Neurology. 2022 Jun 28;10.1212/WNL.0000000000200883. doi: 10.1212/WNL.0000000000200883. Online ahead of print.
Authors: Rachel C Kenney, Mengling Liu, Lisena Hasanaj, Binu Joseph, Abdullah Abu Al-Hassan, Lisanne J Balk, Raed
Behbehani, Alexander Brandt, Peter A Calabresi, Elliot Frohman, Teresa C Frohman, Joachim Havla, Bernhard Hemmer,
Hong Jiang, Benjamin Knier, Thomas Korn, Letizia Leocani, Elena Hernandez Martinez-Lapiscina, Athina Papadopoulou,
Friedemann Paul, Axel Petzold, Marco Pisa, Pablo Villoslada, Hanna Zimmermann, Lorna E Thorpe, Hiroshi Ishikawa, Joel
S Schuman, Gadi Wollstein, Yu Chen, Shiv Saidha, Steven Galetta, Laura J Balcer
Abstract
Background and objectives: Recent studies have suggested that inter-eye differences (IEDs) in peripapillary
retinal nerve fiber layer (pRNFL) or ganglion cell+inner plexiform (GCIPL) thickness by spectral-
domain optical coherence tomography (SD-OCT) may identify people with a history of unilateral
optic neuritis (ON). However, this requires further validation. Machine learning classification may be
useful for validating thresholds for OCT IEDs and for examining added utility for visual function tests,
such as low-contrast letter acuity (LCLA), in the diagnosis of people with multiple sclerosis (PwMS) and
for unilateral ON history.
Methods: Participants were from 11 sites within the International Multiple Sclerosis Visual System (IMSVISUAL)
consortium. pRNFL and GCIPL thicknesses were measured using SD-OCT. A composite score combining
OCT and visual measures was compared individual measurements to determine the best model
to distinguish PwMS from controls. These methods were also used to distinguish those with history of ON
among PwMS. ROC curve analysis was performed on a training dataset (2/3 of cohort), then applied to a
testing dataset (1/3 of cohort). Support vector machine (SVM) analysis was used to assess whether
machine learning models improved diagnostic capability of OCT.
Results: Among 1,568 PwMS and 552 controls, variable selection models identified GCIPL IED, average
GCIPL thickness (both eyes), and binocular 2.5% LCLA as most important for classifying PwMS vs. controls.
This composite score performed best, with AUC=0.89 (95% CI 0.85, 0.93), sensitivity=81% and
specificity=80%. The composite score ROC curve performed better than any of the individual measures
from the model (p<0.0001). GCIPL IED remained the best single discriminator of unilateral ON history
among PwMS (AUC=0.77, 95% CI 0.71,0.83, sensitivity=68%, specificity=77%). SVM analysis performed
comparably to standard logistic regression models.
Conclusions: A composite score combining visual structure and function improved the capacity of
SD-OCT to distinguish PwMS from controls. GCIPL IED best distinguished those with history of unilateral
ON. SVM performed as well as standard statistical models for these classifications.
Classification of evidence: The study provides Class III evidence that SD-OCT accurately distinguishes
multiple sclerosis from normal controls as compared to clinical criteria.
• PMID: 35764402
Curr Opin Neurol. 2022 Jun 1;35(3):319-327. doi: 10.1097/WCO.0000000000001066.
Authors: Maura Pugliatti, Thomas Berger, Hans-Peter Hartung, Celia Oreja-Guevara, Amit Bar-Or
Abstract
Purpose of review: As of January 21st 2022, over 340 million are confirmed cases of coronavirus disease
2019 (COVID-19), including nearly 5.6 million deaths. Severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) is neurotropic and affects the neural parenchyma through direct viral invasion from the nasal
mucosa and postinfectious cytokine storm. Further challenges of SARS-CoV-2 infection are nowadays linked
to variants of concern. Multiple sclerosis is an inflammatory and progressive degenerative disorder of the
central nervous system commonly affecting young adults and potentially generating irreversible disability.
Since the beginning of the SARS-CoV-2 pandemic, people with multiple sclerosis (pwMS) have been considered
'extra' vulnerable because of the immune-mediated nature of the disease, the disability status, and the
immunomodulatory therapies potentially increasing the risk for viral infection. Today multiple sclerosis
neurologists are faced with several challenges in the management of pwMS to both prevent SARS-CoV-2
infection and protection from disease worsening. We aimed to highlight today's most relevant facts about the
complex management of pwMS in the COVID-19 era.
Recent findings: The incidence of COVID-19 among pwMS does not differ from the general population. The
prognosis of COVID-19 among pwMS is driven by older age, male sex, nonambulatory status, comorbidity as
in the general population, as well as by corticosteroid treatment and B-cell depleting agents which decrease
seropositivity from SARS-CoV-2 infection and immune responses to SARS-CoV-2 vaccination.
Summary: Disease modifying treatments (DMTs) should be regularly continued in relation to SARS-CoV-2
vaccination, but an ad hoc timing is required with B-cell depleting agents. SARS-CoV-2 vaccination is recommended
in pwMS with willingness improving through health education programs. Multiple sclerosis does not
seem to worsen after SARS-Cov2 vaccination but COVID-19 may enhance disease activity.
• PMID: 35674075
PLoS One. 2022 Jun 29;17(6):e0264918. doi: 10.1371/journal.pone.0264918. eCollection 2022.
Authors: Eyal Raskin, Anat Achiron, Ofira Zloto, Ron Neuman, Vicktoria Vishnevskia-Dai
Abstract
Objectives: An association between uveitis and multiple sclerosis (MS) is well-established, but the actual
nature of that association remains poorly understood. We sought to determine the association between
the presence of a uveitis diagnosis prior to an MS diagnosis compared to no pre-existing uveitis diagnosis
in MS patients.
Methods: Patients in whom the presentation of uveitis preceded the presentation of MS (study group) and
patients with MS and no uveitis (control group) were randomly selected at a ratio of 1:3 from the Sheba
Multiple Sclerosis Center computerized database. Results: Eleven patients presented with uveitis prior to MS diagnosis (study group), and 31 randomly
selected patients had MS without uveitis (control group). Only one patient in the study group deteriorated
to EDSS 3 during the follow-up period, compared to 15 patients in the control group (9.1% vs 48.4%, P =
0.049). None of the patients in the study group reached EDSS 6 during the 10 years of follow-up compared
to 6 (19.4%) patients in the control group (P = 0.194).
Conclusions: MS patients who presented with uveitis that preceded their neurological symptoms of MS
demonstrated a clinically significant better neurological prognosis, than our MS patients with no uveitis.
• PMID: 35767533
J Neurol. 2022 Jun 27. doi: 10.1007/s00415-022-11227-3. Online ahead of print.
Authors: Miryam Cannizzaro, Laura Ferré, Ferdinando Clarelli, Antonino Giordano, Francesca Sangalli, Bruno Colombo,
Giancarlo Comi, Lucia Moiola, Vittorio Martinelli, Massimo Filippi, Federica Esposito
Abstract
Background: Multiple sclerosis (MS) is a chronic autoimmune disease with huge heterogeneity in terms of
clinical course, disease severity and treatment response. The need for a tailored treatment approach has
emerged over the last few years. The present observational study aims to assess fingolimod (FTY)
effectiveness in RRMS patients, stratifying them according to the disease-modifying treatments used before
FTY, to identify subjects who could benefit more from this treatment.
Methods: We prospectively included 554 RRMS patients who started FTY at San Raffaele Hospital between
2012 and 2018. We classified them into three categories according to previous treatments: naïve patients,
subjects previously treated with first-line drugs, and patients previously treated with second-line drugs. We
compared disease activity during a 2-years follow-up using No-Evidence-of-Disease-Activity (NEDA-3) and
Time-To-First-Relapse (TTFR) outcomes, applying logistic and Cox proportional hazard regression
respectively.
Results: The proportion of patients who maintained NEDA-3 status was higher in the naïve group despite a
higher level of baseline disease activity (naïve versus first-line p = 0.025, naïve versus second-line p < 0.001).
In the multivariable analyses, patients switching to FTY from first- and second-line treatments showed a
higher risk of disease reactivation (p = 0.041, OR = 1.86 and p = 0.002, OR = 2.92, respectively) and a shorter
TTFR (p = 0.017, HR = 4.35 and p = 0.001, HR = 8.19, respectively).
