Tag: multiple-sclerosis

• 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”

  January 21, 2025

  health, mental-health, mri, ms, multiple-sclerosis

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• RAW vs PIRA in MS: RAW is not significant

  1.   “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 

  2. “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…”

  3. “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…”

  4.  “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”

  January 21, 2025

  health, mental-health, ms, multiple-sclerosis, wellness

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• RAW (relapse-associated worsening) vs PIRA (progression independent of relapse activity in Multiple Sclerosis

  115)  “Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis: A Systematic Review” by Jannis Muller, MD et al

  -”In this systematic review of 48 studies, PIRA was found to be the most common form of disability accumulation across all traditional MS phenotypes, including clinically isolated syndrome and early relapsing-remitting MS.”

  116)  “Does initial high efficacy therapy in multiple sclerosis surpass escalation treatment strategy?  A comparison of patients with relapsing-remitting multiple sclerosis in the Czech and Swedish national multiple sclerosis registries” by Tereza Hrnciarova

  -”In contrast to the previous comparison between the Swedish and Danish cohorts (Spelman et al, 2021), the primary outcome (CDW) did not show a significant difference in favor of the Swedish cohort (…p-value 0.2764)

  -”it is reasonable to ask why such a significant reduction in the risk of relapse did not translate into a change in the long-term outcome of CDW”

  117)  “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…”

  -”Nonetheless,

  with more and more disease-modifying treatments (DMTs) available to

  reduce the attack frequency, substantial evidence has shown that

  disability progression in most treated patients can still develop slowly

  over time, independent of relapses and whatever medications applied, in

  whether relapsing-remitting or progressive cases (Cree et al., 2016;

  Reich et al., 2018; Signori et al., 2016).”

  -”Even in the population with

  relapsing MS who initially received ocrelizumab, a B cell-depleting

  agent, the cumulative proportion with disability progression climbed

  at a slow rate in the case of nearly complete and sustained suppression of

  new brain MRI lesion activity (Hauser et al., 2017; Hauser et al., 2020),

  with the similar findings observed in patients treated with other

  high-efficacy DMTs (Coles et al., 2012; Kapoor et al., 2018), implying

  that the neurological deterioration seems unavoidable in this life-long

  Disease.”

  -”On the other hand, compared to that in the early phase, the disability accrual in the later one is not significantly slowed by the reduced relapse frequency, suggesting that the effect of RAW on the disabled outcome may vary in different stages of the disease.“

  -”Annualized relapse rate (ARR), a marker for disease activity, cannot

  reflect the neurological deterioration in patients with MS…”

  -”The key findings were that clinical attack number partly mediated less than half (0.414) of the positive relationship between disease duration and disability worsening in the early phase (i.e., RAW accounted for 41.4% of the disability accrual while PIRA for 58.6%), whereas it was not associated with the disabled outcome in the later phase (i.e., PIRA contributed to the majority of the progression).”

  -”…supporting an immune-mediated or triggered neurodegenerative nature of MS and underlining the importance of the treatment on PIRA even in the initial phase.”

  -”A significant and partial mediator effect of clinical attack number on

  the relationship between disease duration and neurological disability

  accrual was observed in the early phase but not in the later phase herein

  (Table 3), suggesting that the role of RAW on disability accumulation

  differs in different stages of the disease, in line with previous studies

  (Leray et al., 2010; Scalfari et al., 2010; Weinshenker et al., 1989).”

  -”In previous research, when comparing untreated “natural history” and DMT-treated cohorts of patients, Tilling K et al. found that although disability progression was slowed by treatment, the treated patients still worsened considerably over time (Tilling et al., 2016).”

  -”These findings imply that RAW only partly rather than entirely contributes to the irreversible disability accumulation in relapsing MS, and disability would inevitably accrue in the long term, even the relapses are controlled, in keeping with our results that attack number partly mediates the relationship between duration and EDSS scores in the early phase.”

  -”once the patients enter the later phase, the contribution of relapse or RAW to the disabled outcome becomes negligible (indirect/total effect < 10%)…”

  -”In contrast, the disability of the individuals with NMOSD is mainly contributed by one or more severe episodes of attacks and less accumulates over time (Wingerchuk et al., 2007), which

  is one of the pivotal differences between the two diseases. This difference, on the other hand, implies that demyelination alone seems insufficient to explain the entire disability in MS.”

  -”the percent of the direct effect of disease duration on EDSS scores (PIRA) soars from 58.6% in the early phase to 90.8% in the later one (Table 3).”

  -”As demonstrated in Table 3, the significant direct effect of duration on EDSS scores in both early and later phases implies that PIRA may begin as early as the commencement

  of the disease and account for the leading cause of the irreversible disabled outcome. From this point of view, the benefit from most current DMTs may be attained with ease in the first few years and become limited in preventing the disability exacerbation in the long term, consistent with previous studies (Kingwell et al., 2019; Manouchehrinia et al., 2017; Tilling et al., 2016).”

  -”Prior studies have shown that in the early stage, patients with late-onset age are vulnerable to disability accumulation after several relapses, while the young-onset can rehabilitate with little neurological deficit (Cierny et al., 2017; D’Amico et al., 2018; Guillemin et al., 2017).  Nevertheless, we found that the disability accrual accelerated with the increase of onset age only in the early phase (significant total effect of onset age on EDSS scores with adjusting for the duration, Table 3), fully independent of clinical attack number (the direct effect was significant while the indirect effect was not), while the statistical association between onset age and disability progression was absent after that, which is also observed previously (Leray et al., 2010; Scalfari et al., 2011). The exact potential mechanisms remain elusive but may involve the

  age-related decrease in the repair capacity of the CNS (Stankoff et al., 2007) and age-related altered immune response (Ditamo et al., 2005; Weiner, 2009). Of note, although significant, the standardized total effect of onset age on EDSS scores in the early phase was merely 0.205, much smaller than that of duration (0.542) (Table 3), even the effect of attack number/RAW (0.224) or PIRA (0.318), implying that in terms of disability accrual, the cont

  118)  “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

  -”Mean follow-up time was 29 months (range 6 to 51 months). 23.5% developed CDA under ocrelizumab therapy (n = 23). Of those, the majority developed PIRA (87.0% of CDA, n = 20) rather than RAW (13.0% of CDA, n = 3). An exploratory investigation using Cox proportional hazards ratios revealed two possible factors associated with an increased probability of developing PIRA: a shorter disease duration prior to ocrelizumab (p = 0.02) and a lower number of previous DMTs prior to ocrelizumab (p = 0.04). Our data show that in ocrelizumab-treated RRMS patients, the main driver of disability accumulation is PIRA rather than RAW.”

  -”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…”

  -”our data contributes to the notion that in typical RRMS patients under effective, immune-directed therapy PIRA is the primary driver of disability progression rather than RAW.”

  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”

  January 21, 2025

  chronic-illness, health, mental-health, ms, multiple-sclerosis

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• Conversion from CIS to MS Research

  1. “Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study”: J Kuhle et al

  -”At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres”

  2. “The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA”: Andrea Paolillo

  -”Twenty-four (39%) developed clinically definite MS by month 18. Thirty-eight (61%) were relapsefree and completed the MRI follow-up. Relapse-free patients showed a progressive median increase between baseline and month 18 in T1-LL (25%, p<0.001), but not in T2-LL (8.5%, p=ns). PBVC decreased by 1.1% (p<0.001) in a time-dependent pattern (Kendall coefficient of concordance=0.85). Exploratory subgroup analyses showed a trend towards progressive decreases in brain volume in active patients (i. e., those with at least one newly active lesion during monthly MRI scanning; Spearman’s R=-0.61; p<0.001), but not among inactive patients (Spearman’s R=-0.10; p=0.53). Significant differences in median brain volume changes between the active and inactive patient groups were found at months 12 and 18; the difference detected at month 6 was not significant. The cumulative number and volume of new Gd-enhancing lesions developed during the 6 months of frequent MRI scanning were highly correlated with PBVC over the 18-month period (Spearman R values were 0.73 and 0.85, respectively). The strongest predictor of PBVC at 18 months was the cumulative volume of newly active lesions during frequent MRI scanning [ss=-0. 83, standard error (SE)=0.07, p<0.001].”

  -”This study shows that visible inflammation as detected by monthly, triple-dose Gd-enhanced MRI is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: atrophy appeared only after a delay of months following acute inflammation. Frequent MRI scanning allows for the detection of CIS patients who will develop brain atrophy in the short-term.”

  3. “Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis”: L K Fisniku et al

  -”Clinically isolated syndromes (CIS), such as optic neuritis, brainstem or spinal cord syndromes are frequently the first clinical presentations of multiple sclerosis. However, not all CIS patients develop multiple sclerosis and in those who do, disability is highly variable. In previous follow-up studies, brain lesions on T2-weighted MRI are associated with increased risk of multiple sclerosis and to an extent disability. We evaluated the longitudinal relationships between the MRI lesions and clinical course over a period of 20 years. CIS patients were recruited between 1984 and 1987 and previously followed up after 1, 5, 10 and 14 years. Of the 140 subjects who were initially recruited with a CIS for a baseline MRI study, we followed up 107 patients after a mean of 20.2 years (range 18-27.7). Multiple sclerosis was diagnosed as clinically definite on clinical grounds only and disability determined using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) score. Clinically definite multiple sclerosis developed in 67 out of 107 (63%) overall: 60 out of 73 (82%) with abnormal and 7 out of 34 (21%) with normal baseline MRI. Multiple sclerosis was still relapsing-remitting in 39 (58%)–including 26 (39%) with a ‘benign’ course (EDSS < or = 3)–whilst 28 (42%) had developed secondary progression.”

  4. “Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis”: G Filippini

  -”Authors’ conclusions: Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.”

  5. “Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis (Review): Filippini G (Cochrane Review, 2017)

  -”There was a small, non-significant advantage of early treatment compared with placebo in disability worsening (6.4% fewer (13.9 fewer to 3 more) with Rebif

  -”We did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years follow up)

  -”Very low quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses.”

