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  • 1.
    Birnefeld, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Cerebral arterial pulsatility is associated with features of small vessel disease in patients with acute stroke and TIA: a 4D flow MRI study2019In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459Article in journal (Refereed)
    Abstract [en]

    Cerebral small vessel disease (SVD) is a major cause of stroke and cognitive impairment. However, the underlying mechanisms behind SVD are still poorly understood. High cerebral arterial pulsatility has been suggested as a possible cause of SVD. In population studies, arterial pulsatility has been linked to white matter hyperintensities (WMH), cerebral atrophy, and cognitive impairment, all features of SVD. In stroke, pulsatility data are scarce and contradictory. The aim of this study was to investigate the relationship between arterial pulsatility and SVD in stroke patients. With a cross-sectional design, 89 patients with acute ischemic stroke or TIA were examined with MRI. A neuropsychological assessment was performed 1 year later. Using 4D flow MRI, pulsatile indices (PI) were calculated for the internal carotid artery (ICA) and middle cerebral artery (M1, M3). Flow volume pulsatility (FVP), a measure corresponding to the cyclic expansion of the arterial tree, was calculated for the same locations. These parameters were assessed for associations with WMH volume, brain volume and cognitive function. ICA-FVP was associated with WMH volume (β = 1.67, 95% CI: [0.1, 3.24], p = 0.037). M1-PI and M1-FVP were associated with decreasing cognitive function (β = - 4.4, 95% CI: [- 7.7, - 1.1], p = 0.009 and β = - 13.15, 95% CI: [- 24.26, - 2.04], p = 0.02 respectively). In summary, this supports an association between arterial pulsatility and SVD in stroke patients, and provides a potential target for further research and preventative treatment. FVP may become a useful biomarker for assessing pulsatile stress with PCMRI and 4D flow MRI.

  • 2.
    Israelsson Larsen, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Cerebrospinal Fluid Shunting Improves Long-Term Quality of Life in Idiopathic Normal Pressure Hydrocephalus2019In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, article id nyz297Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The short- and long-term impact of cerebrospinal fluid shunting on quality of life (QoL) in idiopathic normal pressure hydrocephalus (INPH) is poorly understood.

    OBJECTIVE: To investigate QoL in shunted INPH patients compared to the population and to investigate which factors influence QoL in INPH.

    METHODS: INPH patients consecutively shunted in Sweden during 2008-2010 were scrutinized. Population-based controls were age- and sex-matched to the patients. Included participants were the following: 176 INPH patients and 368 controls. QoL was assessed using the EuroQol 5-dimension 5-level (EQ5D5L) instrument, which measures overall QoL and health status in 5 dimensions. Independency (accommodation and/or need for in-home care) and comorbidities were assessed. Patients were followed up 6-45 mo after surgery (mean follow-up time: 21 mo).

    RESULTS: Shunting improved QoL (P < .001) and health status in all dimensions (P < .005). Shunted INPH patients had lower QoL than controls (P < .001). The patients' health status in mobility, self-care, daily activities, and anxiety/depression was worse than the controls both before and after surgery (P < .001). The main predictors of low QoL in INPH were symptoms of depression (P < .001) and severity of gait disturbance (P = .001). Fewer INPH patients than controls lived independently (45% vs 85%, P < .001). Time after shunting had no influence on QoL.

    CONCLUSION: QoL remains improved in shunted INPH patients at a mean follow-up time of 21 mo, but the patients do not reach the same QoL as the population. Symptoms of depression and severity of gait disturbance are the strongest predictors of low QoL in INPH.

  • 3.
    Lehtipalo, Stefan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Winsö, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Koskinen, Lars-Owe D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Johansson, Göran
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Biber, Björn
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Cutaneous sympathetic vasoconstrictor reflexes for the evaluation of interscalene brachial plexus block2000In: Acta Anaesthesiol Scand, Vol. 44, no 8, p. 946-52Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although signs of sympathetic blockade following interscalene brachial plexus block include Horner's syndrome, increased skin temperature and vasodilatation, the degree of sympathetic blockade is not easily determined. The aim of this study was, therefore, to use activation of cutaneous finger pad vasoconstrictor reflexes for description and quantification of the degree of sympathetic blockade following unilateral interscalene brachial plexus block. METHODS: Eight patients scheduled for acromioplasty under general anesthesia were studied. An interscalene plexus catheter was inserted preoperatively on the side to be operated upon and used postoperatively for administration of bupivacaine, given as a bolus (1.25 mg kg(-1)) followed by a continuous infusion (0.25 mg kg(-1) h(-1)). Skin blood flow (SBF) in the pad of the index finger was assessed by the laser Doppler technique, and regional skin vascular resistance (RVR) was calculated. The inspiratory gasp test (apnea at end-inspiration) or a local heat provocation were used as provocations of the cutaneous microcirculation. RESULTS: Interscalene brachial plexus block increased SBF and decreased RVR at rest, and produced satisfactory sensory and motor block. The inspiratory gasp test decreased SBF and increased RVR in the unblocked arm, while the opposite, increased SBF and decreased RVR, were observed during local heat provocation. In the blocked arm, these gasp-induced cutaneous vasoconstrictor and heat-induced vasodilator responses were attenuated. CONCLUSIONS: Interscalene brachial plexus block reduces regional sympathetic nervous activity, illustrated by increases in skin blood flow, skin temperature and attenuated vasoconstrictor responses to an inspiratory gasp. The inspiratory gasp vasoconstrictive response is a powerful and sensitive indicator for monitoring the sympathetic blockade following interscalene brachial plexus block.

