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  • 51.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Univ Uppsala Hosp, Dept Neurol, SE-75185 Uppsala, Sweden.
    Svenningsson, Anders
    Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden; Univ Hosp Northern Sweden, Umea, Sweden; Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Cerebrospinal fluid concentration of Galectin-9 is increased in secondary progressive multiple sclerosis.2016In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 292, p. 40-44Article in journal (Refereed)
    Abstract [en]

    Galectin-9 is produced by activated astrocytes, induces a pro-inflammatory response in microglia and may be important to the pathogenesis of secondary progressive MS. In this study, Galectin-9 concentrations in CSF samples from healthy controls and two independent patient cohorts of MS patients were determined by ELISA. Patients from one of the cohorts underwent MRI as well. Galectin-9 concentrations in CSF were higher in SPMS patients than healthy controls and RRMS patients in both cohorts. Galectin-9 concentrations correlated with the number of lesions on T1-weighted images, but not with gadolinium enhancing lesions, IgG index or CSF cell count.

  • 52.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tim-3 and PD-1: Regulators of adaptive immunity in multiple sclerosis2014In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 275, no 1-2, p. 141-141Article in journal (Other academic)
  • 53.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fransson, Moa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica S I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zetterberg, Henrik
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Svenningsson, Anders
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mangsbo, Sara M
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The cerebrospinal fluid cytokine signature of multiple sclerosis: A homogenous response that does not conform to the Th1/Th2/Th17 convention2014In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 277, no 1-2, p. 153-159Article in journal (Refereed)
    Abstract [en]

    In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.

  • 54.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden..
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Svenningsson, Anders
    Department of Pharmacology and Clinical Neuroscience, Umeå University and University Hospital of Northern Sweden, Umeå, Sweden..
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The cerebrospinal fluid cytokine signature of multiple sclerosis: a homogenous response that does not conform to the Th1/Th2/Th17 conventionManuscript (preprint) (Other academic)
    Abstract [en]

    In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS) that could be used as an outcome measure in clinical trials. To this end, cerebrospinal fluid from a cohort of patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Cerebrospinal fluid from a separate confirmatory cohort was used to validate cytokines pertinent to SPMS. Increased levels of CCL22, CXCL10 and sCD40L characterized RRMS patients with presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of RRMS patients irrespectively of presence of gadolinium-enhancing lesions. IL-15 and IL-27 were increased in SPMS patients, but non-significantly in the confirmation cohort. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.

  • 55.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Tolf, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Autologous haematopoietic stem cell transplantation for neurological diseases2018In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 89, no 2, p. 147-155Article, review/survey (Refereed)
    Abstract [en]

    Neuroinflammatory diseases such as multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis are leading causes of physical disability in people of working age. In the last decades significant therapeutic advances have been made that can ameliorate the disease course. Nevertheless, many affected will continue to deteriorate despite treatment, and the costs associated with disease-modifying drugs constitute a significant fiscal burden on healthcare in developed countries. Autologous haematopoietic stem cell transplantation is a treatment approach that aims to ameliorate and to terminate disease activity. The erroneous immune system is eradicated using cytotoxic drugs, and with the aid of haematopoietic stem cells a new immune system is rebuilt. As of today, more than 1000 patients with multiple sclerosis have been treated with this procedure. Available data suggest that autologous haematopoietic stem cell transplantation is superior to conventional treatment in terms of efficacy with an acceptable safety profile. A smaller number of patients with other neuroinflammatory conditions have been treated with promising results. Herein, current data on clinical effect and safety of autologous haematopoietic stem cell transplantation for neurological disease are reviewed.

  • 56.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Zelano, Johan
    University of Gothenburg, Sahlgrenska Academy, Department of Clinical Neuroscience, Gothenburg.; Sahlgrenska University Hospital, Gothenburg.
    Epilepsy in multiple sclerosis: A nationwide population-based register study.2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 24, p. 2462-2468Article in journal (Refereed)
    Abstract [en]

    Objective: To determine the cumulative incidence of epilepsy in a population-based cohort of patients with multiple sclerosis (MS) and to investigate the association between epilepsy and clinical features of MS.

    Methods: All available patients in the Swedish MS register (n = 14,545) and 3 age- and sex-matched controls per patient randomly selected from the population register (n = 43,635) were included. Data on clinical features of MS were retrieved from the Swedish MS register, and data on epilepsy and death were retrieved from comprehensive patient registers.

    Results: The cumulative incidence of epilepsy was 3.5% (95% confidence interval [CI] 3.17–3.76) in patients with MS and 1.4% (95% CI 1.30–1.52) in controls (risk ratio 2.5, 95% CI 2.19–2.76). In a Cox proportional model, MS increased the risk of epilepsy (hazard ratio 3.2, 95% CI 2.64–3.94). Patients with relapsing-remitting MS had a cumulative incidence of epilepsy of 2.2% (95% CI 1.88–2.50), whereas patients with progressive disease had a cumulative incidence of 5.5% (95% CI 4.89–6.09). The cumulative incidence rose continuously with increasing disease duration to 5.9% (95% CI 4.90–7.20) in patients with disease duration ≥34 years. Patients with an Expanded Disability Status Scale (EDSS) score ≥7 had a cumulative incidence of epilepsy of 5.3% (95% CI 3.95–7.00). Disease duration and EDSS score were associated with epilepsy after multiple logistic regression (odds ratio [OR] 1.03, 95% CI 1.01–1.04 per year, p = 0.001; and OR 1.2, 95% CI 1.09–1.26 per EDSS step, p < 0.0001).

    Conclusions: Epilepsy is more common among patients with MS than in the general population, and a diagnosis of MS increases the risk of epilepsy. Our data suggest a direct link between severity of MS and epilepsy.

  • 57.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Zetterberg, H
    Sahlgrenska Academy, University of Gothenburg.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica SI.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Assessing tissue damage in multiple sclerosis: a biomarker approach2014In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 130, no 2, p. 81-89Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS.

    MATERIALS AND METHODS:

    Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted.

    RESULTS:

    Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers.

    CONCLUSIONS:

    Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

  • 58.
    Burt, Richard K.
    et al.
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Balabanov, Roumen
    Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sharrack, Basil
    Sheffield Teaching Hosp NHS Fdn Trust, Dept Neurosci, Sheffield, S Yorkshire, England;Sheffield Teaching Hosp NHS Fdn Trust, Sheffield NIHR Translat Neurosci BBC, Sheffield, S Yorkshire, England;Univ Sheffield, Sheffield, S Yorkshire, England.
    Snowden, John A.
    Univ Sheffield, Sheffield, S Yorkshire, England;Sheffield Teaching Hosp NHS Fdn Trust, Dept Haematol & Oncol, Sheffield, S Yorkshire, England;Sheffield Teaching Hosp NHS Fdn Trust, Dept Metab, Sheffield, S Yorkshire, England.
    Oliveira, Maria Carolina
    Univ Sao Paulo, Ctr Cell Based Therapy, Dept Internal Med, Ribeirao Preto Med Sch, Ribeirao Preto, Brazil.
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Rose, John
    Univ Utah, Dept Neurol, Salt Lake City, UT USA.
    Nelson, Flavia
    Univ Minnesota, Dept Neurol, Div Multiple Sclerosis, Minneapolis, MN 55455 USA.
    Barreira, Amilton Antunes
    Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Neurosci & Behav Sci, Ribeirao Preto, Brazil.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Han, Xiaoqiang
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Moraes, Daniela
    Univ Sao Paulo, Ctr Cell Based Therapy, Dept Internal Med, Ribeirao Preto Med Sch, Ribeirao Preto, Brazil.
    Morgan, Amy
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Quigley, Kathleen
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Yaung, Kimberly
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Buckley, Regan
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Alldredge, Carri
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Clendenan, Allison
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Calvario, Michelle A.
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Henry, Jacquelyn
    Northwestern Univ, Dept Med, Div Immunotherapy, Feinberg Sch Med, Chicago, IL 60611 USA.
    Jovanovic, Borko
    Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA.
    Helenowski, Irene B.
    Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA.
    Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial2019In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 321, no 2, p. 165-174Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).

    OBJECTIVE To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.

    DESIGN, SETTING, AND PARTICIPANTS Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.

    INTERVENTIONS Patients were randomized to receive HSCT along with cyclophosphamide (200mg/kg) and antithymocyte globulin (6mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).

    MAIN OUTCOMES AND MEASURES The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. RESULTS Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference,-1.7; 95% CI,-2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).

    CONCLUSIONS AND RELEVANCE In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

  • 59. Burt, Richard K
    et al.
    Balabanov, Roumen
    Han, Xiaoqiang
    Sharrack, Basil
    Morgan, Amy
    Quigley, Kathleeen
    Yaung, Kim
    Helenowski, Irene B
    Jovanovic, Borko
    Spahovic, Dzemila
    Arnautovic, Indira
    Lee, Daniel C
    Benefield, Brandon C
    Futterer, Stephen
    Oliveira, Maria Carolina
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis2015In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 313, no 3, p. 275-284Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability.

    OBJECTIVE: To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS.

    DESIGN, SETTING, AND PARTICIPANTS: Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014.

    INTERVENTIONS: Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells.

