[Swedish consensus statement for the use of MRI in MS]. / Diagnostik och uppföljning av MS med MR ­ svensk konsensus - Nationell konsensus kan ge mer jämlik MS-vård och bättre möjlighet till rikstäckande forskningsprojekt.

Swedish consensus statement for the use of MRI in MS Despite the importance of MRI in the follow-up of MS, there is currently insufficient evidence to clearly define how it should be utilised in the clinical care of individuals with MS. The Swedish Multiple Sclerosis Association together with the Swedish Neuroradiological Society here present a consensus-based document that gives recommendations on several important aspects of clinical use of MRI for MS.

Brain Parenchymal Fraction in Healthy Adults-A Systematic Review of the Literature.

Brain atrophy is an important feature of many neurodegenerative disorders. It can be described in terms of change in the brain parenchymal fraction (BPF). In order to interpret the BPF in disease, knowledge on the BPF in healthy individuals is required. The aim of this study was to establish a normal range of values for the BPF of healthy individuals via a systematic review of the literature. The databases PubMed and Scopus were searched and 95 articles, including a total of 9269 individuals, were identified including the required data. We present values of BPF from healthy individuals stratified by age and post-processing method. The mean BPF correlated with mean age and there were significant differences in age-adjusted mean BPF between methods. This study contributes to increased knowledge about BPF in healthy individuals, which may assist in the interpretation of BPF in the setting of disease. We highlight the differences between post-processing methods and the need for a consensus gold standard.

Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy.

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.

Brain parenchymal fraction in an age-stratified healthy population - determined by MRI using manual segmentation and three automated segmentation methods.

BACKGROUND AND PURPOSE: Brain atrophy is a prominent feature in many neurodegenerative diseases, such as multiple sclerosis, but age-related decrease of brain volume occurs regardless of pathological neurodegeneration. Changes in brain volume can be described by use of the brain parenchymal fraction (BPF), most often defined as the ratio of total brain parenchyma to total intracranial space. The BPF is of interest both in research and in clinical practice. To be able to properly interpret this variable, the normal range of BPF must be known. The objective of this study is to present normal values for BPF, stratified by age, and compare manual BPF measurement to three automated methods. MATERIALS AND METHODS: The BPFs of 106 healthy individuals aged 21 to 85 years were determined by the automated segmentation methods SyMap, VBM8 and SPM12. In a subgroup of 54 randomly selected individuals, the BPF was also determined by manual segmentation. RESULTS: The median (IQR) BPFs of the whole study population were 0.857 (0.064), 0.819 (0.028) and 0.784 (0.073) determined by SyMap, VBM8 and SPM12, respectively. The BPF decreased with increasing age. The correlation coefficients between manual segmentation and SyMap, VBM8 and SPM12 were 0.93 (P<0.001), 0.77 (P<0.001) and 0.56 (P<0.001), respectively. CONCLUSIONS: There was a clear relationship between increasing age and decreasing BPF. Knowledge of the range of normal BPF in relation to age group will help in the interpretation of BPF data. The automated segmentation methods displayed varying degrees of similarity to the manual reference, with SyMap being the most similar.

How to minimize the risk for headache? A lumbar puncture practice questionnaire study.

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 AAN 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 AAN 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.

Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction.

BACKGROUND: Neurofilament light (NFL) and Glial Fibrillary Acidic Protein (GFAP) are integral parts of the axonal and astrocytal cytoskeletons respectively and are released into the cerebrospinal fluid (CSF) in cases of cellular damage. In order to interpret the levels of these biomarkers in disease states, knowledge on normal levels in the healthy is required. Another biomarker for neurodegeneration is brain atrophy, commonly measured as brain parenchymal fraction (BPF) using magnetic resonance imaging (MRI). Potential correlations between levels of NFL, GFAP and BPF in healthy individuals have not been investigated. OBJECTIVES: To present levels of NFL and GFAP in healthy individuals stratified for age, and investigate the correlation between them as well as their correlation with BPF. METHODS: The CSF was analysed in 53 healthy volunteers aged 21 to 70 (1 sample missing for GFAP analysis) and 48 of the volunteers underwent determination of BPF using MRI. RESULTS: Mean (±SD) NFL was 355 ng/L (±214), mean GFAP was 421 ng/L (±129) and mean BPF was 0.867 (±0.035). All three biomarkers correlated with age. NFL also correlated with both GFAP and BPF. When controlled for age, only the correlation between NFL and GFAP retained statistical significance. CONCLUSIONS: This study presents data on age-stratified levels of NFL and GFAP in the CSF of healthy individuals. There is a correlation between levels of NFL and GFAP and both increase with age. A correlation between NFL and BPF was also found, but did not retain statistical significance if controlled for age.

Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally.

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 × 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.

Lumbar puncture preferences among Swedish neurologists.

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.

Humoral immune response to influenza vaccine in natalizumab-treated MS patients.

OBJECTIVES: Natalizumab is a drug with documented efficacy in relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of natalizumab has immunosuppressive properties and it is not yet investigated if treatment with natalizumab affects the immunological response to vaccination. This study aims to investigate the humoral immune response to influenza vaccine while undergoing treatment with natalizumab. METHODS: A cohort of 17 RRMS patients treated with natalizumab and 10 healthy controls received trivalent influenza A/B vaccine. Influenza-specific immunoglobulin G (IgG) levels were determined at baseline and after 4, 8, and 12 weeks. RESULTS: Both groups experienced a significant increase in anti-influenza B IgG after the vaccination. Both groups also experienced a smaller increase in anti-influenza A IgG, but this was only significant for the natalizumab group. The IgG titers compared between the groups did not differ significantly at any of the time points. DISCUSSION: These results indicate that vaccination against influenza in patients treated with natalizumab yields a humoral immune response comparable to that achieved in healthy individuals.