Conclusion: Naïve patients showed a better response to FTY compared to patients switching to FTY from
other drugs. Our findings support the early use of FTY in patients with active MS.
• PMID: 35759013
Eur J Neurol. 2022 Jun 25. doi: 10.1111/ene.15477. Online ahead of print.
Authors: Gabriel Bsteh, Hamid Assar, Christiane Gradl, Bettina Heschl, Maria-Sophie Hiller, Nik Krajnc, Franziska Di Pauli,
Harald Hegen, Gerhard Traxler, Fritz Leutmezer, Peter Wipfler, Gudrun Zulehner, Michael Guger, Christian Enzinger,
Thomas Berger, AUT-MuSC-19 investigators
Abstract
Background: Long-term outcome after COVID-19 in patients with multiple sclerosis (pwMS) is scarcely
studied and controlled data are lacking.
Objective: To compare long-term outcome after COVID-19 in pwMS to a matched control group of pwMS
without COVID-19.
Methods: We included pwMS with PCR-confirmed diagnosis of COVID-19 and ≥6 months of follow-up
available and, as a control group, pwMS matched 1:1 for age, sex, disability level and disease-modifying
treatment type.
Results: Of 211 pwMS with COVID-19 (mean age 42.6 years [SD 12.2], 69% female, median EDSS 1.5 [range:
0-7.5], 16% antiCD20), 90.5% initially had a mild COVID-19 course. At follow-up, 70% had recovered
completely 3 months (M3) after COVID-19, 83% after 6 months (M6) and 94% after 12 months (M12). Mild
initial COVID-19 course was the only significant predictor of complete recovery (odds ratio [OR]: 10.5;
p<0.001). Most frequent residual symptoms were fatigue (M3: 18.5%, M6: 13.7%, M12: 7.3%), hyposmia (M3:
13.7%, M6: 5.2%, M12: 1.7%) and dyspnea (M3: 7.1%, M6: 6.6%, M12: 2.8%). Compared to matched controls,
fatigue, hyposmia and dyspnea were significantly more frequent at M3 and still slightly at M6, while there was
no difference at M12. PwMS with COVID-19 had neither a significantly increased risk for relapses (OR 1.1;
p=0.70) nor disability worsening (OR 0.96; p=0.60).
Discussion: Long-term outcome of COVID-19 is favourable in a large majority of pwMS with only a small
proportion of patients suffering from persistent symptoms usually resolving after 3-6 months. COVID-19 is
not associated with increased risk of relapse or disability.
• PMID: 35751475
Ann Neurol. 2022 Jun 24. doi: 10.1002/ana.26448. Online ahead of print.
Authors: R Magliozzi, G Fadda, R A Brown, A Bar-Or, O W Howell, S Hametner, D Marastoni, A Poli, R Nicholas, M
Calabrese, S Monaco, R Reynolds
Abstract
Leptomeningeal and perivenular infiltrates are important contributors to cortical grey matter damage
and disease progression in multiple sclerosis (MS). While perivenular inflammation induces
vasculocentric lesions, leptomeningeal involvement follows a subpial 'surface-in' gradient. To determine
whether similar gradient of damage occurs in deep grey matter nuclei, we examined the dorsomedial thalamic nuclei and CSF samples from 41 post-mortem secondary progressive MS cases compared to 5
non-neurological controls and 12 controls with other neurological diseases. CSF/ependyma-oriented
gradient of reduction in NeuN+ neuron density was present in MS thalamic lesions compared to controls,
greatest (26%) in subventricular locations at the ependyma/CSF boundary and least with increasing
distance (12% at 10mm). Concomitant graded reduction in SMI31+ axon density was observed, greatest
(38%) at 2mm from the ependyma/CSF boundary and least at 10mm (13%). Conversely, gradient of
MHC-II+ microglia density increased by over 50% at 2 mm at the ependyma/CSF boundary and only by
15% at 10mm and this gradient inversely correlated with the neuronal (R=-0.91,p<0.0001) and axonal
(R=-0.79,p<0.0001) thalamic changes. Observed gradients were also detected in normal-appearing
thalamus and were associated with: rapid/severe disease progression; presence of leptomeningeal
tertiary lymphoid-like structures; large subependymal infiltrates, enriched in CD20+ B cells and
occasionally containing CXCL13+CD35+ follicular dendritic cells; and high CSF protein expression of a
complex pattern of soluble inflammatory/neurodegeneration factors, including chitinase-3-like-1,
TNFR-1, parvalbumin, neurofilament-light-chains and TNF. Substantial "ependymal-in" gradient of
pathological cell alterations, accompanied by presence of intrathecal inflammation, compartmentalized
either in sub-ependymal lymphoid perivascular infiltrates or in CSF, may play a key role in MS
progression. This article is protected by copyright. All rights reserved.
• PMID: 35748636
Eur J Neurol. 2022 Jun 23. doi: 10.1111/ene.15473. Online ahead of print.
Authors: S Denissen, D A Engemann, A De Cock, L Costers, J Baijot, J Laton , I K Penner, M Grothe, M Kirsch, M B D'hooghe,
M D'Haeseleer, D Dive, J De Mey, J Van Schependom, D M Sima, G Nagels
Abstract
Background: Data from neuro-imaging techniques allow us to estimate a brain's age. Brain age is easily
interpretable as "how old the brain looks", and could therefore be an attractive communication tool for brain
health in clinical practice. This study aimed to investigate its clinical utility by investigating the relationship
between brain age and cognitive performance in multiple sclerosis (MS).
Methods: A linear regression model was trained to predict age from brain MRI volumetric features and sex in
a healthy control dataset (HC_train, n=1673). This model was used to predict brain age in two test sets: HC_test
(n=50) and MS_test (n=201). Brain-Predicted Age Difference (BPAD) was calculated as BPAD=brain age minus
chronological age. Cognitive performance was assessed by the Symbol Digit Modalities Test (SDMT).
Results: Brain age was significantly related to SDMT scores in the MS_test dataset (r=-0.46, p<.001), and
contributed uniquely to variance in SDMT beyond chronological age, reflected by a significant correlation
between BPAD and SDMT (r=-0.24, p<.001) and a significant weight (-0.25, p=0.002) in a multivariate
regression equation with age.
Conclusions: Brain age is a candidate biomarker for cognitive dysfunction in MS and an easy to grasp metric
for brain health.
• PMID: 35737867
J Neurol. 2022 Jun 23. doi: 10.1007/s00415-022-11215-7. Online ahead of print.
Authors: Soizic Leguy, Mathilde Lefort, Lucile Lescot, Audrey Michaud, Sandra Vukusic, Emmanuelle Le Page, Gilles Edan,
Anne Kerbrat, Christine Lebrun-Frenay, Jérôme De Sèze, David-Axel Laplaud, Sandrine Wiertlewski, Emmanuelle Leray,
Laure Michel
Abstract
Background: No specific treatment has demonstrated its effectiveness to prevent post-partum relapses for
multiple sclerosis (MS) women.
Objective: To assess the effectiveness of preventive high-dose corticosteroids in the post-partum period by
comparing two strategies: (1) no preventive treatment and (2) standardized preventive treatment.
Methods: We selected five French Multiple Sclerosis centers using the same post-partum strategy for their
patients-either high-dose steroids (treating centers TC) or no treatment (non-treating centers NTC). We
included relapsing-remitting multiple sclerosis women who delivered between January 2007 and January
2017. Our primary outcomes were the time from delivery to first relapse, EDSS progression and MRI activity
between patients of treating centers and non-treating centers, after propensity-score weighting.
Results: 350 patients were included (116 from treating centers, 234 from non-treating centers). For both
groups, the annualized relapse rate decreased during pregnancy (0.28 in treating centers and 0.34 in
non-treating centers during the third trimester) and increased during the first post-partum trimester (0.45 and
0.69, respectively) with 11% and 14% (NS) of patients facing at least one relapse, respectively. Our primary
outcomes were not statistically different between both groups.
Conclusion: This study provides class III evidence that systematic high-dose corticosteroids are not
associated with a reduced inflammatory activity during the post-partum period in multiple sclerosis patients.
• PMID: 35737108
CNS Drugs. 2022 Jun 20. doi: 10.1007/s40263-022-00927-z. Online ahead of print.