    MAIN OUTCOMES AND MEASURES: Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan.

    RESULTS: Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128).

    CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.

  • 60.
    Burt, Richard K.
    et al.
    Northwestern Univ, Div Immunotherapy, Chicago, IL 60611 USA.
    Balabanov, Roumen
    Northwestern Univ, Dept Neurol, Chicago, IL 60611 USA.
    Snowden, John A.
    Sheffield Teaching Hosp, Dept Haematol, Sheffield, S Yorkshire, England.
    Sharrack, Basil
    Sheffield Teaching Hosp, Dept Neurol, Sheffield, S Yorkshire, England.
    Oliveira, Maria Carolina
    Univ Sao Paulo, Sao Paulo, Brazil.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Non-myeloablative hematopoietic stem cell transplantation (HSCT) is superior to disease modifying drug (DMD) treatment in highly active Relapsing Remitting Multiple Sclerosis (RRMS): interim results of the Multiple Sclerosis International Stem cell Transplant (MIST) Randomized Trial2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90Article in journal (Other academic)
  • 61. Burt, Richard K
    et al.
    Balabanov, Roumen
    Voltarelli, Julio
    Barreira, Amilton
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Autologous hematopoietic stem cell transplantation for multiple sclerosis: if confused or hesitant, remember 'Treat with standard immune suppressive drugs and if no inflammation, no response'2012In: Multiple Sclerosis Journal, ISSN 1352-4585, Vol. 18, no 6, p. 772-775Article in journal (Refereed)
  • 62.
    Burt, Richard K.
    et al.
    Northwestern Univ, Div Immunotherapy, Chicago, IL 60611 USA..
    Snowden, John A.
    Sheffield Teaching Hosp NHS Fdn Trust, Dept Haematol, Sheffield, S Yorkshire, England..
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Oliveira, Maria Carolina
    Univ Sao Paulo, Dept Internal Med, Sao Paulo, Brazil..
    Sharrack, Basil
    Sheffield Teaching Hosp NHS Fdn Trust, Dept Neurol, Sheffield, S Yorkshire, England..
    Blogs cannot separate wheat from chaff2017In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 358, no 6363, p. 602-602Article in journal (Other academic)
  • 63.
    Busk, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Johansson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Long-term efficacy and safety with continuous dopaminergic stimulation pump treatments in Parkinson's disease2011In: European Neurological Review, ISSN 1758-3837, Vol. 6, no 3, p. 156-160Article in journal (Refereed)
    Abstract [en]

    Continuous dopaminergic stimulation (CDS) is important for symptom control in advanced stages of Parkinson’s disease (PD). The most efficacious approaches are pump treatments with dopaminergic drugs: subcutaneous infusion of the dopamine receptor agonist apomorphine and intestinal infusion of levodopa/carbidopa gel. Both methods decrease motor fluctuations in long-term follow-ups, including parkinsonian and dyskinetic states, when compared to conventional optimised oral therapy. Also non-motor symptoms may be improved. Adverse drug reactions are usually less pronounced although high levodopa doses, which are common with levodopa/carbidopa infusion, may cause hyperhomocysteinaemia and cobalamin deficiency. Technical complications are specific for each infusion strategy. Formation of subcutaneous nodules is the most common problem with apomorphine infusion. Dislocation of the intestinal tube is the most common problem with levodopa/carbidopa infusion. Both pump treatments may be used for 24-hour infusion in selected patients. The long-term experience is reviewed. To conclude, CDS pump treatments may be successfully used for several years in advanced PD.

  • 64.
    Busk, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Long-term 24-h levodopa/carbidopa gel infusion in Parkinson's disease2012In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 18, no 8, p. 1000-1001Article in journal (Refereed)
  • 65.
    Carstam, Louise
    et al.
    Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden; Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Milos, Peter
    Linköping Univ Hosp, Dept Neurosurg, Linköping, Sweden.
    Corell, Alba
    Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden.
    Henriksson, Roger
    Reg Canc Ctr Stockholm Gotland, Stockholm, Sweden; Univ Umeå, Dept Radiat Sci & Oncol, Umeå, Sweden.
    Bartek, Jiri Jr
    Karolinska Univ Hosp, Dept Neurosurg, Stockholm, Sweden; Karolinska Inst, Dept Neurosci, Stockholm, Sweden; Karolinska Inst, Dept Med, Stockholm, Sweden; Copenhagen Univ Hosp, Rigshosp, Dept Neurosurg, Copenhagen, Denmark.
    Jakola, Asgeir Store
    Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden; Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden; St Olavs Univ Hosp HF, Dept Neurosurg, Trondheim, Norway.
    Neurosurgical patterns of care for diffuse low-grade gliomas in Sweden between 2005 and 20152018In: Neurooncology Practice, ISSN 2054-2577, Vol. 6, no 2, p. 124-133Article in journal (Refereed)
    Abstract [en]

    Background: In the last decade, increasing evidence has evolved for early and maximal safe resection of diffuse low-grade gliomas (LGGs) regarding survival. However, changes in clinical practice are known to occur slowly and we do not know if the scientific evidence has yet resulted in changes in neurosurgical patterns of care.

    Methods: The Swedish Brain Tumor Registry was used to identify all patients with a first-time histopathological diagnosis of LGG between 2005 and 2015. For analysis of surgical treatment patterns, we subdivided assessed time periods into 2005-2008, 2009-2012, and 2013-2015. Population-based data on patient and disease characteristics, surgical management, and outcomes were extracted.

    Results: A total of 548 patients with diffuse World Health Organization grade II gliomas were identified: 142 diagnosed during 2005-2008, 244 during 2009-2012, and 162 during 2013-2015. Resection as opposed to biopsy was performed in 64.3% during 2005-2008, 74.2% during 2009-2012, and 74.1% during 2013-2015 (P = .08). There was no difference among the 3 periods regarding overall survival (P = .11). However, post hoc analysis of data from the 4 (out of 6) centers that covered all 3 time periods demonstrated a resection rate of 64.3% during 2005-2008, 77.4% during 2009-2012, and 75.4% during 2013-2015 (P = .02) and longer survival of patients diagnosed 2009 and onward (P = .04).

    Conclusion: In this nationwide, population-based study we observed a shift over time in favor of LGG resection. Further, a positive correlation between the more active surgical strategy and longer survival is shown, although no causality can be claimed because of possible confounding factors.

  • 66.
    Cubo, Rubén
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jiltsova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Andersson, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Medvedev, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Calculating Deep Brain Stimulation Amplitudes and Power Consumption by Constrained Optimization2019In: Journal of Neural Engineering, ISSN 1741-2560, E-ISSN 1741-2552, Vol. 16, no 1, article id 016020Article in journal (Refereed)
    Abstract [en]

    Objective: Deep brain stimulation (DBS) consists of delivering electrical stimuli to a brain target via an implanted lead to treat neurological and psychiatric conditions. Individualized stimulation is vital to ensure therapeutic results, since DBS may otherwise become ineffective or cause undesirable side effects. Since the DBS pulse generator is battery-driven, power consumption incurred by the stimulation is important. In this study, target coverage and power consumption are compared over a patient population for clinical and model-based patient-specific settings calculated by constrained optimization.

    Approach: Brain models for five patients undergoing bilateral DBS were built. Mathematical optimization of activated tissue volume was utilized to calculate stimuli amplitudes, with and without specifying the volumes, where stimulation was not allowed to avoid side effects. Power consumption was estimated using measured impedance values and battery life under both clinical and optimized settings.

    Results: It was observed that clinical settings were generally less aggressive than the ones suggested by unconstrained model-based optimization, especially under asymmetrical stimulation. The DBS settings satisfying the constraints were close to the clinical values.

    Significance: The use of mathematical models to suggest optimal patient-specific DBS settings that observe technological and safety constraints can save time in clinical practice. It appears though that the considered safety constraints based on brain anatomy depend on the patient and further research into it is needed. This work highlights the need of specifying the brain volumes to be avoided by stimulation while optimizing the DBS amplitude, in contrast to minimizing general stimuli overspill, and applies the technique to a cohort of patients. It also stresses the importance of considering power consumption in DBS optimization, since it increases with the square of the stimuli amplitude and also critically affects battery life through pulse frequency and duty cycle.

  • 67.
    Cubo, Rubén
    et al.
    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.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Dept Biomed Technol Med Phys & IT, Uppsala, Sweden.
    Jiltsova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Andersson, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Medvedev, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Semi-Individualized electrical models in deep brain stimulation: A variability analysis2017In: 2017 IEEE Conference on Control Technology and Applications (CCTA), IEEE, 2017, p. 517-522Conference paper (Refereed)
    Abstract [en]

    Deep Brain Stimulation (DBS) is a well-established treatment in neurodegenerative diseases, e.g. Parkinson's Disease. It consists of delivering electrical stimuli to a target in the brain via a chronically implanted lead. To expedite the tuning of DBS stimuli to best therapeutical effect, mathematical models have been developed during recent years. The electric field produced by the stimuli in the brain for a given lead position is evaluated by numerically solving a Partial Differential Equation with the medium conductivity as a parameter. The latter is patient- and target-specific but difficult to measure in vivo. Estimating brain tissue conductivity through medical imaging is feasible but time consuming due to registration, segmentation and post-processing. On the other hand, brain atlases are readily available and processed. This study analyzes how alternations in the conductivity due to inter-patient variability or lead position uncertainties affect both the stimulation shape and the activation of a given target. Results suggest that stimulation shapes are similar, with a Dice's Coefficient between 93.2 and 98.8%, with a higher similarity at lower depths. On the other hand, activation shows a significant variation of 17 percentage points, with most of it being at deeper positions as well. It is concluded that, as long as the lead is not too deep, atlases can be used for conductivity maps with acceptable accuracy instead of fully individualized though medical imaging models.

