3.1.14 Disease Modifying Therapies
Most phase III trials on DMTs in PwMS evaluate MS relapses, magnetic resonance imaging (MRI) outcomes, and progression of physical disability as the outcomes of primary interest. Existing DMT practice recommendations generally focus on optimizing these outcomes (Freedman et al., 2020; Montalban et al., 2018; Rae-Grant et al., 2018). The Canadian MS Treatment Optimization Recommendations published in 2020 state that there is insufficient evidence to support switching DMTs to improve cognition. However, cognition is considered in the assessment of disability, with a recommendation to administer the SDMT every two to three years (Freedman et al., 2020). In older adults with non-active MS (Lublin et al., 2020) and/or advanced disability, DMT discontinuation is generally recommended (Knox, Saini, & Levin, 2020). DMTs are not indicated for the treatment of existing MS symptoms. Starting DMTs early in the disease course of MS is more likely to delay the progression of physical disability (Iaffaldano et al., 2021). Most studies to date evaluating cognitive disability and DMT treatment are observational in nature or involve the analysis of secondary cognitive outcomes from RCTs.
Alemtuzumab is a monoclonal antibody directed against the CD52 surface antigen on T- and B-lymphocytes, natural killer cells, monocytes, and macrophages. Although the mechanism of action of alemtuzumab in MS is unknown, its therapeutic effect involves cell surface binding to T- and B-lymphocytes to mediate lysis and depletion of T- and B-cells ("Drug monograph: Alemtuzumab," 2021).
Table 13. Study Examining Alemtuzumab for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
|
Riepl et al. 2018 Alemtuzumab improves cognitive processing speed in active multiple sclerosis – a longitudinal observational study GermanyPre-Post Ninitial=21, Nfinal=21 |
Population: Mean age=32.38yr; Sex: males=11, females=10; Disease course: RRMS; Mean EDSS=2.12; Mean disease duration=4.98yr. Intervention: Participants received treatment with alemtuzumab. Outcomes were assessed at baseline prior to the first infusion of alemtuzumab, and after the second course of alemtuzumab (mean time span: 15.05mo). Cognitive Outcomes/Outcome Measures: Rey Auditory Verbal Learning Test (RAVLT); Digit span forwards, backwards; Rey Complex Figure Test (RCFT); S-words and animals; Trail Making Test (TMT-A, B); Symbol Digit Modalities Test (SDMT); Standard Progressive Matrices (SPM). |
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Discussion
One pre-post study by Riepl et al. (2018) has examined the effect of alemtuzumab on cognitive function in PwMS. Twenty-one participants with RRMS received two treatments of alemtuzumab and were followed for an average duration of 15 months. Cognitive function was assessed using an extensive neuropsychological test battery (verbal learning and memory, visual memory, attentional span, processing speed, visuoconstruction, and executive function). There were non-significant decreases in the percentage of participants with CI at baseline compared to last follow up; however, the only statistically significant improvements pre and post were on two tests of processing speed (SDMT and Rey Complex Figure Test), and these gains were reported as clinically meaningful change for 57% of participants.
Conclusion
There is level 4 evidence that alemtuzumab may have stabilizing effects on overall cognition and may improve processing speed in persons with relapsing-remitting MS (one pre-post study; Riepl et al. 2018).
Preliminary evidence suggests alemtuzumab may have stabilizing effects on overall cognitive function and may be beneficial for improving processing speed in persons with relapsing-remitting MS.
3.1.14.2 Cyclophosphamide (with Methylprednisolone)
Cyclophosphamide is an alkylating chemotherapy drug which targets rapidly dividing cells by binding to deoxyribonucleic acid and interfering with mitosis. Cyclophosphamide crosses the blood brain barrier and therefore has good CNS bioavailability. Its mechanism of action in MS is through generalized suppression of cell-mediated and humoral immunity. Small open-label trials and one small placebo-controlled Canadian study supported the use of cyclophosphamide in MS. However, it is rarely utilized in MS care due to the risk of serious adverse events and the availability of more targeted MS DMTs (Awad & Stuve, 2009; Portaccio et al., 2003; The Canadian Cooperative Multiple Sclerosis Study Group, 1991).
Table 14. Study Examining Cyclophosphamide and Methylprednisolone for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Zephir et al. 2005 One-year cyclophosphamide treatment combined with methylprednisolone improves cognitive dysfunction in progressive forms of multiple sclerosis FrancePre-Post Ninitial=30, Nfinal=24 |
Population: MS participants (n=30): Mean age=40yr; Sex: unspecified; Disease course: PPMS=11, SPMS=19; Median EDSS=6; Mean disease duration=8yr. Healthy controls (n=15): Mean age=37.9; Sex: males=7, females=8. Intervention: Participants received cyclophosphamide treatment in monthly intravenous doses of 700 mg/m2 with methylprednisolone (1g/d) for 12mo. Assessments were performed at baseline (M0) and after 6 (M6) and 12mo (M12). Cognitive Outcomes/Outcome Measures: Wechsler Adult Intelligence Scale-Revised (WAIS-R); Verbal intelligence quotient (VIQ); Performance intelligence quotient (PIQ); Global intelligence quotient (GIQ); Forward span; Backward span; Spatial Span; Grober and Buschke test (GB): immediate recall, free recall; Wechsler memory scale logical memory subtest: retention; Rey retention; Phonemic fluency; Semantic fluency; Go/no-go; Crossed tapping; Stroop Test 2-1; T/V fluency; Trail making test A; Trail making test B-A; Stroop 1. |
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Discussion
One study, a prospective uncontrolled 12-month study, examined cognitive outcomes in PwMS treated with cyclophosphamide in combination with methylprednisolone in progressive MS participants. When compared to baseline, there was a significant improvement on several cognitive measures at six and 12 months (Zephir et al., 2005). However, the study did not include an untreated MS control group.
Conclusion
There is level 4 evidence that cyclophosphamide combined with methylprednisolone may improve general cognitive impairment, verbal memory, inhibition, and verbal language skills in persons with progressive MS (one pre-post study; Zephir et al. 2005).
Preliminary evidence suggests cyclophosphamide combined with methylprednisolone may improve general cognitive impairment efficiency, verbal memory, inhibition, and phonemic fluency in persons with progressive MS.