  • 4.
    Linden, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Svenningsson, Anders
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Inflammatory activity and vitamin D levels in an MS population treated with rituximab2019In: Multiple Sclerosis Journal, Experimental, Translational and Clinical, E-ISSN 2055-2173, Vol. 5, no 1, article id 2055217319826598Article in journal (Refereed)
    Abstract [en]

    Background: Most multiple sclerosis patients on disease-modifying treatment at Umeå University Hospital are treated with rituximab and the prevalence of vitamin D supplementation has increased over time. Follow-up studies of these off-label treatments are needed.

    Objective: To study inflammatory activity and adverse effects in rituximab-treated multiple sclerosis patients, and associations with 25-hydroxy-vitamin D levels.

    Methods: Retrospectively collected data on repeated estimates of relapses, disability, side effects, magnetic resonance imaging, laboratory measures including 25-hydroxy-vitamin D levels and self-perceived health.

    Results: In 272 multiple sclerosis patients with a mean follow-up of 43 months, we identified seven possible relapses during active rituximab treatment. On magnetic resonance imaging examination, new T2 lesions were seen in 1.3% (10 out of 792 scans), and 0.25% (two out of 785 scans) showed contrast enhancement. Adjusted 25-hydroxy-vitamin D levels in samples drawn close to all magnetic resonance images with new T2 lesions were lower compared to the remainder (62 vs. 81 nmol/l; P = 0.030). Levels of 25-hydroxy-vitamin D were associated with self-perceived health (r = 0.18, P = 0.041, n = 130) and C-reactive protein (r = -0.13, P = 0.042) but not with the risk of side effects.

    Conclusion: The inflammatory activity in this rituximab-treated multiple sclerosis population that increasingly used vitamin D supplementation was extremely low. Higher 25-hydroxy-vitamin D levels were associated with beneficial outcomes.

  • 5. Luna, Gustavo
    et al.
    Alping, Peter
    Burman, Joachim
    Fink, Katharina
    Fogdell-Hahn, Anna
    Gunnarsson, Martin
    Hillert, Jan
    Langer-Gould, Annette
    Lycke, Jan
    Nilsson, Petra
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Vrethem, Magnus
    Olsson, Tomas
    Piehl, Fredrik
    Frisell, Thomas
    Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies2019In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157Article in journal (Refereed)
    Abstract [en]

    Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.

    Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.

    Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.

    Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA.

    Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.

    Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).

    Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.

  • 6. Neuwirth, Christoph
    et al.
    Braun, Nathalie
    Claeys, Kristl G
    Bucelli, Robert
    Fournier, Christina
    Bromberg, Mark
    Petri, Susanne
    Goedee, Stephan
    Lenglet, Timothée
    Leppanen, Ron
    Canosa, Antonio
    Goodman, Ira
    Al-Lozi, Muhammad
    Ohkubo, Takuya
    Hübers, Annemarie
    Atassi, Nazem
    Abrahao, Agessandro
    Funke, Andreas
    Appelfeller, Martin
    Tümmler, Anke
    Finegan, Eoin
    Glass, Jonathan D
    Babu, Suma
    Ladha, Shafeeq S
    Kwast-Rabben, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Juntas-Morales, Raul
    Coffey, Amina
    Chaudhry, Vinay
    Vu, Tuan
    Saephanh, Chow
    Newhard, Colleen
    Zakrzewski, Marion
    Rosier, Esther
    Hamel, Nancy
    Raheja, Divisha
    Raaijman, Jesper
    Ferguson, Toby
    Weber, Markus
    Implementing Motor Unit Number Index (MUNIX) in a large clinical trial: Real world experience from 27 centres2018In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 129, no 8, p. 1756-1762, article id S1388-2457(18)30917-9Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of motor neurons in Amyotrophic Lateral Sclerosis (ALS) in longitudinal studies. It has been utilized in one natural history ALS study and one drug trial (Biogen USA) after training and qualification of raters.

    METHODS: Prior to testing patients, evaluators had to submit test-retest data of 4 healthy volunteers. Twenty-seven centres with 36 raters measured MUNIX in 4 sets of 6 different muscles twice. Coefficient of variation of all measurements had to be <20% to pass the qualification process. MUNIX COV of the first attempt, number of repeated measurements and muscle specific COV were evaluated.

    RESULTS: COV varied considerably between raters. Mean COV of all raters at the first measurements was 12.9% ± 13.5 (median 8.7%). Need of repetitions ranged from 0 to 43 (mean 10.7 ± 9.1, median 8). Biceps and first dorsal interosseus muscles showed highest repetition rates. MUNIX variability correlated considerably with variability of compound muscle action potential.