Authors: Stanley L Cohan, Ralph H B Benedict, Bruce A C Cree, John DeLuca, Le H Hua, Jerold Chun
Abstract
Siponimod is a selective sphingosine 1-phosphate receptor subtype 1 (S1P1) and 5 (S1P5) modulator
approved in the United States and the European Union as an oral treatment for adults with relapsing forms of
multiple sclerosis (RMS), including active secondary progressive multiple sclerosis (SPMS). Preclinical and
clinical studies provide support for a dual mechanism of action of siponimod, targeting peripherally
mediated inflammation and exerting direct central effects. As an S1P1 receptor modulator, siponimod
reduces lymphocyte egress from lymph nodes, thus inhibiting their migration from the periphery to the
central nervous system. As a result of its peripheral immunomodulatory effects, siponimod reduces both
magnetic resonance imaging (MRI) lesion (gadolinium-enhancing and new/enlarging T2 hyperintense) and
relapse activity compared with placebo. Independent of these effects, siponimod can penetrate the blood-brain barrier and, by binding to S1P1 and S1P5 receptors on a variety of brain cells, including
astrocytes, oligodendrocytes, neurons, and microglia, exert effects to modulate neural inflammation and
neurodegeneration. Clinical data in patients with SPMS have shown that, compared with placebo, siponimod
treatment is associated with reductions in levels of neurofilament light chain (a marker of neuroaxonal
damage) and thalamic and cortical gray matter atrophy, with smaller reductions in MRI magnetization transfer
ratio and reduced confirmed disability progression. This review examines the preclinical and clinical data
supporting the dual mechanism of action of siponimod in RMS.
• PMID: 35725892
J Neurol. 2022 Jun 19. doi: 10.1007/s00415-022-11205-9. Online ahead of print.
Authors: Brian M Sandroff, Robert W Motl, Cristina A F Román, Glenn R Wylie, John DeLuca, Gary R Cutter, Ralph H B
Benedict, Michael G Dwyer, Robert Zivadinov
Abstract
Background and objectives: Thalamic atrophy (TA) represents a biomarker of neurodegeneration and
associated dysfunction/decline in physical and cognitive functioning among persons with multiple sclerosis
(MS). Aerobic fitness, as an end point of exercise training, represents a promising target for restoring function
in MS, but it is unknown if such effects differ by TA. This cross-sectional study examined whether aerobic
fitness was differentially associated with cognitive processing speed and walking endurance in persons with
MS who present with and without TA.
Methods: 44 fully ambulatory persons with MS completed a graded exercise test for measuring aerobic
fitness (VO2peak) and underwent 3T MRI for measuring TA, the Symbol Digit Modalities Test (SDMT), and the
6-min walk (6MW). We performed Spearman correlations (rs) among VO2peak, SDMT, and 6MW scores overall,
and in persons with and without TA. We applied Fisher's z-test for comparing correlations based on TA status.
Results: When controlling for age, EDSS score, and global MRI measures of atrophy, VO2peak was strongly
associated with SDMT scores (prs = 0.74, p < 0.01) and 6MW performance (prs = 0.77, p < 0.01) in persons
with TA, whereas VO2peak was not associated with SDMT scores (prs = - 0.01, p = 0.99) or 6MW performance
(prs = 0.25, p = 0.38) in those without TA. The correlations between VO2peak and SDMT (z = 2.86, p < 0.01) and
VO2peak and 6MW (z = 2.33, p = 0.02) were significantly stronger in the TA group.
Discussion: This study provides initial evidence of strong, selective associations among aerobic fitness,
cognitive processing speed, and walking endurance in persons with TA as a biomarker for MS-related
neurodegeneration. Such data support TA as a moderator of the association among aerobic fitness, cognitive
processing speed, and walking endurance in persons with MS. Future research should carefully consider the
role of TA when designing trials of aerobic exercise, cognition, and mobility in MS.
• PMID: 35718819
J Neurol Sci. 2022 Jun 13;439:120320. doi: 10.1016/j.jns.2022.120320. Online ahead of print.
Authors: Simone Hjæresen, Tobias Sejbaek, Markus Axelsson, Sif Kløvedal Mortensen, Helle Vinsløv-Jensen, Gorm
Pihl-Jensen, Lenka Novakova, Christian Bonde Pedersen, Bo Halle, Frantz Rom Poulsen, Mengliang Zhang, Eirikur
Benedikz, Jette Lautrup Frederiksen, Jan Lycke, Zsolt Illes, Åsa Fex-Svenningsen
Abstract
Background: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate
and adaptive immune systems and in neuroprotection and has recently been implicated in multiple
sclerosis (MS).
Objectives: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct
subtypes of MS and the cellular localization of MIF in human brain tissue.
Methods: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS)
(n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy
controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS
cohorts were examined. Cellular distribution of MIF in the human brain was studied using
immunochemistry and the newly available OligoInternode database.
Results: MIF was significantly decreased in treatment-naïve CIS and RRMS patients compared to HCs but
was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly higher in women
with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes,
and oligo5 oligodendrocytes but not in microglia.
Conclusion: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was
high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor
expression that affects the overall MIF signaling in the brain and may represent a protective mechanism
that eventually fails.
• PMID: 35717879
Eur J Neurol. 2022 Jun 18. doi: 10.1111/ene.15453. Online ahead of print.
Authors: Frauke Stascheit , Anne Rübsam, Carolin Otto, Andreas Meisel, Klemens Ruprecht, Uwe Pleyer
Abstract
Background: About 1% of patients with multiple sclerosis (MS) suffer from uveitis, but data on the effects
of immunotherapies for MS on MS-associated uveitis are scarce.
Objective: To investigate the ophthalmological outcomes in patients with MS-associated uveitis treated
with anti-CD20 therapy.
Methods: Retrospective study of 12 eyes of 6 patients with MS-associated uveitis, refractory to previous
immunotherapies. Uveitis activity was assessed before initiation of anti-CD20 therapy and at regular follow-up visits. Primary outcome measures were vitreous haze score, retinal vasculitis score determined
on fluorescein angiography images, macular edema as quantified by central retinal thickness (CRT) on
optical coherence tomography, and visual acuity. Secondary outcomes included the number of
annualized uveitis or MS relapses, disease activity on cerebral magnetic resonance imaging (cMRI) and
the expanded disability status scale (EDSS).
Results: After a median (IQR) treatment time of 28.5 (8-43) months, anti-CD20 therapy was associated
with an improvement of vitreous haze score (p=0.002), retinal vasculitis score (p=0.001), CRT (p=0.002),
and visual acuity (p=0.007). The median (IQR) annualized uveitis relapse rate declined from 0.59
(0.56-0.94) before to 0 (0-0.49) after the start of anti-CD20 therapy. The median (IQR) annualized MS
relapse rate declined from 0.62 (0.26-2.84) before to 0 (0-0) after the start of anti-CD20 therapy. After
initiation of anti-CD20 therapy, there was no disease activity on cMRI and the EDSS improved (n=2) or
remained stable (n=4). No severe adverse events were observed.
Conclusion: These findings suggest that anti-CD20 therapy may be a valuable treatment option for
MS-associated uveitis.
• PMID: 35716269
Neurol Sci. 2022 Jun 17. doi: 10.1007/s10072-022-06197-3. Online ahead of print.
Authors: Katarzyna Śladowska, Paweł Kawalec, Przemysław Holko, Oktawia Osiecka
Abstract
Objective: This study aimed to compare the safety profile of high-efficacy disease-modifying therapies (DMTs)
natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, as well as a potentially
high-efficacy DMT, ponesimod, in adult patients with relapsing-remitting multiple sclerosis (RRMS).
Methods: A systematic review with frequentist network meta-analysis (NMA) was performed according to the
Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We included
randomized controlled trials (RCTs) with at least 48-week follow-up investigating the use of natalizumab,
fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, and ponesimod, as well as other
DMTs, in adult patients with RRMS. Eligible studies were identified by two reviewers in MEDLINE (via PubMed),
EMBASE, and Cochrane Library. The Cochrane Collaboration tool to assess the risk of bias for RCTs was used.
Results: A total of 33 RCTs were included in the systematic review and NMA. A higher rate of adverse events
(AEs) was revealed for alemtuzumab versus all other high-efficacy DMTs; for alemtuzumab (average probability
of an event: 98.2%) versus placebo (86.2%); for cladribine (3.5 mg; 90.5%) versus ozanimod (1 mg; 84.2%) and
placebo; as well as for ocrelizumab (95.5%) versus ozanimod, ofatumumab (88.9%), fingolimod (87.4%),
natalizumab (82.8%), and placebo. No significant differences were found between drugs in terms of serious AEs
except for cladribine (3.5 mg, 17.3%) versus ocrelizumab (10.3%) and ofatumumab (16.6%) versus ocrelizumab.
