- “Disability Outcomes in Patients With Active Secondary Progressive Multiple Sclerosis” by Nathaniel Lizak et al
-”the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions”
Category: Uncategorized
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“Disability Outcomes in Patients With Active Secondary Progressive Multiple Sclerosis” by Nathaniel Lizak et al
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“Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS” by Johannes Lorscheider et al
- “Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS” by Johannes Lorscheider et al
-”Our pooled analysis of the currently available DMTs used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years; class IV evidence that for patients with SPMS, DMT has no beneficial effect on short-term disability progression”
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“Defining secondary progressive multiple sclerosis” by Johannes Lorscheider et al
- “Defining secondary progressive multiple sclerosis” by Johannes Lorscheider et al
-67% of those on DMTs converted to SPMS
-patients identified as SP spent 58-68% of their previous follow-up time on DMT
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“Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis” by Christaine Gasperi MD et al
- “Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis” by Christaine Gasperi MD et al
-intrathecal IgG synthesis was associated with earlier EDSS worsening
-no association of other routine CSF parameters with EDSS worsening was found
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“Toxicity of Released B Cell Products in Multiple Sclerosis: Effects on Neurons and Oligodendrocytes” by Leah Zuroff, Amit Bar-Or et al
- “Toxicity of Released B Cell Products in Multiple Sclerosis: Effects on Neurons and Oligodendrocytes” by Leah Zuroff, Amit Bar-Or et al
-”Although over a dozen disease-modifying therapies are approved for the treatment of RRMS, none are meaningfully effective at limiting disease progression”
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“Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS” by Sinah Engel et al
- “Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS” by Sinah Engel et al
-typical CSF findings in MS include: slightly elevated leukocyte count; presence of mononuclear cells; OCBs; elevated IgG synthesis; increased synthesis of intrathecally produced immunoglobulins against measles, rubella and varicella zoster (MRZ) viruses
-an increase in the CSF/serum IgG ratio (QIgG) and the presence of OCBs reflect chronic CNS-intrinsic immune reactions whereas the CSF leukocyte count is a dynamic parameter of acute inflammatory activity.
-we hypothesized that both chronic and acute inflammation influence sNfL levels in patients with MS
-we did not observe an association between clinical prognostic factors (sensory
compared with motor symptoms and complete compared with incomplete remission) and sNfL levels in patients with cerebral relapses. SNfL levels also demonstrated no significant correlation with EDSS, independent of whether the cohort was stratified for disease activity at the time of sample collection. There was no significant correlation between any of the inflammation-related CSF parameters and the EDSS, except for Qalb
-CSF leukocyte count was higher during relapse than in clinically stable patients and correlated with sNfL levels
-presence of OCBs was significantly related to increased sNfL levels
-intrathecal fraction of the Ig subclasses IgA and IgM and their CSF/serum ratios and QIgM were unrelated to sNfL levels
-unclear whether the sNfL level increase rather reflects acute focal inflammatory activity or chronic widespread diffuse neurodegenerative processes
-IgG synthesis (intrathecal) is an established marker of chronic CSF inflammation; it can be detected by an elevation of QIgG, the presence of OCBs, or by positive MRZ reaction
-sNfL levels were significantly higher in OCB-positive patients and correlated with CSF IgG levels and QIgG
-significant correlation between sNfL levels and CSF leukocyte count
-snFL levels increase during relapses compared with stable disease phases and correlate with the number of CELs in MRI which suggests exacerbated acute focal inflammation as the underlying cause
-in CSF, acute inflammation is reflected by an increase in the leukocyte count and Qalb
-ocrelizumab appears to reduce CSF leukocyte count and sNfL
-in progressive MS, no correlation of CSF NfL with CSF count; indicates a less pronounced acute inflammatory activity in progressive MS
-albumin is exclusively of extrathecal origin; is a reliable indicator of BBB integrity; majority of MS patients have normal albumin levels
-we suggest that NfL levels in blood will only be affected by severe disruption of BBB Integrity
-the effect of acute inflammatory activity on sNfL may outweigh the effect of underlying chronic inflammation
-lower SNfL concentrations in patients presenting with ON than in patients with symptoms suggestive of cerebral or spinal inflammation
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“Patterns and predictors of multiple sclerosis phenotype transition” by Luigi Pontieri et al
- “Patterns and predictors of multiple sclerosis phenotype transition” by Luigi Pontieri et al
-”these therapies (current DMTs) are insufficient in preventing progression and disability accumulation”
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“Association of Higher Ocrelizumab Exposure With Reduced Disability Progression in Multiple Sclerosis” by Stephen Hauser et al
- “Association of Higher Ocrelizumab Exposure With Reduced Disability Progression in Multiple Sclerosis” by Stephen Hauser et al
-”Unlike RMS, in patients with PPMs there was no association of grouped median
B-cell levels during the DP with rates of 24 W-CDP during the combined DBP
and OLE”
-”Exposure dependency analysis of 24 W-cCDP was directionally consistent with RMS but did not reach statistical significance”
-”An exposure dependency trend on 24 W-cCDP was also observed across quartiles in patients with PPMS”
-”In RMS, all subgroups with the exceptions of religion the United States and EDSS greater than or equal to 4 showed numerically greater reduction in risk of disability progression in the high-exposure group compared with the low-exposure group”
-”where the treatment effect in high exposure patients with PPMS was markedly reduced”
–greater brain volume reduction was seen in RRMS patients with higher ocrelizaumab exposure; no such association was seen in patients with PPMS
-less grey matter volume reduction aws seen with higher ocrelizumab exposure
-”an increasing body of evidence suggests that progression observed in patients with RMS treated with highly effective DMTs reflects the same or at least very similar pathology with progression observed in SPMS and PPMS. At present, it is not known to what degree each of these pathologies contributes to progression in different patients and/or different stages of disease”
-”the majority of disability progression was relapse-independent and when relapse-independent CDP (PIRA) was investigated separately here, similar associations were found (data not shown)”: WHY WAS DATA NOT SHOWN? LIKELY BECAUSE OCRELIZUMAB WAS NOT EFFECTIVE AGAINST PIRA!!!