Dimethyl fumarate is indicated for the treatment of relapsing forms of MS. Dimethyl fumarate has anti-inflammatory and neuroprotective properties, and thus can have beneficial effects on inflammation and oxidative stress which are central pathologic factors in MS. As such, dimethyl fumarate may help delay disability and disease progression in MS ("Drug monograph: Dimethyl Fumarate," 2021). For other studies on dimethyl fumarate see also section 3.1.14.7.2 of this module.
Table 15. Study Examining Dimethyl Fumarate for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Amato et al. 2020 Effects of 2-year treatment with dimethyl fumarate on cognition and functional impairment in patients with relapsing remitting multiple sclerosis ItalyPre-Post Ninitial=217, Nfinal=156 |
Population: Mean age=37.17yr; Sex: males=56, females=161; Disease course: RRMS; Mean EDSS=1.98; Mean disease duration=78.93mo. Intervention: Participants received dimethyl fumarate (120mg 2x/d increased to 240mg 2x/d) for 24mo. Outcomes were assessed at baseline and every 3mo thereafter. Cognitive Outcomes/Outcome Measures: Cognitive impairment (i.e., impaired cognitive function on ≥2 cognitive tests from the Brief Repeatable Battery and the Stroop Test): Paced Auditory Serial Addition Test 20, 30 seconds (PASAT-2, -3); Symbol Digit Modalities Test (SDMT); Spatial Recall Test (SPART); SPART delayed recall (SPART-D); Selective reminding test (SRT): consistent long-term retrieval (SRT-CLTR), delayed (SRT-D), long-term storage (SRT-LTS); Word List Generation (WLG); Cognitive Impairment Index (CII). |
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Discussion
Amato et al. (2020) conducted a pre-post study to examine the effect of dimethyl fumarate on CI in 217 participants with RRMS over 24 months. At baseline, 22.6% of participants exhibited CI, as defined by a failure in ≥2 of 10 tests from the BRB and the Stroop Test. The proportion of participants with CI remained stable at one year (n=59, 27.2%) and declined at two years (n=21, 9.7%). Of participants exhibiting CI at baseline who had available data at two years (n=34), 44.1% worsened and 55.9% did not experience worsening of cognition following treatment. The CI index improved significantly in one third of participants at two years compared to the first year (p<0.0001). Furthermore, there were significant improvements in most neuropsychological tests included in the battery over the study duration compared to baseline. Larger trials with a randomized design are needed to confirm the benefit of dimethyl fumarate on cognition in PwMS.
Conclusion
There is level 4 evidence that dimethyl fumarate may slow cognitive decline or improve cognitive impairment in persons with relapsing-remitting MS (one pre-post study; Amato et al. 2020).
Preliminary evidence suggests dimethyl fumarate may slow cognitive decline or improve cognitive impairment in persons with relapsing-remitting MS.
Glatiramer acetate is an immunomodulating, subcutaneous injectable therapy for use in RRMS. It is a synthetic protein composed of four amino acids. A proposed mechanism of action is through cross-reactivity with myelin basic protein, inhibiting the cell-mediated immune response to this antigen. For other studies on glatiramer acetate see also sections 3.1.14.5.2, 3.1.14.5.8, and 3.1.14.7.2 of this module.
Table 16. Studies Examining Glatiramer Acetate for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Weinstein et. al 1999 Neuropsychologic status in multiple sclerosis after treatment with glatiramer USARCT PEDro=9 Ninitial=251, Nfinal=248 |
Population: Glatiramer (n=125): Mean age=34.6yr; Sex: males=37, females=88; Disease course: RRMS; Mean EDSS=2.8; Mean disease duration=7.3yr. Placebo (n=126): Mean age=34.3yr; Sex: males=30, females=96; Disease course: RRMS; Mean EDSS=2.4; Mean disease duration=6.6yr. Intervention: Patients were randomized to receive daily subcutaneous injections of 20mg glatiramer acetate or matching placebo for 2yr. Outcomes were assessed at baseline and after 12 and 24mo of treatment. Cognitive Outcomes/Outcome Measures: Buschke Selective Reminding Test; 10/36 Spatial Recall Test; Symbol Digit Modalities Test (SDMT); Paced Auditory Serial Addition Test (PASAT); Word List Generation (WLG). |
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Ziemssen et al. 2016 QualiCOP: real-world effectiveness, tolerability, and quality of life in patients with relapsing-remitting multiple sclerosis treated with glatiramer acetate, treatment-naïve patients, and previously treated patients GermanyPre-Post Ninitial=754, Nfinal=754 |
Population: Mean age=38.6yr; Sex: males=204, females=550; Disease course: RRMS=709, SPMS=25, PPMS=8; Mean EDSS=unspecified; Mean disease duration=56.53mo. Intervention: Patients received glatiramer acetate in daily subcutaneous doses of 20mg/mL over 24mo. Assessments were performed at baseline and after every subsequent 3mo period. Cognitive Outcomes/Outcome Measures: Paced Auditory Serial Addition Test (PASAT); Multiple Sclerosis Inventory Cognition (MUSIC) scale: cognition. |
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Ziemssen et al. 2014 A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial GermanyPre-Post Ninitial=672, Nfinal=423 |
Population: Mean age=39.9yr; Sex: males=196, females=476; Disease course: RRMS=647, clinically isolated syndrome=1, other=9; Mean EDSS=3.0; Mean disease duration=97.2mo. Intervention: Patients who did not benefit from previous disease modifying treatment lasting 3-6mo were converted to receive glatiramer acetate at 20mg daily for 24mo. Assessments were performed at baseline and at 6, 12, 18, and 24mo. Cognitive Outcomes/Outcome Measures: Paced Auditory Serial Addition Test (PASAT). |
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Discussion
Only one RCT (Weinstein et al., 1999) compared the effects of glatiramer acetate to placebo on cognitive outcomes. The study sample included those enrolled in a phase III RCT of glatiramer acetate where the primary outcome pertained to MS relapse rates (Johnson et al., 1995). The neuropsychological results were published separately and included assessment of sustained attention, perceptual processing, verbal and visual special memory, and verbal fluency. There were no between group differences for any of the cognitive outcomes at 12 and 24 months. A statistically significant improvement in both groups was observed over time for components of the Buschke Selective Reminding Test, the 10/36 Spatial Recall Test, and the PASAT. At baseline, only the Word List Generation test (assessing verbal fluency) was impaired by greater than two standard deviations for both groups. In both groups, the Word List Generation test trended towards improvement over the study period.