  -”is early treatment better than later treatment”; Avonex, Betaferon, Copaxone or Rebif; “the great variability between the studies and the low quality of the evidence makes our confidence in this result low”

  6. “MRI characteristics are predictive for CDMS in monofocal but not in multifocal patients with a clinically isolated syndrome:: Jessica M Nielsen et al

  -”in monofocal patients, the risk for CDMS over 2 years was significantly higher when greater than or equal to 9T2 lesions or at least one Gd-enhancing lesion were present at the first even tor 3 or 6 months after the first event” (*This is M’s situation*)

  7. “The Prognostic Utility of MRI in Clinically Isolated Syndrome: A Literature Review” by C. Odenthal et al

  -”Published rates of conversion CIS to CDMS differ according to length of study follow-up.  Five studies were identified in which subjects were followed for greater than 6 years.  For follow up of 6.9, 7.2, 7.3, 14 and 20 years, total conversion rates were 48%, 60%, 85%, 68%, and 63%.  

  -”The risk of conversion to CDMS is greater in patients presenting with abnormal T2WI.  Subjects with CIS subjects in the range of 50-70% with abnormal T2WI.” 

  -”Fisniku et al followed 107 subjects with CIS to 20.2 years; 82% with abnormal baseline MRI converted to CDMS, compared with 21% with normal MRI imaging”

  -”In another study, 88% of subjects with abnormal MR imaging converted by 14 years, compared to 19% of those with normal scans”

  -”A recent meta-analysis concluded that abnormal T2WI, regardless of lesion number, was associated with increased risk of conversion”

  -”In addition to T2 lesions, increased risk of conversion to MS is associated with the presence of gadolinium-enhancing lesions”

  -”The presence of at least 1 Gd-enhancing lesion is predictive of time to CDMS in monofocal but not in multifocal presentations”

  -”the prognostic significance of T1 lesions has been infrequently addressed.  Summers et al found that in addition to Gd-enhancing lesions, T1 lesions were predictive of cognitive dysfunction after 7 years”

  -”Baseline T2 lesion number is associated with EDSS at long-term follow up to 14 years”

  -”while baseline T2 lesion number was not associated with disability, the increase in T2 lesion number over the first year after presentation was predictive of EDSS at 6 years”

  -”The risk of disease progression is associated with lesion location, with periventricular, callosal and cerebellar distributions being most associated with conversion to CDMS”

  -”Infratentorial lesion location may be associated with increased risk of disease and disability.  Since infratentorial lesions are likely to affect clinically eloquent areas, they may have greater contribution to future disability.” 

  -”In a large multicenter study of 468 subjects with CIS, infratentorial lesions (including the brainstem and cerebellum) were not associated with increased risk of conversion”

  -”It is uncertain whether neurodegeneration is present in subjects with CIS”

  -”Subjects with CIS who convert to CDMS demonstrate a greater T2LV at presentation compared with those who do not convert”

  -”baseline T2LV was an independent predictor of conversion to MS by 4 years”

  -”T2LV is associated with the development of future disability”

  -”the rate of increase in T2LV in the first year is associated with greater long-term disability”

  -”T2 lesion volume may be better suited to the prediction of disability scores other than EDSS….(T1 lesion volume) did correlate with the Multiple Sclerosis Functional Composite at 6 years. Another study found that both T1 lesion number and volume were predictive of future cognitive dysfunction” 

  -”reported volume reduction in a number of deep GM structures of subjects with CIS, compared with controls, including the thalamus and caudate nucleus.

  -”cerebellar volume was associated with baseline tests of cerebellar function” 

  -”A recent study of 212 subjects did find that increased T2LV was associated with reduced volume of a number of deep GM structures”

  -”In a longitudinal study of 24 subjects with CIS, Audoin et al found that the midsagittal corpus callosal area was significantly reduced at 12 months.  Callosal area also correlated with progression in EDSS….in a larger cohort of 220 subjects with CIS, change in callosal area in the first 6 months after presentation was predictive of conversion to CDMS by 2 years”

  -”patients with CIS had increased mean diffusivity in all WM tracts”

  -”widespread reduced fractional anistropy in the WM of subjects with CIS”

  -”the magnetization transfer ratio of patients with CIS differed significantly from healthy controls”

  -”magnetization transfer ratio has been shown to be predictive of conversion to CDMS”

  -”NAA is a metabolite considered to be exclusive to neurons”

  -”Other studies found that only those patients with clinical progression demonstrated reduced NAA at presentation” 

  -”Myo-inositol (MIns or Ins) is a metabolite primarily concentrated in glial cells

  –”They demonstrated baseline reduced NAA and increased choline”

  -”The rate of increase in MIns concentration in normal-appearing WM over the first year was predictive of poor executive function at 7.2 years”

  -”Functional cortical changes are present from the earliest stages of CIS.  Compared with healthy controls, subjects with CIS demonstrate increased cortical activation in both cerebral hemispheres”

  -”T2 hypointensity, attributable to iron deposition, is a frequent finding in subjects with MS”

  -”While regional atrophy is not present at patient presentation (CIS), changes in DTI and MR spectroscopy parameters demonstrate that there is functional change occurring in normal-appearing brain tissue.  Widespread increased motor cortical activation visualized on fMRI suggests that neuroplasticity is already a factor at initial presentation”

  -”subjects with CIS demonstrate brain iron deposition, a feature that is characteristic of MS” 

  8. “Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis”: M Filippi

  -”Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.”

  9. “Combined analysis of global and compartmental brain volume changes in early multiple sclerosis in clinical practice:  A Pichler

  -”At baseline, all the brain volume metrics, except cGMV, were significantly lower; and the T2-LL was significantly higher, in patients with MS rather than CIS. During the follow-up, only the PBVC was higher in MS (p = 0.008) and this difference was driven by converters from CIS to MS. Quartiles of PBVC did not allow us to predict conversion to MS, but were associated with the degree of disability.”

  10.  “Cognitive impairment in clinically isolated syndrome: A systematic review”: Carolina Fiorin Anhoque

  -”Seven studies fulfilled the selection criteria adopted in this review. The pattern of cognitive abnormalities in CIS resembles that found in patients with MS and is characterized by attention deficit, reduced information processing speed and impaired working memory and executive functions. The frequency of cognitive impairment in CIS seems to be lower than in MS.”

  11.  “Cognitive impairment in patients with clinically isolated syndrome”: 

  Carolina Fiorin Anhoque

  -” CIS patients had significantly worse performance on the Paced Auditory Serial Addition Test (PASAT) 2 seconds (P=0.009) and on verbal fluency tests (P=0.0038) than controls.”

  -”CIS patients had worse cognitive performance than controls on neuropsychological tests evaluating executive functioning”

  12.   “Cortical involvement determines impairment 30 years after a clinically isolated syndrome”: Lukas Haider

  -”Many studies report an overlap of MRI and clinical findings between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), which in part is reflective of inclusion of subjects with variable disease duration and short periods of follow-up. To overcome these limitations, we examined the differences between RRMS and SPMS and the relationship between MRI measures and clinical outcomes 30 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis. Sixty-three patients were studied 30 years after their initial presentation with a clinically isolated syndrome; only 14% received a disease modifying treatment at any time point. Twenty-seven patients developed RRMS, 15 SPMS and 21 experienced no further neurological events; these groups were comparable in terms of age and disease duration. Clinical assessment included the Expanded Disability Status Scale, 9-Hole Peg Test and Timed 25-Foot Walk and the Brief International Cognitive Assessment For Multiple Sclerosis. All subjects underwent a comprehensive MRI protocol at 3 T measuring brain white and grey matter (lesions, volumes and magnetization transfer ratio) and cervical cord involvement. Linear regression models were used to estimate age- and gender-adjusted group differences between clinical phenotypes after 30 years, and stepwise selection to determine associations between a large sets of MRI predictor variables and physical and cognitive outcome measures. At the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS. Across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the Expanded Disability Status Scale; cortical lesions alone explained 43%. Grey matter volume, cortical lesions and gender explained 43% of the variance of Timed 25-Foot Walk. Reduced cortical magnetization transfer ratios emerged as the only significant explanatory variable for the symbol digit modality test and explained 52% of its variance. Cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogeneous disease duration, indicating that this should be the target of therapeutic interventions.”

  12)  “Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome”: Ismail Koubiyr et al

  -At baseline, GM volumes did not differ between PwCIS and HC, but hippocampal MD (mean diffusivity) was higher in PwCIS than HC (p < 0.01). Over 1 year, GM alterations became more widespread with putamen and hippocampus volumes decreasing in PwCIS (p < 0.01), and cortical thinning in different parts of the cortex along with a significant increase of MD. Hippocampus MD at baseline could predict its volume loss (R² = 0.159; p < 0.05) and cortical thinning was associated to microstructural damage (Spearman’s rho ranging from −0.424 to −0.603 with p < 0.003).

  -Along with MS being a diffuse inflammatory disease, GM showed a differential vulnerability at the early stage spreading from hippocampus to the cortex. Hippocampus volume loss could be predicted by its MD at baseline.
  

  13.  “A 30-Year Clinical and Magnetic Resonance Imaging Observational Study of Multiple Sclerosis and Clinically Isolated Syndromes” by Karen K Chung, MBBS et al

  -used 2010 McD criteria

  -120 participants over 30 years; 80 developed MS by 30 years; in terms of EDSS: 

  42% remained full ambulatory (EDSS scores less than or equal to 3.5), all of 

  whom had RRMS; 4% had RRMS and EDSS greater than 3.5; 34% had SPMS with 

  EDSS greater than 3.5; and MS contributed to death in 20%

  -the strongest early predictors (within 5 years of presentation) of secondary 

  progressive MS at 30 years were presence of baseline infratentorial lesions and 

  deep white matter lesions at 1 year

  -people presenting with a brainstem CIS were at greater risk than those 

  presenting with either ON or transverse myelitis; this was consistent with the higher proportion of brainstem subjects with baseline IT lesion present compared to ON and transverse myelitis; the change in EDSS scores from nadir to 5 years was also largest in the brainstem CIS group

  –Baseline EDSS scores were not significantly associated with 30-year outcome

  -5-year EDSS scores greater than or equal to 2.5 was a significant predictor of SPMS following a CIS

  -13 of 14 (93%) of people who progressed by greater than or equal to 2 EDSS points between nadir and 5 years had transitioned to SPMS

  -for predicting 30-year EDSS score less than or equal to 3.5 vs EDSS score greater than 3.5 outcome, EDSS scores at nadir and 5 years were significant, more so than EDSS changes between these time points, and the predictive value of EDSS scores at 5 years was, unsurprisingly, greater than at earlier time points

  -a greater proportion of people with nadir EDSS scores greater than or equal to 2.5 progressed to 3 year EDSS scores greater than 3.5