  • 68.
    Dagiasi, Loanna
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Gothenburg, Sweden;NAL Hosp Trollhattan, Trollhattan, Sweden.
    Vall, Victor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Zelano, Johan
    Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Gothenburg, Sweden;Sahlgrens Univ Hosp, Gothenburg, Sweden.
    Treatment of epilepsy in multiple sclerosis2018In: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 58, p. 47-51Article in journal (Refereed)
    Abstract [en]

    Purpose: The prevalence of epilepsy is increased in multiple sclerosis (MS), but information on AED treatment and seizure outcome is scarce. We describe epilepsy characteristics including the use of AEDs and proportion of seizure-free patients at two tertiary hospitals in Sweden. Method: We retrospectively studied electronic medical records of all patients with a diagnosis of MS and seizures at Sahlgrenska university hospital and Uppsala university hospital. Clinical data were reviewed until 2017. Results: We identified a total of 62 MS patients with at least one seizure. Median age at the first seizure (before or after MS) was 41 years (range 0-80). The most common MS disease course at the first seizure was secondary progressive MS, the neurological disability was considerable, and most patients had several MRI lesions at their first seizure. The first EEG demonstrated epileptiform discharges in 38% and unspecific pathology in 40%. Current seizure status could be determined for 37 patients. Out of these, 46% had been seizure free for more than one year at last follow-up. The majority of patients (65%) were on monotherapy at last follow-up. Carbamazepine was the most commonly used first AED, with a retention rate of 52%. No individual AED was associated with a particularly high rate of seizure freedom. The most common reason for discontinuation of the first AED was side-effects. Conclusion: Seizure freedom rates were low, perhaps indicating a need for higher ambitions in management. Side effects of AEDs may be a particular concern when treating epilepsy in patients with MS.

  • 69.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    11C Molecular Imaging in Focal Epilepsy2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Epilepsy is a common neurological disease affecting 6 million people in Europe. Early prevention and accurate diagnosis and treatment are of importance to obtain seizure freedom. In this thesis new applications of carbon-11-labelled tracers in PET and autoradiographic studies were explored in focal epilepsy.

    Patients with low-grade gliomas often experience epileptic seizures. A retrospective PET-study assessing seizure activity, metabolic rate measured with 11C-methionine and other known prognostic factors was performed in patients with glioma. No correlation was found between seizure activity and uptake of methionine. The presence and termination of early seizures was a favourable prognostic factor.

    Activation of the neurokinin-1 (NK1) receptor by substance P (SP) induces epileptic activity. PET with the NK1 receptor antagonist GR205171 was performed in patients with temporal lobe epilepsy (TLE) and healthy controls. In TLE patients an increased NK1 receptor availability was found in both hemispheres, most pronounced in anterior cingulate gyrus ipsilateral to seizure onset. A positive correlation between NK1 receptors and seizure frequency was observed in ipsilateral medial structures consistent with an intrinsic network using the NK1-SP receptor system for transmission of seizure activity.

    The uptake of 18F-fluoro-deoxy-glucose (FDG) is related to cerebral blood flow (CBF). Previously, methods to estimate blood flow from dynamic PET data have been described. A retrospective study was conducted in 15 patients undergoing epilepsy surgery investigation, including PET with 11C-FDG and 11C-Flumazenil (FMZ). The dynamic FMZ dataset and pharmacokinetic modeling with a multilinear reference tissue model were used to determine images of relative CBF. Agreement between data of FDG and CBF was analyzed showing a close association between interictal brain metabolism and relative CBF.

    Epilepsy often occurs after traumatic brain injuries. Changes in glia and inhibitory neuronal cells contribute to the chain of events leading to seizures. Autoradiography with 11C-PK11195, 11C-L-deprenyl and 11C-Flumazenil in an animal model of posttraumatic epilepsy studied the temporal and spatial distribution of microglia, astrocytes and GABAergic neurons. Results showed an instant increase in microglial activity that subsequently normalized, a late formation of astrogliosis and an instant and prolonged decease in GABA binding. The model can be used to visualize pathophysiological events during the epileptogenesis.

    List of papers
    1. Epileptic seizures and survival in early disease of grade 2 gliomas
    Open this publication in new window or tab >>Epileptic seizures and survival in early disease of grade 2 gliomas
    2009 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 16, no 7, p. 823-831Article in journal (Refereed) Published
    Abstract [en]

    Background and purpose

    The aims of this study were (i) to determine the correlation between seizure activity and the metabolic rate of the tumour measured by 11Cmethionine PET (MET PET) in patients with grade 2 gliomas, and (ii) to assess the prognostic impact of early seizure manifestations on patient survival.

    Methods

    In this retrospective review, early seizure manifestations were studied in 101 patients with supratentorial grade 2 gliomas subjected to MET PET as part of the pretreatment tumour investigation. Seizure manifestations as a variable was then used in multivariate survival analyses, together with established prognostic factors for this patient group.

    Results

    Of all 101 cases, 88 patients had seizures at tumour presentation. Fortyseven were seizure free at the early stage of the disease, whereas 54 had recurrent seizures. Patients with seizures at tumour presentation had a more favourable outcome before and after (P = 0.006) adjustment for conventional prognostic factors. However, for those who continued to have seizures early in the disease, the outcome was worse (P = 0.003). We found no significant correlation between MET PET and the seizure manifestations of the patients.

    Conclusion

    The presence and termination of early seizure manifestations may be favourable prognostic factors in patients with low-grade gliomas.

     

    Keywords
    11C methionine positron emission tomography, epileptic seizures, low-grade glioma, survival
    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-105434 (URN)10.1111/j.1468-1331.2009.02599.x (DOI)000266637000012 ()
    Available from: 2009-06-03 Created: 2009-06-03 Last updated: 2017-12-13Bibliographically approved
    2. Increased neurokinin-1 receptor availability in temporal lobe epilepsy: A positron emission tomography study using [(11)C]GR205171
    Open this publication in new window or tab >>Increased neurokinin-1 receptor availability in temporal lobe epilepsy: A positron emission tomography study using [(11)C]GR205171
    Show others...
    2011 (English)In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 97, no 1-2, p. 183-189Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Activation of the neurokinin-1 (NK1) receptor by neuropeptide substance P (SP) induces and maintains epileptic activity in various experimental models of epilepsy. The primary objective of this study was to investigate whether neurobiological changes linked to NK1-SP receptor system are associated with hyperexcitability in patients with temporal lobe epilepsy (TLE). A secondary objective was to investigate the relationship between seizure frequency and NK1 receptor availability.

    METHODS: A positron emission tomography study was conducted with the selective NK1 receptor antagonist [(11)C]GR205171 in nine patients with TLE and 18 healthy control participants. Parametric PET images were generated using the Patlak graphical method, with cerebellum as reference region. Data analyses including group comparisons were performed using statistical parametric mapping.

    RESULTS: Patients with TLE showed increased NK1 receptor availability in both hemispheres with the most pronounced increase in anterior cingulate gyrus ipsilateral to seizure onset. A positive correlation between NK1 receptor availability and seizure frequency was observed in the medial temporal lobe and in the lentiform nucleus ipsilateral to the seizure onset.

    CONCLUSION: Our results suggest that there is an intrinsic network using the NK1-SP receptor system for synaptic transmission and epileptiform activity in TLE.

    Keywords
    Epilepsy, PET, NK1, Substance P, TLE
    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-159946 (URN)10.1016/j.eplepsyres.2011.08.006 (DOI)00297873800021 ()21925840 (PubMedID)
    Available from: 2011-10-12 Created: 2011-10-12 Last updated: 2017-12-08Bibliographically approved
    3. Relative Cerbral Blood Flow Measurement using dynamic Flumazenil-PET may Replace Fluorodeoxyglucose-PET in Epilepsy Surgical Investigations
    Open this publication in new window or tab >>Relative Cerbral Blood Flow Measurement using dynamic Flumazenil-PET may Replace Fluorodeoxyglucose-PET in Epilepsy Surgical Investigations
    2012 (English)Article in journal (Other academic) Submitted
    National Category
    Neurosciences Other Basic Medicine
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-180846 (URN)
    Available from: 2012-09-11 Created: 2012-09-11 Last updated: 2018-01-12Bibliographically approved
    4. 11C-autoradiographic studies of dynamic changes in glial cells and benzodiazepine receptor binding in a model of posttraumatic epilepsy
    Open this publication in new window or tab >>11C-autoradiographic studies of dynamic changes in glial cells and benzodiazepine receptor binding in a model of posttraumatic epilepsy
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-180847 (URN)
    Available from: 2012-09-11 Created: 2012-09-11 Last updated: 2018-06-18
  • 70.
    Danfors, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Epileptic seizures and survival in early disease of grade 2 gliomas2009In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 16, no 7, p. 823-831Article in journal (Refereed)
    Abstract [en]

    Background and purpose

    The aims of this study were (i) to determine the correlation between seizure activity and the metabolic rate of the tumour measured by 11Cmethionine PET (MET PET) in patients with grade 2 gliomas, and (ii) to assess the prognostic impact of early seizure manifestations on patient survival.