Two pre-post studies reported on the effects of glatiramer acetate on cognition. Both studies provide limited information since cognitive outcomes were available for only a portion of the study cohorts at last follow up. In the first multicentre study (Ziemssen et al., 2014), 672 participants switched from another disease-modifying therapy to 20mg of glatiramer acetate once daily. After two years of glatiramer acetate treatment, data on the PASAT was available for only 72 participants (PASAT scores improved compared to baseline by 4.29 ± 9.28, p<0.0001).
The second pre-post study (Ziemssen et al., 2016) also included participants already on a treatment for MS (previously treated group [n=237], of which 38 had been on glatiramer acetate) and those who had never been on a treatment for MS (treatment naïve group, n=481). The treatment naïve group was subsequently started on 20mg daily of glatiramer acetate. The 24-month study was a multicentre, prospective observational real-world study (n=754 participants enrolled). There were no significant differences between the previously treated and treatment-naïve groups in the cognitive outcomes at two years. Cognitive data (PASAT and Multiple Sclerosis Inventory scale outcomes) were available for less than 50% of the cohort at last follow up. The Multiple Sclerosis Inventory scale assesses verbal short- and long-term memory, interference susceptibility, processing speed, and verbal fluency. The Multiple Sclerosis Inventory and PASAT scores both improved compared to baseline in both groups. For the PASAT, the treatment-naïve group improved +3.65 points (n=246) and the previously treated group improved +4.13 points (n=103). No studies extended beyond twenty-four months of follow up.
Conclusion
There is level 1b evidence that glatiramer acetate compared to placebo may not improve cognitive impairment in persons with relapsing-remitting MS (one randomized controlled trial; Weinstein et al. 1999).
Glatiramer acetate may not improve cognitive function more than placebo over two years in persons with relapsing-remitting MS.
Interferon beta (IFN-β) are injectable immunomodulatory medications with IFN-β-1b being the first DMT approved for the treatment of RRMS. The full mechanism of action is not known, although long-term safety of interferon use is well established. Phase III trials have demonstrated efficacy in reducing and preventing relapses in RRMS, but results are less consistent for trials in SPMS (Kappos et al., 2001; Panitch, Miller, Paty, Weinshenker, & North American Study Group on Interferon beta-1b in Secondary Progressive MS, 2004). The interferon trials leading to their approval for the treatment of MS did not include cognitive outcomes a priori. The majority of the data on interferons with respect to cognition are from registry or post-marketing studies. For other studies on IFN see also sections 3.1.14.5.1 to 3.1.14.5.8 and 3.1.14.7.2 of this module.
Table 17. Studies Examining Interferon Beta for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Rieckmann et al. 2019 Adherence to subcutaneous IFN β-1a in multiple sclerosis: final analysis of the non-interventional study READOUTsmart using the dosing log and readout function of Rebismart® GermanyCohort Ninitial=392, Nfinal=368 |
Population: Mean age=36.8yr; Sex: females=69.6%; Disease course: RRMS=83.7%; Severity: unspecified; Mean disease duration: 2.7yr. Intervention: 22ug or 44ug interferon beta-1a (single arm) 3x/wk for 24mo. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT); Fatigue scale for motor and cognitive functions (FSMC) cognitive subscale at 3, 6, 12, 18 and 24mo. |
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Kleiter et al. 2017 Adherence, satisfaction and functional health status among patients with multiple sclerosis using the BETACONNECT® autoinjector: a prospective observational cohort study GermanyCohort Ninitial=116, Nfinal=75 |
Population: Median age=40yr; Sex: females=69.2%; Disease course: RRMS=95.1%, CIS=4.9%; Median EDSS=2.0; Median disease duration=29.9mo (range 0–372.6). Intervention: Interferon beta-1b every other day for 24wks. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT); Fatigue Scale for Motor and Cognitive Functions (FSMC). |
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Mokhber et al. 2014 Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: a randomized clinical trial IranRCT PEDro=6 Ninitial=69, Nfinal=63 |
Population: Avonex (n=20): Mean age=31.11yr; Sex: males=8, females=12; Disease course: unspecified; Mean EDSS=1.52; Mean disease duration: unspecified. Rebif (n=23): Mean age=27.78yr; Sex: males=9, females=14; Disease course: unspecified; Mean EDSS=2.32; Mean disease duration: unspecified. Betaferon (n=22): Mean age=28.95yr; Sex: males=6, females=16; Disease course: unspecified; Mean EDSS=2.16; Mean disease duration: unspecified. Intervention: Patients were randomized to one of three forms of interferon beta for 12mo: Avonex (IFN-β-1a), Rebif (IFN-β-1a), or Betaferon (IFN-β-1b). Avonex was administered 30mcg 1x/wk via intramuscular injection; Rebif was administered 44mcg 3x/wk via subcutaneous injection; Betaferon was administered 0.25mg every other day via subcutaneous injection. Assessments were performed at baseline and after 12mo. Cognitive Outcomes/Outcome Measures: Selective Reminding Test (SRT): total, delayed recall (SRTD); Paced Auditory Serial Addition Test: 2,3 seconds (PASAT); Word List Generation (WLG); 10/36 Spatial Recall Test (SPART); Symbol Digit Modalities Test (SDMT). |
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Fischer et al. 2000 Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis USARCT PEDro=8 Ninitial=276, Nfinal=166 |
Population: Interferon beta 1a group (n=83): Mean age=36.1yr; Disease course: relapsing MS; Mean EDSS=2.3; Mean disease duration=6.7yr. Placebo group (n=83): Mean age=36.2yr; Disease course: relapsing MS; Mean EDSS=2.4; Mean disease duration=6.4yr.
For total study sample: Sex: males=38, females=128.