  -the strongest early MRI predictors of 30-year EDSS scores greater than 3.5 were the presence of (1) baseline IT lesions, with 86% progressing to EDSS scores greater than 3.5 by 30 years vs 34% of those without and (2) 1 year DWM lesions, with 60% reaching EDSS scores greater than 3.5 vs 13% of those without

  -30 year outcomes could, in part, be predicted by early EDSS scores and more robustly by MRI-derived regional lesion counts

  -MRI lesion counts provided to be better predictors than EDSS scores and lesion location was more important than lesion number

  -it was early IT and DWM lesions that had the greatest long term prognostic value…in people with baseline IT and DWM lesions by 1 year, the chances of having SPMS were 94%…those with 1 or more IT lesions by 1 year were 5 times more likely to have died due to MS than the rest of the cohort

  -IT lesions have previously been linked with less favorable outcomes in people with MS after a mean follow-up of 7.7 years

  14.  “Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome” by Ismail Koubiyr et al

  -at baseline, GM volumes did not differ between PwCIS and HC, but hippocampal MD (mean diffusivity) was higher in PwCIS than HC

  -over 1 year, GM alterations became more widespread with putamen and hippocampal volumes decreasing in PwCIS and cortical thinning in different parts of the cortex along with a significant increase of MD

  -Hippocampus MD at baseline could predict its volume loss and cortical thinning was associated to microstructural damage

  -GM showed a differential vulnerability at the early stage spreading from hippocampus to the cortex; hippocampus volume loss could be predicted by its MD at baseline

  -in order to study the selective vulnerability of GM, diffusion tensor imaging (DTI) allows to explore the microstructural integrity of the structures; a few studies used this technique in CIS, showing abnormal results in the thalamus, hippocampus, and cerebellum, suggesting microstructural changes from the early stages of MS

  -there was a differential vulnerability of the hippocampus compared to the rest of the GM

  -in PwCIS lateral ventricles volumes increased, reflecting deep brain atrophy, whereas putamen and hippocampus volumes significantly decreased

  -the mean CTh significantly decreased in 1 year; regionally, multiple brain areas of significant cortical thinning in both hemispheres were observed; this cortical thinning was noticed in the bilateral frontal and temporal lobes, left insula and right parietal lobe

  -regarding microstructural changes, PwCIS showed significantly higher MD in the left frontal, left temporal, left cingulate and bilateral parietal lobes

  -baseline hippocampus MD was able to predict hippocampus volume loss after 1 year; T2 LL was taken into account in this model and was not responsible for the volume loss

  -mean diffusivity change from year 0 to year 1 was strongly correlated to the cortical thinning in the left frontal lobe, the right parietal lobe, and the left temporal lobe

  -no correlation found between EDSS and MRI (volumetric and DTI) abnormalities; these abnormalities were not able to predict the conversion to MS after 1 year

  -the present study showed differential GM vulnerability as microstructural damage spread from the deep gray matter (hippocampus) to the cortex 1 year after the CIS; this microstructural damage occurred before irreversible gray matter atrophy

  -at baseline, there was no sign of GM atrophy in PwCIS compared to HC; however, microstructural damage was already present and the hippocampus was the first and only GM structure altered; the hippocampus showed increased MD compared to controls

  -the damage occurring to the hippocampus was further confirmed by a significant volume loss after 1 year of follow up; the putamen showed also a significant volume loss at follow up

  -the hippocampus MD was able to predict its volume loss independently of lesion volume

  -microstructural abnormalities as detected by DTI in the hippocampus, preceding volume loss and predicting it, suggested that a primary tissue alteration within this structure is involved in the neurodegenerative process

  -activation of microglia/macrophages, associated with demyelination and neurodegeneration, has been pathologically observed in DGM, including the hippocampus, in MS

  -in EAE, microglial activation within the hippocampus has been observed in association with neuronal dysfunction and memory impairment independently of demyelination

  -the persistence of the prediction after adjustment on lesion load suggests an independent mechanism

  -it is well-established that GM atrophy including cortical and DGM atrophy is mainly responsible for the development of the whole brain atrophy

  -it has also been suggested that meningeal inflammation and microglial activation could lead to direct pathology of the GM and some evidence of this mechanism has been observed in progressive MS

  -in 1 study showing some level of DGM atrophy, lesion volume was superior to 2 cm cubed

  -in another study, CIS patients with lesion load superior to 4.49 cm cubed had lower DGM volumes than those with a median lesion load inferior to 4.49cm cubed

  -this suggests that in the CIS samples with lower lesion load, the pre-clinical stage developed before CIS was shorter, explaining why atrophy was not developed

  -we did not observe significant cortical thinning at baseline

  -we observed some cortical thinning during the follow-up period in bilateral frontal lobes, bilateral temporal lobes and left insular and right parietal lobes; these results are in line with the study by Rocca et al showing GM atrophy of frontal, temporal, and parietal lobes in CIS patients 1 year after the onset of the disease; microstructural abnormalities in the cortex appeared only after 1 year of follow up as opposed to hippocampuses 

  -MD of bilateral parietal lobes, left frontal, left temporal and left cingulate lobes was not only significantly increased after 1 year in PwCIS; this result did not only reflect atrophy because of CSF contamination

  -A recent studying using 7 Tesla MRI showed the existence of a gradient of pathology in the cortex of MS patients, suggesting that the pathological process was driven from the pial surface and supported the role of inflammation within the cortex in relation with meningeal inflammation

  -cortical volume loss seems to parallel DGM volume loss at these very early stages of MS; however, microstructural damage starts within the hippocampus first

  15.  “Cortical involvement determines impairment 30 years after a clinically isolated syndrome” by Lukas Haider et al

  -63 patients were studied 30 years after their initial presentation with a clinically isolated syndrome; 27 developed RRMS; 15 SPMS; and 21 experienced no further neurological events

  -at the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS

  -across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the EDSS; cortical lesions alone explained 43%

  -grey matter volume cortical lesions and gender explained 43% of the variance of T25FW

  -reduced cortical magentization transfer ratios emerged as the only significant explanatory variable for the SDMT and explained 52% of its variance

  -cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogenous disease duration

  -cortical MTR emerged as the strongest significant predictive factor in all models to explain cognitive outcome measures

  -cortical lesions were the clearest determinant of a progressive disease course and that cortical involvement 30 years after symptom onset was the dominant factor explaining both physical and cognitive outcomes

  -cortical lesions were absent in all individuals who remained CIS; found in 3 of 27 who developed RRMS; present in all 15 individuals who developed SPMSe

  -subpial demyelination accounted quantitatively for most of the cortical involvement

  -leukocortical lesions only reveal the tip of the iceberg

  -primary cortical demyelination is highly specific for MS

  -disability measures were frequently explained by grey matter related to MRI measures 

  -a dominant role for cortical involvement for prediction of current and future disability 

  -current structural MRI sequences are relatively insensitive to biologically and clinically relevant aspects of tissue injury, and the networked nature of the brain

  -thalamic atrophy has been repeatedly suggested as an early correlate of present and subsequent disability in MS; group differences for thalamic volume in our study were significant comparing CIS and RRMS and CIS and SPMS, RRMS compared with SPMS was far from the significance level

  -cortical involvement was the main MRI feature that distinguished SPMS from RRMS

  16. “Lesion location across diagnostic regions in multiple sclerosis” by Viola Pongratz et al

  -in patients with CIS, lesion clusters in white matter tracts in the subcortical area have been shown to predict conversion to RRMS as did lesion clusters in the diagnostic regions

  -a new subcortical lesion in a follow up MRI of a patient with CIS demonstrates dissemination in time according to the diagnostic criteria and has also been interpreted as active disease in pivotal clinical trials

  -supratentorial white matter lesions neither directly abutting the ventricles nor the cortical ribbon were classified as subcortical lesions

  -at baseline: subcortical lesions found in 93%

  -follow up EDSS correlated with total lesion numbers in all regions but not with the number of new lesions; EDSS at baseline correlated with periventricular lesion volume only

  January 21, 2025

  dementia, health, mental-health, mri, multiple-sclerosis

  ---

• Neurofilament Light as a marker/predictor of severity, progression, conversion to SPMS, etc in MS

  1. “NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study”: Timo Uphaus et al

  -age at diagnosis, sNflL greater than or equal to 7.3 pg/ml are independent predictors of the relapse-free progression outcome

  -overall predictive accuracy of sNfL at baseline for prediction of relapse-free progression 12 months prior to FU of 82%

  -patients experiencing transition to SPMS had higher sNfL values at FU compared to patients without transition (conversion: 10.4 pg/ml vs non-conversion: 6.9 pg/ml) whereas baseline sNfL levels did not differ between later SPMS converters and non-converters

  -individual longitudinal sNfL increases (FU higher than baseline) were more frequent in patients transition to SPMS (70.4%) than non-converters (47.3%)

  -patients with both progression only and inflammation and progression at FU showed increased sNfL levels at baseline compared to patients with stable disease (progression only: 13.8 pg/ml; inflammation and progression: 12.3 pg/ml; stable: 5.3 pg/ml

  -patients with inflammation and progression at FU exhibited the highest sNfL values at FU (sNfL inflammation and progression: 7.9 pg/ml vs patients without signs of inflammation or progression: 4.8 pg/ml

  -patients experiencing inflammation only at FU showed higher sNfL values at FU compared to stable patients (sNfL inflammation only: 7.1 pg/ml)

  -we aimed to unravel the ability of sNfL assessment to dissect inflammatory activity from disease progression

  -patients with sNfL levels below 7.3 pg/ml have a rather low probability of experiencing disability progression; this might help to stratify immunomodulatory treatment strategies on an individual level and thereby enable patients to balance the potential long-term risk of side effects vs necessary treatment strength

  -sNfL remained in the model after multivariable correction for age at sampling

  -our observations expand previous findings, demonstrating an increased risk of EDSS worsening within the 12 months after sampling in patients with sNfL above the 80th percentile of healthy controls and increased to 15% in patients with sNfL values above the 97.5% percentile

  -we observed the highest sNfL values in patients with disability relevant inflammatory activity (inflammation and progression), suggesting a role of sNfL for monitoring both disease progression and inflammatory activity

  -sNfL at baseline was increased in patients with progression in presence and absence of inflammatory activity at FU