Significant differences in AEs leading to the discontinuation of study drug were found only for ponesimod
(10.1%) versus alemtuzumab (12 mg, 3.0%) and placebo (4.2%). No differences were found in terms of upper
respiratory tract infections, nasopharyngitis, fatigue, and nausea between individual high-efficacy DMTs as well
as between DMTs and placebo. The results of the NMA indicated a higher risk of infections for alemtuzumab (12 mg) versus ocrelizumab, for cladribine (3.5 mg) versus ofatumumab and placebo, and for ofatumumab versus
placebo. For serious infections and urinary tract infections, a significant increase was found only for
alemtuzumab (12 mg) versus ocrelizumab, while no differences were found between the other DMTs or between
DMTs and placebo. Headache was more common for alemtuzumab (12 mg) as compared with all the other
high-efficacy DMTs and placebo, as well as for cladribine versus natalizumab and fingolimod versus natalizumab.
Conclusion: The commonly reported AEs are generally similar among high-efficacy DMTs. However, based on
P scores for most analyzed endpoints, natalizumab and ocrelizumab were shown to be the safest DMTs.
Considering the limitations of indirect comparisons, further research is needed to confirm our findings,
preferably head-to-head RCTs and large observational studies.
• PMID: 35713731
Ann Neurol. 2022 Jun 17. doi: 10.1002/ana.26441. Online ahead of print.
Authors: Reza Rahmanzadeh, Riccardo Galbusera, Po-Jui Lu, Erik Bahn, Matthias Weigel, Muhamed Barakovic , Jonas
Franz, Thanh D Nguyen, Pascal Spincemaille, Simona Schiavi, Alessandro Daducci, Francesco La Rosa, Martina Absinta,
Pascal Sati, Meritxell Bach Cuadra, Ernst-Wilhelm Radue, David Leppert, Jens Kuhle, Ludwig Kappos, Wolfgang Brück,
Daniel S Reich, Christine Stadelmann, Yi Wang, Cristina Granziera
Abstract
Objectives: Neuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in
terms of myelin/axon damage and repair as well as iron content. However, it remains a challenge to identify
specific chronic lesion types, especially remyelinated lesions, in vivo in MS patients.
Methods: We performed three studies: (i) a cross-sectional study in a prospective cohort of 115 MS patients
and 76 healthy controls, who underwent 3T MRI for Quantitative susceptibility mapping (QSM), myelin water
fraction (MWF), neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into five
QSM lesion types (isointense, hypointense, hyperintense, lesions with hypointense rims, and lesions with
paramagnetic rims (PRL)); (ii) a longitudinal study of 40 MS patients to study the evolution of lesions over 2
years; (iii) a postmortem histopathology-QSM validation study in three MS brains to assess the accuracy of
QSM classification to identify neuropathological lesion types in 63 WM lesions.
Results: At baseline, hypo- and isointense lesions showed higher mean MWF and NDI values compared to
other QSM lesion types (P<0.0001). Further, at 2-year follow-up hypo-/ iso-intense lesions showed an increase
in MWF. Post-mortem analyses revealed that QSM highly accurately identifies (i) fully remyelinated areas as
hypo-/iso-intense (sensitivity: 88.89%, specificity: 100%) (ii) chronic inactive lesions as hyperintense
(sensitivity: 71.43%, specificity: 92.00%) and (iii) chronic active/smoldering lesions as PRLs (sensitivity:
92.86%, specificity: 86.36%).
Interpretation: These results provide the first evidence that it is possible to distinguish chronic MS lesions in
a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments.
This article is protected by copyright. All rights reserved.
• PMID: 35713309
J Neurol Neurosurg Psychiatry. 2022 Jun 16;jnnp-2022-329221. doi: 10.1136/jnnp-2022-329221. Online ahead of print.
Authors: Ahmed Abdelhak, Christian Cordano, W John Boscardin, Eduardo Caverzasi, Jens Kuhle, Brandon Chan,
Jeffrey M Gelfand, Hao H Yiu, Frederike C Oertel, Alexandra Beaudry-Richard, Shivany Condor Montes, Jorge R Oksenberg,
Argentina Lario Lago, Adam Boxer, Julio C Rojas-Martinez, Fanny M Elahi, Jonah R Chan, Ari J Green
Abstract
Background: Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS).
Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study
showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS)
with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with
neuroprotection remains unexplored.
Methods: Plasma neurofilament light chain (NfL) levels were measured from ReBUILD trial's participants. Mixed
linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL
concentrations between samples collected during the active and placebo treatment period.
Results: NfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine
(n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00
pg/mL) (B=-0.035 [-0.068 to -0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores
and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher
NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In
addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values
(B=0.003 [-0.0004 to 0.007], p=0.081). Based on a Cohen's d of 0.248, a future 1:1 parallel-arm
placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202
subjects per group to achieve 80% power.
Conclusions: In pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of
blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination.
Trial registration number: NCT02040298.
• PMID: 35710320
Eur J Neurol. 2022 Jun 14. doi: 10.1111/ene.15445. Online ahead of print.
Author: Adriana L Ruiz-Rizzo, Peter Bublak, Steffen Kluckow, Kathrin Finke, Christian Gaser, Matthias Schwab, Daniel Güllmar,
Hermann J Müller, Otto W Witte, Sven Rupprecht
Abstract
Background and purpose: Fatigue and low sleep quality in multiple sclerosis (MS) are closely related
symptoms. Here, the associations between the brain's functional connectivity (FC) and fatigue and low sleep
quality were investigated to determine the degree of neural distinctiveness of these symptoms.
Method: A hundred and four patients with relapsing-remitting MS (age 38.9 ± 10.2 years, 66 females) completed the Modified Fatigue Impact Scale and the Pittsburgh Sleep Quality Index and underwent
resting-state functional magnetic resonance imaging. FC was analyzed using independent-component
analysis in sensorimotor, default-mode, fronto-parietal and basal-ganglia networks. Multiple linear regression
models allowed us to test the association between FC and fatigue and sleep quality whilst controlling for one
another as well as for demographic, disease-related and imaging variables.
Results: Higher fatigue correlated with lower sleep quality (r = 0.54, p < 0.0001). Higher fatigue was associated
with lower FC of the precentral gyrus in the sensorimotor network, the precuneus in the posterior default-mode
network and the superior frontal gyrus in the left fronto-parietal network, independently of sleep quality. Lower
sleep quality was associated with lower FC of the left intraparietal sulcus in the left fronto-parietal network,
independently of fatigue. Specific associations were found between fatigue and the sensorimotor network's
global FC and between low sleep quality and the left fronto-parietal network's global FC.
Conclusion: Despite the high correlation between fatigue and low sleep quality in the clinical picture, our
findings clearly indicate that, on the neural level, fatigue and low sleep quality in MS are associated with
decreased FC in distinct functional brain networks.
• PMID: 35699354
Nat Rev Neurol. 2022 Jun 13. doi: 10.1038/s41582-022-00675-0. Online ahead of print.
Authors: Jiwon Oh , Amit Bar-Or
Abstract
The rapidly evolving therapeutic landscape of multiple sclerosis (MS) has contributed to paradigm shifts in
our understanding of the biological mechanisms that contribute to CNS injury and in treatment philosophies.
Opportunities remain to further improve treatment of relapsing-remitting MS, but two major therapeutic
gaps are the limiting of progressive disease mechanisms and the repair of CNS injury. In this Review, we
provide an overview of selected emerging therapies that predominantly target processes within the CNS that
are thought to be involved in limiting non-relapsing, progressive disease injury or promoting tissue repair.
Among these, we consider agents that modulate adaptive and innate CNS-compartmentalized inflammation,
which can be mediated by infiltrating immune cells and/or resident CNS cells, including microglia and
astrocytes. We also discuss agents that target degenerative disease mechanisms, agents that might confer
neuroprotection, and agents that create a more favourable environment for or actively contribute to
oligodendrocyte precursor cell differentiation, remyelination and axonal regeneration. We focus on agents
that are novel for MS, that are known to or are presumed to penetrate the CNS, and that have already entered
early stages of development in MS clinical trials.