Intervention: Participants were randomized to receive interferon beta 1a (IFNβ-1a) or placebo. IFNβ-1a 30µg or placebo were administered intramuscularly 1x/wk for 104wks (2yr). Assessments were performed at baseline and 2yr. Cognitive Outcomes/Outcome Measures: Comprehensive Neuropsychological (NP) Battery: Set A (information processing/memory), Set B (visuospatial abilities/executive functions), Set C (verbal abilities/attention span); Brief NP Battery; Paced Auditory Serial Addition Test (PASAT). |
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Benešová & Tvaroh 2017 Cognition and fatigue in patients with relapsing multiple sclerosis treated by subcutaneous interferon β-1a: an observational study SKORE Czech RepublicPre-Post Ninitial=300, Nfinal=272 |
Population: Mean age=36.33yr; Sex: males=102, females=198; Disease course: RRMS; Mean EDSS=2.85; Mean disease duration=61.6mo. Intervention: Participants were treated with subcutaneous interferon β-1a over 2yr. Assessments were performed at baseline, and after 6, 12 and 24mo. Patients were subdivided into low-dose (22 mcg 3x/wk), high-dose (44 mcg 3x/wk), and dose escalation subgroups. Cognitive Outcomes/Outcome Measures: Paced Auditory Serial Addition Task (PASAT). |
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Hamdy et al. 2013 Does the disease course or treatment type have impact on executive functions and cognition in multiple sclerosis patients? A clinical and 3 tesla MRI study EgyptCohort Ninitial=30, Nfinal=30 |
Population: Mean age=24yr; Sex: males=8, females=22; Disease course: RRMS=25, SPMS=5; Mean EDSS=2.22; Mean disease duration=3.54yr. Intervention: 16 MS patients who were treated with interferon-β therapy were compared to non-interferon treated patients. Cognitive Outcomes/Outcome Measures: California Verbal Learning Test-2nd edition (CVLT-II); Brief Visuospatial Memory Test-Revised (BVMT-R); Paced Auditory Serial Addition Task (PASAT); Symbol Digit Modalities Test (SDMT); Wisconsin Card Sorting Test (WCST); Controlled Oral Word Association Test (COWAT). |
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Lacy et al. 2013 The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study USAPCT Ninitial=16, Nfinal=16 |
Population: Interferon beta (IFN-β-1b) group (n=9): Mean age=37.11yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=3.72; Disease duration: unspecified. Placebo/IFN-β-1b group (n=7): Mean age=33.14yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=2.29; Disease duration: unspecified. Intervention: Patients received IFN-β-1b treatment or placebo. After 5yr of treatment, all participants started IFN-β-1b for the remainder of the study. Assessments were performed after 2 and 4yr of treatment, and again at the 16yr mark. Cognitive Outcomes/Outcome Measures: Overall cognitive index score; Wechsler Memory Scale (WMS): Logical Memory subtest, Visual Reproduction subtest; Trail Making Test B (TMT-B); Stroop Color-Word Test (SCWT). |
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Patti et al. 2013 Subcutaneous interferon β-1a may protect against cognitive impairment in patients with relapsing-remitting multiple sclerosis: 5-year follow-up of the COGIMUS study ItalyCohort Ninitial=265, Nfinal=201 |
Population: Total population (n=201): Mean age=39yr; Sex: unspecified; Disease course: RRMS; Median EDSS=2.0; Mean disease duration=8yr. Low dose group (n=93). High dose group (n=108). Intervention: Patients received interferon beta-1a subcutaneously at a dose of 44 (high dose) or 22mcg (low dose) 3x/wk. This was a 5yr analysis; assessments were performed at baseline and every 12mo for 5yr. Cognitive Outcomes/Outcome Measures: Cognitive impairment (i.e., impaired cognitive function on ≥3 cognitive tests from Rao's Brief Repeatable Battery and the Stroop Test): Paced Auditory Serial Addition Test 20, 30 seconds (PASAT-20, -30); Symbol Digit Modalities Test (SDMT); Spatial Recall Test (SPART); Selective reminding test (SRT): consistent long-term retrieval (SRT-CLTR), delayed (SRT-D), long-term storage (SRT-LRS); Word List Generation (WLG); Cognitive impairment index. |
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Mori et al. 2012 Early treatment with high-dose interferon beta-1a reverses cognitive and cortical plasticity deficits in multiple sclerosis ItalyPre-Post Ninitial=80, Nfinal=76 |
Population: Presence of gadolinium-enhancing lesions (Gd+) group (n=38): Mean age=33yr; Sex: males=8, females=30; Disease course: RRMS; Mean EDSS=1.9; Mean disease duration=4.2yr. Absence of gadolinium-enhancing lesions (Gd-) group (n=42): Mean age=35yr; Sex: males=8, females=34; Disease course: RRMS; Mean EDSS=1.5; Mean disease duration=3.6yr. Intervention: Patients received high dose interferon beta-1a treatment, administered subcutaneously at a dose of 44mcg 3x/wk. Patients were grouped based on the presence of Gd-enhancing lesions on magnetic resonance imaging. Assessments were performed at baseline and after 6 and 24mo of treatment. Cognitive Outcomes/Outcome Measures: Paced Auditory Serial Addition Test (PASAT). |
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Melanson et al. 2010 Fatigue and cognition in patients with relapsing multiple sclerosis treated with interferon beta CanadaPCT Ninitial=50, Nfinal=40 |
Population: Subcutaneous (SC) interferon beta (IFNβ)-1a group (n=18): Mean age=38.33yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=1.49; Mean disease duration=5.45yr. Intramuscular (IM) IFNβ-1a group (n=8): Mean age=36.50yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=1.72; Mean disease duration=5.04yr. SC IFNβ-1b group (n=14): Mean age=39.14yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=1.71; Mean disease duration=4.21yr. Intervention: Participants received IFNβ therapy in one of three conditions: SC IFNβ-1a, SC IFNβ-1b, or IM IFNβ-1a. Assessments were performed at baseline, and at 6 and 12mo. Cognitive Outcomes/Outcome Measures: Buschke Selective Reminding Test (BSRT); 10/36 spatial recall test (SPART); Symbol Digit Modalities Test (SDMT); Paced Auditory Serial Addition Task (PASAT); Word List Generation (WLG). |
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Patti et al. 2010 Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis ItalyCohort Ninitial=459, Nfinal=331 |
Population: Total population (n=459): Mean age=33.3yr; Sex: males=158, females=301; Disease course: RRMS; Mean EDSS: 1.8; Mean disease duration=3.8yr. Low dose group (n=223): Mean age=33.8yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=1.8; Mean disease duration=4.0yr. High dose group (n=236): Mean age=32.8yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=1.8; Mean disease duration=3.6yr. Intervention: Patients received interferon beta-1a subcutaneously at a dose of 44 (high dose) or 22mcg (low dose) 3x/wk. This was a 3yr interim analysis; assessments were performed at baseline and every 12mo for 3yr. Cognitive Outcomes/Outcome Measures: Cognitive impairment (i.e., impaired cognitive function on ≥3 cognitive tests from Rao's Brief Repeatable Battery and the Stroop Test): Paced Auditory Serial Addition Test 20, 30 seconds (PASAT-20, -30); Symbol Digit Modalities Test (SDMT); Spatial Recall Test (SPART); Selective reminding test (SRT): consistent long-term retrieval (SRT-CLTR), delayed (SRT-D), long-term storage (SRT-LRS); Word List Generation (WLG); Cognitive impairment index (CII). |
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Patti et al. 2009 Subcutaneous interferon beta-1a has a positive effect on cognitive performance in mildly disabled patients with relapsing-remitting multiple sclerosis: 2-year results from the COGIMUS study ItalyCohort Ninitial=459, Nfinal=358 |
Population: Total population (n=459): Mean age=33yr; Sex: males=158, females=301; Disease course: RRMS; Severity: unspecified; Mean disease duration=4.0yr.