  -while elevated sNfL levels reflect currency ongoing inflammatory-driven (focal) damage, they more importantly identify those early inflammatory processes resulting in later axonal loss associated with EDSS progression in the long run

  -sNfL measures are capable of predicting disability progression at 12 months prior to 6 year follow up due to their ability to reflect disability relevant neuronal damage and are able to discriminate SPMS patients thereby facilitating an earlier diagnosis of patients at risk

  2. “Serum Neurofilament Light: A Biomarker of Neuronal Damage in Multiple Sclerosis” by Giulio Disanto et al

  -sNfL percentiles for age 45: 80th: 29.1 pg/ml; 90th: 33.9 pg/ml;  95th: 38.9 pg/ml; 97.5th: 44.1 pg/ml; 99th: 51.9 pg/ml

  -greater than 9 brain T2 lesions: 48 pg/ml

  -2-9 brain T2 lesions: 30.2 pg/ml

  -negative OCBs: 26.8 pg/ml

  -male gender: 44.2 pg/ml

  -this implies disease duration as a proxy for age

  -sNfL concentrations were higher in PPMS/SPMS than CIS/RRMS

  -positive associations were also found in univariate analyses between sNfL and EDSS

  -increase in sNfL per EDSS unit increase was lower in PPMS/SPMS than in CIS/RRMs

  -the decrease in SNfL with time since start of new treatment appeared similar across different DMTs

  -the probability of having experienced worsening of EDSS within 6-12 months before

  sampling was higher in patients with sNfL values above vs below the 90th, 95th, 97.5th 

  and 99th percentiles

  -patients with sNfL above the 97.5th percentile had greater than 4-fold odds of having 

  experienced EDSS worsening in the previous 6-12 months

  -the proportion of patients experiencing EDSS worsening within 12 months after sampling gradually increased with increasing sNfL percentile category

  -sNfL is best explained by ongoing age-related neuronal degeneration

  -ECL assay is less sensitive than SIMOA

  -results in MS strongly suggest that sNfL levels reflect ongoing neuronal damage irrespective of the underlying pathogenic mechanism

  -clear positive association between sNfL and focal inflammatory MRI lesions 

  -weak associations between sNfL and brain T2 and GE lesions in CIS patients

  -sNfL measurements could be used to indicate recent neuronal damage and this could be particularly useful in cases of “clinically silent disease” or when clinical changes are difficult to interpret

  -high sNfL levels were also associated with a higher risk of future clinical relapses and EDSS worsening

  3. “Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis”: Pietro Maggi, MD et al

  -patients with greater than or equal to 2 PRLs compared to those with greater than or equal to 1 PRL had higher age-adjusted sNfL percentiles

  -sNfL percentile levels were higher in PRLS greater than or equal to 2 cases

  -MSSS (MS Severity Score scale) was not affected by DMT or T2 lesion load

  -PRL in greater than or equal to 2 cases had on average 16 percentile point higher sNfL

  -higher T2 lesion load and shorter disease duration were associated with 21% and 7% higher odds of having greater than or equal to 2 PRLs

  -most patients with 2 or more PRLs had sNfL levels above the 80th percentile

  January 21, 2025

  health, inflammation, multiple-sclerosis, nutrition, wellness

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• Brain Atrophy in MS Research

  1. “Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes”: N De Stefano et al

  -” There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease.”

  -”This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.”

  2. “Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets”: N De Stefano et al

  -”Compared with placebo (-0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (-0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (-0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p < 0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at 2 years and vice versa”

  -”Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.”

  3. “Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study”: Cecilie Jacobsen et al

  -”Over 5 years, patients with disability progression showed significantly increased loss of whole brain (-3.8% vs -2.0%, p<0.001), cortical (-3.4% vs -1.8%, p=0.009) and putamen volume changes (-10.6% vs -3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (-5.5% vs -3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression.”

  -”This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up”

  4. “Brain atrophy and lesion load predict long term disability in multiple sclerosis”: Veronica Popescu et al

  -”In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R(2)=0.74 in the whole group and R(2)=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R(2)=0.68), lesion volumes in moderately impaired relapse onset patients (R(2)=0.21) and whole brain atrophy in primary progressive MS (R(2)=0.34).”

  -”This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.”

  5. “Eight-year follow-up study of brain atrophy in patients with MS”: E Fisher et al

  -”Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial.”

  -”The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.”

  6. “A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG)”: J H Simon

  -”Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement.”

  -”In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.”

  7.  “Cerebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years”: Benjamin Turner 

  -”Pathology and magnetic resonance imaging (MRI) studies have provided evidence of widespread axonal loss and reductions of cerebral and spinal cord volume in multiple sclerosis (MS). Atrophy measures on MRI may be a useful surrogate marker of worsening disability in MS, but the published studies are of relatively short duration. Change in brain volume (atrophy) was measured over a four-year period in 20 patients with relapsing-remitting (RR) and 18 with secondary progressive (SP) MS using three-dimensional (3D) MRI acquired during treatment trials of interferon-beta-1a (Rebif). Brain parenchymal and lateral ventricle volume changes were determined and correlated with clinical measures. Over four years, brain parenchymal volume (BPV) decreased in RRMS and SPMS patients by 0.9% (P = 0.006) and 0.3% (P = 0.118), respectively, and the lateral ventricle volumes increased by 15% (P < 0.0001) and 13% (P < 0.0001), respectively. In RRMS patients both lateral ventricle volume (r = 0.63, P = 0.004) and BPV change (r = -0.47, P = 0.037) were related to disability change, as measured by the Expanded Disability Status Scale. Even though a small study and despite the possible confounding effects of interferon treatment, this study demonstrated an association between measures of cerebral atrophy and worsening disability. The data also provides evidence that brain atrophy can be detected early in the disease course and central white matter atrophy as reflected by ventricle enlargement appears to be a continuous process.”

  8.  “Cortical atrophy is relevant in multiple sclerosis at clinical onset” by Massimiliano Calabrese et al

  -”Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset.  It correlates with clinical disability and is partially independent from WM inflammatory pathology”

  9.  “Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes” by Catherine M Dalton et al

  -”change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3”

  -”these results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis and this is only moderate related to lesion accumulation”

  10.  “Brain atrophy at onset and physical disability in multiple sclerosis”: Juan Ignacio Rojas et al

  -”Brain atrophy rates during the first year of disease were predictive of disease progression in our population.”

  11.  “Correlation of clinical findings and brain volume data in multiple sclerosis”: Yara Dadalti Fragoso

  -”There was a significant correlation between higher disability and decreased brain volume (total and grey matter). Increased lesion load in the brain and higher number of relapses in the previous year were also independently correlated with decreased brain tissue volume and with increased disability. “

  12. “Combined analysis of global and compartmental brain volume changes in early multiple sclerosis in clinical practice:  A Pichler

  -”At baseline, all the brain volume metrics, except cGMV, were significantly lower; and the T2-LL was significantly higher, in patients with MS rather than CIS. During the follow-up, only the PBVC was higher in MS (p = 0.008) and this difference was driven by converters from CIS to MS. Quartiles of PBVC did not allow us to predict conversion to MS, but were associated with the degree of disability.”

  -”PBVC is the most sensitive marker of progressing atrophy and a higher PBVC was generally associated with more active disease; however, it did not serve to predict the course of MS on an individual basis, in this study.”

  13.   “Cortical atrophy is relevant in multiple sclerosis at clinical onset”: Massimiliano Calabrese 

  -”We found a significant global cortical thinning in p-MS (2.22 +/- 0.09 mm), RR-MS (2.16 +/- 0.10 mm) and SP-MS (1.98 +/- 0.11 mm) compared to CIS (2.51 +/- 0.11 mm) and HV (2.48 +/- 0.08 mm). The correlations between mean CTh and white matter (WM) lesion load was only moderate in MS (r = -0.393, p = 0.03) and absent in p-MS (r = -0.147, p = 0.422). Analysis of regional CTh revealed that the majority of cortical areas were involved not only in MS, but also in p-MS. The type of clinical picture at onset (in particular, pyramidal signs/symptoms and optic neuritis) correlated with atrophy in the corresponding cortical areas”

  -”Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology.”

  14. “Brain atrophy in relapsing-remitting multiple sclerosis: relationship with ‘black holes’, disease duration and clinical disability”: A Paolillo

  -”MS patients had significantly lower supratentorial, infratentorial brain volume and corpus callosum area than healthy subjects (P<0.01). Supratentorial brain volume was significantly related to corpus callosum area (r=0.58; P<0.01) and T1 hypointense lesion load (r=0.48; P<0.01), but not with T2 hyperintense lesion load. Infratentorial/supratentorial ratio was significantly associated with disease duration and EDSS score (r=-0.34; P=0.02 and r=-0.49; P<0.01, respectively). This study documents that brain atrophy is an early MRI finding in RR MS and it is closely related to ‘black holes’ burden. The use of relative values (infratentorial/supratentorial ratio) may increase the conspicuity of correlation between clinical and MRI findings.”

  15. “Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study”:

  Cecilie Jacobsen

  -”Over 5 years, patients with disability progression showed significantly increased loss of whole brain (-3.8% vs -2.0%, p<0.001), cortical (-3.4% vs -1.8%, p=0.009) and putamen volume changes (-10.6% vs -3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (-5.5% vs -3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression.”

  -”This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.”

  14)  “Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine”: E Ghione et al

  -”All brain volume measures differentiated MS and healthy individuals and were associated with disability progression, but the lateral ventricle volume assessment was the most feasible”

  15) “Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging”:

  Declan Chard

  -”In multiple sclerosis (MS) it is emerging that the most visible element of pathology, white matter (WM) lesions, represents only a fraction of the disease burden borne by the brain; non-lesional WM is also damaged, as is the grey matter (GM). Evidence is also accruing that GM damage may be a major determinant of longer-term outcomes in MS, and that such damage occurs from the earliest clinical stages of the disease”

  16. “Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis”: R Zivadinov

  -”Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy”

  17.  “Optical coherence tomography reflects brain atrophy in multiple sclerosis: A four-year study”: Shiv Saidha 

  -”Rates of ganglion cell + inner plexiform layer (GCIP) and whole-brain (r = 0.45; p < 0.001), gray matter (GM; r = 0.37; p < 0.001), white matter (WM; r = 0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r = 0.67; p < 0.001) than relapsing-remitting MS (RRMS; r = 0.33; p = 0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r = -0.30; p = 0.02) and inner nuclear layer (r = -0.25; p = 0.04) atrophy rates.”

