Novel and Emerging Treatments to Target Pathophysiological Mechanisms in Various Phenotypes of Multiple Sclerosis.

The objective is to comprehensively review novel pharmacotherapies used in multiple sclerosis (MS) and the possibilities they may carry for therapeutic improvement. Specifically, we discuss pathophysiological mechanisms worth targeting in MS, ranging from well known targets, such as autoinflammation and demyelination, to more novel and advanced targets, such as neuroaxonal damage and repair. To set the stage, a brief overview of clinical MS phenotypes is provided, followed by a comprehensive recapitulation of both clinical and paraclinical outcomes available to assess the effectiveness of treatments in achieving these targets. Finally, we discuss various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials. SIGNIFICANCE STATEMENT: This comprehensive review discusses pathophysiological mechanisms worth targeting in multiple sclerosis. Various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials, are reviewed.

Ocrelizumab in MS patients with persistence of disease activity after alemtuzumab: A multi-center Italian study.

BACKGROUND: The reason why some multiple sclerosis (MS) patients show disease activity after alemtuzumab (ALM) is still unclear, but ocrelizumab (OCR) could represent an interesting sequential therapeutic approach. OBJECTIVES: To investigate safety and efficacy of OCR in MS patients with disease activity after two ALM courses. METHODS: Observational retrospective multi-centers Italian cohort study. RESULTS: Seventy-two subjects were included. Mean follow-up (FU) was 2.4 (±1) years. Forty-five patients (62.5%) experienced at least one adverse event (AE), with infections accounting for 96.7% of cases. A reduction in total lymphocytes was observed between OCR start and 6 months FU, driven by BCD19+ lymphocytes depletion (p < 0.001). Immunoglobulin M (IgM) levels decreased between OCR start and 6 months FU (p < 0.001). At 2-year FU, relapse, magnetic resonance imaging (MRI) activity and disability worsening-free survival were 92.1%, 90.8%, and 89.2%. The evidence of inflammatory activity between the two ALM courses was associated with higher risk of relapse, MRI activity, and NEDA-3 status loss in relapsing-remitting multiple sclerosis (RRMS; p = 0.02, p = 0.05, p = 0.01, respectively). CONCLUSIONS: OCR after two ALM courses seemed to be safe and effective. Early IgM hypogammaglobulinemia occurred in a high proportion of patients. The evidence of inflammatory activity between ALM courses seemed to increase the risk of MS re-activation on OCR treatment.

Multiple Sclerosis Onset before and after COVID-19 Vaccination: Can HLA Haplotype Be Determinant?

A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing-remitting MS before and after the outbreak of the COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. This is a single-centre retrospective cohort study including all patients who presented with relapsing-remitting MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. A total of 266 patients received a new diagnosis of relapsing-remitting MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020), and 123 during the COVID-19 era (from April 2020). The mean number of new MS onset cases per year was not different before and during the COVID-19 era and neither were baseline patients' characteristics, type of onset, clinical recovery, or radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients' characteristics, type of onset, clinical recovery, and radiological patterns did not differ from those of patients with non-vaccine-related new diagnoses of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with non-vaccine-related disease onset before and during the COVID-19 era, respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast, HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Although a causal link between COVID-19 vaccination and relapsing-remitting MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetics and the environment could be crucial also for the follow-up and the evaluation of therapeutic options.

Super-resolution QSM in little or no additional time for imaging (NATIve) using 2D EPI imaging in 3 orthogonal planes.

Quantitative Susceptibility Mapping has the potential to provide additional insights into neurological diseases but is typically based on a quite long (5-10 min) 3D gradient-echo scan which is highly sensitive to motion. We propose an ultra-fast acquisition based on three orthogonal (sagittal, coronal and axial) 2D simultaneous multi-slice EPI scans with 1 mm in-plane resolution and 3 mm thick slices. Images in each orientation are corrected for susceptibility-related distortions and co-registered with an iterative non-linear Minimum Deformation Averaging (Volgenmodel) approach to generate a high SNR, super-resolution data set with an isotropic resolution of close to 1 mm. The net acquisition time is 3 times the volume acquisition time of EPI or about 12 s, but the three volumes could also replace "dummy scans" in fMRI, making it feasible to acquire QSM in little or No Additional Time for Imaging (NATIve). NATIve QSM values agreed well with reference 3D GRE QSM in the basal ganglia in healthy subjects. In patients with multiple sclerosis, there was also a good agreement between the susceptibility values within lesions and control ROIs and all lesions which could be seen on 3D GRE QSMs could also be visualized on NATIve QSMs. The approach is faster than conventional 3D GRE by a factor of 25-50 and faster than 3D EPI by a factor of 3-5. As a 2D technique, NATIve QSM was shown to be much more robust to motion than the 3D GRE and 3D EPI, opening up the possibility of studying neurological diseases involving iron accumulation and demyelination in patients who find it difficult to lie still for long enough to acquire QSM data with conventional methods.