    Methods

    In this retrospective review, early seizure manifestations were studied in 101 patients with supratentorial grade 2 gliomas subjected to MET PET as part of the pretreatment tumour investigation. Seizure manifestations as a variable was then used in multivariate survival analyses, together with established prognostic factors for this patient group.

    Results

    Of all 101 cases, 88 patients had seizures at tumour presentation. Fortyseven were seizure free at the early stage of the disease, whereas 54 had recurrent seizures. Patients with seizures at tumour presentation had a more favourable outcome before and after (P = 0.006) adjustment for conventional prognostic factors. However, for those who continued to have seizures early in the disease, the outcome was worse (P = 0.003). We found no significant correlation between MET PET and the seizure manifestations of the patients.

    Conclusion

    The presence and termination of early seizure manifestations may be favourable prognostic factors in patients with low-grade gliomas.

     

  • 71.
    Danfors, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Samuelsson, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Mats, Bergström
    Ronne-Engström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    11C-autoradiographic studies of dynamic changes in glial cells and benzodiazepine receptor binding in a model of posttraumatic epilepsyManuscript (preprint) (Other academic)
  • 72.
    Danfors, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Relative Cerbral Blood Flow Measurement using dynamic Flumazenil-PET may Replace Fluorodeoxyglucose-PET in Epilepsy Surgical Investigations2012Article in journal (Other academic)
  • 73.
    Danfors, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Linnman, Clas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Increased neurokinin-1 receptor availability in temporal lobe epilepsy: A positron emission tomography study using [(11)C]GR2051712011In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 97, no 1-2, p. 183-189Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Activation of the neurokinin-1 (NK1) receptor by neuropeptide substance P (SP) induces and maintains epileptic activity in various experimental models of epilepsy. The primary objective of this study was to investigate whether neurobiological changes linked to NK1-SP receptor system are associated with hyperexcitability in patients with temporal lobe epilepsy (TLE). A secondary objective was to investigate the relationship between seizure frequency and NK1 receptor availability.

    METHODS: A positron emission tomography study was conducted with the selective NK1 receptor antagonist [(11)C]GR205171 in nine patients with TLE and 18 healthy control participants. Parametric PET images were generated using the Patlak graphical method, with cerebellum as reference region. Data analyses including group comparisons were performed using statistical parametric mapping.

    RESULTS: Patients with TLE showed increased NK1 receptor availability in both hemispheres with the most pronounced increase in anterior cingulate gyrus ipsilateral to seizure onset. A positive correlation between NK1 receptor availability and seizure frequency was observed in the medial temporal lobe and in the lentiform nucleus ipsilateral to the seizure onset.

    CONCLUSION: Our results suggest that there is an intrinsic network using the NK1-SP receptor system for synaptic transmission and epileptiform activity in TLE.

  • 74.
    Das, J.
    et al.
    Sheffield Teaching Hosp NHS Fdn Trust, Acad Dept Neurol, Sheffield, S Yorkshire, England.
    Snowden, J.
    Sheffield Teaching Hosp NHS Fdn Trust, Dept Haematol, Sheffield, S Yorkshire, England.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Freedman, M.
    Univ Ottawa, Dept Med Neurol, Ottawa, ON, Canada;Ottawa Hosp Res Inst, Ottawa, ON, Canada.
    Atkins, H.
    Univ Ottawa, Dept Med Neurol, Ottawa, ON, Canada;Ottawa Hosp Res Inst, Ottawa, ON, Canada.
    Bowman, M.
    Univ Ottawa, Dept Med Neurol, Ottawa, ON, Canada;Ottawa Hosp Res Inst, Ottawa, ON, Canada.
    Burt, R.
    Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Sarccardi, R.
    Careggi Univ Hosp, Dept Cellular Therapies & Transfus Med, Florence, Italy.
    Innocenti, C.
    Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Mistry, S.
    Univ Sheffield, Sheffield Med Sch, Sheffield, S Yorkshire, England.
    Bell, S.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England.
    Ismail, A.
    Sheffield Teaching Hosp NHS Fdn Trust, Acad Dept Neurol, Sheffield, S Yorkshire, England.
    Jessop, H.
    Sheffield Teaching Hosp NHS Fdn Trust, Dept Haematol, Sheffield, S Yorkshire, England.
    Sharrack, B.
    Sheffield Teaching Hosp NHS Fdn Trust, Acad Dept Neurol, Sheffield, S Yorkshire, England;Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England.
    The use of autologous haematopoietic stem cell transplantation as a first line disease modifying therapy in patients with 'aggressive' multiple sclerosis.2018In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 87-88Article in journal (Other academic)
  • 75. de Flon, Pierre
    et al.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Reuterwall, C.
    Mattsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Empirical evidence of underutilization of referrals for epilepsy surgery evaluation2010In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 17, no 4, p. 619-625Article in journal (Refereed)
    Abstract [en]

    Background: Epilepsy surgery is a treatment that can cure patients with intractable epilepsy. This study investigates whether referrals for epilepsy surgery evaluation are underutilized.

    Methods: Patients with epilepsy aged 18–60 years were identified in a computerized registry held by public health care providers in a Swedish county using ICD codes. Clinical data and data on referral status for epilepsy surgery were obtained from the patients' medical records. Potential candidates for epilepsy surgery evaluation were identified using pre-specified criteria. Obstacles for referral were analysed by comparing clinical data in patients who were considered for referral and those who were not. Appropriateness of non-referral was evaluated against recommendations from the Swedish Council on Technology in Health Care (SBU).

    Results: Of 378 patients with epilepsy in the registry, 251 agreed to participate. Of 251, 40 were already referred patients and 48 patients were identified as potential candidates for epilepsy surgery evaluation by study criteria. Referral had been considered but not performed in 15 of the potential candidates. Potential candidates not considered for referral were less likely to have seen a neurologist, to have had an EEG, CT and MRI, and more likely to have cognitive disturbances. Following the recommendations by the SBU, 28 of 48 potential candidates were identified as inappropriately not referred patients.

    Conclusion: The number of missed referrals for epilepsy surgery evaluation was estimated to be 60 per 100 000 inhabitants. Several important obstacles were found for not referring patients for epilepsy surgery evaluation.

  • 76.
    de Roos, Paul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bloem, Bastiaan R
    Kelley, Thomas A
    Antonini, Angelo
    Dodel, Richard
    Hagell, Peter
    Marras, Connie
    Martinez-Martin, Pablo
    Mehta, Shyamal H
    Odin, Per
    Chaudhuri, Kallol Ray
    Weintraub, Daniel
    Wilson, Bil
    Uitti, Ryan J
    A Consensus Set of Outcomes for Parkinson's Disease from the International Consortium for Health Outcomes Measurement2017In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 7, no 3, p. 533-543Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative condition that is expected to double in prevalence due to demographic shifts. Value-based healthcare is a proposed strategy to improve outcomes and decrease costs. To move towards an actual value-based health care system, condition-specific outcomes that are meaningful to patients are essential.

    OBJECTIVE: Propose a global consensus standard set of outcome measures for PD.

    METHODS: Established methods for outcome measure development were applied, as outlined and used previously by the International Consortium for Health Outcomes Measurement (ICHOM). An international group, representing both patients and experts from the fields of neurology, psychiatry, nursing, and existing outcome measurement efforts, was convened. The group participated in six teleconferences over a six-month period, reviewed existing data and practices, and ultimately proposed a standard set of measures by which patients should be tracked, and how often data should be collected.

    RESULTS: The standard set applies to all cases of idiopathic PD, and includes assessments of motor and non-motor symptoms, ability to work, PD-related health status, and hospital admissions. Baseline demographic and clinical variables are included to enable case mix adjustment.

    CONCLUSIONS: The Standard Set is now ready for use and pilot testing in the clinical setting. Ultimately, we believe that using the set of outcomes proposed here will allow clinicians and scientists across the world to document, report, and compare PD-related outcomes in a standardized fashion. Such international benchmarks will improve our understanding of the disease course and allow for identification of 'best practices', ultimately leading to better informed treatment decisions.