  -”Over time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression.”

  18.   “Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes”: Catherine M Dalton

  -”While brain atrophy occurs early in the clinical course of multiple sclerosis, exactly how early, which tissues are affected and the rate at which early atrophy occurs are unclear. Regional brain atrophy was investigated in 58 patients recruited within 3 months of onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis, who were followed-up for 3 years. At 3 years, 31 subjects had developed multiple sclerosis as defined by the McDonald criteria, while 27 had not (13 had MRI-visible brain lesions and 14 did not). In those who developed multiple sclerosis, the mean decrease in grey matter fractional volume (GMF, as a fraction of total intracranial volume) was -0.017 (-3.3%) and was significantly larger than in the combined lesion-positive and lesion-negative CIS subjects [-0.005 (-1.1%), P = 0.001]. No decrease in white matter fractional volumes (WMF) was seen. Change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3 (r = -0.428, P = 0.004). These results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis, and this is only moderately related to lesion accumulation. Longer-term follow-up is required to determine whether early grey matter atrophy is associated with subsequent disability or cognitive impairment.”

  19.  “The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study”: D T Chard 

  -”Change in lesion load in the first five years was more closely correlated to disease related brain atrophy at 14 years than later changes in lesion load, although the correlation was only moderate (Spearman correlation = -0.528, p = 0.004”

  -” From this, it appears that early rather than later focal lesion accumulation relates to subsequent brain atrophy, but factors unconnected directly with lesion formation probably also play a significant role in determining such atrophy”

  20.   “Brain atrophy in clinically early relapsing-remitting multiple sclerosis”: D T Chard

  -” These results indicate that significant brain atrophy, affecting both grey and white matter, occurs early in the clinical course of multiple sclerosis. The lack of correlation between lesion load measures and WMF suggests that pathological changes in white matter may occur by mechanisms which are at least partly independent from overt lesion genesis in early multiple sclerosis.”

  21.   “Deep gray matter volume loss drives disability worsening in multiple sclerosis”: Arman Eshaghi

  -”Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001).”

  -”This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.”

  22.   “Regional brain atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype”: Elisabetta Pagani 

  -”During follow-up, patients with relapsing-remitting MS (RRMS) differences significant atrophy around the ventricular system; pericerebellar spaces; cerebellar tentorium; putamen; corpus callosum; cingulate sulcus; hippocampus; parieto-occipital fissure; lateral fissure; and frontal, parietal, temporal, and occipital cortex. Patients with secondary progressive MS developed significant atrophy of the cingulate sulcus; pulvinar; caudate nucleus; anterior orbital gyrus; mammillary body; fourth ventricle; and regions of frontal, parietal, temporal, and occipital cortex. Patients with primary progressive MS developed significant atrophy of the bilateral central sulcus; caudate nucleus; prepontine and quadrigeminal cisterns; lateral ventricle; and regions of frontal, parietal, temporal, and occipital cortex. In all phenotypes, the development of atrophy in some regions was significantly correlated with the accumulation of T2- and T1-visible lesions and clinical disability (r = -0.57 to -0.86).”

  -”In MS, brain atrophy develops involving different structures in the different phenotypes. While ventricular enlargement is predominant in RRMS, cortical atrophy seems to be more important in the progressive forms. Measures of regional brain atrophy were significantly correlated with disability, suggesting that this approach is promising for bridging the gap between clinical and MR imaging findings in MS.”

  23.   “Accelerated evolution of brain atrophy and “black holes” in MS patients with APOE-epsilon 4”: Christian Enzinger

  -”Apolipoprotein E (APOE)-epsilon4 has been associated with an unfavorable course of multiple sclerosis (MS). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of “black holes” (BHs) in such patients. Here, we have studied the impact of the APOE genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine MS patients underwent ApoE genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 +/- 1.1 years to assess lesion load (LL) and BVC. In APOE-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without APOE-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in MS patients with APOE-epsilon4.”

  24.   “Eight-year follow-up study of brain atrophy in patients with MS”: E Fisher

  -”Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial.”

  -”The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.”

  25.   “A serial 10-year follow-up study of brain atrophy and disability progression in RRMS patients”: Robert Zivadinov

  -”In multiple sclerosis (MS) patients with CDP compared to those without, the greatest effect size percentage volume change from baseline to follow-up was detected for WB (d = 0.55, -7.5% vs -5.2%, p < 0.001), followed by vCSF (d = 0.51, +41.1% vs +25.7%, p < 0.001), cortical (d = 0.49, -7.7% vs -6.2%, p = 0.001), and GM (d = 0.40, -7.1% vs -5.8%, p = 0.006) volumes. Mixed-effects model analysis, adjusted for age, sex, and treatment change, showed significant interactions between CDP status and percentage changes for WB and vCSF (p < 0.001), cortical (p = 0.02), and GM (p = 0.04) volumes.”

  -”WB and cortical atrophy, and enlargement of vCSF spaces are associated with development of CDP on serial yearly MRI assessments over a period of 10 years.”

  26.  “A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis”: R Zivadinov

  -” In the 2 years of the study the mean change for T2 and T1 lesion volumes and brain parenchymal volumes were +1.7 ml (95% confidence interval (95% CI) 1.3-2.2, p=0.005, (29.8%); +0.2 ml, 95% CI 0.15-0.26, p=0.004, (25%); and -32.3 ml, 95% CI 24.2-42.3, p<0.0001, (2.7%), respectively. Overall, 14 patients (26.4%) were judged to be cognitively impaired at baseline and 28 (52.8%) at the end of the follow up. Of the 18 neuropsychological tests and subtests employed in the study, patients with multiple sclerosis failed 5.8 (SD 2.3) tests at the baseline and 8.4 (SD 2.9) (p<0.0001) tests at the end of the study. When the cognitive changes were examined in individual patients, five (9.4%) of them were considered cognitively improved, 33 (62.3%) remained stable, and 15 (28.3%) worsened over 2 years. T2 and T1 volume changes in improved, stable, and worsened patients did not show any significant difference, whereas brain parenchymal volume decrease in cognitively worsened patients was significantly greater (-66 ml (5.4%), 95% CI 37-108.9, p=0.0031). The cognitive impairment was independently predicted over 2 years only by the change of brain parenchymal volumes (R=0.51, p=0.0003). Ten patients (18.9%), who worsened by one or more points in the EDSS during the follow up period had significant decreases in brain parenchymal volumes (-99 ml (8%), 95% CI 47.6-182.3, p=0.005). At the end of the study the loss of brain parenchyma correlated significantly with change in EDSS (r= 0.59, p<0.0001).”

  -”In the early phase of relapsing-remitting multiple sclerosis the cognitive deterioration relies more on the development of brain parenchymal volume atrophy than on the extent of burden of disease in the brain. The loss of brain parenchymal volume underlies the progressive accumulation of physical disability from the initial phase of the disease, which becomes more demonstrable only if studied with longer observation periods. Probably, the main pathological substrate of brain atrophy in the early stage of the disease is early axonal loss, which causes the progression of neurological deficits and the development of cognitive impairment. These data support the debated opinion that disease modifying therapy should be initiated as early as possible.”

  27.   “Brain Atrophy Is Associated With Disability Progression in Patients with MS Followed in a Clinical Routine”: E Ghione et al

  -brain atrophy assessment is an important biomarker in MS because of its relationship with neurodegeneration and disability progression

  -is partially independent from lesion burden

  -predicts development of physical and cognitive disability

  -patients with CIS showed the highest annualized cumulative percentage LVV (lateral ventricle volume)change among all 3 study groups-

  -a greater LVV change in patients with CIS who developed CDMS compared w those who remained stable was found within 1 year of follow-up

  -brain atrophy rates are independent of MS phenotype

  28.  “Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options” by Athina Andravizou et al

  -tissue loss in the CNS represents the net effect of all destructive pathogenic processes during the disease course

  -neurons occupy 46% of the tissue volume; myelin: 24%; and glial and other cells: 30%

  -GM holds much less myelin than WM (about 1/10th) while neurons comprise the most abundant component

  -atrophy rates may also be influenced to some extent by the genetic makeup of a person; HLA genotypes considered as ‘high risk for MS” (DRB1 and DQB1) have been associated with significantly lower WM and GM volumes alongside with higher mean annualized percentage of brain volume change compared with medium and low risk HLA genotypes

  -the correlation between demyelination foci and whole brain atrophy is still a matter of debate; some studies have found a strong association while others have not, suggesting that separate pathologic processes may also contribute to tissue destruction

  -a longitudinal 14-year study found that atrophy is more related to early rather than late focal lesion volumes

  -microglia activation, meningeal inflammation, iron deposition, oxidative stress and diffuse axonal damage in the NAWM are additional mechanisms that are at least partly independent from WM injury; the lack of a significant relationship between white matter fraction (WMF) and T2 lesion load further support this hypothesis; biopsy studies also confirm that atrophy may proceed even in the absence of inflammation

  -it has been suggested that the pathogenic trajectory of brain atrophy changes with disease progression from primarily inflammatory to less inflammatory and primarily neurodegenerative in the late stages of the disease

  -NfL protein is only expressed in neurons; reflects the axonal integrity and stability of neurons

  -whole brain atrophy has a significant imaging association with physical disability as measured by EDSS

  -brain volume changes during the first year after disease onset, estimated by PBVC, were the best predictor of future neurologic impairment regardless of the intermediate relapse rate

  -increased BVL has been correlated with disability progression independent from the number of previous relapses or the T2 lesion load in RRMS

  -when patients with CDMS were compared to patients with CIS, at baseline, all brain volume metrics except for cortical GM were significantly lower in the MS cohort; over a mean follow-up period of about 3 years, the annual PBVC values were significant lower in CIS patients when compared to the MS cohort

  -changes of brain parenchymal fraction (BPF) have been shown to predict cognitive impairment over 2 years in patients with MS

  -cortical atrophy was the best predictor of poor cognitive functioning even while mild impairment was detected; poor cognitive functioning has been associated with significant cortical thinning, esp in the fronto-parietal cortical and subcortical regions

  -brain atrophy occurs as early as CIS

  January 21, 2025

  brain, dementia, health, mental-health, multiple-sclerosis

  ---

• Lack of Efficacy of DMTs: in general and based on age and disease stage Research

  1. “Relapsing-remitting and primary progressive multiple sclerosis treated with ocrelizumab: A comparative study” by Luis A Rodriguez de Antonio et al

