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- Platten, Michael
(författare)
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Quantitative MRI Biomarkers of Neurodegeneration in Multiple Sclerosis
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease that targets myelin in the brain and spinal cord. The corpus callosum connects the cerebral hemispheres and is composed of heavily myelinated axons. Atrophy of the corpus callosum has been explored as a more sensitive marker of disease status and neurodegeneration relative to other neuroanatomical structures. However, development of more accurate, precise and less labor demanding tools for characterizing callosal atrophy would increase its potential as a proxy marker of MS evolution.Purpose: The primary objective of this thesis was to evaluate and develop quantitative methods for measuring neurodegeneration in MS with a focus on the corpus callosum. This was achieved through the comparison of the accuracy and precision of manual delineation, conventional volumetric methods, and machine learning approaches.Study I: In a prospective study, 9 MS patients underwent scan/re-scanning with and without repositioning to measure the precision and accuracy of manual versus volumetric cross-sectional and longitudinal FreeSurfer analyses. While the longitudinal stream of FreeSurfer revealed the highest precision, the overall limitations on accuracy warrants caution.Study II: In a prospective study, 553 MS patients with 704 2D T2-weighted MRI acquisitions were used to train and validate a machine learning algorithm for segmenting a marker of neurodegeneration. The algorithm quickly produced highly accurate segmentations of the corpus callosum and brain (Dice Coefficient: 89% and 98%, respectively). The algorithm had numerically higher correlations to neurologic disability as compared to FreeSurfer.Study III: Analogous to Study II, in a prospective study, 631 MS patients with 3D T1-weighted and T2-weighted FLAIR acquisitions were used to train and validate a machine learning algorithm for segmenting the mid-sagittal normalized corpus callosum area. The algorithm performed better with T1-weighted scans and less atrophied patients. Scanner parameters had no significant effect on the T1-weighted output. The algorithm produced segmentations in less than a minute per scan, with similar correlations to neurologic disability, as compared to FreeSurfer.Study IV: In a prospective study, 92 MS patients acquired both 3 and 7 Tesla brain MRI scans to reveal the lobe-specific lesion volumes’ association to corpus callosum atrophy, where lesion burden was found to be greatest in the frontal and parietal lobes. In addition, the posterior portions of the corpus callosum provided the strongest fit linear regression models, with a combination of white matter lesions and intracortical lesions predicting atrophy.Conclusions: Creating and evaluating novel tools for measuring neurodegeneration over time is important both for monitoring disease progression and to evaluate therapeutic responses with current drugs. As novel therapeutic strategies appear, it may also help in assessing neuroregenerative approaches.
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| 3. |
- Salzer, Jonatan, et al.
(författare)
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How to minimize the risk for headache? : a lumbar puncture practice questionnaire study
- 2016
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Ingår i: IDEGGYOGYASZATI SZEMLE-CLINICAL NEUROSCIENCE. - : Ideggyogyaszati Szemle Journal. - 0019-1442. ; 69:11-12, s. 397-402
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Tidskriftsartikel (refereegranskat)abstract
- Background - To lower the risk for post lumbar puncture (LP) headache the American Academy of Neurology (AAN) recommended using small bore atraumatic needles together with stylet reinsertion in a report from 2005. It is unclear whether these recommendations are followed or not. Objectives To investigate the diagnostic LP preferences with respect to the AAN guidelines among neurologists by use of a short online questionnaire, and to review previously published literature on the subject. Results - A total of 284 respondents who performed diagnostic LPs completed the questionnaire. Almost half (41%) answered that they always use atraumatic needles. The most common reason (73%) for not using atraumatic needles was that these were not available. Less than half of the respondents who performed LPs had knowledge about the MN guidelines for diagnostic LPs, and 48-76% agreed with the different recommendations therein. Five previously (1998-2015) published studies investigating LP practice among neurologists were identified. The reported frequency of atraumatic needle use (always/routinely) varied between 2 and 16%. Discussion - Atraumatic needle use was more common in this study compared with previous publications. There is still skepticism regarding some of the MN recommendations, and needle availability appears to be the most important factor preventing atraumatic needle use. To increase the use of atraumatic needles we may perform additional studies investigating their potential benefits, and arrange training sessions for neurologists to increase their awareness and level of comfort with the atraumatic LP technique.
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| 4. |
- Salzer, Jonatan, et al.
(författare)
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Lumbar puncture preferences among Swedish neurologists.