  • 77.
    Demirbuker, S. Safer
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Kagström, S.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Fält, A.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Berglund, A.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Hillert, J.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Nilsson, P.
    Lund Univ, Dept Neurol, Lund, Sweden.
    Dahle, C.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Svenningsson, A.
    Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Lycke, J.
    Univ Gothenburg, Dept Clin Neurosci & Rehabil, Gothenburg, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sundström, P.
    Umea Univ, Dept Clin Neurosci, Umea, Sweden.
    Martin, C.
    Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Gunnarsson, M.
    Orebro Univ, Dept Neurol, Orebro, Sweden.
    Piehl, F.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Olsson, T.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of dimethyl fumarate (IMSE 5)2018In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 701-702Article in journal (Other academic)
  • 78.
    Demirbuker, S. Safer
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Kågström, S.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Fält, A.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Hillert, J.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Nilsson, P.
    Lund Univ, Dept Neurol, Lund, Sweden.
    Dahle, C.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Svenningsson, A.
    Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Lycke, J.
    Univ Gothenburg, Dept Clin Neurosci & Rehabil, Gothenburg, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sundström, P.
    Umea Univ, Dept Clin Neurosci, Umea, Sweden.
    Martin, C.
    Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Gunnarsson, M.
    Orebro Univ, Dept Neurol, Orebro, Sweden.
    Piehl, F.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Olsson, T.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    A Swedish nationwide pharmaco-epidemiological study of the long-term safety and effectiveness of teriflunomid (IMSE 4)2018In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 922-923Article in journal (Other academic)
  • 79.
    Dennis, Martin
    et al.
    Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland.
    Forbes, John
    Univ Limerick, Hlth Res Inst, Limerick, Ireland.
    Graham, Catriona
    Univ Edinburgh, Edinburgh Clin Res Facil, Edinburgh, Midlothian, Scotland.
    Hackett, Maree
    Univ New South Wales, George Inst Global Hlth, Kensington, NSW, Australia;Univ Cent Lancashire, Fac Hlth & Wellbeing, Preston, Lancs, England.
    Hankey, Graeme J.
    Univ Western Australia, Med Sch, Perth, WA, Australia.
    House, Allan
    Univ Leeds, Inst Hlth Sci, Leeds, W Yorkshire, England.
    Lewis, Stephanie
    Univ Edinburgh, Edinburgh Clin Trials Unit, Edinburgh, Midlothian, Scotland.
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Karolinska Inst, Dept Clin Neurosci, Solna, Sweden.
    Sandercock, Peter
    Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland.
    Mead, Gillian
    Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland.
    Anderson, Rosemary
    Buchanan, David
    Deary, Ann
    Drever, Jonathan
    Fraser, Ruth
    Innes, Karen
    McGill, Connor
    McGrath, Aileen
    Perry, David
    Walker, Pauli
    Williams, Carol
    Chun, Yvonne
    Dinsmore, Lynn
    Maschauer, Emma
    Fraser, Greig
    Lawrence, Katherine
    Shaw, Alison
    Barugh, Amanda
    Mikhail, Shadia
    Blair, Gordon
    Hoeritzauer, Ingrid
    Scott, Maggie
    Lewis, Steff
    Williamson, Judith
    Murray, Veronica
    French, Ray
    Stott, David
    Burgess, David
    Emberson, Jonathan
    Ellis, Graham
    Tyrrell, Pippa
    Brady, Marian
    MacLeod, Malcolm
    Milligan, Hazel
    Sullivan, Frank
    van Wijck, Frederike
    Watkins, Caroline
    Anderson, Craig
    Morales, D.
    Langhorne, Peter
    Reid, Fiona
    Rodgers, Helen
    Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial2019In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 393, no 10168, p. 265-274Article in journal (Refereed)
    Abstract [en]

    Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.

    Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.

    Findings Between Sept 10,2012, and March 31,2017,3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99.3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0.951 [95% CI 0.839-1.079]; p=0.439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13.43%] patients vs 269 [17.21%]; difference 3.78% [95% CI 1.26-6.30]; p=0.0033), but they had more bone fractures (45 [2.88%] vs 23 [1.47%]; difference 1.41% [95% CI 0.38-2.43]; p=0.0070). There were no significant differences in any other event at 6 or 12 months.

    Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.

  • 80.
    Drissi, Natasha M.
    et al.
    Linkoping Univ, Dept Med & Hlth Sci IMH, Linkoping, Sweden; Linkoping Univ, Ctr Med Image Sci & Visualizat CMIV, Linkoping, Sweden.
    Szakács, Attila
    Univ Gothenburg, Sahlgrenska Acad, Dept Paediat, Inst Clin Sci, Gothenburg, Sweden.
    Witt, Suzanne T
    Linkoping Univ, Ctr Med Image Sci & Visualizat CMIV, Linkoping, Sweden.
    Wretman, Anna
    Linkoping Univ, Dept Behav Sci & Learning, Linkoping, Sweden.
    Ulander, Martin
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Ståhlbrandt, Henriettae
    Darin, Niklas
    Univ Gothenburg, Sahlgrenska Acad, Dept Paediat, Inst Clin Sci, Gothenburg, Sweden.
    Hallböök, Tove
    Univ Gothenburg, Sahlgrenska Acad, Dept Paediat, Inst Clin Sci, Gothenburg, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Engström, Maria
    Linkoping Univ, Dept Med & Hlth Sci IMH, Linkoping, Sweden; Linkoping Univ, Ctr Med Image Sci & Visualizat CMIV, Linkoping, Sweden.
    Altered Brain Microstate Dynamics in Adolescents with Narcolepsy2016In: Frontiers in Human Neuroscience, ISSN 1662-5161, E-ISSN 1662-5161, Vol. 10, article id 369Article in journal (Refereed)
    Abstract [en]

    Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin-1 producing neurons in the hypothalamus. Previous neuroimaging studies have investigated brain function in narcolepsy during rest using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In addition to hypothalamic and thalamic dysfunction they showed aberrant prefrontal perfusion and glucose metabolism in narcolepsy. Given these findings in brain structure and metabolism in narcolepsy, we anticipated that changes in functional magnetic resonance imaging (fMRI) resting state network (RSN) dynamics might also be apparent in patients with narcolepsy. The objective of this study was to investigate and describe brain microstate activity in adolescents with narcolepsy and correlate these to RSNs using simultaneous fMRI and electroencephalography (EEG). Sixteen adolescents (ages 13-20) with a confirmed diagnosis of narcolepsy were recruited and compared to age-matched healthy controls. Simultaneous EEG and fMRI data were collected during 10 min of wakeful rest. EEG data were analyzed for microstates, which are discrete epochs of stable global brain states obtained from topographical EEG analysis. Functional MRI data were analyzed for RSNs. Data showed that narcolepsy patients were less likely than controls to spend time in a microstate which we found to be related to the default mode network and may suggest a disruption of this network that is disease specific. We concluded that adolescents with narcolepsy have altered resting state brain dynamics.

