    Hankey, Graeme J
    Fluoxetine for stroke recovery: Meta-analysis of randomized controlled trials.2019In: International Journal of Stroke, ISSN 1747-4930, E-ISSN 1747-4949, article id 1747493019879655Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine whether fluoxetine, at any dose, given within the first year after stroke to patients who did not have to have mood disorders at randomization reduced disability, dependency, neurological deficits and fatigue; improved motor function, mood, and cognition at the end of treatment and follow-up, with the same number or fewer adverse effects.

    METHODS: Searches (from 2012) in July 2018 included databases, trials registers, reference lists, and contact with experts. Co-primary outcomes were dependence and disability. Dichotomous data were synthesized using risk ratios (RR) and continuous data using standardized mean differences (SMD). Quality was appraised using Cochrane risk of bias methods. Sensitivity analyses explored influence of study quality.

    RESULTS: The searches identified 3414 references of which 499 full texts were assessed for eligibility. Six new completed RCTs (n = 3710) were eligible, and were added to the seven trials identified in a 2012 Cochrane review (total: 13 trials, n = 4145). There was no difference in the proportion independent (3 trials, n = 3249, 36.6% fluoxetine vs. 36.7% control; RR 1.00, 95% confidence interval 0.91 to 1.09, p = 0.99, I2 = 78%) nor in disability (7 trials n = 3404, SMD 0.05, -0.02 to 0.12 p = 0.15, I2 = 81%) at end of treatment. Fluoxetine was associated with better neurological scores and less depression. Among the four (n = 3283) high-quality RCTs, the only difference between groups was lower depression scores with fluoxetine.

    CONCLUSION: This class I evidence demonstrates that fluoxetine does not reduce disability and dependency after stroke but improves depression.

  • 25.
    Niemelä, Valter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Mapping the Huntington's disease process using cerebrospinal fluid analysis2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a CAG-repeat expansion in the HTT-gene. Today there are no disease-modifying therapies (DMTs), but several promising clinical trials are underway, including therapies that reduce mutant huntingtin expression.

    Reliable biomarkers could empower such trials and guide the timing for initiation of future DMTs.

    Neurofilament light (NFL) and tau, which are cerebrospinal fluid markers of neuronal death, have been implicated as markers of disease progression. Increased levels of the inflammatory marker YKL-40 have also been reported in HD.

    The aim was to validate and compare the above biomarker candidates by targeted analyses, while explorative liquid chromatography-mass spectrometry (LC-MS) was used to identify new candidates. Clinically well-characterized HD patients, premanifest gene expansion carriers (pGECs), and controls were enrolled from Uppsala University Hospital in Sweden.

    In contrast to tau, NFL levels differed between all three groups and NFL had stronger correlations with symptom severity compared with total-tau and phospho-tau. Longitudinally, only NFL maintained intergroup differences and rose with disease progression.

    Soluble CD27, a marker of T cell-mediated inflammation, differed between all three groups, with the highest levels in manifest HD, and mostly undetectable levels in controls. YKL-40 showed a non-significant trend toward increase in manifest HD. 

    We applied LC-MS metabolomics and discovered a metabolite signature unique to manifest HD, with deranged tyrosine metabolism including L-DOPA, dopamine, and thyroxine. Utilizing LC-MS we also identified altered proteins in manifest HD, including proenkephalin that was decreased and associated with symptom severity. 

    In conclusion, NFL may be used as a pharmacodynamic marker in intervention trials. Interestingly, elevated sCD27 implies a role of adaptive immunity before disease onset, but validation is needed. YKL-40 is not suitable as an early marker in HD. The CSF metabolome constitutes a new compartment of potential biomarkers but challenges in metabolite identification should be addressed in future studies. Proenkephalin levels potentially reflect the remaining number of striatal medium spiny neurons and hold promise as a marker of disease progression. 

    List of papers
    1. Tau or neurofilament light - Which is the more suitable biomarker for Huntington’s disease?
    Open this publication in new window or tab >>Tau or neurofilament light - Which is the more suitable biomarker for Huntington’s disease?
    2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0172762Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Previous studies have suggested cerebrospinal fluid (CSF) levels of neurofilament light (NFL) and total tau are elevated in Huntington's disease (HD) and may be used as markers of disease stage. Biomarkers are needed due to the slow disease progression and the limitations of clinical assessment. This study aims to validate the role of NFL and tau as biomarkers in HD.

