Martin Gunnarsson

Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab

The impact of present disease‐modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2 brain‐specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.

Neurofilament and glial fibrillary acidic protein in multiple sclerosis

Objective: To evaluate levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) in CSF from patients with multiple sclerosis (MS) in relation to clinical progress of the disease. Methods: CSF levels of NFL and GFAP were determined by sensitive ELISAs in 99 patients with different subtypes of MS, classified in terms of “ongoing relapse” or “clinically stable disease,” and 25 control subjects. Levels were compared with paraclinical data such as immunoglobulin G index and inflammatory cell count in the CSF, and the levels were related to Expanded Disability Status Scale score and progression index at clinical follow-up evaluations later in the disease course. Results: NFL and GFAP levels were elevated in MS patients as compared with control subjects (p < 0.001). The NFL levels were higher at relapses, whereas GFAP levels were unaffected. High NFL levels correlated with progression in patients with an active relapse (r = 0.49; p < 0.01) and in clinically stable patients (r = 0.29; p < 0.05). GFAP correlated to progression in the total patient cohort (r = 0.24; p < 0.05). Moreover, a strong correlation between NFL levels and inflammatory cell counts was evident in the group of patients with an ongoing relapse (r = 0.52; p = 0.001). Conclusions: CSF levels of neurofilament light and glial fibrillary acidic protein may have prognostic value in multiple sclerosis.

Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience

Background Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. Methods Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. Results At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). Conclusions HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis

Background: In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression. Objective: The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13). Methods: CSF was obtained from 35 patients with PMS before and after 12–24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays. Results: The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline. Conclusions: Our data imply that 12–24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.

Accuracy and reproducibility of a quantitative magnetic resonance imaging method for concurrent measurements of tissue relaxation times and proton density.

PURPOSE To evaluate the accuracy and reproducibility of a quantitative magnetic resonance (qMR) imaging method (QRAPMASTER) for simultaneous measurements of T1 and T2 relaxation times, and proton density (PD). MATERIALS AND METHODS Measurements of T1, T2, and PD with qMR were performed using phantoms with different relaxation times and concentrations of heavy water. Healthy volunteers were examined with different head coils. Regional measurements were performed in normal-appearing white and gray matter from the healthy control subjects, and in multiple sclerosis (MS) patients. RESULTS In phantom measurements, QRAPMASTER slightly underestimated T1, and T2 variations between repeated measurements were modest. PD was generally overestimated. The overall relative difference was -1.2±5.3% (T1), -6.6±1.9% (T2), and 0.7±5.1% (PD). In healthy volunteers, there were no statistically significant differences of T1, T2 or PD using different head coils. Values of T1, T2, and PD obtained in healthy controls and MS patients were within reference ranges. However, significant differences were found in normal-appearing gray and white matter. CONCLUSION QRAPMASTER can be considered a sufficiently accurate and reproducible method for use in clinical practice. Neuropathology in normal-appearing brain tissue may be revealed using this MR method, with putative implications for quantification of tissue damage in neurological diseases.

Monitoring disease activity in multiple sclerosis using serum neurofilament light protein

Objective: To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS). Methods: NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay. Results: In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6–32.7) ng/L to 15.7 (IQR 9.6–22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001). Conclusions: Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab

Objective: To describe the effects of switching treatment from ongoing first-line injectable therapies to rituximab on inflammatory activity measured by MRI and levels of CSF neurofilament light chain (CSF-NFL) in a cohort of patients with clinically stable relapsing-remitting multiple sclerosis (RRMS). Method: Seventy-five patients with clinically stable RRMS treated with the first-line injectables interferon-β (IFN-β) and glatiramer acetate (GA) at 3 Swedish centers were switched to rituximab in this open-label phase II multicenter study. After a run-in period of 3 months, 2 IV doses of 1,000 mg rituximab were given 2 weeks apart followed by repeated clinical assessment, MRI, and CSF-NFL for 24 months. Results: The mean cumulated number of gadolinium-enhancing lesions per patient at months 3 and 6 after treatment shift to rituximab was reduced compared to the run-in period (0.028 vs 0.36, p = 0.029). During the first year after treatment shift, the mean number of new or enlarged T2 lesions per patient was reduced (0.01 vs 0.28, p = 0.004) and mean CSF-NFL levels were reduced by 21% (p = 0.01). Conclusions: For patients with RRMS, a treatment switch from IFN or GA to rituximab is associated with reduced inflammatory activity measured by MRI and CSF-NFL. Classification of evidence: This study provides Class IV evidence that rituximab has an equal or superior effect in reducing inflammatory activity in RRMS measured by MRI and CSF-NFL compared to first-line injectables during the first year after treatment shift.

Characteristics in childhood and adolescence associated with future multiple sclerosis risk in men : cohort study

Associations with multiple sclerosis (MS) of living conditions in childhood and characteristics in adolescence including physical fitness, cognitive function and psychological stress resilience were investigated.

Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS.

Objective: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab. Method: A total of 75 patients with clinically stable relapsing–remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period. Results: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1–7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment (p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression. Conclusion: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.