  • 81.
    Duffau, Hugues
    et al.
    Montpellier Med Univ Ctr, Hop Guide Chauliac, Dept Neurosurg, Montpellier, France.;Inst Neurosci, INSERM U1051, Montpellier, France.;Univ Montpellier, Montpellier, France..
    Mandonnet, Emmanuel
    Lariboisiere Hosp, AP HP, Dept Neurosurg, Paris, France.;Univ Paris 07, Paris, France.;IMNC, UMR 8165, Orsay, France..
    Pallud, Johan
    St Anna Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Sorbonne Paris Cite, Paris, France.;INSERM, U894, Ctr Psychiat & Neurosci, Paris, France..
    Krieg, Sandro
    Tech Univ Munich, Klinikum Rechts Isar, Dept Neurosurg, Munich, Germany..
    Gil Robles, Santiago
    Hosp Univ Quiron, Madrid, Spain.;Bio Cruces Res, Bilbao, Spain..
    Hamer, Philip de Witt
    Vrije Univ Amsterdam Med Ctr, Neurosurg Ctr Amsterdam, Amsterdam, Netherlands..
    Schucht, Philippe
    Univ Hosp Bern, Dept Neurosurg, Bern, Switzerland..
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Santarius, Thomas
    Univ Cambridge, Addenbrookes Hosp, Dept Neurosurg, Cambridge, England..
    Colle, Henry
    AZ St Luca, Funct Neurosurg, Ghent, Belgium..
    Ryan, Mathew
    Leeds Gen Infirm, Dept Neurosurg, Leeds, W Yorkshire, England..
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Gothenburg, Sweden..
    von Campe, Gord
    Med Univ Graz, Dept Neurosurg, Graz, Austria..
    Bello, Lorenzo
    Univ Milan, Dept Oncol & Hematooncol, Neurosurg Oncol Unit, Milan, Italy.;IRCCS, Humanitas Res Hosp, Milan, Italy..
    Forster, Marie-Therese
    Goethe Univ, Dept Neurosurg, Frankfurt, Germany..
    Sarubbo, Silvio
    Santa Chiara Hosp, Struct & Funct Connectiv Lab, Trento, Italy..
    Spena, Giannantonio
    Spedali Civil Brescia, Clin Neurochirurg, Brescia, Italy..
    Baron, Marie-Helene
    CHRU Jean Minjoz, Dept Oncol Radiotherapie, Besancon, France..
    Yordanova, Yordanka
    Percy Army Training Hosp, Neurosurg Dept, Clamart, France..
    Darlix, Amelie
    Inst Regional Canc Montpellier ICM, Dept Med Oncol, Montpellier, France..
    Viegas, Catarina
    Hosp Garcia Orta, Dept Neurosurg, Almada, Portugal..
    Almairac, Fabien
    Univ Hosp Nice, Dept Neurosurg, Nice, France..
    Martino, Juan
    Hosp Univ Marques Valdecilla, Fdn Inst Invest Marques Valdecilla IDIVAL, Dept Neurol Surg, Avda Valdecilla S-N, Santander, Spain.;Inst Salud Carlos III, Avda Valdecilla S-N, Santander, Spain..
    Goodden, John
    Dept Neurosurg, Leeds, W Yorkshire, England..
    Chumas, Paul
    Dept Neurosurg, Leeds, W Yorkshire, England..
    Freyschlag, Christian
    Med Univ Innsbruck, Dept Neurosurg, Innsbruck, Austria..
    Robe, Pierre
    Univ Med Ctr Utrecht, Dept Neurosurg, Utrecht, Netherlands..
    Wager, Michel
    Univ Poitiers Hosp, INSERM U1084, Neurosurg Dept, Poitiers, France..
    Polivka, Marc
    Lariboisiere Hosp, AP HP, Dept Neuropathol, Paris, France..
    Giakoumettis, Dimitris
    Neurosurg Evangelismos Hosp, Athens, Greece..
    Robert, Erik
    AZ SintLucas & AZ Maria Middelares, Dept of Aphasiol, Ghent, Belgium..
    Guillevin, Remy
    Univ Poitiers Hosp, Neuroradiol Dept, Poitiers, France..
    Grivas, Athanasios
    Univ Glasgow, Queen Elizabeth Univ Hosp, Inst Neurol Sci, Dept Neurosurg, Glasgow, Lanark, Scotland..
    Fontaine, Denys
    Univ Hosp Nice, Dept Neurosurg, Nice, France..
    van Geemen, Kim
    Brain Res Ctr Amsterdam, Amsterdam, Netherlands..
    Lubrano, Vincent
    Univ Toulouse, CHU Toulouse, Toulouse NeuroImaging Ctr, INSERM UMR 1214,ToNIC, Toulouse, France..
    Rutten, Geert-Jan
    St Elisabeth Tweesteden Hosp, Dept Neurosurg, Tilburg, Netherlands..
    Barone, Fabio
    Cannizzaro Gen Hosp, Dept Neurosurg & Gamma Knife, Catania, Italy..
    Rofes, Adria
    Trinity Coll Dublin, Global Brain Hlth Inst, Dublin, Ireland..
    Rech, Fabien
    CHRU Nancy, Serv Neurochirurg, Nancy, France..
    Rigau, Valerie
    Gui Chauliac Hosp, Dept Pathol, Montpellier, France..
    Wagemakers, Michiel
    Univ Med Ctr, Neurosurg Dept, Groningen, Belgium..
    Papagno, Costanza
    Univ Trento, CeRiN & CIMeC, Rovereto, Italy..
    Aerts, Annelies
    AZ Sint Lucas, Ghent, Belgium.;Artevelde Univ Coll, Ghent, Belgium..
    Visch-Brink, Evy
    Erasmus MC, Dept Neurol, Rotterdam, Netherlands.;Erasmus MC, Dept Neurosurg, Rotterdam, Netherlands..
    Tate, Matthew
    Northwester Med Group, Dept Neurosurg, Chicago, IL USA..
    Garg, Neha
    Univ Delhi, Delhi, India..
    Klein, Martin
    Vrije Univ Amsterdam Med Ctr, Clin Neuropsychol Dept, Amsterdam, Netherlands..
    Satoer, Djaina
    Erasmus MC, Dept Neurol, Rotterdam, Netherlands.;Erasmus MC, Dept Neurosurg, Rotterdam, Netherlands..
    de Witte, Elke
    Vrije Univ Brussel, Neurolinguist Dept, Brussels, Belgium..
    Van Brussel, Lore
    Onze Lieve Vrouw Hosp, Neurosurg Dept, Moorselbaan, Aalst, Belgium..
    Reyes, Andres
    Univ Groningen, Dept Clin Linguist, Groningen, Netherlands.;EMCL Univ Potsdam, Potsdam, Germany.;El Bosque Univ, Expt Psychol Lab, Fac Psychol, Bogota, Colombia.;Inst Neurosci, Bogota, Colombia..
    van Ierschot, Fleur
    Univ Trent, Ctr Mind Brain Sci, Trento, Italy.;Univ Groningen, Fac Arts, Groningen, Belgium.;Macquarie Univ, Dept Cognit Sci, Sydney, NSW, Australia..
    Veenstra, Wencke
    Univ Groningen, Dept Linguist, Groninge, Belgium..
    Snijders, Tom
    Univ Med Ctr Utrecht, Dept Neurol & Neurosurg Hosp, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Taillandier, Luc
    CHU Nancy, Neurol Dept, Nancy, France..
    Blonski, Marie
    CHU Nancy, Neurol Dept, Nancy, France..
    Evidenced-based medicine in glioma: molecular biology is only part of the story2017In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 18, no 8, p. E429-E429Article in journal (Refereed)
  • 82. Eatough, Virginia
    et al.
    Santini, Helen
    Eiser, Christine
    Goller, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Krysa, Wioletta
    de Nicola, 'Annunziata'
    Paduanello, Matteo
    Petrollini, Martina
    Rakowicz, Maria
    Squitieri, Ferdinando
    Tibben, Aad
    Weille, Katie Lee
    Landwehrmeyer, Bernhard
    Quarrell, Oliver
    Smith, Jonathan A.
    The personal experience of parenting a child with Juvenile Huntington's Disease: perceptions across Europe2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 10, p. 1042-1048Article in journal (Refereed)
    Abstract [en]

    The study reported here presents a detailed description of what it is like to parent a child with juvenile Huntington's disease in families across four European countries. Its primary aim was to develop and extend findings from a previous UK study. The study recruited parents from four European countries: Holland, Italy, Poland and Sweden,. A secondary aim was to see the extent to which the findings from the UK study were repeated across Europe and the degree of commonality or divergence across the different countries. Fourteen parents who were the primary caregiver took part in a semistructured interview. These were analyzed using an established qualitative methodology, interpretative phenomenological analysis. Five analytic themes were derived from the analysis: the early signs of something wrong; parental understanding of juvenile Huntington's disease; living with the disease; other people's knowledge and understanding; and need for support. These are discussed in light of the considerable convergence between the experiences of families in the United Kingdom and elsewhere in Europe.

  • 83. Edelvik, Anna
    et al.
    Rydenhag, Bertil
    Olsson, Ingrid
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kallen, Kristina
    Malmgren, Kristina
    Long-term outcomes of epilepsy surgery in Sweden A national prospective and longitudinal study2013In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 81, no 14, p. 1244-1251Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate prospective, population-based long-term outcomes concerning seizures and antiepileptic drug (AED) treatment after resective epilepsy surgery in Sweden. Methods: Ten-and 5-year follow-ups were performed in 2005 to 2007 for 278/327 patients after resective epilepsy surgery from 1995 to 1997 and 2000 to 2002, respectively. All patients had been prospectively followed in the Swedish National Epilepsy Surgery Register. Ninety-three patients, who were presurgically evaluated but not operated, served as controls. Results: In the long term (mean 7.6 years), 62% of operated adults and 50% of operated children were seizure-free, compared to 14% of nonoperated adults (p < 0.001) and 38% of nonoperated children (not significant). Forty-one percent of operated adults and 44% of operated children had sustained seizure freedom since surgery, compared to none of the controls (p < 0.0005). Multivariate analysis identified >= 30 seizures/month at baseline and long epilepsy duration as negative predictors and positive MRI to be a positive predictor of long-term seizure-free outcome. Ten years after surgery, 86% of seizure-free children and 43% of seizure-free adults had stopped AEDs in the surgery groups compared to none of the controls (p < 0.0005). Conclusions: This population-based, prospective study shows good long-term seizure outcomes after resective epilepsy surgery. The majority of the patients who are seizure-free after 5 and 10 years have sustained seizure freedom since surgery. Many patients who gain seizure freedom can successfully discontinue AEDs, more often children than adults. Classification of evidence: This study provides Class III evidence that more patients are seizure-free and have stopped AED treatment in the long term after resective epilepsy surgery than nonoperated epilepsy patients.

  • 84. Ek, Lena
    et al.
    Almkvist, Ove
    Kristoffersen Wiberg, Maria
    Stragliotto, Giuseppe
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Early cognitive impairment in a subset of patients with presumed low-grade glioma2010In: Neurocase, ISSN 1355-4794, E-ISSN 1465-3656, Vol. 16, no 6, p. 503-511Article in journal (Refereed)
    Abstract [en]

    We investigated the presence of cognitive impairment, in adults with presumed low-grade glioma at early stage of disease prior to major treatments, in relation to neurological symptoms and radiological characteristics of the tumour. Sixteen patients were evaluated. A subset of patients was identified with clearly impaired cognition. Patients with cognitive impairment often had large tumours in the left frontal lobe, were relatively young, and most of them were males. We conclude that cognitive dysfunction may be present already at early stage of disease, and that early identification of patients at risk is warranted.