Low dose group (n=223): Mean age=33.8yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=1.8; Mean disease duration=4.0yr. High dose group (n=236): Mean age=32.8yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=1.8; Mean disease duration=3.6yr.
Intervention: Patients received interferon beta-1a subcutaneously at a dose of 44 (high dose) or 22 μg (low dose) 3x/wk. This was a 2yr interim analysis; assessments were performed at baseline, and every 12mo for 2yr. Cognitive Outcomes/Outcome Measures: Cognitive impairment (i.e., impaired cognitive function on ≥3 cognitive tests from Rao's Brief Repeatable Battery and the Stroop Test): Paced Auditory Serial Addition Test 20, 30 seconds (PASAT-20, -30); Symbol Digit Modalities Test (SDMT); Spatial Recall Test (SPART); Selective reminding test (SRT): consistent long-term retrieval (SRT-CLTR), delayed (SRT-D), long-term storage (SRT-LRS); Word List Generation (WLG); Cognitive impairment index (CII). |
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Flechter et al. 2007 Cognitive dysfunction evaluation in multiple sclerosis patients treated with interferon beta-1b: An open-label prospective 1 year study IsraelPre-Post Ninitial=16, Nfinal=16 |
Population: Mean age=37.6yr; Sex: males=5, females=11; Disease course: relapsing forms of MS; Mean EDSS=2.9; Mean disease duration=6.2yr. Intervention: Participants received interferon beta-1b on alternate days for 1yr. Assessments were performed at baseline and after 1yr. Cognitive Outcomes/Outcome Measures: Wisconsin Card Sorting Test (WCST). |
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Lanzillo et al. 2006 Neuropsychological assessment, quantitative MRI and ApoE gene polymorphisms in a series of MS patients treated with IFN beta-1b ItalyPre-Post Ninitial=52, Nfinal=46 |
Population: Median age=30yr; Sex: males=19, females=33; Disease course: RRMS; Median EDSS=2.0; Median disease duration=3.4yr Intervention: Patients received interferon beta-1b treatment for 2yr. Assessments were performed at baseline and at 2yr follow-up. Cognitive Outcomes/Outcome Measures: Mini Mental State Examination (MMSE); Weigl Test; Raven Matrices Test; Verbal Fluency Test; Stroop Test; Paced Auditory Serial Addition Test 2, 3 seconds (PASAT-2, -3); Corsi spatial span; Verbal span; Rey short-term test; Rey long-term test; Story recall test; Token test; Constructive apraxia test; Rey's figure test. |
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Barak & Achiron 2002 Effect of interferon-beta-1b on cognitive functions in multiple sclerosis IsraelPCT Ninitial=46, Nfinal=41 |
Population: Interferon-beta-1b (IFNβ-1b) group (n=23): Mean age=47.4yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=3; Mean disease duration=14.5yr. Control group (n=23): Mean age=40.1yr; Sex: unspecified; Disease course: RRMS; Mean EDSS=2.9; Mean disease duration=9.6yr. Intervention: The IFNβ-1b group received IFNβ-1b on alternate days for 1yr. The control group did not receive treatment. Assessments were performed at baseline and after 1yr. Cognitive Outcomes/Outcome Measures: Selective Reminding Test (SRT); 10/36 Spatial Recall Test (SPART); Symbol Digit Modalities Test (SDMT); Paced Auditory Serial Addition Task (PASAT); Word List Generation (WLG). |
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Gerschlager et al. 2000 Electrophysiological, neuropsychological and clinical findings in multiple sclerosis patients receiving interferon β-1b: A 1-year follow-up AustriaCohort Ninitial=28, Nfinal=28 |
Population: MS participants (n=14): Mean age=37.5yr; Sex: males=3, females=11; Disease course: RRMS; Mean EDSS=3.14; Mean disease duration=10yr. Healthy controls (n=14). Intervention: Participants were treated with interferon beta-1b for 1yr. Assessments were performed at baseline and 12mo later. Cognitive Outcomes/Outcome Measures: Selective Reminding Test (SRT); Concentration endurance test (d2); 7/24 Spatial Recall Test (SRT 7/24); Paced Auditory Serial Addition Test; Verbal fluency test. |
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Pliskin et al. 1996 Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon beta-1b USAPCT Ninitial=30, Nfinal=30 |
Population: Total population (n=30): Mean age=37yr; Sex: males=11, females=19. High-dose group (n=9): Mean age=38.9yr; Disease course: RRMS. No further information provided. Low-dose group (n=8): Mean age=38.0yr; Disease course: RRMS. No further information provided. Placebo group (n=13): Mean age=36.2yr; Disease course: RRMS. No further information provided. Intervention: Patients received either high or low dose interferon beta (IFN-β) 1b or placebo for 4yr. IFN-β-1b was administered at a dose of 8 million units (8 MIU, high-dose), or 1.6 MIU (low-dose). Assessments were performed at baseline, and after 2 and 4yr. Cognitive Outcomes/Outcome Measures: Wechsler Memory Scale (WMS): Logical Memory subtest, Visual Reproduction subtest; Trail Making Test B (TMT-B); Stroop Color-Word Test (SCWT). |
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Discussion
Two non-randomized studies investigated IFN-β for CI, compared to untreated controls. Barak and Achiron (2002) compared IFN-β-1b treated RRMS participants to an equal number of untreated participants on cognitive measures over a one-year period. The untreated cohort group had less CI at baseline compared to the treated cohort and they demonstrated significant worsening on the 10/36 Spatial Recall Test, Word List Generation, and PASAT over the year. The IFN-β treated cohort from this study significantly improved in two of these same measures (10/36 Spatial Recall Test, PASAT), in addition to improving on the SRT, and there was no significant deterioration on other cognitive measures. The second small study by Hamdy et al. (2013) compared IFN-treated patients to non-treated patients and found that the treated group demonstrated significantly improved visuospatial memory, visual processing speed, working memory and auditory processing speed, and cognitive reasoning, but not verbal learning and memory, or verbal fluency. This study did not specify the type of IFN used.