• PMID: 35697862
J Neuroimmunol. 2022 Jun 2;369:577904. doi: 10.1016/j.jneuroim.2022.577904. Online ahead of print.
Authors: Fiona Chan, D Sean Riminton, Sudarshini Ramanathan, Stephen W Reddel, Todd A Hardy
Abstract
Neurosarcoidosis is an important diagnosis to exclude in the work-up for suspected multiple sclerosis (MS).
The distinction between the two conditions is usually possible due to characteristic clinical manifestations,
magnetic resonance imaging (MRI) findings, and the results of other supportive investigations such as
CT-PET. Definitive diagnosis can be made by histopa thological examination, but this is not always practical.
Misdiagnosis can occur when the clinical characteristics and MRI findings of both conditions overlap. Those
patients with characteristic findings of MS but extraneural histopathological evidence of sarcoidosis are a
particularly difficult diagnostic group. Diagnostic clarity is essential to inform treatment, especially as certain
treatments for one disorder can exacerbate the other. This article summarises the clinical, laboratory and
radiological findings that aid the clinician in distinguishing between the two conditions. It also discusses the
literature on the potential for sarcoidosis and MS to co-exist in some patients, and how to approach the
treatment of these "overlap" patients.
• PMID: 35689980
J Neurol Sci. 2022 Jun 2;439:120306. doi: 10.1016/j.jns.2022.120306. Online ahead of print.
Authors: Marcello Moccia, Antonio Riccardo Buonomo, Riccardo Scotto, Giulio Viceconte, Mariano Nobile, Roberta
Lanzillo, Vincenzo Brescia Morra, Ivan Gentile, on the behalf of the Federico II COVID-19 Team
Abstract
We reported on five people with MS, using immunodepleting disease modifying treatments (anti-CD20
monoclonal antibodies and sphingosine-one-phosphate modulators) and with reduced COVID-19 vaccine
response, who had mild-to-moderate symptomatic COVID-19, and were treated with anti-SARS-CoV-2
monoclonal antibodies. In particular, we showed the possibility to use monoclonal antibodies to speed-up
recovery from COVID-19 in MS, in the absence of any COVID-19 residuals or MS changes (e.g., relapses or
disability).
• PMID: 35689866
J Neurol Neurosurg Psychiatry. 2022 Jun 10;jnnp-2022-329058. doi: 10.1136/jnnp-2022-329058. Online ahead of print.
Authors: Malthe Faurschou Wandall-Holm, Mathias Due Buron, Tine Iskov Kopp, Karsten Thielen, Finn Sellebjerg,
Melinda Magyari
Abstract
Background: Initiation of disease-modifying therapy early in the disease course of relapsing-remitting multiple
sclerosis (RRMS) has demonstrated beneficial effects on clinical outcomes, but socioeconomic outcomes remain
largely unexplored.
Objective: To investigate the association between the delay from disease onset to first treatment and the hazard
of disability pension.
Methods: We performed a population-based cohort study with data from the nationwide Danish Multiple
Sclerosis Registry and Danish nationwide registries. Patients with a disease onset between 1 January 1996 to 5 April
2016 were followed until disability pension or a competing risk/censoring event. 7859 patients were assessed for
eligibility of which 5208 were included in the final cohort. Key inclusion criteria were: a diagnosis of multiple
sclerosis, relapsing-remitting phenotype, treatment in history, age 18-65 years and an Expanded Disability Status
Scale≤4. Patients were categorised according to time from onset to first treatment: within 1 year (early), between 1
and 4 years (intermediate) and from 4 to 8 years (late).
Results: Of the 5208 patients, 1922 were early, 2126 were intermediate and 1160 were late. Baseline clinical and
socioeconomic variables were well balanced. The hazard of receiving disability pension increased with increasing
delay of treatment initiation compared with the early group. Cox regression estimates adjusted for clinical and
socioeconomic confounders: intermediate (HR, 1.37; 95% CI, 1.12 to 1.68) and late (HR, 1.97; 95% CI, 1.55 to 2.51).
Conclusion: Early treatment initiation is associated with a reduced risk of disability pension in patients with RRMS.
This finding underlines the importance of early diagnosis and treatment on a patient-centred, socioeconomic
disability milestone.
• PMID: 35688630
J Neurol Neurosurg Psychiatry. 2022 Jun 10;jnnp-2022-329123. doi: 10.1136/jnnp-2022-329123. Online ahead of print.
Authors: Masoud Etemadifar, Hosein Nouri, Maristella Pitzalis, Maria Laura Idda, Mehri Salari, Mahshid Baratian, Sepide
Mahdavi, Amir Parsa Abhari, Nahad Sedaghat
Abstract
Studies among people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have
provided adequate evidence for an appraisal of COVID-19 vaccination policies among them. To synthesise the
available evidence addressing the effect of MS DMTs on COVID-19 vaccines' immunogenicity and effectiveness,
following the Cochrane guidelines, we systematically reviewed all observational studies available in MEDLINE,
Scopus, Web of Science, MedRxiv and Google Scholar from January 2021 to January 2022 and extracted their
relevant data. Immunogenicity data were then synthesised in a quantitative, and other data in a qualitative manner. Evidence from 28 studies suggests extensively lower B-cell responses in sphingosine-1-phosphate
receptor modulator (S1PRM) treated and anti-CD20 (aCD20) treated, and lower T-cell responses in
interferon-treated, S1PRM-treated and cladribine-treated pwMS-although most T cell evidence currently
comprises of low or very low certainty. With every 10-week increase in aCD20-to-vaccine period, a 1.94-fold
(95% CI 1.57 to 2.41, p<0.00001) increase in the odds of seroconversion was observed. Furthermore, the
evidence points out that B-cell-depleting therapies may accelerate postvaccination humoral waning, and
boosters' immunogenicity is predictable with the same factors affecting the initial vaccination cycle. Four
real-world studies further indicate that the comparative incidence/severity of breakthrough COVID-19 has been
higher among the pwMS treated with S1PRM and aCD20-unlike the ones treated with other DMTs. S1PRM and
aCD20 therapies were the only DMTs reducing the real-world effectiveness of COVID-19 vaccination among
pwMS. Hence, it could be concluded that optimisation of humoral immunogenicity and ensuring its durability
are the necessities of an effective COVID-19 vaccination policy among pwMS who receive DMTs.
• PMID: 35688629
AJNR Am J Neuroradiol. 2022 Jun 9. doi: 10.3174/ajnr.A7536. Online ahead of print.
Authors: M Tranfa, G Pontillo, M Petracca, A Brunetti, E Tedeschi, G Palma, S Cocozza
Abstract
Quantitative MR imaging techniques allow evaluating different aspects of brain microstructure, providing
meaningful information about the pathophysiology of damage in CNS disorders. In the study of patients with
MS, quantitative MR imaging techniques represent an invaluable tool for studying changes in myelin and iron
content occurring in the context of inflammatory and neurodegenerative processes. In the first section of this
review, we summarize the physics behind quantitative MR imaging, here defined as relaxometry and
quantitative susceptibility mapping, and describe the neurobiological correlates of quantitative MR imaging
findings. In the second section, we focus on quantitative MR imaging application in MS, reporting the main
findings in both the gray and white matter compartments, separately addressing macroscopically damaged
and normal-appearing parenchyma.
• PMID: 35680161
Curr Opin Neurol. 2022 Jun 1;35(3):313-318. doi: 10.1097/WCO.0000000000001062.
Authors: Svetlana Bezukladova, Angela Genchi, Paola Panina-Bordignon, Gianvito Martino
Abstract
Purpose of the review: Despite the significant progress in the development of disease-modifying
treatments for multiple sclerosis (MS), repair of existing damage is still poorly addressed. Current research
focuses on stem cell-based therapies as a suitable alternative or complement to current drug therapies.
Recent findings: Myelin damage is a hallmark of multiple sclerosis, and novel approaches leading to remyelination represent a promising tool to prevent neurodegeneration of the underlying axon. With
increasing evidence of diminishing remyelination capacity of the MS brain with ageing and disease
progression, exogenous cell transplantation is a promising therapeutic approach for restoration of
oligodendrocyte precursor cell pool reserve and myelin regeneration.
Summary: The present review summarizes recent developments of remyelinating therapies in multiple
sclerosis, focusing on exogenous cell-based strategies and discussing related scientific, practical, and ethical
concerns.
