Summary
Data regarding effectiveness and safety of ocrelizumab in the post-marking setting are lacking. The aim of our study was to provide effectiveness and safety data of ocrelizumab treatment in ...patients with relapsing–remitting (RR-) and progressive multiple sclerosis (PMS) and to evaluate clinical and immunological predictors of early treatment response. In this single-center prospective observational study, we investigated effectiveness outcomes (time-to-confirmed disability worsening, time-to-first relapse, time-to-first evidence of MRI activity and time-to-first evidence of disease activity), clinical and immunological predictors of early treatment response, and incidence of adverse events (AEs). One hundred and fifty-three subjects were included (93 RRMS; 84 females). Median follow-up was 1.9 (1.3–2.7). At 2-year follow-up (FU), disability worsening-free survival were 90.5%, 64.7%, and 68.8% for RRMS, primary-progressive MS (PPMS), and secondary-progressive MS (SPMS) patients, respectively. At 2-year FU, 67.1%, 72.7%, and 81.3% of patients with RRMS, PPMS, and SPMS were free of MRI activity, with NEDA-3 percentages of 62.1%, 54.6%, and 55.1%, respectively. Lower baseline EDSS was independently associated with a reduced risk of disability worsening (HR(95%CI) = 1.45(1.05–2.00),
p
= 0.024) and previous treatment exposure was independently associated with increased probability of radiological activity (HR = 2.53(1.05–6.10),
p
= 0.039). At 6-month FU, CD8 + cell decrease was less pronounced in patients with inflammatory activity (
p
= 0.022). Six patients (3.9%) discontinued ocrelizumab due to severe AEs. Our findings suggest that ocrelizumab is an effective treatment in real-world patients with RRMS and PMS, with a manageable safety profile. Better outcomes were observed in treatment-naïve patients and in patients with a low baseline disability level. Depletion of CD8 + cells could underlie early therapeutic effects of ocrelizumab.
Isolated cognitive relapses (ICRs) are transient deficits in cognitive performance that are the only presentation of a multiple sclerosis (MS) relapse. Here, we evaluated the impact of ICRs on ...cognitive difficulties in daily activities (assessed with the Multiple Sclerosis Neuropsychological Screening Questionnaire, Informant Version (MSNQ-I)) to characterize ICRs’ clinical relevance. We used 2-year-long retrospective data to compare 15 relapsing-remitting MS (RRMS) patients with ICRs with 57 RRMS patients presenting an asymptomatic gadolinium enhancing lesion (and no-ICRs). ICRs were associated not only with neuropsychological performance decline but also with an increase in the daily cognitive difficulties. These findings support the ecological relevance of ICRs.
The management of multiple sclerosis patients with persistent disease activity under alemtuzumab treatment is not established yet. Concerns have been raised on the safety of autologous haematopoietic ...stem cell transplantation (aHSCT) after alemtuzumab treatment because of the risk of serious infectious adverse events. We report short-term safety and efficacy data from three patients treated with aHSCT following alemtuzumab treatment. Early adverse events were consistent with expected transplant toxicities. All patients were free of disease activity at the last follow-up. Our data suggest that aHSCT can be considered as a rescue treatment strategy for MS patients with persistent disease activity during alemtuzumab treatment.
Fast, accurate and reliable methods to quantify the amount of myelin still lack, both in humans and experimental models. The overall objective of the present study was to demonstrate that ...sphingomyelin (SM) in the cerebrospinal fluid (CSF) of patients affected by demyelinating neuropathies is a myelin biomarker. We found that SM levels mirror both peripheral myelination during development and small myelin rearrangements in experimental models. As in acquired demyelinating peripheral neuropathies myelin breakdown occurs, SM amount in the CSF of these patients might detect the myelin loss. Indeed, quantification of SM in 262 neurological patients showed a significant increase in patients with peripheral demyelination (p = 3.81 * 10 - 8) compared to subjects affected by non-demyelinating disorders. Interestingly, SM alone was able to distinguish demyelinating from axonal neuropathies and differs from the principal CSF indexes, confirming the novelty of this potential CSF index. In conclusion, SM is a specific and sensitive biomarker to monitor myelin pathology in the CSF of peripheral neuropathies. Most importantly, SM assay is simple, fast, inexpensive, and promising to be used in clinical practice and drug development.
Background:
The use of composite magnetic resonance imaging (MRI) measures has been suggested to better explain disability in patients with multiple sclerosis (MS). However, little is known about the ...utility of composite scores at the earliest stages of the disease.