    METHODS: CSF was obtained from a cohort of HD patients and premanifest HD-mutation carriers. Unified Huntington's Disease Rating Scale (UHDRS) testing was performed on all subjects at the time of sampling. NFL and tau concentrations were determined by ELISA. Spearman correlations were calculated with R version 3.2.3.

    RESULTS: 11 premanifest HD and 12 manifest HD subjects were enrolled. NFL and tau levels were correlated. NFL showed strong correlations with all items included in the clinical assessment (for example the total functional capacity (TFC) (r = - 0.70 p < 0.01) and total motor score (TMS) (r = 0.83p < 0.01). Tau showed slightly weaker correlations (eg. TMS (r = 0.67 p < 0.01); TFC (r = - 0.59 p < 0.01)). NFL was significantly correlated with 5-year probability of disease onset, whereas tau was not.

    CONCLUSION: This study strengthens the case for NFL as a useful biomarker of disease stage. NFL was strongly correlated to all evaluated items in the UHDRS assessment. Tau also has a potential for use as a biomarker but correlations to clinical tests are weaker in this study. We suggest that NFL and possibly tau be used in clinical drug trials as biomarkers of disease progression that are potentially influenced by future disease-modifying therapies.

    Keywords
    Huntingtons disease
    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-317298 (URN)10.1371/journal.pone.0172762 (DOI)000395934400040 ()28241046 (PubMedID)
    Projects
    https://www.researchgate.net/project/Mapping-the-Huntingtons-disease-process-by-analyses-of-cerebrospinal-fluid
    Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2019-10-23Bibliographically approved
    2. Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease
    Open this publication in new window or tab >>Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease
    Show others...
    2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2, article id e0193492Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Huntington's disease (HD) is a neurodegenerative disorder, but evidence also suggests neuroinflammation in the pathogenesis. The immune mechanisms involved and the timing of their activation need further clarification.

    METHODS: A clinically well-characterized HD cohort and gene negative controls were enrolled. YKL-40 reflecting innate immunity and sCD27, a marker of adaptive immunity, were measured across disease stages. Comparisons were made with markers of neurodegeneration: neurofilament light (NFL), total-tau (T-tau), and phospho-tau (P-tau).

    RESULTS: 52 cross-sectional cerebrospinal fluid samples and 23 follow-up samples were analyzed. sCD27 was elevated in manifest HD and premanifest gene expansion carriers, whereas controls mostly had undetectable levels. YKL-40 showed a trend toward increase in manifest HD. sCD27 correlated with YKL-40 which in turn was closely associated to all included markers of neurodegeneration. YKL-40, NFL, and both forms of tau could all independently predict HD symptoms, but only NFL levels differed between groups after age-adjustment.

    CONCLUSION: Increased sCD27 in premanifest HD is a sign of T cell-mediated neuroinflammation. This finding is novel since other reports almost exclusively have found early involvement of innate immunity. Validation of sCD27 in a larger HD cohort is needed. The role of adaptive immunity in HD needs further clarification, as it may hasten disease progression.

    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-342996 (URN)10.1371/journal.pone.0193492 (DOI)000426049500119 ()29474427 (PubMedID)
    Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2019-10-23Bibliographically approved
    3. Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects
    Open this publication in new window or tab >>Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects
    Show others...
    2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4129Article in journal (Refereed) Published
    Abstract [en]

    Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2019
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-379886 (URN)10.1038/s41598-019-40186-5 (DOI)000460754600020 ()30858393 (PubMedID)
    Funder
    Åke Wiberg FoundationEU, Horizon 2020, 654241
    Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-10-23Bibliographically approved
    4. CSF Proenkephalin decreases with the progression of Huntington's disease
    Open this publication in new window or tab >>CSF Proenkephalin decreases with the progression of Huntington's disease
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 presymptomatic gene expansion carriers (pGEC) and 38 controls. In ManHD compared to pGEC 10 proteins were downregulated, and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin along with upregulated proteins (VASN, STC2, SGCE and C7) were all closely linked to HD symptom severity. The decreased PENK levels were replicated in a separate cohort of 23 ManHD and 23 controls where absolute quantitation was performed. We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK, and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD.   