  -”Ocrelizumab was very effective in reducing relapses and MRI activity.  The rate of progression was slowed down; however, the effect was more evident for pwRRMS than for pwPPMS over time”

  2. “Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments” by Ann Marie Weideman et al

  -More than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis 

  -the efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age

  -the regression predicts zero efficacy beyond approximately age 53 years

  -high-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years

  -this meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy

  -higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and after, age 53, the model suggests there there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient

  3. “Effectiveness of Ocrelizumab in Primary Progressive Multiple Sclerosis: a Multicenter, Retrospective, Real-world Study (OPPORTUNITY) by Clara G Chisari et al

  -Ocrevus does not affect the B cell reconstitution and pre-existing humoral immunity

  -Ocrevus reduced the percentage of patients with 12-week confirmed EDSS disability progression

  -another recent observational comparative study of a small cohort of 13 PPMS and 29 RRMS indicated that the effect of Ocrevus on disability progression was more evident for RRMS

  -our results showed that disease activity, disease duration and EDSS at the time of Ocrevus initiation seem to not impact the disability outcomes (hard to believe; other studies have not found this to be the case; very suspicious) 

  4. “Data-driven risk/benefit estimator for multiple sclerosis therapies” by Bibiana Bielekova et al

  -current DMTs inhibit disability caused by lesion activity only

  -DMTs ineffective against PILA

  -not every CEL causes an MS relapse

  -Ocrevus has no efficacy on PILA after 12 weeks

  -DMT efficacy decreases with increasing age at treatment onset

  5. “Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis (Review) by Filippini G et al (Cochrane Review): 

  6. “Alemtuzumab versus interferon beta1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial”

  -”Alemtuzumab’s consistent safety profile and benefit in terms of reductions of relapses support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here” (Dr. Cohen lead author/investigator)

  7. “Natalizumab strongly suppresses cortical pathology in relapsing-remitting multiple sclerosis”: F Rinaldi

  -Natalizumab significantly reduced accumulation of new cortical lesions (0.2±0.6,range 0-3) compared to immunomodulatory agents (1.3±1.1 togli spazio, range 1-6, p=0.001) and no treatment (2.9±1.5, range 1-8, p<0.001). The percentage of patients with new cortical lesions was also lower in natalizumab-treated patients (20%) compared to IMA-treated and untreated patients (68.0% and 74.2%; p<0.001 for both comparisons). Furthermore, the progression of cortical atrophy was significantly reduced by natalizumab (% change=1.7%) compared to IMA (3.7%, p=0.003) and no therapy (4.6%, p<0.001). Finally, a greater percentage (51.4%) of natalizumab-treated patients remained disease-free (no clinical or MRI evidence of disease activity or progression) compared to IMA-treated (18%, p=0.001) and untreated patients (5.7%, p<0.001).

  -Natalizumab treatment significantly decreases cortical lesion accumulation and cortical atrophy progression in severe relapsing-remitting MS. While supporting the inflammatory origin of cortical lesions, our results highlight the significant impact of natalizumab on cortical pathology.

  8. Regarding fingolimod

  –

  9. Regarding siponimod

  -6% difference in 3 month CDP between siponimod and placebo in SPMS (EXPAND study; *Dr Bar-Or on this study) 

  -”no treatment has consistently shown efficacy in slowing disability progression in patients with SPMS” (EXPAND study)

  10. SUNBMEM trial: Ozanimod: did not prove efficacy in delaying confirmed disability progression

  11. Ponesimod: OPTIMUM trial: did not prove efficacy in reducing confirmed disability progression but reduced brain volume loss

  12. x) “Bioavailable central nervous system disease-modifying therapies for multiple sclerosis” by Hans-Peter Hartung, Amit Bar-Or, et al

  -DMTs have limited efficacy in progressive forms of the disease where cells in the CNS play a crucial role; DMTs for relapsing MS reduce relapse rates by suppressing peripheral immune cells

  -most therapies for RMS have limited efficacy in treating progressive forms of MS and targeting peripheral inflammation is not sufficient to slow disease progression

  -for DMTs to be effective in progressive MS, they must also target chronic CNS inflammation

  -as the disease progresses, compartmentalized inflammatory mechanisms that predominantly involve microglia, B cells and other innate cells of the CNS become more prominent, leading to neurodegeneration, CNS atrophy, and disability worsening

  -CNS inflammation persists from resident innate immune cells contributing to a chronic, localized inflammatory response

  -Fingolimod: when compared with IFN Beta-1a treatment, there were no significant differences in time to disability progression or the proportion of participants with confirmed progression at 12 months

  -Ozanimod: proportions of participants with CDP at 3 and 6 months were not significantly different between treatment groups in the phase 3 clinical trials

  -ponesimod: did not impact time to 12 or 24 week confirmed disability accumulation compared with teriflunomide in participants with RMS

  -an observational, multicenter study provided Class IV evidence for aHSCT as an immunosuppressant MS therapy because treatment induced durable disease remission for over 10 years in most participants with RRMS (including extremely aggressive forms of MS) (Boffa G: “Long-term clinical outcomes of hematopoietic stem cell transplantation in multiple sclerosis”) (Class IV evidence is a classification of evidence that represents the lowest level of quality in a study)

  13.   “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 (EDSS 6) in patients with PIRA within the first 5 years of MS compared with patients whose first PIRA appeared later in the disease course

  -TREAT-MS study: outcome: intermediate-term risk of disability (*not significant-what needs to be measured is whether these DMTs reduce the actual disability, not the risk of it, and also, this needs to be evaluated over the long-term, not just the intermediate-term, to see whether the DMTs alter the natural history of the disease or not)

  -DELIVER-MS study: outcome: slowing brain volume (*not significant because the tolebrutinib trial showed that it slowed disability progression but not brain volume loss, as I understand it)

  14.  “Evolution of Disease-Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients with Multiple Sclerosis” by Brandi L Vollmer et al

  -among those 45 years and older, there was no different between oral DMTs vs infusible DMTs in terms of odds of greater disease activity 

  -current techniques to evaluate disease activity (including markers of progressive disease) are inadequate and there is likely “silent” worsening separate from overt relapses 

  15.   “DMT Use in Progressive MS”: Cleveland Clinic

  -growing evidence suggests that relapsing and progressive MS are not distinct entities but rather gradual accumulation of disability independent of inflammatory disease activity can conceivably occur at any stage of the disease; both processes can occur simultaneously within a single patient

  -ORATORIO trial: benefit of Ocrevus in patients younger than or equal to 45 years old was not statistically significant 

  -DMT risks include: infection and malignancy 

  16. “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”

  17. From: “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

  18. “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”

  19. “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”

  20. “Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic”: Jerome de Seze et al

  1. Rituximab in RRMS: RIFUND-MS trial: no significant difference was observed between the groups (rituximab and tecfidera) for the EDSS, even though rituximab outperformed tecfidera in terms of reducing relapses/ARR, no new MRI activity, and reduced numbers of T2 and GD+ lesions
  2. Ocrevus, Phase II trials (OPERA I and OPERA II): results were inconclusive due to a failure of the statistical hierarchical testing procedure; in the OLE, patients switching from IFN-B-1a to Ocrevus (at 2 years) had a similar ARR at 5 years; the proportion of patients withCDP at five years was lower with Ocrevus compared to patients switching from IFN-B-1a to Ocrevus (16.1% to 21.3%, respectively); brain volume loss was unchanged in patients treated with Ocrevus for 5 years
  3. Kesimpta in RMS: ASCLEPIOS I and ASCLEPIOS II: annualized rate of brain volume loss did not differ significantly between patients treated with Kesimpta vs Aubagio, even though Kesimpta outperformed Aubagio in terms of T1 GD+ lesions; in ASCLEPIOS I, patients on Kesimpta had a lower adjusted ARR than those in the Aubagio group (similar results seen in ASCLEPIOS II)
  4. Briumvi in RMS:
  5. ULTIMATE II trial: 43% of Briumvi group showed NEDA vs 11.4% in Aubagio group; however, no significant difference in the worsening of disability at 12 weeks was found between Briumvi and Aubagio patients in the pooled analysis of the 2 trials (5.2% vs 5.9%); brain volume change was not significant between the 2 groups

  21) “Understanding multiple sclerosis as a disease spectrum: above and below the clinical threshold” by Stephen Kireger, Karin Cook and Carrie M Hersh

  -Indeed, if progressive mechanisms start early, and MS is a disease spectrum, then all RRMS trials are SPMS trials if analyzed carefully enough

  22) “Changes in disability in people with multiple sclerosis: a 10-year prospective study” by David Conradsson et al

  -The large proportion of our sample receiving immunomodulatory treatment at baseline needs to be taken into account when interpreting the study results.  The increase in EDSS scores in our study was similar to previous -1year follow-ups, monitoring cohorts, where a low proportion received immunomodulatory treatment.  The similarities in disease progression between our cohort and previous cohort studies might indicate that changes in severity of MS, as measured with EDSS, occur regardless of immunomodulatory treatment.  

  23) “Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS”: Lorscheider J et al

  -this study provides class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression

  -SPECTRUM and IMPACT trials

  -In line with the outcomes of most of the previous trials, our present study shows that, on average, the currently available anti-inflammatory drugs do not prevent relapse-unrelated disability accumulation of disability in patients with established SPMS in the short-term-our recent study showed that highly-effective immunotherapy mitigates predominantly relapse-dependent disability accrual over 11 years in patients with moderately advanced or advanced relapse-onset MS (regardless of their SPMS)

  24) “The Faces of “To Late”-A Surprisingly Progressive Cohort of “Stable” Relapsing Remitting Multiple Sclerosis Patients”: Alin Ciubotaru et al

  -80% of RRMS patients in this study (65% were on high efficacy DMTs) showed some type of PIRA after 12 months

  -an elevated level of PIRA was found in our cohort, with high efficacy drugs providing no supplementary protection

  25) “Disease-modifying therapies for relapsing/active secondary progressive multiple sclerosis-a review of population-specific evidence from randomized clinical trials”: Antonios Bayas et al

  -the potential of these drugs to reduce relapse-independent progression remains unclear

  -The authors suggested that anti-inflammatory DMTs have no substantial effect on relapse-independent disability progression in SPMS without a distinct inflammatory phenotype

  26) “Late-Onset MS: Disease Course and Safety-Efficacy of DMTS: Maria Chaira Buscarinu et al

  -In AFFIRM (NCT00027300) and SENTINEL (NCT00030966) studies, Natalizumab failed to reduce progression in patients with MS older than 40 years; in this case factors such as male sex, EDSS score higher than 3.5 and fewer than 9 baseline T2 lesions turn out to be predictors of non-responsiveness (30). Fingolimod showed similar results in the FREEDOMS trial (NCT00289978), being not able to reduce disability progression and relapses in patients older than 40 years, compared to placebo

  -Among the other first-line DMT, dimethyl fumarate (CONFIRM trial; NCT00451451) (26), peginterferon-β-1a (ADVANCE trial; NCT00906399) (27), and teriflunomide (TEMSO trial; NCT00134563) (28) reduced annual relapses rate (ARR) in both young and old patients (threshold of 38 years for teriflunomide and 40 years for the others); however, all these DMTs failed to reduce the risk of disability accumulation.