Three studies investigated IFN-β for CI, compared to placebo. Fischer et al. (2000) compared IFN-β-1a to placebo over a duration of two years. Comprehensive and brief neuropsychological batteries were used to evaluate cognitive function. At the end of the study, a significant beneficial effect of IFN-β-1a was demonstrated in terms of reduced cognitive deterioration compared to placebo. The two other studies used a subset of participants who were included in the pivotal randomized placebo-controlled trial for IFN-β-1b in RRMS (The IFNB Multiple Sclerosis Study Group, 1993; The IFNβ Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, 1995). The study by Pliskin et al. (1996) compared participants receiving high-dose IFN-β-1b, low-dose IFN-β-1b, and placebo. Results demonstrated a significant improvement in delayed visual memory performance in participants treated with high-dose IFN-β-1b compared to low-dose IFN-β-1b and placebo between years two and four of the pivotal clinical trial but did not find other significant between-group differences for verbal memory, processing speed, or selective attention. The third study by Lacy et al. (2013) was a small longitudinal extension study using a subset of 16 participants from Pliskin et al. (1996). The findings from this small extension trial are subject to bias from attrition. At the 16-year assessment, the original placebo group (later treated with IFN-β-1b) performed significantly better than the original IFN-β group in the domain of visual memory performance. Contrary to this, on further within group analysis, only the originally treated IFN-β-1b group improved from year two to year 16 on measures of processing speed and selective attention. The original placebo group worsened on measures of verbal memory but exhibited increased visual memory and selective attention performance. For this extension study, cognitive measures were administered two years into the trial, and repeated at year four. At year five, subjects originally treated with placebo (n=7) were switched to receive IFN-β-1b, and cognitive assessments were performed again at year 16. This study found that the cohort as a whole did demonstrate worsening performance on verbal memory measures over time, but improved on measures of visual memory, processing speed, and selective attention. However, when the two groups were examined separately, it was found that those participants originally randomized to IFN-β-1b demonstrated an improvement from year two to year 16 on measures of processing speed and selective attention, while those participants who were originally randomized to placebo worsened on measures of verbal memory but exhibited increased visual memory and selective attention performance. At the 16-year assessment, there were significant differences between the original placebo group and IFN-β-1b group in visual memory performance, with members of the placebo group performing better than the IFN-β group.
Three studies investigated comparisons between IFN-β doses or formulations. The Cognitive Impairment in Multiple Sclerosis (COGIMUS) study was a prospective, non-randomized cohort study comparing low dose IFN-β-1a (22 mcg) and high dose (44 mcg) at two, three, and five years (Patti et al. 2009, 2010, 2013). The COGIMUS study used a liberal definition of CI, defined as scoring one standard deviation below the mean on at least three cognitive tests from Rao's Battery. Other studies have applied a more stringent criterion of 1.5 or 2 standard deviations below the mean. After two years, the proportion of participants with CI was significantly lower in the high dose group (17%) compared to the low dose group (26.5%; p=0.034). The low dose group started with a higher proportion of people with CI at baseline compared to the high dose group (18.6% vs. 24.2%; p=0.145). After three years, the proportion of participants with CI remained significantly lower in the high dose group (15.2%) compared to the low dose group (24.8%; p=0.030). Finally, five-year results indicated that the proportion of patients with CI remained stable between three and five years of treatment. Another study by Mokhber et al. (2014) compared the effects of three different interferon treatments on cognitive outcomes over a 12-month period. Participants with relapsing MS were randomized to either IFN-β-1a (Avonex or Rebif) or IFN-β-1b (Betaferon). Cognitive assessments were performed at baseline and after 12 months. Within all three treatment groups, there was improvement on the cognitive test scores over time, although both IFN-β-1a groups improved on a greater number of cognitive outcome measures compared to the IFN-β-1b group. Differences in cognition at baseline between the groups and comparison between groups over time limit the interpretation of these results. Finally, Melanson et al. (2010) investigated three preparations of IFN-β; subcutaneous IFN-β-1a, subcutaneous IFN-β-1b, and intramuscular IFN-β-1a. For the total study group, there were significant improvements from baseline to six and 12 months in several cognitive domains; however, there were no differences in efficacy between groups in terms of improving cognitive function.