• PMID: 35674074
Curr Opin Neurol. 2022 Jun 1;35(3):307-312. doi: 10.1097/WCO.0000000000001064.
Authors: Catherine Lubetzki, Bernard Zalc, David Kremer, Patrick Küry
Abstract
Purpose of review: The introduction some 30 years ago of β-interferon, followed by a panel of
immunomodulators and immunosuppressants has led to a remarkable improvement in the management
of multiple sclerosis (MS) patients. Despite these noticeable progresses, which lower the number of
relapses and thereby ameliorate patients' quality of life, preventing long-term progression of disability
is still an unmet need, highlighting the necessity to develop therapeutic strategies aimed at repairing
demyelinated lesions and protecting axons from degeneration. The capacity of human brain to
self-regenerate demyelinated lesion has opened a field of research aimed at fostering this endogenous
potential.
Recent findings: The pioneer electron microscopic evidence by Périer and Grégoire [Périer O, Grégoire
A. Electron microscopic features of multiple sclerosis lesions. Brain 1965; 88:937-952] suggesting the
capacity of human brain to self-regenerate demyelinated lesion has opened a field of research aimed at
fostering this endogenous potential. Here we review some recently identified mechanisms involved in
the remyelination process, focusing on the role of electrical activity and the involvement of innate
immune cells. We then provide an update on current strategies promoting endogenous myelin repair.
Summary: Identification of therapeutic targets for remyelination has opened an active therapeutic field
in MS. Although still in early phase trials, with heterogenous efficacy, the door for myelin regeneration in
MS is now opened.
• PMID: 35674073
Curr Opin Neurol. 2022 Jun 1;35(3):299-306. doi: 10.1097/WCO.0000000000001045.
Authors: Laura Airas, V Wee Yong
Abstract
Purpose of review: Microglia normally protects the central nervous system (CNS) against insults. However,
their persistent activation in multiple sclerosis (MS) contributes to injury. Here, we review microglia activation
in MS and their detection using positron emission tomography (PET).
Recent findings: During lesion evolution and the progression of MS, microglia activity may contribute to
neurotoxicity through the release of pro-inflammatory cytokines, reactive oxidative species, proteases and
glutamate. A means to detect and monitor microglia activation in individuals living with MS is provided by
positron emission tomography (PET) imaging using the mitochondrial 18-kDa translocator protein (TSPO)
ligand. TSPO PET imaging shows increased microglial activation within the normal appearing white matter
that precedes radiological signs of neurodegeneration measured by T2 lesion enlargement. PET-detected
microglia activation increases with progression of MS. These findings demand the use of CNS penetrant
inhibitors that affect microglia. Such therapies may include hydroxychloroquine that is recently reported in a
small study to reduce the expected progression in primary progressive MS, and Bruton's tyrosine kinase
inhibitors for which there are now eleven Phase 3 registered trials in MS.
Summary: Microglial activation drives injury in MS. PET imaging with microglia-specific ligands offer new
insights into progression of MS and as a monitor for treatment responses.
• PMID: 35674072
Curr Opin Neurol. 2022 Jun 1;35(3):293-298. doi: 10.1097/WCO.0000000000001044.
Authors: Stefan Bittner, Frauke Zipp
Abstract
Purpose of review: Disability progression in multiple sclerosis (MS) is strongly linked to central nervous
system (CNS)-specific pathological processes that occur throughout all disease stages, but that become
clinically evident in later phases of the disease. We here discuss current views and concepts for targeting
progressive MS.
Recent findings: Detailed clinical assessment of MS patients has identified an even closer entanglement of
relapse-remitting and progressive disease, leading to novel concepts such as 'progression independent of
relapse activity'. Evolving clinical concepts together with a focus on molecular (neurofilament light chain) and
imaging (paramagnetic rim lesions) biomarkers might specifically identify patients at risk of developing
progressive MS considerably earlier than before. A multitude of novel treatment approaches focus either on
direct neuroaxonal protection or myelin regeneration or on beneficially modulating CNS-intrinsic or innate
immune inflammation. Although some long-awaited trials have recently been unsuccessful, important
lessons could still be drawn from novel trial designs providing frameworks for future clinical studies. Summary: Targeting progressive disease biology and repairing established damage is the current central
challenge in the field of MS. Especially, the compartmentalized adaptive and innate CNS inflammation is an
attractive target for novel approaches, probably as a combinatory approach together with neuroprotective or
myelin regenerating strategies.
• PMID: 35674071
Curr Opin Neurol. 2022 Jun 1;35(3):286-292. doi: 10.1097/WCO.0000000000001058.
Authors: Krzysztof W Selmaj, Marcin P Mycko, Roberto Furlan, Konrad Rejdak
Abstract
Purpose of review: Multiple sclerosis (MS) is highly heterogenic disorder with respect to clinical course,
diagnosis, and treatment response. There is an urgent need to search for simply and reliable fluid body
biomarker which would assist the diagnosis and pr ediction of clinical and treatment prognosis.
Recent findings: 'Traditional' MS biomarkers, with exception of cerebrospinal fluid oligoclonal bands,
still are having limited clinical value. Therefore, there is growing interest in novel molecules and
ingredients. The most robust results have been generated with regard to cerebrospinal fluid and serum
levels of neurofilament light chains (NfL). However, there are still some limitations related to specificity of
NfL which delays its use in everyday practice. We present a new approach to search for biomarkers
involving extracellular RNA, particularly microRNA (miRNA), and small extracellular vesicles. MiRNA
represents an important molecular mechanism influencing gene expression, including those involved in
MS pathogenesis and extracellular vesicles transfer multiple cargo, including myelin molecules from
parental cells of central nervous system to the long-distance targets.
Summary: MiRNAs which control gene expression in cells involved in autoimmune processes in MS as
well as extracellular vesicles transferring myelin content might generate a new promising categories of
biomarkers of MS.
• PMID: 35674070
Curr Opin Neurol. 2022 Jun 1;35(3):271-277. doi: 10.1097/WCO.0000000000001057.
Authors: Maria Trojano, Tomas Kalincik, Pietro Iaffaldano, Maria P Amato
Abstract
Purpose of review: Although substantial progress has been made in understanding the natural history
of multiple sclerosis (MS) and the development of new therapies, many questions concerning disease
behavior and therapeutics remain to be answered. Data generated from real-world observational studies, based on large MS registries and databases and analyzed with advanced statistical methods, are
offering the scientific community answers to some of these questions that are otherwise difficult or
impossible to address. This review focuses on observational studies published in the last 2 years
designed to compare the effectiveness of escalation vs. induction treatment strategies, to assess the
effectiveness of treatment in pediatric-onset and late-onset MS, and to identify the clinical phenotype of
secondary progressive (SP)MS.
Recent findings: The main findings originating from real-world studies suggest that MS patients who
will qualify for high-efficacy disease-modifying therapies (DMTs) should be offered these as early as
possible to prevent irreversible accumulation of neurological disability. Especially pediatric patients
derive substantial benefits from early treatment. In patients with late-onset MS, sustained exposure to
DMTs may result in more favorable outcomes. Data-driven definitions are more accurate in defining
transition to SPMS than diagnosis based solely on neur ologists' judgment.
Summary: Patients, physicians, industry, and policy-makers have all benefited from real-world evidence
based on registry data, in answering questions of diagnostics, choice of treatment, and timing of
treatment decisions.
• PMID: 35674068
Curr Opin Neurol. 2022 Jun 1;35(3):262-270. doi: 10.1097/WCO.0000000000001063.
Authors: Bruce A C Cree, Hans-Peter Hartung, Michael Barnett
Abstract
Background: Purpose of review: To discuss recent changes in the multiple sclerosis (MS) treatment
algorithm and to present therapies currently in MS clinical trials.
Recent findings: High efficacy disease modifying therapies are optimally beneficial when used in the early,
inflammatory phase of MS. Bruton's tyrosine kinase has emerged as an important therapeutic target for both
relapsing and progressive forms of MS. Multiple therapies targeting remyelination failed to provide
conclusive evidence of broad therapeutic benefit; however, more targeted approaches offer hope that
myelin repair might be achieved resulting in specific clinical improvements. Strategies targeting chronic
Epstein-Barr virus infection and dysbiosis of the gut microbiome are the first to link microbial risk factors for
MS and therapeutic interventions.