Objective:
To investigate whether, in patients with clinically isolated syndrome (CIS), a composite MRI measure, rather than the single metrics, would explain conversion to MS and would better correlate with disability at baseline and at 1 year of follow-up.
Methods:
Corticospinal tract (CST), corpus callosum (CC) and optic radiation (OR) volume, fractional anisotropy (FA), and mean diffusivity (MD) values were measured in 27 CIS patients and 24 healthy controls (HCs). Z-scores of FA, MD, and tract volume measures were calculated in patients, based on the corresponding measures obtained from HCs, and then combined in a composite score for each tract. Correlations between Z-scores at baseline and both the Expanded Disability Status Scale (EDSS) at baseline and at follow-up (FU-EDSS) were investigated.
Results:
Only CST, CC, and OR composite scores as well as the CST volume were significantly associated with FU-EDSS (p = 0.005, p = 0.007, p = 0.020, and p = 0.010, respectively).
Conclusion:
The combination of MRI measures rather than the individual metrics better captured the association between tissue damage in both the CC, OR and CST and short-term follow-up disability.
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder. Since acetylcholine (ACh) is known to participate in the inflammatory response, we investigated the ...possible relationship between pro-inflammatory cytokines and acetylcholine levels in relapsing-remitting multiple sclerosis (RR-MS) patients. Levels of ACh and pro-inflammatory cytokines IL1-β and IL-17 were measured both in cerebrospinal fluid (CSF) and sera of 22 RR-MS patients in the relapsing phase and in 17 control subjects affected by other non-neurological diseases (OND). We observed higher levels of pro-inflammatory cytokines such as IL-1β and IL-17 in both CSF and serum of RR-MS patients compared to control subjects. Moreover, ACh levels were lower in CSF and serum of RR-MS patients compared to levels of control subjects. Although the relationship between high inflammatory cytokine levels and low ACh levels need to be further investigated in the future, our data suggest that IL-1β, and cytokines induced by it, such as IL-17 and ACh, may be involved in the pathogenesis of MS.
Background: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon ...proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides.
Objectives: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease.
Methods: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis).
Results: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing–remitting MS during relapses and in progressive MS patients, compared with relapsing–remitting MS patients during remissions and with non-inflammatory controls.
Conclusions: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.
To investigate prevalence of EMG patterns underlying hypertonia in multiple sclerosis (MS) and whether these patterns indicate different levels of spinal excitability.
We investigated the EMG ...activity recorded from 108 hypertonic muscles of 59 consecutive MS patients. To investigate spastic dystonia (SD), we looked for the presence of EMG activity in muscles in a resting position. To investigate dynamic stretch reflex (DSR) and static stretch reflex (SSR), we looked for the presence of EMG activity in response to a manually performed passive stretch of the muscle.
DSR was evoked in 104 muscles. In 51 muscles, DSR was the sole EMG activity. This pattern corresponds to the classical notion of spasticity, and was predominant in extensors. In contrast, SSR was detected in 48 muscles – predominantly in flexors. SD was observed in 28 muscles, showing even distribution in flexor and extensor muscles. Only in the flexors, SSR was associated with a larger DSR compared to spasticity.
These findings likely depend on the central effects of both flexor and extensor spindle afferents on the homonymous spinal motor neurons.
Improving our capacity to assess spinal excitability in MS patients.
The recruitment of lymphocytes across the blood brain barrier (BBB) is mediated by adhesion molecules and chemokines. The expression of activation markers and of chemokine receptors on T cells homing ...to the nervous system (NS) may help define their functional state. In the cerebrospinal fluid (CSF) of subjects with inflammatory neurological diseases (IND), including multiple sclerosis, we observed an increased number of T cells coexpressing CXCR3 and CCR5 as well as T cells with a CD45RO+ CCR7+ CD27+ memory phenotype. A subset of CCR7+ T cells coexpressed CXCR3 and CCR5. We also detected an increased number of interferon-gamma-producing T cells in the CSF compared with peripheral blood, mostly but not exclusively in the CD45RO+ CCR7- CD27- compartment. T helper 1 (Th1) clones, established from the CSF of individuals with IND and from a healthy subject, similarly migrated to CXCL10, CXCL12, and CCL5. CXCL10, CXCL12, and CCL19 were increased in the CSF of individuals with neuroinflammation. These findings suggest that CSF is enriched in Th1-polarized memory T cells capable of differentiating into effector cells upon antigen encounter. These cells are recruited into the CSF by inducible chemokines. Thus, CSF represents a transitional station for T cells trafficking to and from the NS.
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