B Cell Depletion and SARS-CoV-2 Vaccine Responses in Neuroimmunologic Patients.

OBJECTIVE: The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in patients with various neuroimmunologic disorders on anti-CD20 therapy. This included an analysis of the T cell vaccine response to the SARS-CoV-2 Delta variant. METHODS: We investigated prospectively humoral and cellular responses to SARS-CoV-2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti-CD20 therapy and 82 age- and sex-matched healthy controls. For quantification of antibodies, the Elecsys anti-SARS-CoV-2 viral spike (S) immunoassay against the receptor-binding domain (RBD) was used. IFN-gamma enzyme-linked immunosorbent spot assays were performed to assess T cell responses against the SARS-CoV-2 Wuhan strain and the Delta variant. RESULTS: SARS-CoV-2-specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti-CD20 treated patients. In contrast to the antibody response, the T-cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B-cell depleted compared to nondepleted patients. INTERPRETATION: Antibody responses to SARS-CoV-2 mRNA vaccinnation can be attained in patients on anti-CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID-19) in this high-risk population. ANN NEUROL 2022;91:342-352.

Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis.

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening.

Association of paramagnetic rim lesions and retinal layer thickness in patients with multiple sclerosis.

BACKGROUND: Paramagnetic rim lesions (PRLs) are chronic active lesions associated with a more severe disease course in multiple sclerosis (MS). Retinal layer thinning measured by optical coherence tomography (OCT) is a biomarker of neuroaxonal damage associated with disability progression in MS. OBJECTIVE: We aimed to determine a potential association between OCT parameters (peripapillary retinal nerve fiber layer (pRNFL) ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL) thickness), and PRLs in patients with MS (pwMS). METHODS: In this cross-sectional retrospective study, we included pwMS with both 3T brain MRI and an OCT scan. Regression models were calculated with OCT parameters (pRNFL, GCIPL, INL) as dependent variables, and the number of PRLs as an independent variable adjusted for covariates. RESULTS: We analyzed data from 107 pwMS (mean age 34.7 years (SD 10.9), 64.5% female, median disease duration 6 years (IQR 1-13), median EDSS 1.5 (range 0-6.5)). Higher number of PRLs was associated with lower pRNFL (ß = -0.18; 95% CI -0.98, -0.03; p = 0.038) and GCIPL thickness (ß = -0.21; 95% CI -0.58, -0.02; p = 0.039). CONCLUSION: The association between higher number of PRLs and lower pRNFL and GCIPL thicknesses provides additional evidence that pwMS with PRLs are affected by a more pronounced neurodegenerative process.

Paramagnetic rim lesions lead to pronounced diffuse periplaque white matter damage in multiple sclerosis.

BACKGROUND: Paramagnetic rim lesions (PRLs) are an imaging biomarker in multiple sclerosis (MS), associated with a more severe disease. OBJECTIVES: To determine quantitative magnetic resonance imaging (MRI) metrics of PRLs, lesions with diffuse susceptibility-weighted imaging (SWI)-hypointense signal (DSHLs) and SWI-isointense lesions (SILs), their surrounding periplaque area (PPA) and the normal-appearing white matter (NAWM). METHODS: In a cross-sectional study, quantitative MRI metrics were measured in people with multiple sclerosis (pwMS) using the multi-dynamic multi-echo (MDME) sequence post-processing software "SyMRI." RESULTS: In 30 pwMS, 59 PRLs, 74 DSHLs, and 107 SILs were identified. Beside longer T1 relaxation times of PRLs compared to DSHLs and SILs (2030.5 (1519-2540) vs 1615.8 (1403.3-1953.5) vs 1199.5 (1089.6-1334.6), both p < 0.001), longer T1 relaxation times were observed in the PRL PPA compared to the SIL PPA and the NAWM but not the DSHL PPA. Patients with secondary progressive multiple sclerosis (SPMS) had longer T1 relaxation times in PRLs compared to patients with late relapsing multiple sclerosis (lRMS) (2394.5 (2030.5-3040) vs 1869.3 (1491.4-2451.3), p = 0.015) and also in the PRL PPA compared to patients with early relapsing multiple sclerosis (eRMS) (982 (927-1093.5) vs 904.3 (793.3-958.5), p = 0.013). CONCLUSION: PRLs are more destructive than SILs, leading to diffuse periplaque white matter (WM) damage. The quantitative MRI-based evaluation of the PRL PPA could be a marker for silent progression in pwMS.

Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome.