Summary: A striking number of diverse treatments under investigation bodes well for development of
better and more effective therapies in MS.
• PMID: 35674067
BMC Neurol. 2022 Jun 7;22(1):211. doi: 10.1186/s12883-022-02738-7.
Authors: Robert J Fox, Rina Mehta, Timothy Pham, Julie Park, Kathleen Wilson, Machaon Bonafede
Abstract
Background: Over a dozen disease-modifying therapies (DMTs) have been approved for treatment of
multiple sclerosis (MS). Treatment guidelines focus on when to initiate, change, and discontinue
treatment but provide little guidance on how to select or sequence DMTs. This study assessed
sequencing patterns of DMTs in patients with newly diagnosed MS.
Methods: Adults newly diagnosed with MS in the United States were identified from January 2007 to
October 2017 using IBM MarketScan database. Patients had ≥12 months of continuous enrollment prior
to diagnosis and ≥ 2 years of follow-up. Treatment pathways consisting of up to 3 DMT courses were
reported, and each treatment course ended with discontinuation, switch, or end of follow-up.
Results: In total, 14,627 MS patients were treated with DMTs and had ≥2 years of follow-up. More than
400 DMT treatment pathways were observed. Glatiramer acetate was the most common DMT; 40% of
patients initiated this treatment. Among these, 51.3% had 2 DMT courses during follow-up and 26.5%
had 3 DMT courses. Approximately 70% of patients switched or discontinued their initial DMT, and rates
of switch and discontinuation differed by initial DMT. Injectable DMTs were used most commonly over
the study period (87.5% as first course to 66.6% as third course). Oral DMTs were more common as
second or third treatment courses (29.9% and 31.8%, respectively).
Conclusions: A wide variety in treatment patterns were observed among patients newly diagnosed with
MS. Further examination of DMT prescribing practices is needed to understand the reasons behind
treatment discontinuation and treatment cycling.
• PMID: 35672686
Neurol Sci. 2022 Jun 7. doi: 10.1007/s10072-022-06169-7. Online ahead of print.
Authors: Roberto Bergamaschi, Ettore Beghi, Cristina Bosetti, Michela Ponzio, Claudia Santucci, Vito Lepore, Paola
Mosconi, Italian Multiple Sclerosis and Related Disorders Register Centers Group and the Scientific Committee of
Italian SM and Related Disorders Register; U Aguglia, M P Amato, A L Ancona, B Ardito, C Avolio, R Balgera, P Banfi, V
Barcella, P Barone, P Bellantonio, A Berardinelli, R Bergamaschi, P Bertora, M Bianchi, P Bramanti, V Brescia Morra, G
Brichetto, A M Brioschi, M Buccafusca, S Bucello, V Busillo, B Calchetti, R Cantello, M Capobianco, F Capone, L
Capone, D Cargnelutti, M Carrozzi, E Cartechini, G Cavaletti, P Cavalla, M G Celani, R Clerici, M Clerico, E Cocco, P
Confalonieri, M G Coniglio, A Conte, F Corea, S Cottone, P Crociani, F D'Andrea, M C Danni, G De Luca, D de Pascalis,
M De Riz, F De Robertis, G De Rosa, N De Stefano, M Della Corte, A Di Sapio, R Docimo, M Falcini, N Falcone, S Fermi,
E Ferraro, M T Ferrò, M Fortunato, M Foschi, A Gajofatto, A Gallo, P Gallo, M Gatto, P Gazzola, A Giordano, F Granella,
M F Grasso, M G Grasso, L M E Grimaldi, P Iaffaldano, D Imperiale, M Inglese, R Iodice, S Leva, V Luezzi, A Lugaresi, G
Lus, D Maimone, L Mancinelli, G T Maniscalco, G A Marfia, B Marini, A Marson, N Mascoli, L Massacesi, F Melani, M
Merello, G Meucci, M Mirabella, S Montepietra, D Nasuelli, P Nicolao, F Passantino, F Patti, M Peresson, I Pesci, C
Piantadosi, M L Piras, M Pizzorno, K Plewnia, C Pozzilli, A Protti, R Quatrale, S Realmuto, G Ribizzi, S Rinalduzzi, A Rini, S Romano, M Romeo, M Ronzoni, P Rossi, M Rovaris, G Salemi, G Santangelo, M Santangelo, G Santuccio, P Sarchielli,
L Sinisi, P Sola, C Solaro, D Spitaleri, S Strumia, T Tassinari, S Tonietti, C Tortorella, R Totaro, A Tozzo, G Trivelli, M
Ulivelli, P Valentino, S Venturi, M Vianello, M Zaffaroni, R Zarbo, Maria Trojano, Mario Alberto Battaglia, Marco
Capobianco, Maura Pugliatti, Monica Ulivelli, Paola Mosconi, Claudio Gasperini, Francesco Patti, Maria Pia Amato,
Roberto Bergamaschi, Giancarlo Comi
Abstract
Background: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting
from demographic and environmental risk factors. Socio-economic factors and the characteristics of
local MS facilities might also play a par t.
Methods: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and
Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically
isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR),
or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers'
characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for
CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects
logistic regression models.
Results: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS
phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period.
Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS,
PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS
phenotype, but higher for PP/PR and SP. The probability of SP at first visit wa
Neurology. 2022 Jun 6;10.1212/WNL.0000000000200606. doi: 10.1212/WNL.0000000000200606. Online ahead of print.
Authors: Mark S Freedman, Carlo Pozzilli, Eva Kubala Havrdova, Alexandre Lemle, Michel Burcklen, Anna Larbalestier,
Brian Hennessy, Tatiana Sidorenko, Andrea Vaclavkova, Tomas Olsson, onbehalf of Ponesimod Phase II Study Group
Abstract
Objective: To evaluate the dose-response relationship of 10, 20 and 40-mg ponesimod and long-term
efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and
Extension studies in relapsing-remitting multiple sclerosis (RRMS) patients.
Methods: In the Core study, 464 patients were randomized (1:1:1:1): placebo (n=121), 10-mg (n=108),
20-mg (n=116), or 40-mg ponesimod (n=119) once-daily for 24 weeks. Patients who completed the Core
study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks), TP2 and TP3 (up to 432 weeks). The 40-mg dose was discontinued due to low tolerability at the end of TP1 and 10-mg dose
was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients
received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed
disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated.
Results: A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg=139, 20
mg=145, 40 mg=151) at any time during the Core and/or the Extension study. As of 31 March 2019, 214 patients
were still on ponesimod treatment. Median (range) of ponesimod exposure was 7.95 (0-9.36) years. Ponesimod
20-mg, from Core up to end of TP3, was associated with sustained low clinical activity (ARR for confirmed
relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9% and 6-month CDA was
20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common
adverse events were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%).
Conclusion: The effects on MS disease control were maintained with ponesimod 20 mg for approximately 8
years with no new safety concerns identified.
Classification of evidence: This study provides Class IV evidence that in individuals with relapsing-remitting
multiple sclerosis, long-term treatment with ponesimod 20mg was associated with sustained low annualized
confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free.
Trial registration information: EudraCT Number 2008-006786-92 (Core study) and EudraCT Number
2009-011470-15 (Extension study).
• PMID: 35667837
Value Health. 2022 Jun;25(6):984-991. doi: 10.1016/j.jval.2021.11.1363. Epub 2021 Dec 15.
Authors: Matthijs M Versteegh, Simone A Huygens, Beatrijs W H Wokke, Joost Smolders
Abstract
Objectives: The rapid expansion in treatment options for relapsing-remitting multiple sclerosis (RRMS) of
the past decade requires clinical decision making on the sequential prescription of these treatments.
Here, we compare 360 treatment escalation sequences for patients with RRMS in terms of health
outcomes and societal costs in The Netherlands.
Methods: We use a microsimulation model with a societal perspective, developed in collaboration with
MS neurologists, to estimate the effectiveness and cost-effectiveness of 360 treatment sequences
starting with first-line therapies in RRMS. This model integrated data on disease progression,
disease-modifying treatment efficacy, clinical decision rules, age-dependent relapse rates, quality of life,
healthcare, and societal costs.
Results: Costs and health outcomes were overlapping among different treatment escalation sequences.