- 2015
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Ingår i: Neurological Research. - 0161-6412 .- 1743-1328. ; 37:1, s. 92-4
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Tidskriftsartikel (refereegranskat)abstract
- Lumbar puncture (LP) with cerebrospinal fluid analysis is a common diagnostic tool in neurology, and may be complicated by post-LP headache (PLPHA). The American Academy of Neurology (AAN) has published guidelines for performing diagnostic LPs with the aim to reduce PLPHA risk, but our clinical hands-on experience suggests that these are not followed. We performed a questionnaire study among Swedish neurologists to investigate the acceptance and implementation of the AAN guidelines. Only one-eighth (22/174) of the respondents performed their LPs according to the AAN guidelines. The poor adherence to the AAN guidelines among Swedish neurologists may be due to perceived low credibility, as the current guidelines cite only one study to support the recommendation to use atraumatic needles, and only one study to support the recommendation to replace the stylet before needle withdrawal. An international survey has been posted ( https://www.surveymonkey.com/s/lumbarpuncturesurvey ) to investigate whether the results of this Swedish questionnaire are representative of neurologists worldwide.
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| 5. |
- Salzer, Jonatan, et al.
(författare)
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Prevention of post-dural puncture headache : a randomized controlled trial
- 2020
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Ingår i: European Journal of Neurology. - : Wiley-Blackwell. - 1351-5101 .- 1468-1331. ; 27:5, s. 871-877
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: We investigated 952 subjects undergoing diagnostic lumbar puncture (LP) to study the effects of needle size, needle design and stylet reinsertion on the risk of post‐dural puncture headache (PDPH).Methods: This randomized double‐blind study was performed at Umeå University Hospital in Sweden during 2013–2018. Subjects were randomly assigned one of three needles [22 gauge (G) atraumatic, 25G atraumatic and 25G cutting] and stylet reinsertion before needle withdrawal or not. The main outcome measure was PDPH assessed by standardized telephone interview(s) 5 days after the LP, repeated until headache cessation. We used logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PDPH.Results: The mean (SD) age was 51.1 (16.7) years and 53.6% were females. The smaller bore (25G) atraumatic needle incurred a lower risk of headache compared with the larger bore (22G) atraumatic needle [22.0% (69/314) vs. 30.2% (98/324); OR, 0.65; 95% CI, 0.45–0.93] and compared with the cutting needle [32.8% (103/314); OR, 0.58; 95% CI, 0.40–0.82]. Reinserting the stylet before needle withdrawal did not reduce the risk of headache.Conclusions: These data suggest that a 25G atraumatic needle is superior to a larger atraumatic needle, and to a same‐sized cutting needle, in preventing PDPH after diagnostic LP. In contrast to one earlier report, this study did not find that stylet reinsertion was effective in preventing PDPH. This study provides class I evidence that a small atraumatic needle decreases the risk of PDPH and that stylet reinsertion does not influence PDPH risk.
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| 7. |
- Salzer, Jonatan, et al.
(författare)
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Rituximab in multiple sclerosis : a retrospective observational study on safety and efficacy
- 2016
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 87:20, s. 2074-2081
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded. Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades >= 2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.
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| 8. |
- Svenningsson, Anders, et al.
(författare)
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Increasing prevalence of multiple sclerosis in Vasterbotten County of Sweden
- 2015
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 132:6, s. 389-394
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To update the incidence and prevalence of multiple sclerosis (MS) in Vasterbotten County, Sweden, and to compare this to previous investigations in the same area. Background Northern Sweden is a high-risk area for developing MS. Vasterbotten County has previously been surveyed in detail regarding the occurrence of MS. In several countries, increases in MS prevalence and incidence as well as a change in the sex ratio have been reported. Materials and methods Multiple sources were used to identify MS cases in Vasterbotten that either had their onset of the disease from 1998 to 2010 and/or lived in Vasterbotten, the two dates chosen for prevalence calculation: the 31st of December 2005 and 2010. Results The mean yearly incidence of MS in Vasterbotten during the entire period 1998-2010 was 6.0/100,000. The female to male ratio was 2.1. The prevalence of MS in Vasterbotten was 188/100,000 on 31st of December 2005 and 215/100,000 on 31st of December 2010. The MS prevalence increased over time from 1990 to 2010. Conclusions The prevalence of MS in Vasterbotten County has increased between 1990 and 2010, while no statistically significant increase in incidence was seen.
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| 9. |
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| 10. |
- Svenningsson, Anders, et al.
(författare)
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Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally
- 2015
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 2332-7812. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year posttreatment.Methods: Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n=3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 x 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2-3 months.Results: The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3-6 month period.Conclusions: Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments.Classification of evidence: This study provides Class IV evidence that for patients with PMS, rituximab provided via an Ommaya reservoir depletes peripheral blood B lymphocytes.
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