BACKGROUND AND PURPOSE: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. METHODS: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. RESULTS: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). CONCLUSION: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.

A true isolated cognitive relapse in multiple sclerosis.

Isolated cognitive relapses (ICRs) have been a matter of debate for the past few years. Currently, there is no clear consensus on such an entity, as cognitive decline usually accompanies typical multiple sclerosis (MS) relapses. Herein, we present the neuropsychological and neurophysiological manifestations of a patient who suddenly complained of confusion and memory loss, showing insight into her deficit, in absence of sensorimotor disturbances. Neuroimaging revealed a large tumefactive gadolinium-enhancing lesion localized in the left medial temporal lobe. The patient's symptoms persisted for months afterwards, despite corticosteroid treatment. We believe our patient experienced a true ICR. ICRs are rare entities in MS, but we should be alert to their existence in order to treat them promptly. Deepening their pathophysiology is equally important and neuropsychology combined with neurophysiology may be useful in this regard.

Extensive Brain Pathologic Alterations Detected with 7.0-T MR Spectroscopic Imaging Associated with Disability in Multiple Sclerosis.

Background MR spectroscopic imaging (MRSI) allows in vivo assessment of brain metabolism and is of special interest in multiple sclerosis (MS), where morphologic MRI cannot depict major parts of disease activity. Purpose To evaluate the ability of 7.0-T MRSI to depict and visualize pathologic alterations in the normal-appearing white matter (NAWM) and cortical gray matter (CGM) in participants with MS and to investigate their relation to disability. Materials and Methods Free-induction decay MRSI was performed at 7.0 T. Participants with MS and age- and sex-matched healthy controls were recruited prospectively between January 2016 and December 2017. Metabolic ratios were obtained in white matter lesions, NAWM, and CGM regions. Subgroup analysis for MS-related disability based on Expanded Disability Status Scale (EDSS) scores was performed using analysis of covariance. Partial correlations were applied to explore associations between metabolic ratios and disability. Results Sixty-five participants with MS (mean age ± standard deviation, 34 years ± 9; 34 women) and 20 age- and sex-matched healthy controls (mean age, 32 years ± 7; 11 women) were evaluated. Higher signal intensity of myo-inositol (mI) with and without reduced signal intensity of N-acetylaspartate (NAA) was visible on metabolic images in the NAWM of participants with MS. A higher ratio of mI to total creatine (tCr) was observed in the NAWM of the centrum semiovale of all MS subgroups, including participants without disability (marginal mean ± standard error, healthy controls: 0.78 ± 0.04; EDSS 0-1: 0.86 ± 0.03 [P = .02]; EDSS 1.5-3: 0.95 ± 0.04 [P < .001]; EDSS ≥3.5: 0.94 ± 0.04 [P = .001]). A lower ratio of NAA to tCr was found in MS subgroups with disabilities, both in their NAWM (marginal mean ± standard error, healthy controls: 1.46 ± 0.04; EDSS 1.5-3: 1.33 ± 0.03 [P = .03]; EDSS ≥3.5: 1.30 ± 0.04 [P = .01]) and CGM (marginal mean ± standard error, healthy controls: 1.42 ± 0.05; EDSS ≥3.5: 1.23 ± 0.05 [P = .006]). mI/NAA correlated with EDSS (NAWM of centrum semiovale: r = 0.47, P < .001; parietal NAWM: r = 0.43, P = .002; frontal NAWM: r = 0.34, P = .01; frontal CGM: r = 0.37, P = .004). Conclusion MR spectroscopic imaging at 7.0 T allowed in vivo visualization of multiple sclerosis pathologic findings not visible at T1- or T2-weighted MRI. Metabolic abnormalities in the normal-appearing white matter and cortical gray matter were associated with disability. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Barker in this issue.

Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI.

Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6-62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation period were 1 (0-7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34-88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.

Kurt Jellinger 90: his contribution to neuroimmunology.

This review honors Kurt Jellinger on his 90th birthday as one of the most outstanding neuropathologists, who has contributed immensely to neuroscience due to his vast experience and collection of excellently documented autopsy cases. Two of his many insightful reports are highlighted here. One report focuses on the pathogenesis of inflammatory demyelinating diseases and investigates the neuropathology in autopsy tissue of a patient, who developed an MS-like disease after repeated treatment with lyophilized bovine brain cells in 1958. More than 60 years later, after reinvestigation of the historic samples in 2015 and subsequent mRNA isolation, next generation sequencing and reconstruction of the antibody, we succeeded in identifying myelin oligodendrocyte glycoprotein (MOG) as the target antigen and provided the missing element between the pathomechanisms in classic EAE animal models and transfer of this disease process into humans. A second significant example of Kurt Jellinger's contribution to neuroscience was a report on the role of MS in the development of Alzheimer's disease (AD), which found that AD pathology is present to the same extent in demyelinated and non-demyelinated cortical areas in MS and the incidence for AD pathology in elderly MS patients is comparable to the normal-aging population. This indicates that chronic inflammation in the MS cortex alone does not significantly predispose to the development of cortical AD pathology. These and other findings were only possible due to the broad collection of extremely well-defined material established by Kurt Jellinger, which ultimately continues to contribute to translational neuroscience, even decades later.