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Association between conventional MRI activity and disability in MS
57) “A Longitudinal Study of Abnormalities on MRI and Disability From Multiple Sclerosis” by Peter A Brex, MD et al
-”Clinically definite multiple sclerosis developed in 48 of 71 patients (68 percent) and probably multiple sclerosis in a further 5 (7 percent)”
-”Clinically definite multiple sclerosis developed in…9 of the 14 patients with brain stem syndromes (64%)…”
-”Clinically definite multiple sclerosis developed in 44 of 50 patients with abnormal MRI scans at base line (88 percent)”
-”Overall, 49 of 50 patients (98 percent) had clinical or radiological evidence of multiphasic disease consistent with multiple sclerosis”
-”The change in lesion volume on MRI correlated moderately with the change in the EDSS score over the first 5 years (r=0.58) and was weaker though still significant over the 5-to-10-year and 10-to-14-year periods (Table 5)”
-”…after 15 years, 50 percent will require aid to walk (equivalent to an EDSS score of 6)
-”…suggesting that the development of lesions in the early years has an important influence on long-term disability”
-”The present MRI study and previous clinical studies suggest that both MRI and clinical measures of disease activity in the first two to five years after the development of an isolated syndrome are important in the long-term prognosis for disability in patients with multiple sclerosis”
-”The extent of inflammation and demyelination early in the disease course may influence the extent of later axonal loss in several ways. First, acute inflammation is associated with axonal damage, including transection, widespread axonal loss will diminish the amount of axonal reserved, and a threshold may be reached at an early point when continuing axonal loss-by whatever mechanism-begins to manifest as disability. Second, widespread inflammation could expose a range of potential autoantigens to immune surveillance, resulting in complex immunopathogenic events due to epitope spreading; such a process may be less regulated and may be likely to cause axonal damage. Third, widespread early demyelination itself may create an environment that is not conducive to long-term axonal survival”
112) “Correlation Analysis of MRI Lesion Load and Clinical Measures in Multiple Sclerosis Cohort Using Structured Clinical Documentation Support Toolkit (1880)”: Afif Hentati, Tiffani Stroup Franada, John Pula, Darryck Maurer, Bryce Hadsell, Alexander Epshteyn, Samuel Tideman, Anna Pham, Roberta Frigerio, Demetrius Maraganore, and Susan Rubin
-”A weak or absent correlation between MRI lesion load and clinical disability including physical, cognitive and psychological in MS has been the prevailing view. “
113) “The Relevance of Neuroimaging Findings to Physical Disability in Multiple Sclerosis”: Rahşan Göçmen
-”Although T2 hyperintense lesions accrual is the radiological hallmarks of disease activity in MS, a weak correlation was found between T2 lesions disability (32, 33). This weak correlation suggests that silent T2 lesions occur commonly in MS and this describes the clinico-radiological paradox (34). The possible explanations for this may be as follows: Firstly, the MRI lesions in MS occurs commonly “non-eloquent” areas of the brain. Secondly, histopathological correlates of the lesions are not so severe as to cause symptoms, for instance, mild inflammation. Thirdly, histopathologic changes in the normal-appearing white matter (NAWM) on conventional MRI contribute to clinical symptoms. And finally, all compartments of CNS such as spinal cord are not imaged. Many studies have shown that locations of T2 lesions have a more decisive influence on disability than overall lesion load in relapsing-remitting MS (RRMS) (18, 35). Although the correlation between T2 lesion load and disability is weak in the more advanced stage of the disease, T2 lesion load has a prognostic value in the onset of MS (Figure 1). Higher T2 lesion load has been associated with an increased risk of subsequent conversion to definite MS and long-term disability in patients with CIS (18, 35). However, this paradox relatively disappears regarding the topographic distribution of T2 lesions. For instance, infratentorial spinal cord lesions have more determinative value predicting the disability.”