  • 85.
    Ek, Miika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Malign media patienter på Akademiska sjukhuset 2004-20062007Student paper other, 5 credits / 7,5 HE creditsStudent thesis
  • 86.
    Ekegren, Titti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Grundström, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Lindholm, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Upregulation of Bax protein and increased DNA degradation in ALS spinal cord motor neurons1999In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 100, no 5, p. 317-321Article in journal (Refereed)
    Abstract [en]

    Objectives

    To investigate if degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is related to altered levels of the apoptosis regulating proteins Bcl-2 and Bax. In addition, immunoreactivity of the cysteine protease ICH-1L and detection of motor neurons with DNA fragmentation, indicative of apoptosis, was also studied.

    Material and methods

    The immunoreactivity of Bcl-2, Bax and ICH-1L were compared in ALS and control spinal cord motor neurons by immunohistochemical analysis and motor neurons with DNA fragmentation were identified by the TUNEL-method.

    Results

    The results demonstrate an increased expression of Bax in the ALS material as compared to controls but no change in Bcl-2 and ICH-1L expressions. Moreover, a larger proportion of motor neurons stained positive for TUNEL in ALS spinal cords.

    Conclusion

    Present study suggest an upregulation of the cell death promoting protein Bax and increased DNA degradation, indicative of apoptosis, in spinal motor neurons of ALS patients.

  • 87.
    Ekegren, Titti
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Hanrieder, Jörg
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Focused proteomics in post-mortem human spinal cord2006In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 5, no 9, p. 2364-2371Article in journal (Refereed)
    Abstract [en]

    With a highly sensitive electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) system, proteins were identified in minimal amounts of spinal cord from patients with the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and compared to proteins in spinal cord from control subjects. The results show 18 versus 16 significantly identified ( p < 0.05) proteins, respectively, all known to be found in the central nervous system. The most abundant protein in both groups was the glial fibrillary acidic protein, GFAP. Other proteins were, for example, hemoglobin alpha- and, chain, myelin basic protein, thioredoxin, R enolase, and cholin acetyltransferase. This study also includes the technique of laser microdissection in combination with pressure catapulting (LMPC) for the dissection of samples and specific neurons. Furthermore, complementary experiments with nanoLC-matrix assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-TOF MS) confirmed the results of the ESI-FTICR MS screening and provided additional results of further identified proteins.

  • 88.
    Elf, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Punga, Anna Rostedt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Vitamin D deficiency in patients with primary immune-mediated peripheral neuropathies2014In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 345, no 1-2, p. 184-188Article in journal (Refereed)
    Abstract [en]

    PURPOSE: T cells are important in the immunopathology of immune-mediated peripheral neuropathies (PNP) and activated vitamin D regulates the immune response through increasing the amount of regulatory T cells. An association between vitamin D deficiency and polyneuropathy has been stipulated; hence we assessed whether patients with primary immune-mediated PNP have low vitamin D [25(OH)D] levels.

    METHODS: Plasma levels of 25(OH)D were analyzed in 26 patients with primary immune-mediated PNP, 50 healthy matched blood donors and 24 patients with motor neuron disease (MND). INCAT score was assessed in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. ALSFRS-R score was applied to MND patients and the modified Rankin (mRankin) scale compared disability among patient groups.

    RESULTS: Mean 25(OH)D value in PNP patients was 40±16nmol/l, compared to 69±21nmol/l in healthy blood donors (p<0.001). MND patients had a higher mean 25(OH)D than PNP patients (59±26nmol/L; p=0.006) and comparable levels to healthy blood donors (p=0.15). Mean 25(OH)D value was not higher in PNP patients with pre-existing vitamin D3 supplementation of 800IU/day (N=6; 35±18nmol/L) than in unsupplemented PNP patients (42±16nmol). INCAT score ranged from 0 to 10 (mean 3.5) and ALSFRS-R ranged from 11 to 44 (mean 31). mRankin score was more severe in MND patients (mean 3.5) compared to PNP patients (mean 2.1).

    CONCLUSIONS: All patients with primary immune-mediated PNP were diagnosed with vitamin D deficiency and they had significantly lower 25(OH)D values than healthy control persons and MND patients. We suggest monitoring of vitamin D status in patients with autoimmune PNP, since immune cells are responsive to the ameliorative effects of vitamin D.

  • 89.
    Elf, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Alterations in muscle proteome of patients diagnosed with amyotrophic lateral sclerosis2014In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 108, p. 55-64Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle paralysis. Currently clinical tools for ALS diagnostics do not perform well enough and their improvement is needed. The objective of this study was to identify specific protein alterations related to the development of ALS using tiny muscle biopsies. We applied a shotgun proteomics and quantitative dimethyl labeling in order to analyze the global changes in human skeletal muscle proteome of ALS versus healthy subjects for the first time. 235 proteins were quantified and 11 proteins were found significantly regulated in ALS muscles. These proteins are involved in muscle development and contraction, metabolic processes, enzyme activity, regulation of apoptosis and transport activity. In order to eliminate a risk to confuse ALS with other denervations, muscle biopsies of patients with postpolio syndrome and Charcot Marie Tooth disease (negative controls) were compared to those of ALS and controls. Only few proteins significantly regulated in ALS patients compared to controls were affected differently in negative controls. These proteins (BTB and kelch domain-containing protein 10, myosin light chain 3, glycogen debranching enzyme, transitional endoplasmic reticulum ATPase), individually or as a panel, could be selected for estimation of ALS diagnosis and development. Biological significance ALS is a devastating neurodegenerative disease, and luckily, very rare: only one to two people out of 100,000 develop ALS yearly. This fact, however, makes studies of ALS very challenging since it is very difficult to collect the representative set of clinical samples and this may take up to several years. In this study we collected the muscle biopsies from 12 ALS patients and compared the ALS muscle proteome against the one from control subjects. We suggested the efficient method for such comprehensive quantitative analysis by LC-MS and performed it for the first time using human ALS material. This gel- and antibody-free method can be widely applied for muscle proteome studies and has been used by us for revealing of the specific protein alterations associated with ALS.

  • 90. Elsir, T.
    et al.
    Qu, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Orrego, A.
    Olofsson, T.
    Lindström, M. S.
    Nistér, M.
    von Deimling, A.
    Hartmann, C.
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    PROX1 is a predictor of survival for gliomas WHO grade II2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 11, p. 1747-1754Article in journal (Refereed)
    Abstract [en]

    Background:The clinical course of World Health Organisation grade II gliomas remains variable and their time point of transformation into a more malignant phenotype is unpredictable. Identification of biological markers that can predict prognosis in individual patients is of great clinical value. PROX1 is a transcription factor that has a critical role in the development of various organs. PROX1 has been ascribed both oncogenic and tumour suppressive functions in human cancers. We have recently shown that PROX1 may act as a diagnostic marker for high-grade gliomas. The aim of this study was to address the prognostic value of PROX1 in grade II gliomas.Methods:A total of 116 samples were evaluated for the presence of PROX1 protein. The number of immunopositive cells was used as a variable in survival analysis, together with established prognostic factors for this patient group.Results:Higher PROX1 protein was associated with poor outcome. In the multivariate analysis, PROX1 was identified as an independent factor for survival (P=0.024), together with the presence of mutated isocitrate dehydrogenase 1 R132H protein, and with combined losses of chromosomal arms 1p/19q in oligodendrocytic tumours.Conclusion:PROX1 is a novel predictor of survival for grade II gliomas.

  • 91. Elsir, T.
    et al.
    Qu, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Berntsson, Shala
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Orrego, A.
    Olofsson, T.
    Lindström, M.
    Nister, M.
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    PROX1 IS A PREDICTOR OF SURVIVAL FOR ASTROCYTIC GLIOMAS BUT NOT FOR OLIGODENDROGLIOMAS GRADE II2010In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 12, p. 51-51Article in journal (Other academic)
  • 92.
    Elsir, Tamador
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlson, Joseph
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Popova, Svetlana N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nistér, Monica
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    A study of embryonic stem cell-related proteins in human astrocytomas: Identification of Nanog as a predictor of survival2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 5, p. 1123-1131Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO grade II) and 98 high-grade human gliomas (WHO grade III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n=42) with high levels of Nanog protein (p=0.0067) and of Klf4 protein (p=0.0368), in high-grade astrocytomas (n=85) with high levels of Nanog (p=0.0042), Klf4 (p=0.0447), and c-Myc (p=0.0078) and in glioblastomas only (n=71) with high levels of Nanog (p=0.0422) and of c-Myc (p= 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p=0.0039), high-grade astrocytomas (p=0.0124) and glioblastomas only (p=0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.

  • 93.
    Elsir, Tamador
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Lindström, Mikael S
    Nistér, Monica
    Transcription factor PROX1: its role in development and cancer.2012In: Cancer Metastasis Review, ISSN 0167-7659, E-ISSN 1573-7233, Vol. 31, no 3-4, p. 793-805Article, review/survey (Refereed)
    Abstract [en]

    The homeobox gene PROX1 is critical for organ development during embryogenesis. The Drosophila homologue, known as prospero has been shown to act as a tumor suppressor by controlling asymmetric cell division of neuroblasts. Likewise, alterations in PROX1 expression and function are associated with a number of human cancers including hematological malignancies, carcinomas of the pancreas, liver and the biliary system, sporadic breast cancer, Kaposiform hemangioendothelioma, colon cancer, and brain tumors. PROX1 is involved in cancer development and progression and has been ascribed both tumor suppressive and oncogenic properties in a variety of different cancer types. However, the exact mechanisms through which PROX1 regulates proliferation, migration, and invasion of cancer cells are by large unknown. This review provides an update on the role of PROX1 in organ development and on its emerging functions in cancer, with special emphasis on the central nervous system and glial brain tumors.