Six other studies with pre-post designs evaluated interferons and cognitive outcomes. Mori et al. (2012) and Benešová and Tvaroh (2017) both studied IFN-β-1a and demonstrated improvement on working memory and auditory processing speed. Lanzillo et al. (2006) and Flechter et al. (2007) investigated IFN-β-1b and found beneficial effects for cognitive stability and cognitive reasoning, respectively. Rieckmann et al. (2019) and Kleiter et al. (2017) both reported 24 week follow up data on the Fatigue Scale for Motor and Cognitive Functions (FSMC). In the Rieckmann study, mean total scores on this scale worsened from the “mild fatigue” range at baseline to the “moderate fatigue” range at 24 weeks. The Kleiter et al. study reported relatively stable FSMC scores over time. However incomplete follow up on cognitive outcomes was a limitation. Both of these studies also reported on the SDMT which, contrary to the FSMC, showed improvement over time.
Conclusion
Healthy control comparison:
There is level 2 evidence that interferon beta 1b treated healthy controls without MS and people with relapsing-remitting MS improve on cognitive testing, but healthy controls show greater improvement on verbal memory than those with relapsing-remitting MS (one cohort study; Gerschlager et al. 2000).
Comparing formulations:
There is conflicting evidence regarding whether or not different interferon beta (IFN-β) preparations (subcutaneous IFN-β-1a, subcutaneous IFN-β-1b, intramuscular IFN-β-1a) compared to one another improve verbal learning and memory, spatial memory, auditory processing speed, and verbal fluency (one randomized controlled trial and one prospective controlled trial; Mokhber et al. 2014; Melanson et al. 2010).
There is level 1b evidence that interferon beta 1a compared to interferon beta 1b may not be more effective for improving visual processing speed in persons with relapsing-remitting MS (one randomized controlled trial and one prospective controlled trial; Mokhber et al. 2014; Melanson et al. 2010).
There is level 2 evidence that different interferon beta (IFN-β) preparations (subcutaneous IFN-β-1a, subcutaneous IFN-β-1b, intramuscular IFN-β-1a) compared to one another may not be more effective for improving visual processing speed in persons with relapsing-remitting MS (one prospective controlled trial; Melanson et al. 2010).
Specific interferon formulations:
There is level 2 evidence that interferon beta compared to no treatment may improve visuospatial memory, visual processing speed and auditory processing speed, and cognitive reasoning, but not verbal learning and memory, or verbal fluency (one cohort study; Hamdy et al. 2013).
There is level 2 evidence that interferon beta 1b compared to no treatment may improve spatial memory, auditory processing speed, and may have stabilizing effects on verbal fluency in persons with relapsing-remitting MS (one prospective controlled trial; Barak & Achiron 2002).
There is level 4 evidence that interferon beta 1b may stabilize or improve cognitive function in persons with relapsing-remitting MS (one pre-post study; Lanzillo et al. 2006).
There is level 4 evidence that interferon beta 1b may improve cognitive reasoning in persons with relapsing MS (one pre-post study; Flechter et al. 2007).
There is level 2 evidence that interferon beta 1b may improve or stabilize visual processing speed in relapsing-remitting MS (one cohort study; Kleiter et al. 2017).
There is level 1b evidence that interferon beta 1a compared to placebo may be more effective for reducing cognitive deterioration in persons with relapsing MS (one randomized controlled trial; Fischer et al. 2000).
There is level 4 evidence that interferon beta 1a may improve auditory processing speed in persons with relapsing-remitting MS (two pre-post studies; Mori et al. 2012; Benešová & Tvaroh et al. 2017).
There is level 2 evidence that interferon beta 1a may improve or stabilize visual processing speed, but not cognitive fatigue symptoms, in relapsing-remitting MS (one cohort study; Rieckmann et al. 2019).
High dose versus low dose interferon:
There is level 2 evidence that high-dose interferon beta 1b compared to low dose interferon beta 1b or placebo may improve visual memory, but not verbal memory, processing speed, or selective attention in persons with relapsing-remitting MS (one prospective controlled trial; Pliskin et al. 1996).
There is level 2 evidence that high dose interferon beta 1a compared to low dose may be more effective for protecting against cognitive decline in persons with relapsing-remitting MS (one cohort study; Patti et al. 2009; 2010; 2013).
Interferon formulations may reduce the rate of cognitive decline in some cognitive domains for persons with relapsing MS. It is unclear if there is a dose-dependant protective effect against cognitive decline.
There is mixed evidence regarding the effect of different interferon beta preparations on cognitive impairment in relation to one another in persons with MS.
3.1.14.5.1 Interferon Beta vs. Interferon Beta plus Estroprogestins
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Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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De Giglio et al. 2017 Effect on cognition of estroprogestins combined with interferon beta in multiple sclerosis: Analysis of secondary outcomes from a randomised controlled trial ItalyRCT PEDro=6 NInitial=150, NFinal=128 |
Population: Group 1 (n=46): Mean age=30.4yr; Sex: males=0, females=46; Disease course: RRMS; Mean EDSS=1.7; Mean disease duration=4.2yr. Group 2 (n=48): Mean age=29.1yr; Sex: males=0, females=48; Disease course: RRMS; Mean EDSS=1.8; Mean disease duration=3.3yr. Group 3 (n=48): Mean age=30.6yr; Sex: males=0, females=48; Disease course: RRMS; Mean EDSS=1.6; Mean disease duration=3.5yr. Intervention: Patients were randomly assigned to receive subcutaneous IFN-β-1a 44mcg 3x/wk (group 1), subcutaneous IFN-β-1a 44mcg 3x/wk plus ethinyl estradiol 20mcg and desogestrel 150mcg (group 2), or subcutaneous IFN-β-1a 44mcg 3x/wk plus ethinyl estradiol 40mcg and desogestrel 125mcg (group 3). Assessments were performed at baseline, and at 12 and 24mo. Cognitive Outcomes/Outcome Measures: Paced Auditory Serial Addition Test: 2,3 seconds (PASAT-2, PASAT-3); Symbol Digit Modalities Test (SDMT); 10/36 Spatial Recall Test (10/36-SPART); 10/36-SPART-delayed recall (10/36-SPART-D); Selective Reminding Test (SRT)-Long Term Storage (SRT-LTS); SRT-Consistent Long-Term Recall (SRT-CLTR); SRT-delayed recall (SRT-D); Word List Generation (WLG). |
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Discussion
One RCT by De Giglio et al. (2017) compared the addition of estroprogestins in different doses to IFN-β treatment on cognitive outcomes. All participants were treated with IFN-β-1a 44mcg three times per week and were randomized to either low or high doses of estroprogestins or no estroprogestin. At 12 months, the proportion of people with CI was similar in each group. While the high dose estroprogestin plus IFN-β group had a significantly smaller proportion of cognitively impaired participants when compared to the IFN-β only group at 24 months (p=0.03), after 24 months all groups demonstrated improvement on most of the cognitive measures.