In our model for RRMS treatment, optimal lifetime health outcomes (20.24 ± 1.43 quality-adjusted
life-years [QALYs], 6.11 ± 0.30 relapses) were achieved with the sequence peginterferon-dimethyl
fumarate-ocrelizumab-natalizumab-alemtuzumab. The most cost-effective sequence
(peginterferon-glatiramer acetate-ocrelizumab-cladribine-alemtuzumab) yielded numerically worse
health outcomes per patient (19.59 ± 1.43 QALYs, 6.64 ± 0.43 relapses), but resulted in €98 127 ± €19 134 less costs than the most effective treatment sequence.
Conclusions: Effectiveness estimates of treatments have overlapping confidence intervals but the
treatment sequence that yields most QALYs is not the most cost-effective option, also when taking
uncertainty into account. It is important that neurologists are aware of cost constraints and its
relationship with prescription behavior, but treatment decisions should be individually tailored.
• PMID: 35667786
Brain. 2022 Jun 2;awac203. doi: 10.1093/brain/awac203. Online ahead of print.
Authors: Mads A J Madsen, Vanessa Wiggermann, Marta F M Marques, Henrik Lundell, Stefano Cerri, Oula
Puonti, Morten Blinkenberg, Jeppe Romme Christensen, Finn Sellebjerg, Hartwig R Siebner
Abstract
Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and
cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute
to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional
study, we assessed how cortical lesions in the primary sensorimotor hand area (SM1-HAND) relate to
corticomotor physiology and sensorimotor function of the contralateral hand. 50 relapse-free patients with
relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched
participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate
normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract,
infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested
sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37
patients and 20 healthy controls, we measured maximal motor evoked potential (MEP) amplitude, resting
motor threshold and corticomotor conduction time with transcranial magnetic stimulation (TMS) and the N20
latency from somatosensory evoked potentials (SSEPs). Patients showed at least one cortical lesion in the
SM1-HAND in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral
sensory (P = 0.014) and motor (P = 0.009) composite scores. TMS of a lesion-positive SM1-HAND revealed a
decreased maximal MEP amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to
a lesion-negative SM1-HAND. Stepwise mixed linear regressions showed that the presence of an SM1-HAND
lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area
and higher infratentorial lesion volume were associated with reduced contralateral motor hand function.
Cortical lesions in SM1-HAND, spinal cord cross-sectional area and normalized brain volume were also
associated with smaller maximal MEP amplitude and longer corticomotor conduction times. The effect of
cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates.
Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function,
intracortical lesions on reduced MEP amplitude and leukocortical lesions on delayed corticomotor
conduction. Together, this comprehensive multi-level assessment of sensorimotor brain damage shows that
the presence of a cortical lesion in SM1-HAND is associated with impaired corticomotor function of the hand,
after accounting for damage at the subcortical level. The results also provide preliminary evidence that
cortical lesion types may affect the various facets of corticomotor function differentially.
• PMID: 35653498
J Neurol. 2022 Jun 2;1-11. doi: 10.1007/s00415-022-11197-6. Online ahead of print.
Authors: Guillaume Dorcet, Hugo Migné, Damien Biotti, Chloé Bost, Fleur Lerebours, Jonathan Ciron, Emmanuel Treiner
Abstract
Background: It is currently unknown whether early B cell reconstitution (EBR) in MS patients under rituximab
is associated with a risk of relapse or progression.
Objectives: Analyzing EBR in rituximab-treated patients and its putative association with clinical findings.
Methods: Prospective lymphocytes immunophenotyping was performed in a monocentric cohort of MS
patients treated by rituximab for 2 years. EBR was defined when B cells concentration was > 5 cells/mm3. B
cell subsets were retrospectively associated with clinical data. Clinical and radiological monitoring included
relapses, EDSS (Expanded Disability Status Scale), SDMT (Symbol Digit Modalities Test), and MRI.
Results: 182 patients were analyzed (61 remitting-relapsing and 121 progressive-active). 38.5% experienced
EBR at least once, but very few (7/182) showed systematic reconstitution. Most patients remained stable upon
treatment, regardless of the occurrence of EBR. Dynamics of B cell reconstitution featured increased
naïve/transitional B cells, and decreased memory subsets. Homeostasis of the B cell compartment differed at
baseline between patients experiencing or not EBR upon treatment. In patients with EBR, reciprocal
dynamics of transitional and pro-inflammatory double-negative B cell subsets was associated with better
response to rituximab treatment.
Conclusion: EBR is common in rituximab-treated MS patients and is not associated with clinical disease activity.
EBR in the peripheral blood may reflect regulatory immunological phenomena in subgroup of patients.
• PMID: 35652942
J Neurol Neurosurg Psychiatry. 2022 Jun 1;jnnp-2021-328568. doi: 10.1136/jnnp-2021-328568. Online ahead of print.
Authors: Ingrid Anne Lie, Sezgi Kaçar, Kristin Wesnes, Iman Brouwer, Silje S Kvistad, Stig Wergeland, Trygve Holmøy,
Rune Midgard, Alla Bru, Astrid Edland, Randi Eikeland, Sonia Gosal, Hanne F Harbo, Grethe Kleveland, Yvonne S
Sørenes, Nina Øksendal, Kristin N Varhaug, Christian A Vedeler, Frederik Barkhof, Charlotte E Teunissen, Lars Bø, Øivind
Torkildsen, Kjell-Morten Myhr, Hugo Vrenken
Abstract
Background: The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in
multiple sclerosis (MS) is still unclear.
Objective: Investigate the relation between sNfL levels over a 2-year period in patients with
relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years.
Methods: 85 patients, originally enrolled in a multicentre, randomised trial of ω-3 fatty acids, participated in
a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24.
The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained
using FreeSurfer.
Results: Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or
recently present) predicted lower total (β=-0.399, p=0.040) and deep (β=-0.556, p=0.010) GM volume, lower
mean cortical thickness (β=-0.581, p=0.010) and higher T2 lesion count (β=0.498, p=0.018). Of the clinical
outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant
hand Nine-Hole Peg Test (β=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions
present or recently present) did not predict GM atrophy or disability progression.
Conclusion: Higher sNfL levels during periods of active inflammation predicted more GM atrophy and
specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM
atrophy is mainly due to neuroaxonal degradation within new lesions.
• PMID: 35649699
J Neurol. 2022 Jun 1. doi: 10.1007/s00415-022-11183-y. Online ahead of print.
Authors: Alessandro Miscioscia, Marco Puthenparampil, Silvia Miante, Marta Pengo, Francesca Rinaldi, Paola Perini,
Paolo Gallo
Abstract
Background: Ocrelizumab was found to decrease brain atrophy rate in primary progressive multiple
sclerosis (PPMS), but no data are currently available on the effect of ocrelizumab on retinal layer thicknesses
in the PPMS population.
Objective: To assess retinal layer changes in ocrelizumab-treated PPMS and test their possible application as
biomarkers of therapy response.
Methods: 36 PPMS patients, treated with ocrelizumab for at least 6 months, and 39 sex- and age-matched
healthy controls (HC) were included in a blind, longitudinal study. Spectrum-domain optical coherence
tomography (SD-OCT) was performed at study entry (T0) and after 6 (T6) and 12 months (T12). At month 24
(T24), patients were divided into responders (no evidence of 1-year confirmed disability progression,
1y-CDP) and non-responders (evidence of 1y-CDP).
Results: At T24, 23/36 (64%) patients were considered responders and 13/36 (36%) non-responders. At T0,
peripapillary retinal nerve fiber layer (pRNFL) thickness, macular ganglion cell-inner plexiform layer (GCIPL)
and inner retinal layer (IRL) volume were significantly lower in PPMS compared to HC (p = 0.001 for all
comparisons). At T6 and T12, non-responders significantly differed in the inner nuclear layer (INL) thinning
rate compared to responders (p = 0.005 at both time-points).
Conclusions: Ocrelizumab significantly slows down INL thinning rate in PPMS responders. The longitudinal analysis
of retina layer changes by means of OCT may be a promising prognostic test, and merits further investigations.
• PMID: 35648233
Nat Rev Neurol. 2022 Jun 30. doi: 10.1038/s41582-022-00695-w. Online ahead of print.
Author: Ian Fyfe
No abstract available
• PMID: 35773476
Neurology. 2022 Jun 28;10.1212/WNL.0000000000200862. doi: 10.1212/WNL.0000000000200862. Online ahead of print.
Authors: Ahmed T Toosy, Arman Eshaghi
No abstract available
• PMID: 35764398
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