    CONCLUSION: MUNIX revealed generally good reliability, but was rater dependent and ongoing support for raters was needed.

    SIGNIFICANCE: MUNIX can be implemented in large clinical trials as an outcome measure after training and a qualification process.

  • 7. Ryska, Pavel
    et al.
    Slezak, Ondrej
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Zizka, Jan
    Radiological markers of idiopathic normal pressure hydrocephalus: Relative comparison of their diagnostic performance2020In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 408, article id 116581Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Numerous radiological measures have been proposed as imaging biomarkers of idiopathic normal pressure hydrocephalus (iNPH), however, the number of studies systematically comparing their diagnostic values remains limited. The study objective was to compare the diagnostic performance of fifteen cross-sectional imaging iNPH biomarkers.

    MATERIALS AND METHODS: Eighty subjects were prospectively enrolled in the study: 35 subjects with clinically confirmed iNPH and 45 matched healthy controls (HC). Values of linear, angular and index measurements including three newly proposed biomarkers were obtained from 3T brain MRI studies by two independent readers. Diagnostic performance of biomarkers was studied by using receiver operating characteristic (ROC) analysis and t-statistic.

    RESULTS: All biomarkers studied were able to reliably differentiate iNPH subjects from HC (p < .001) except for cella media-to-temporal horn ratio. Z-Evans index, vertical cella media and vertical frontal horn diameters showed the highest discriminatory power between iNPH and HC groups (area under curve >0.99). Simple linear measurements of vertical (0.99) or horizontal (0.95) frontal horn diameters showed results comparable to calculated ratios, i.e. z-Evans (0.99) and Evans (0.96) indexes, respectively.

    CONCLUSION: The best diagnostic performance among fifteen radiological iNPH biomarkers was found in linear measurements referring to caudocranial alterations of the ventricular geometry, outweighing those referring to laterolateral ventricular enlargement (as e.g. commonly used Evans index). Simple linear measurements of vertical or horizontal frontal horn diameters showed comparable results to calculated, more time-consuming z-Evans or Evans indexes, respectively.

  • 8.
    Sjöberg, Rickard L
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Department of Neurosurgery, University Hospital of Northern Sweden, 901 85 Umeå, Sweden.
    Wu, Wendy Yi-Ying
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tsavachidis, Spiridon
    Bondy, Melissa L.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study2019In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 145, no 2, p. 287-294Article in journal (Refereed)
    Abstract [en]

    Background: The Mono-amine oxidase-A (MAO-A) enzyme is involved in the degradation and regulation of catecholamines such as serotonin, dopamine, epinephrine and nor-epinephrine. Preclinical studies suggest that this enzyme may contribute to an environment favorable for growth of malignant glioma. The MAO-A gene is located on the X-chromosome and has at least one functional genetic polymorphism. The aim of the present study was to explore possible effects of MAO-A genotype on development of glioblastoma in males.

    Methods: Genotypes for 437 glioma cases and 876 population-based controls from the Swedish Glioma International Case–Control study (GICC) were compared. We analyzed the germline DNA using the Illumina Oncoarray. We selected seven single nucleotide polymorphisms (SNPs) located in the MAO-A gene, and imputed genotypes based on data from the 1000 genomes project. We used 1579 male glioblastoma cases and 1875 controls comprising the whole GICC cohort for subsequent validation of findings.

    Results: The rs144551722 SNP was a significant predictor of development of glioblastoma in males (p-value = 0.0056) but not in females even after correction for multiple testing. We conducted haplotype analysis to confirm an association between MAO-A gene and risk of glioblastoma (p-value = 0.016). We found similar results in the validation sample.

    Conclusions: These results suggest the possibility of a role for the MAO-A enzyme and the MAO-A gene in the development of glioblastoma in males.

  • 9.
    Steensland, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Koskinen, Lars-Owe D.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Lindvall, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Treatment of Restless legs with a pump; efficacy and complications2019In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Restless legs (RLS) has a prevalence of 2.5-15 % in the general population.. For those who suffer from a medically refractory RLS, intrathecal morphine treatment has been shown to be effective. The aim of this retrospective study was to investigate efficacy, complications and side effects in patients treated over several years with an implantable pump. A comparison was done to a group of patients treated with a similar pump system due to spasticity.

    MATERIALS AND METHODS: The charts of ten patients with severe or very severe RLS have been reviewed. These patients have received an intrathecal drug delivery system during 2000 -2016. To compare the rate of complications, a control group of 20 patients treated with intrathecal baclofen due to spasticity was included in the study. Their time of treatment corresponded to the RLS patients'.

    RESULTS: The severity of symptoms related to RLS decreased significantly after treatment. Doses required ranged from 68 to 140 µg/day. Two cases of side effects were detected; one case with nausea and dizziness and one case with headache and fatigue. The rate of mechanical-, infectious- and other complications were similar between the two groups.

    CONCLUSIONS: In light of the decrease in symptom severity and the low rate of side effects, intrathecal morphine can be considered an adequate treatment for those suffering from medically refractory RLS. The occurrence of complications did not differ between subjects with RLS and spasticity.

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