114) “‘Usual Suspect’ lesions appear not to cause most severe disability in MS patients” by Buffalo Neuroimaging Analysis Center: Friday, February 24th, 2023
-“The absence of material differences in white matter brain lesion burden means this is not a significant driver of severe disability progression, despite the fact that many MS disease-modifying treatments are focused on slowing accumulation of white matter lesions,” said Robert Zivadinov, MD, PhD, principal investigator and director of UB’s Buffalo Neuroimaging Analysis Center and the Center for Imaging in UB’s Clinical and Translational Science Institute.
-It is widely accepted that MS is characterized by the formation of brain white matter lesions. Yet in this study participants with severe MS disability showed significantly more gray matter loss in the cortex and thalamus compared to their less-disabled “twin.” Surprisingly, the loss of whole brain volume was comparable among both groups.
-Severely affected people exhibited lower efficiency in thalamic structural connectivity, meaning they demonstrated lower structural connectivity of the associated brain networks than their less disabled counterparts.
-Called Comprehensive Assessment of Severely Affected – Multiple Sclerosis, or CASA-MS, the investigator-initiated, privately funded UB study is focused on identifying biomarkers and cognitive differences among people whose MS disability has become severe compared to others whose disease progresses slowly
119) “Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras” by Noemi Montobbio, PhdD et al
-”The average contribution of PIRA to overall EDSS progression, already predominant in patients diagnosed in 1980-1996 (78%)…and in 1997-2008 (76%)…was significantly increased….in patients diagnosed in later years (87%…)”
-”However, although clinical relapses are almost completely eliminated by modern high-efficacy DMTs, the underlying disability progression independent of relapse activity is far from being halted or reversed. Our results showed a progressive shift toward a mostly relapse-independent progression”
120) “MRI measures and their relations with clinical disability in relapsing-remitting and secondary progressive multiple sclerosis” by E Giugni et al
-”A weak relationship between disability and total lesion volume on both T1 and T2 weighted images was found in relapsing-remitting Multiple Sclerosis.”
-”In secondary progressive Multiple Sclerosis, infratentorial lesion volume on T2 weighted images represents the only marker of disability”
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RAW vs PIRA in MS: RAW is not significant
- “Disease Progression in Multiple Sclerosis”: Genentech (2024)
-relapses were not associated with long-term disability worsening or confirmed disability worsening
-data were consistent with 2 simultaneous processes: focal demyelinating lesions and a more diffuse process that contributes to brain and spinal cord atrophy: this is largely independent of relapses or focal lesion formation and may be the most important contributor to long-term MS disability
-PIRA was seen early in the MS disease course in a cohort study; 66% had at least 1 PIRA event; 31% developed PIRA within the first 5 years of the disease; 34% had all of their CDA episodes qualify for RAW; 26x greater risk of developing severe disability
- “Contribution of relapse-associated worsening in overall disability accrual in patients with relapsing-onset multiple sclerosis: A mediation analysis” by Bo Chen et al
-”In relapsing-onset MS, PIRA is the major contributor to the irreversible disability accrual throughout the whole disease course…”
- “Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials” by J Ingwersen et al
-”Using data from the pivotal phase 3 randomized controlled trials (RCTs) OPERA I and OPERA II, Kappos et al. investigated RAW and PIRA contributions to the disability accumulation of ocrelizumab-treated vs. interferon-treated patients. They found that (A) PIRA was responsible for most of the disability accumulation rather than RAW irrespective of the treatment arm (later confirmed by the findings of Lublin et al.) and (B) ocrelizumab was superior in preventing PIRA compared to interferon. However, it was less effective in preventing PIRA than RAW.”
-”In both, the interferon and ocrelizumab groups, PIRA (rather than RAW) was responsible for 80–90% of the clinical worsening…”
- “Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras” by Noemi Montobbio, PhdD et al
-”The average contribution of PIRA to overall EDSS progression, already predominant in patients diagnosed in 1980-1996 (78%)…and in 1997-2008 (76%)…was significantly increased….in patients diagnosed in later years (87%…)”
-”However, although clinical relapses are almost completely eliminated by modern high-efficacy DMTs, the underlying disability progression independent of relapse activity is far from being halted or reversed. Our results showed a progressive shift toward a mostly relapse-independent progression”
Multiple Sclerosis Research Repository 