    Keywords
    Proteomics, Mass spectrometry, Neurodegeneration, Cerebrospinal fluid, Huntington's disease
    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-395606 (URN)
    Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23
  • 26. Niemelä, Valter
    et al.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kneider, Maria
    Sahlrenska akademin, Göteborgs universitet.
    Constantinescu, Radu
    Sahlrenska akademin, Göteborgs universitet.
    Paucar, Martin
    Karolinska institutet.
    Svenningsson, Per
    Karolinska institutet.
    Abujrais, Sandy
    Uppsala University.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundblom, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    CSF Proenkephalin decreases with the progression of Huntington's diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 presymptomatic gene expansion carriers (pGEC) and 38 controls. In ManHD compared to pGEC 10 proteins were downregulated, and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin along with upregulated proteins (VASN, STC2, SGCE and C7) were all closely linked to HD symptom severity. The decreased PENK levels were replicated in a separate cohort of 23 ManHD and 23 controls where absolute quantitation was performed. We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK, and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD.   

  • 27. Roaldsen, M. B.
    et al.
    Soyland, M. -H
    Jusufovic, M.
    Tveiten, A.
    Lundström, E
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Petersson, J.
    Putaala, J.
    Korv, J.
    Christensen, H. K.
    Jatuzis, D.
    Engelter, S.
    de Marchis, G. M.
    Werring, D.
    Robinson, T.
    Mathiesen, E.
    Berge, E.
    TWIST tenecteplase in wake-up ischaemic stroke trial2019In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 26, no 1, SIArticle in journal (Refereed)
  • 28.
    Tolf, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Granberg, Tobias
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden; Karolinska Univ Hosp, Dept Radiol, Div Neuroradiol, Stockholm, Sweden.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation2019In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 140, no 5, p. 320-327Article in journal (Refereed)
    Abstract [en]

    Objectives: To determine whether treatment with autologous hematopoietic stem cell transplantation (HSCT) can induce sustained complete remission in patients with multiple sclerosis (MS).

    Material and methods: Case series of patients with relapsing‐remitting MS (n = 10) treated at a single center between 2004 and 2007 and followed up for 10 years. The patients were treated with a BEAM/ATG conditioning regimen (n = 9) or a cyclophosphamide/ATG conditioning regimen (n = 1) followed by infusion of unmanipulated autologous hematopoietic stem cells. The primary endpoint was sustained complete remission. Sustained complete remission was defined as “no evidence of disease activity‐4,” sustained for a period of at least 5 years without any ongoing disease‐modifying treatment. Furthermore, MS was considered as “resolved” if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.

    Results: Five out of 10 patients were in sustained complete remission at the end of the study. In three of them, MS was resolved.

    Conclusions: Our data demonstrate that sustained complete remission after autologous HSCT for MS is possible.

     

  • 29.
    Weber, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Gustafsson, Cecilia
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden;Sahlgrens Univ Hosp, Gothenburg, Sweden.
    Malmgren, Kristina
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden;Sahlgrens Univ Hosp, Gothenburg, Sweden.
    Strandberg, Moa
    Lund Univ Hosp, Dept Clin Sci, Dept Neurol, Lund, Sweden.
    Can, Umran
    Lund Univ Hosp, Dept Clin Sci, Dept Neurol, Lund, Sweden.
    Strandberg, Maria Compagno
    Lund Univ Hosp, Dept Clin Sci, Dept Neurol, Lund, Sweden.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Evaluation for epilepsy surgery - Why do patients not proceed to operation?2019In: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 69, p. 241-244Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the reasons for not proceeding to surgery in patients undergoing presurgical evaluation for epilepsy. Methods: A retrospective cohort study of 401 consecutive patients who were evaluated for but did not proceed to surgery for epilepsy between 1990 and 2016 at three Swedish epilepsy surgery centers was performed. Reasons for not proceeding to surgery were categorized as inconclusive investigation, seizure onset within eloquent cortex, evidence of multiple seizure foci, infrequent seizures, risk of postoperative severe cognitive decline, patient or caregiver declining surgery or invasive investigation, severe psychiatric or somatic comorbidity, patient death during evaluation and complications during the evaluation. Chi-square tests were performed to compare ordered categorical variables. Results: During the entire time period the main reasons for rejection were inconclusive investigation (34,4%) and multifocal seizure onset (20,0%). The risk for severe cognitive decline postoperatively was more often a cause for rejection in more recent years. Patients declining invasive EEG or surgery accounted for a minor but not insignificant proportion (14,2%) of rejections. Conclusions: Inconclusive results from the presurgical evaluation and multifocal epilepsy were the main causes for not proceeding to surgery. The proportion of patients opting to abstain from surgery was low compared to other recent studies.