  • 94.
    Engström, Maria
    et al.
    Linkoping Univ, Dept Med & Hlth Sci IMH, Div Radiol Sci, Linkoping, Sweden; Linkoping Univ, Ctr Med Image Sci & Visualizat CMIV, Linkoping, Sweden.
    Hallböök, Tove
    Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Pediat, Gothenburg, Sweden.
    Szakacs, Attila
    Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Pediat, Gothenburg, Sweden; Halmstad Cty Hosp, Dept Pediat, Halmstad, Sweden.
    Karlsson, Thomas
    Linkoping Univ, Ctr Med Image Sci & Visualizat CMIV, Linkoping, Sweden; Linkoping Univ, Div Disabil Res, Linkoping, Sweden; Linkoping Univ, Linnaeus Ctr HEAD, Dept Behav Sci & Learning, Linkoping, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Linkoping Univ, Ctr Med Image Sci & Visualizat CMIV, Linkoping, Sweden; Linkoping Univ, Dept Neurol, Dept Clin & Expt Med IKE, Linkoping, Sweden; Linkoping Univ, Dept Med & Hlth Sci, Dept Med Specialist, Motala, Sweden.
    Functional magnetic resonance imaging in narcolepsy and the Kleine-Levin syndrome2014In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 5, article id 105Article in journal (Refereed)
    Abstract [en]

    This work aims at reviewing the present state of the art when it comes to understanding the pathophysiology of narcolepsy and the Kleine-Levin syndrome (KLS) from a neuroimaging point of view. This work also aims at discussing future perspectives of functional neuroimaging in these sleep disorders. We focus on functional magnetic resonance imaging (fMRI), which is a technique for in vivo measurements of brain activation in neuronal circuitries under healthy and pathological conditions. fMRI has significantly increased the knowledge on the affected neuronal circuitries in narcolepsy and the Kleine-Levin syndrome. It has been shown that narcolepsy is accompanied with disturbances of the emotional and the closely related reward systems. In the Kleine Levin syndrome, fMRI has identified hyperactivation of the thalamus as a potential biomarker that could be used in the diagnostic procedure. The fMRI findings in both narcolepsy and the Kleine-Levin syndrome are in line with previous structural and functional imaging studies. We conclude that fMRI in combination with multi-modal imaging can reveal important details about the pathophysiology in narcolepsy and the Kleine-Levin syndrome. In the future, fMRI possibly gives opportunities for diagnostic support and prediction of treatment response in individual patients.

  • 95. Engström, Maria
    et al.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Karlsson, Thomas
    New hypothesis on pontine-frontal eye field connectivity in Kleine-Levin syndrome2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, no 6, p. 716-719Article in journal (Refereed)
    Abstract [en]

    Previous studies have indicated involvement of the thalamus and the pons in Kleine-Levin syndrome. In the present study, functional connectivity of the thalamus and the pons was investigated in asymptomatic patients with Kleine-Levin syndrome and healthy controls. Twelve patients and 14 healthy controls were investigated by functional magnetic resonance imaging during rest. Resting state images were analysed using seed regions of interest in the thalamus and the pons. The results showed significantly lower functional connectivity between the pons and the frontal eye field in persons with Kleine-Levin syndrome compared with healthy controls. There were no connectivity differences involving the thalamus. Based on these findings, a relation is proposed between the sleep disorder Kleine-Levin syndrome and cerebral control of eye movements, which in turn is related to visual attention and working memory. This hypothesis has to be tested in future studies of oculomotor control in Kleine-Levin syndrome.

  • 96.
    Engström, Maria
    et al.
    Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden; CMIV, Linköpings universitet, Linköping, Sweden.
    Latini, Francesco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
    Neuroimaging in the Kleine-Levin Syndrome2018In: Current Neurology and Neuroscience Reports, ISSN 1528-4042, E-ISSN 1534-6293, Vol. 18, no 9, article id 58Article, review/survey (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: The purpose was to review the most recent literature on neuroimaging in the Kleine-Levin syndrome (KLS). We aimed to investigate if frontotemporal and thalamic dysfunction are key KLS signatures, and if recent research indicates other brain networks of interest that elucidate KLS symptomatology and aetiology.

    RECENT FINDINGS: In a comprehensive literature search, we found 12 original articles published 2013-2018. Most studies report deviations related to cerebral perfusion, glucose metabolism, or blood-oxygen-level-dependent responses in frontotemporal areas and/or the thalamus. Studies also report dysfunction in the temporoparietal junction and the oculomotor network that also were related to clinical parameters. We discuss these findings based on recent research on thalamocortical networks and brain stem white matter tracts. The hypothesis of frontotemporal and thalamic involvement in KLS was confirmed, and additional findings in the temporoparietal junction and the oculomotor system suggest a broader network involvement, which can be investigated by future high-resolution and multimodal imaging.

  • 97. Ervasti, Jenni
    et al.
    Virtanen, Marianna
    Lallukka, Tea
    Friberg, Emilie
    Mittendorfer-Rutz, Ellenor
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Alexanderson, Kristina
    Permanent work disability before and after ischaemic heart disease or stroke event: a nationwide population-based cohort study in Sweden.2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 9, article id e017910Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: We examined the risk of disability pension before and after ischaemic heart disease (IHD) or stroke event, the burden of stroke compared with IHD and which factors predicted disability pension after either event.

    DESIGN: A population-based cohort study with follow-up 5 years before and after the event. Register data were analysed with general linear modelling with binary and Poisson distributions including interaction tests for event type (IHD/stroke).

    SETTING AND PARTICIPANTS: All people living in Sweden, aged 25‒60 years at the first event year, who had been living in Sweden for 5 years before the event and had no indication of IHD or stroke prior to the index event in 2006‒2008 were included, except for cases in which death occurred within 30 days of the event. People with both IHD and stroke were excluded, resulting in 18 480 cases of IHD (65%) and 9750 stroke cases (35%).

    PRIMARY OUTCOME MEASURES: Disability pension.

    RESULTS: Of those going to suffer IHD or stroke event, 25% were already on disability pension a year before the event. The adjusted OR for disability pension at first postevent year was 2.64-fold (95% CI 2.25 to 3.11) for people with stroke compared with IHD. Economic inactivity predicted disability pension regardless of event type (OR=3.40; 95% CI 2.85 to 4.04). Comorbid mental disorder was associated with the greatest risk (OR=3.60; 95% CI 2.69 to 4.83) after an IHD event. Regarding stroke, medical procedure, a proxy for event severity, was the largest contributor (OR=2.27, 95% CI 1.43 to 3.60).

    CONCLUSIONS: While IHD event was more common, stroke involved more permanent work disability. Demographic, socioeconomic and comorbidity-related factors were associated with disability pension both before and after the event. The results help occupational and other healthcare professionals to identify vulnerable groups at risk for permanent labour market exclusion after such an event.

  • 98.
    Fagius, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Normal outcome of pregnancy with ongoing treatment with natalizumab2014In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 129, no 6, p. e27-e29Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur.

    CASE: A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term.

    CONCLUSIONS: This is the second known case where natalizumab treatment continued throughout the whole gestational period.

  • 99.
    Fagius, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Feresiadou, Amalia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Severe relapses and rebound activity after natalizumab discontinuation in MS patients with more than five years of treatment with stable disease course2015In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, p. 297-297Article in journal (Other academic)
  • 100.
    Fagius, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Feresiadou, Amalia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    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, Neurology.
    Discontinuation of disease modifying treatments in middle aged multiple sclerosis patients: First line drugs vs natalizumab2017In: Multiple Sclerosis and Related Disorders, ISSN 2211-0348, E-ISSN 2211-0356, Vol. 12, p. 82-87, article id S2211-0348(17)30010-XArticle in journal (Refereed)
    Abstract [en]

    BACKGROUND: Several disease-modifying drugs (DMD) are available for the treatment of MS, and most patients with relapsing-remitting disease are currently treated. Data on when and how DMD treatment can be safely discontinued are scarce.

    METHODS: Fifteen MS patients, treated with natalizumab for >5 years without clinical and radiological signs of inflammatory disease activity, suspended treatment and were monitored with MRI examinations and clinical follow-up to determine recurrence of disease activity. This group was compared with a retrospectively analysed cohort comprising 55 MS patients treated with first-line DMDs discontinuing therapy in the time period of 1998-2015 after an analogous stable course.

    RESULTS: Natalizumab discontinuers were followed for on average 19 months, and follow-up data for 56 months were available for first-line DMD quitters. Two-thirds of natalizumab treated patients experienced recurrent inflammatory disease activity, and one third had recurrence of rebound character. In contrast, 35% of first-line DMD quitters had mild recurrent disease activity, and no one exhibited rebound.

    CONCLUSIONS: Withdrawal of a first-line DMD after prolonged treatment in middle-aged MS patients with stable disease appears to be relatively safe, while natalizumab withdrawal in a similar group of patients cannot be safely done without starting alternative therapy.

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