  -they found that IFN-β use was not statistically related with a slowing of disability progression

  -ozanimod failed to reduce both relapses and disability progression. (NCT02047734; NCT02294058)

  -Among the more recent DMTs, Ocrelizumab, a B cell-depleting anti-CD20 antibody, failed to reduce ARR in patients older than 40 years (33)

  -The age-related changes that take place in the immune system, a process known as immunosenescence generally result in a higher susceptibility to infections, a reduced response to vaccines and a higher prevalence of autoimmunity and neurodegenerative disorders. These processes may affect the safety of DMT, so that potentially severe adverse events are more common in elderly patients.

  -A pressing problem in clinical practice is the safety of certain DMT in LOMS people: especially the depleting drugs seem to pose older subjects at higher risk of serious infections or cancer.

  x)  “Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis”: Katharine Harding et al

  -In this cohort study including 592 people, those who received high-efficacy treatment initially had a smaller increase in Expanded Disability Status Scale score at 5 years vs those who first received moderate-efficacy disease-modifying therapy.

  -These findings suggest that real-world escalation approaches may be inadequate to prevent unfavorable long-term outcomes 

  x) “Early use of high-efficacy disease‑modifying therapies makes the difference in people with multiple sclerosis: an expert opinion”: Massimo Filippi et al

  -Growing evidence is suggesting that disability progression in MS patients is only partially secondary to the occurrence of new focal inflammatory demyelinating lesions and clinical relapses (i.e., relapse-associated worsening), whereas progression independent of relapse activity (PIRA) starts from the biological onset of MS and becomes the principal and most relevant driver of disability accumulation in the progressive forms of MS [21,22,23].

  – The neurologists of this Expert Opinion paper agreed that a drug should be defined as HE-DMT if its substantial therapeutic effect can be proven on ≥ 1 outcome of inflammation/demyelination but also on ≥ 1 outcome of disease progression (Table 1).

  x)  “A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives”:by Emanuele D’Amico

  -However, preliminary results from a phase III trial of Natalizumab in patients with SPMS (ASCEND; NCT01416181) showed no efficacy in terms of delaying disability assessed by EDSS, Timed 25-Foot Walk, and 9-Hole Peg Test [101].

  -Rituximab did not delay the disability progression compared to placebo.

  x) “Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis”: Brandi L Vollmer et al

  –Results: Younger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration

  –Conclusion: In a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks.

  1. “Multiple Sclerosis: Current and Emerging Disease-Modifying Therapies and Treatment Strategies”: Dean M. Wingerchuk, MD, MSc, FRCP(C) et al

  – Two of the greatest are lack of therapies that convincingly slow or halt progressive forms of the disease

  -Furthermore, epidemiologic studies124 and therapeutic studies in established SPMS125 suggest that there may be an important dissociation between the inflammatory and neurodegenerative phases of MS. In other words, successful elimination of early inflammation may not necessarily translate into an effect on degenerative progression, the mechanisms of which could be operative even early in relapsing disease.

  x) “The association between disability progression, relapses, and treatment in early relapse onset MS: an observational, multi-centre, longitudinal cohort study”: 

  • Valery Fuh-Ngwa et al
  • -disability worsening outcomes significantly contributed to relapse risk each year (HR = 2.96, C.I 2.91–3.02), and persisted over time (HR = 3.34, C.I 2.90–3.86), regardless of DMT treatments. 

  x) “The Effect of Disease Modifying Therapies on Disability Progression in 

  Multiple Sclerosis: A Systematic Overview of Meta-Analyses”: Suzi B Claflin et al

  -Overall, the meta-analyses included in this overview offer good evidence that, 

  in general, DMT improve short-term (≤2–3 years) disability progression 

  outcomes in adults with relapsing forms of MS compared to placebo. 

  x) “The Effect of Disease Modifying Therapies on Disease Progression in Patients 

  with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis”: Georgios Tsivgoulis 

  -In subsequent subgroup analyses, neither dichotomization of DMDs as “first” and “second” line RRMS therapies [(RR = 0.72, 95% CI = 0.65–0.80) vs. (RR = 0.72, 95% = 0.57–0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64–0.87) vs. RR = 0.74 (95% CI = 0.66–0.83); p = 0.92] had a differential effect on the risk of disability progression

  x) “Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis”: Gabriel Bsteh et al

  -evidence is growing that even in RMS patients treated with highly efficacious DMT, long-term disability worsening is not uncommon and associated with accelerated brain atrophy but largely independent of relapse activity 

  -a high proportion of disability worsening events occur in the absence of relapses even in RMS patients treated with high efficacious DMT

  -PIRA might represent the stratum of MS-associated neurodegeneration that is largely unaffected by DMTs predominantly targeting CNS-inflammation

  x)  “Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning”: Ratchford JN et al

  -A relevant proportion of patients classified as RRMS experienced PIRA within a 5-year period, accounting for 59-66% of all CDW events. While highly effective DMT reduced the risk of CDW, we could not demonstrate a consistent effect on PIRA in patients with RRMS in our prospectively followed cohort study.

  x) “Macular ganglion cell-inner plexiform layer thinning as a biomarker of disability progression in relapsing multiple sclerosis”: Bsteh G et al

  -Results: Baseline mGCIPL thickness <77 µm was associated with an increased risk (hazard ratio: 2.7, 95% confidence interval (CI): 1.5-4.7, p < 0.001) of disability progression. An aLmGCIPL cut-off ⩾1 µm accurately identified clinically progressing patients (87% sensitivity at 90% specificity) and was a strong predictor of clinical progression (odds ratio: 18.3, 95% CI: 8.8-50.3).

  -Conclusion: We present evidence that cross-sectionally measured mGCIPL thickness and annualized thinning rates of mGCIPL are able to identify clinically progressing RMS with high accuracy.

  x) “Disability progression unrelated to relapses in relapsing-remitting multiple sclerosis: insights from the Swiss multiple sclerosis cohort study”: Lorscheider J et al

  -Methods: Using the Swiss Multiple Sclerosis Cohort Study, we included patients with RRMS and ≥3 prospective visits with available EDSS and Functional System (FS) scores. Confirmed disability worsening (CDW) was defined as EDSS increase of ≥1.5 steps if baseline EDSS step was 0, ≥1.0 step if 1.5-5.5, or ≥0.5 steps if >5.5, confirmed after ≥6 months. A roving baseline approach was applied to maximise sensitivity (Kappos et al., MSJ 2018), whereas re-baselining and a fixed baseline were used for a more conservative estimate. For PIRA, absence of a relapse between baseline, index event and confirmation visit was required. Influence of exposure to disease modifying treatment (DMT) was both modeled as categorical and as time-dependent covariate and analysed with Cox proportional hazards models adjusted for gender, age, disease duration, baseline EDSS and pre-baseline relapse activity. DMT was categorised in highly effective DMT, i.e. monoclonal antibodies, oral DMT and platform injectables.

  Results: We included 917 RRMS patients with a median follow-up of 4.6 years. The roving baseline approach identified 198 (22%) patients experiencing CDW. Of these, 131 fulfilled the definition for PIRA (66% of patients with CDW, 14% of all eligible patients). The number of identified PIRA and CDW decreased when using a fixed baseline (92/157, 59%) or re-baselining (93/157, 59%). Highly effective DMT was associated with a lower risk for CDW (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2-0.7, p< 0.001) compared to no treatment. However, we observed only a trend regarding PIRA (HR 0.5, 95% CI 0.3-1.1, p=0.08), which disappeared when modelling treatment as a time-dependent covariate (HR 0.8, 95%CI 0.4-1.4, p= 0.393).

  x) “AAN Summary of Practice Guidelines for Clinicians: Practice Guideline: Disease-Modifying Therapies for Adults with Multiple Sclerosis” (April 24, 2018)

  -Nothing in this document states that DMTs slow or work on disease worsening or progression aside from Ocrelizumab for PPMS (Starting: Recommendation 17, page 3)

  -”Switching: Recommendation 1: “Now that several DMTs…have demonstrated efficacy for the prevention of clinical relapses and new MRI-detected lesions…” (page 4)

  -Switching: Recommendation 2: “None of the available DMTs is completely effective against relapses and MRI activity” (page 4)

  -Starting: Recommendation 3 (page 1): “Clinicians should counsel people with MS that DMTs are prescribed to reduce relapses and new MRI lesion activity”

  -Starting: Recommendation 9: “Multiple studies of DMTs in people with relapsing forms of MS who have had recent relapses or MRI activity or both have shown benefit of DMT in terms of reducing relapses and reducing MRI activity…Clinicians should offer DMTs to people with relapsing forms of MS with recent clinical relapses or MRI activity”

  -Starting: Recommendation 14: “…pivotal trials of alemtuzumab, fingolimod, and natalizumab showed a reduction in relapses and MRI measures in people with MS with highly active disease…Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab for people with MS with highly active MS”

  -Switching: Recommendation 1: “Ongoing disease activity, measured either by clinical relapses or new MRI-detected lesions…Now that several DMTs are available and have demonstrated efficacy for the prevention of clinical relapses and new MRI-detected lesions…”

  -Stopping: Recommendation 2: “…interferon beta reduces the risk of relapse but does not delay disability progression as measured by the EDSS”

  x) “AAN Summary of Practice Guideline for Patients and their Families: Starting Disease-modifying Therapies for Multiple Sclerosis”

  -”DMTs help slow the disease process”

  -”and might help keep your condition stable”

  -”Disease-modifying therapies (DMTs) for MS help slow the disease process…”: “Lesions”; “Relapses”

  -*How come the AAN DMT Guideline document for clinicians doesn’t say anything or make any claims about DMTs slowing disease process?”-SUPER ODD! 