  • 30. Werlenius, Katja
    et al.
    Fekete, Boglarka
    Blomstrand, Malin
    Carén, Helena
    Jakola, Asgeir S
    Rydenhag, Bertil
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Patterns of care and clinical outcome in assumed glioblastoma without tissue diagnosis: A population-based study of 131 consecutive patients.2020In: PLoS ONE, E-ISSN 1932-6203, Vol. 15, no 2, article id e0228480Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Elderly patients with glioblastoma and an accumulation of negative prognostic factors have an extremely short survival. There is no consensus on the clinical management of these patients and many may escape histologically verified diagnosis. The primary aim of this study was to characterize this particular subgroup of patients with radiological glioblastoma diagnosis without histological verification. The secondary aim was to evaluate if oncological therapy was of benefit.

    METHODS: Between November 2012 and June 2016, all consecutive patients presenting with a suspected glioblastoma in the western region of Sweden were registered in a population-based study. Of the 378 patients, 131 (35%) met the inclusion criteria of the present study by typical radiological features of glioblastoma without histological verification.

    RESULTS: The clinical characteristics of the 131 patients (72 men, 59 women) were: age ≥ 75 (n = 99, 76%), performance status according to Eastern Cooperative Oncology Group ≥ 2 (n = 93, 71%), significant comorbidity (n = 65, 50%) and multilobular tumors (n = 90, 69%). The overall median survival rate was 3.6 months. A subgroup of 44 patients (34%) received upfront treatment with temozolomide, with an overall radiological response rate of 34% and a median survival of 6.8 months, compared to 2.7 months for those receiving best supportive care only. Good performance status and temozolomide treatment were statistically significant favorable prognostic factors, while younger age was not.

    CONCLUSION: Thirty-five percent of patients with a radiological diagnosis of glioblastoma in our region lacked histological diagnosis. Apart from high age and poor performance status, they had more severe comorbidities and extensive tumor spread. Even for this poor prognostic group upfront treatment with temozolomide was shown of benefit in a subgroup of patients. Our data illustrate the need of non-invasive diagnostic methods to guide optimal individualized therapy for patients considered too fragile for neurosurgical biopsy.

  • 31.
    Westerberg, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rostedt Punga: Clinical Neurophysiology.
    Lifestyle factors and disease-specific differences in subgroups of Swedish Myasthenia Gravis2018In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 138, no 6, p. 557-565Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To evaluate disease-specific differences between Myasthenia Gravis (MG) subgroups and compare patterns of lifestyle between MG patients and population controls.

    METHODS: All MG patients (n=70) in Jönköping County, Sweden, were invited to answer a disease-specific questionnaire, containing questions about disease-specific data, lifestyle, co-morbidity and mental fatigue. The patients were clinically evaluated. Four hundred age- and gender matched population controls were invited to answer the non-disease-specific part of the questionnaire. Disease-specific issues were compared between MG subgroups. Lifestyle related factors and concomitant conditions were compared to the population controls.

    RESULTS: Forty MG patients and 188 population controls participated in the study. In the late onset MG (LOMG; N=18) subgroup, the male predominance was higher than previously reported. In the early onset MG (EOMG; N=17) subgroup, time to diagnosis was longer, fatigue was higher and bulbar weakness was the dominant symptom (65%). Compared to their matched population controls, LOMG patients were more obese (OR 13.7, p=0.015), ate less fish (OR 4.1, p=0.012), tended to smoke more (OR 4.1, p=0.086) and tended to be employed as manual laborers more often (OR 2.82, p=0.083). Mental health problems and sickness benefits were more common among MG patients than in controls and MG patients were less regularly doing focused physical activity.

    CONCLUSIONS: It is important to consider disease-specific differences when tailoring the management of individual MG patients. There is a need for improved knowledge on how to apply primary and secondary prevention measures to lifestyle disorders in MG patients without risk of deterioration.

  • 32.
    Wiberg, Anna
    et al.