Nabiximols discontinuation rate in a large population of patients with multiple sclerosis: a 18-month multicentre study.

INTRODUCTION: Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation. MATERIALS AND METHODS: This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline. RESULTS: A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months. DISCUSSION: THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.

Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study.

INTRODUCTION: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. MATERIALS AND METHODS: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. RESULTS: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. CONCLUSION: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients.

Do elevated autoantibodies in patients with multiple sclerosis matter?

OBJECTIVES: The incidence and clinical impact of serum autoantibodies in patients with multiple sclerosis (MS) are controversially discussed. The aim of the study was to reassess the value of elevated serum autoantibodies in our MS study cohort. MATERIAL & METHODS: In total, 176 MS patients were retrospectively analyzed for coexistence and clinical impact of increased serum autoantibody levels. RESULTS: The 18.8% of the MS cohort showed elevated serum autoantibody levels, but only 10.2% of all MS patients were diagnosed with a further autoimmune disease (AI). Patients with elevated serum autoantibodies (AABS) were not significantly more often diagnosed with a clinical manifest AI as compared to patients with negative autoantibodies (P = 0.338). MS patients with disease duration of more than 10 years showed no significant increase of positive autoantibodies as compared to patients with a more recent disease onset (P = 1). MS patients with elevated serum autoantibodies did not exhibit a significantly worse disease course (P = 0.428). CONCLUSIONS: According to our data, elevated serum autoantibodies do not have the potential to serve as a prognostic tool for disease severity in patients with MS Since MS patients with positive serum AABS did not significantly more often suffer from clinical manifest AIs than MS patients with negative serum AABS, the role of routine testing of serum AABS in MS patients should be critically called into question.

Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging.

In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions. We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims. Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages. Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging. In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence. Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques. Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes. Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible. Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003). We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003). Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS.

Epidemiology of Multiple Sclerosis in Austria.

BACKGROUND: To assess the incidence rate and prevalence ratio of multiple sclerosis (MS) in Austria. METHODS: Hospital discharge diagnosis and MS-specific immunomodulatory treatment prescriptions from public health insurances, covering 98% of Austrian citizens with health insurance were used to extrapolate incidence and prevalence numbers based on the capture-recapture method. RESULTS: A total of 1,392,629 medication prescriptions and 40,956 hospitalizations were extracted from 2 data sources, leading to a total of 13,205 patients. The incidence rate and prevalence ratio of MS in Austria based on the capture-recapture method were 19.5/100,000 person-years (95% CI 14.3-24.7) and 158.9/100,000 (95% CI 141.2-175.9), respectively. Female to male ratio was 1.6 for incidence and 2.2 for prevalence. CONCLUSIONS: Incidence rates and prevalence ratios of MS in our study are within the upper range of comparable studies across many European countries as well as the United States.

Veins in plaques of multiple sclerosis patients - a longitudinal magnetic resonance imaging study at 7 Tesla.

OBJECTIVE: To monitor the venous volumes in plaques of patients with multiple sclerosis (MS) compared to an age-matched control group over a period of 3.5 years. METHODS: Ten MS patients underwent an annual neurological examination and MRI. Susceptibility-weighted imaging (SWI) combined with fluid-attenuated inversion recovery (FLAIR) or FLAIR-like contrast at 7 Tesla (7 T) magnetic resonance imaging (MRI) was used for manual segmentation of veins in plaques, in the normal-appearing white matter (NAWM) and in location-matched white matter of 9 age-matched controls. Venous volume to tissue volume ratio was assessed for each time point in order to describe the dynamics of venous volumes in MS plaques over time. RESULTS: MS plaques, which were newly detected during the study period, showed significantly higher venous volumes compared to the preplaque area 1 year before plaque detection and the corresponding NAWM regions. Venous volumes in established MS plaques, which were present already in the first scans, were significantly higher compared to the NAWM and controls. CONCLUSIONS: Our data underpin a relation of veins and plaque development in MS and reflect increased apparent venous calibers due to increased venous diameters or increased oxygen consumption in early MS plaques. KEY POINTS: • Longitudinal 7 T Magnetic Resonance Imaging study of intralesional veins in MS patients. • Venous volumes are significantly increased in newly detected and established MS plaques. • Venous volumes in established MS plaques show a trend to decrease with time.