  “The table at the end of this sheet shows the evidence for lowering risk of relapse in relapsing-remitting multiple sclerosis”

  x) “Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis”: Alexander Rae-Grant, MD et al

  -”in-study disease progression”

  -”The following DMTs are more effective than placebo in reducing the risk of disability progression…”

  -”The following DMTs are more effective than other DMTs in reducing the risk of disability progression in people with RRMS…alemtuzumab (vs IFN-B) and ocrelizumab (vs IFN-B)

  -The following DMTs are probably more effective than placebo in reducing the risk of in-study disability progression…

  -”Cladribine is probably more effective than placebo in reducing the risk of disability progression…”

  -*everything in here uses “probably,” “possibly,” “reducing the risk,” etc*

  x) “Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis”: Harding K

  -Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).

  – Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD)

  -After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. 

  -However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.

  x)  “Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis”: Brown JWL

  -Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta.

  x) ”Initial high-efficacy disease-modifying therapy in multiple sclerosis: a nationwide cohort study”: 

  -We found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT.

  -This study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.

  -*”Class III evidence”

  January 21, 2025

  health, mental-health, ms, multiple-sclerosis, wellness

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• Kesimpta  FDA Approval Package (APPLICATION NUMBER: 125326Orig1s070)

  Kesimpta  FDA Approval Package (APPLICATION NUMBER: 125326Orig1s070)

  -Kesimpta treatment reduced the relative risks of 3-month and 6- month confirmed disability worsening by 34.4% and 32.5%, respectively, as compared to teriflunomide.  The pooled results from two adequate and well-controlled trials provided substantial evidence of efficacy that Kesimpta reduced the likelihood of accumulation of disability in patients with relapsing forms of MS relative to an active comparator with a significant effect on disability worsening.

  -To support an indication for the treatment of relapsing forms of MS, clinical trials should demonstrate that a therapy is associated with a significant, clinically meaningful decrease in the frequency of MS-associated relapses, typically measured as an annual relapse rate (ARR). Some therapies approved for the treatment of relapsing forms of MS, including another anti-CD20 therapy, have also demonstrated an additional significant reduction of the accrual of disability over three-month or six-month observational periods.

  -The applicant presents results from two adequate and well-controlled Phase 3 clinical trials as the basis of support for the effectiveness of ofatumumab for the treatment of relapsing forms of MS. These two efficacy and safety studies, Studies COMB157G2301 and COMB157G2302, were both randomized, double-blind, double-dummy, active-controlled studies comparing ofatumumab to teriflunomide treatment in adult patients with relapsing forms of MS. These trials were identical in design with the same primary efficacy outcome measure, ARR, along with the same secondary endpoints (3- month confirmed disability worsening, the number of gadolinium-enhancing T1 lesions, the number of new or enlarging T2 lesions, 6-month confirmed disability worsening, serum neurofilament light chain levels at 3 months, brain volume loss, and 6-month confirmed disability improvement) that were analyzed in a hierarchical analysis. 

  -A meta-analysis for the combined data (pooled from Studies G2301 and G2302) was prespecified for the key secondary disability-related endpoints, 3-month confirmed disability worsening, and 6-month confirmed disability worsening because the individual studies were not powered for these analyses. If both studies successfully rejected the null-hypothesis of the primary endpoint, disability-related endpoints could be tested at 1-sided significance level of 0.024 using the combined data from both studies, regardless of the outcomes of MRI- and neurofilament-related endpoints.

  -Pooled Disability Outcome Findings As per prior agreement, the disability-related key secondary outcome assessments of disability at 3-month and 6-months were to be based on analyses of the pooled data from Studies G2301 and G2302 because each individual trial would not be adequately powered to provide individual study outcome analyses of these relatively small number of outcomes. 3-month Confirmed Disability Worsening (*see Table 11, page 31*)

  -The time to 3-month disability worsening was statistically significant (p=0.002) in favor of Kesimpta treatment. Patients treated with Kesimpta had a lower rate of confirmed 3-month disability worsening as compared to patients treated with teriflunomide. Even though the individual studies were not powered for this endpoint, analysis of Study G2301 and G2302 individually yielded statistically significant results for the 3-month disability worsening endpoint (p=0.029 and p=0.036, respectively.) In prior clinical trials, teriflunomide reduced the confirmed disability progression at a 3-month interval relative to placebo; Kesimpta is therefore demonstrating superiority over a treatment that has a significant effect on disability progression in relapsing forms of MS.

  -The biometrics reviewer confirmed the findings of the pre-specified secondary outcome analysis and several sensitivity analyses including a “worst-case” analysis in which Kesimpta-treated patients who discontinued from the study due to lack of efficacy were considered as having a confirmed 3-month disability worsening outcome (a risk reduction for ofatumumab vs. teriflunomide of 32.9%, p=0.004). The confirmed sensitivity analyses replicated the pre-specified analysis result, which is a significant effect on prevention of 3-month disability worsening in patients treated with Kesimpta. 

  -The time to 6-month disability worsening was statistically significant (p=0.012) in favor of Kesimpta treatment. Patients treated with Kesimpta had a lower rate of confirmed 6-month disability worsening as compared to patients treated with teriflunomide. Even though the individual studies were not powered for this endpoint, analysis of Study G2301 and G2302 individually yielded statistically significant results for the 6-month disability worsening endpoint for Study G2301 (p=0.022) but the result for Study G2302 was not significant (p=0.209). In clinical trials, teriflunomide reduced the confirmed disability worsening relative to placebo; in the pooled analysis, Kesimpta is therefore demonstrating superiority over a treatment that has a significant effect on disability worsening in relapsing forms of MS. The biometrics reviewer confirmed the findings of the pre-specified secondary outcome analysis and several sensitivity analyses including a “worst-case” analysis in which Kesimpta-treated patients who discontinued from the study due to lack of efficacy were considered as having a confirmed 6-month disability worsening outcome (a risk reduction for ofatumumab vs. teriflunomide of 29.6%, p=0.022). The confirmed sensitivity analyses largely replicated the pre-specified analysis result, which is a significant effect on prevention of 6-month disability worsening in patients treated with Kesimpta. (*See Table 12 (page 33) and Figure 3 (page 34)

  -6-month Confirmed Disability Improvement The following table and figure, taken from the biometrics review, summarizes the time to 6-month confirmed disability improvement in both trials (*See Table 13, page 35).  The analysis of confirmed disability improvement at 6-months was not statistically significant (p=0.094).
  -Conclusions on the Substantial Evidence of Effectiveness:  Approval for Kesimpta (ofatumumab) for relapsing forms of MS is supported by efficacy findings from two adequate and well-controlled clinical trials, Studies G2301 and G2302. These studies demonstrated that Kesimpta treatment yielded consistent statistically significant reductions of over 50% (50.5% and 58.5%) in ARR relative to an active comparator. teriflunomide. A reduction of over 50% in ARR is a robust and meaningful outcome for a therapeutic to treat relapsing forms of MS; in these studies, a significant treatment effect on ARR is established relative to teriflunomide, an active comparator with its own significant treatment effect on ARR. The significant MRI findings in these two studies provide additional supportive findings for the primary clinical outcome analysis. With respect to the primary efficacy endpoint, these studies have provided substantial evidence of effectiveness for Kesimpta in the treatment of patients with relapsing forms of MS and a strong treatment effect on relapses. The disability assessment outcomes from Studies G2301 and G2302 support the conclusion that Kesimpta is superior to the active comparator with respect to reducing the likelihood of confirmed disability worsening. Various sensitivity analyses demonstrate that this effect on disability worsening is independent of relapse occurrences in the trial and is maintained through more conservative sensitivity analyses that assume worsening with missing final confirmation assessments. Drs. Rodichok and Ling note that the applicant’s methodology for calculating disability “worsening” at both time points differed from the conventions used for some historical assessments of confirmed disability “progression” in other development programs. Dr. Rodichok asked for, via an information request, an exploratory analysis from the applicant that utilized calculation methods excluding patient relapse visits as events that initiated or confirmed EDSS progression assessment and assumed patients with any worsening, but without confirmation of disability visits, had confirmed disability progression. The results of this exploratory analysis were confirmed by Dr. Ling and are discussed in the biometrics review. This confirmed disability progression analysis is conservative, even more so than the “worst case” scenario in the applicant’s sensitivity analyses, but the findings from this analysis remained significant for the 3-month confirmed disability progression endpoint (nominal p=0.012) and revealed a strong trend (nominal p=0.074) for the 6- month confirmed disability progression endpoint. Thus, the requested exploratory analysis of outcomes using this conservative approach were consistent with the applicant’s primary analysis and did not suggest that the applicant’s findings regarding disability worsening were driven entirely by relapses and absent confirmatory visits. Finally, the Division requested an analysis that allowed a clinical relapse to occur at the initiation of a disability progression, but excluded relapses that occurred within 30 days of a disability worsening confirmation visit for the 3- month disability confirmation endpoint. This analysis, verified by biometrics reviewer, again demonstrates a significant effect of Kesimpta on disability progression at 3 months (relative risk reduction of 34.9%, nominal p=0.002) in comparison to teriflunomide. The findings of this exploratory analysis are nearly identical to the prespecified primary analysis findings, and this analysis aligns with the Division’s current approach to disability outcome assessment. Thus, there is confidence that the robust treatment effect on disability progression from the applicant’s pre-specified primary analysis that is described in Section 14 of the labeling is comparable to the disability progression outcomes obtained in both historical and contemporary analyses, regardless of the differences in the definition of progression and how relapses were considered within the analytical methods. Furthermore, disability worsening or progression as an endpoint is considered to be a singular concept. A treatment effect that prevents an increase in disability as measured by EDSS over 3 months and 6 months represents only a difference in time of observed persistence, not an achievement of a treatment effect on two entirely unrelated, unique, clinically relevant outcomes. Achieving a significant finding on a single disability outcome, or both 3-month and 6-month outcomes, represents the same fundamental finding, that is, a relative prevention of a clinically relevant accumulation of disability over a quantum of time (*Underlining mine*)

  January 21, 2025

  back-pain, cancer, health, mental-health, multiple-sclerosis

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