Conclusion
There is level 1b evidence that high dose estroprogestins in combination with interferon beta may be more effective for protecting against cognitive decline compared to interferon beta alone in females with relapsing-remitting MS, but may not be more effective than low dose estroprogestins combined with interferon beta (one randomized controlled trial; De Giglio et al. 2017).
There is level 1b evidence that interferon beta in combination with either high dose or low dose estroprogestins may not be more effective than interferon-beta alone for improving cognitive function in females with relapsing-remitting MS (one randomized controlled trial; De Giglio et al. 2017).
High dose or low dose estroprogestins in combination with interferon beta may improve cognition similar to interferon beta alone in persons with relapsing-remitting MS.
3.1.14.5.2 Interferon Beta vs. Glatiramer Acetate
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Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Cinar et al. 2017 Cognitive dysfunction in patients with multiple sclerosis treated with first-line disease-modifying therapy: a multi-center, controlled study using the BICAMS battery TurkeyCohort NInitial=163, NFinal=161 |
Population: MS participants (n=161): Mean age=30.4yr; Sex: males=51, females=110; Disease course: RRMS; Severity: unspecified; Mean disease duration=2.02yr. Healthy controls (n=102): Mean age=31.5yr; Sex: males=37, females=65. Intervention: Patients receiving disease-modifying drugs were monitored for 12mo. They were categorized into three groups: interferon beta 1a SC (IFNB1-a; n=53), interferon beta 1b (IFNB1-b; n=52), and glatiramer acetate (GA; n=56). Assessments were performed before treatment and 12mo after treatment. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT); California Verbal Learning Test, second edition (CVLT-II); Brief Visuospatial Memory Test Revised (BVMT-R). |
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Discussion
Cinar et al. (2017), in a non-randomized prospective study, evaluated cognitive function in newly diagnosed PwMS at baseline and 12 months after treatment with IFN-β-1a, IFN-β-1b, or glatiramer acetate. After 12 months, all MS participant subgroups demonstrated a significant increase in all three cognitive measure scores compared to baseline, with no differences based on the DMT used. The mean scores for all three cognitive tests were significantly higher in the healthy control group compared to the MS participants (p<0.001). For other studies on glatiramer acetate see also sections 3.1.14.4, 3.1.14.5.8, and 3.1.14.7.2 of this module.
Conclusion
There is level 2 evidence that interferon beta 1a, interferon beta 1b, and glatiramer acetate may not be more effective compared to one another for cognitive impairment in persons with relapsing-remitting MS (one cohort study; Cinar et al. 2017).
Preliminary evidence supports that interferon beta 1a, 1b, and glatiramer acetate may have similar effects on cognitive impairment in persons with relapsing-remitting MS.
3.1.14.5.3 Interferon Beta vs. Daclizumab Beta
Daclizumab Beta is a humanized monoclonal antibody directed against the α subunit (CD25) of the interleukin-2 receptor. The mechanism of action is not fully delineated; however, it is believed to inhibit the activation of lymphocytes. Two phase III trials (SELECT (Gold et al., 2013) and DECIDE (Kappos et al., 2015)) led to the approval of daclizumab as a DMT for relapsing MS. Daclizumab was subsequently pulled from the market by the manufacturers following reports of inflammatory encephalitis and meningoencephalitis in patients in Europe.
Table 20. Study Comparing Interferon Beta vs. Daclizumab Beta for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Benedict et al. 2018 Improved cognitive outcomes in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta: results from the DECIDE study USARCT PEDro=10 NInitial=1841, NFinal=1841 |
Population: Daclizumab beta (n=919): Mean age=36.4yr; Sex: males=294, females=625; Disease course: RRMS; Median EDSS=2.0; Mean disease duration=4.2yr. Interferon beta-1a (n=922): Mean age=36.2yr; Sex: males=295, females=627; Disease course: RRMS; Median EDSS=2.2; Mean disease duration=4.1yr. Intervention: Participants were randomized to receive daclizumab beta 150mg subcutaneously every 4wks and intramuscular placebo 1x/wk, or intramuscular interferon beta-1a 30µg 1x/wk and subcutaneous placebo every 4wks, for at least 96wks and no more than 144 wks. Outcomes were assessed at baseline and at 24wk intervals. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT). |
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Discussion
A secondary analysis of the phase III DECIDE trial (Kappos et al. 2015) by Benedict et al. (2018) suggested that daclizumab may be more protective against CI and/or worsening of cognitive function over a 24-month period when compared to IFN-β. It is important to note that the SDMT was a tertiary outcome and the clinical significance of these findings is uncertain. Furthermore, daclizumab is no longer available.
Conclusion
There is level 1b evidence that daclizumab may be more effective at improving and preventing worsening of processing speed compared to interferon beta 1a after 92 weeks of treatment in relapsing-remitting MS (from one randomized controlled trial; Benedict et al. 2018).
Daclizumab may be more effective than interferon beta 1a for preventing worsening of processing speed; however, daclizumab is no longer available.
3.1.14.5.4 Interferon Beta vs. Ozanimod
Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that demonstrated superiority to IFN-β in two phase III pivotal trials (RADIANCE (Cohen, Comi, et al., 2019) and SUNBEAM (Comi et al., 2019)). The trials included relapsing-remitting MS participants where the primary outcomes were the annualized relapse rate. Secondary MRI outcomes also significantly favoured ozanimod. Ozanimod binds to S1P1 receptors on lymphocytes, preventing lymphocyte egress from lymph nodes and reducing the number of lymphocytes in circulation. Ozanimod is associated with reduced cardiac risk compared to non-specific SP1 receptor modulators by selectively blocking S1P receptors 1 and 5.
Table 21. Study Comparing Interferon Beta vs. Ozanimod for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Comi et al. 2019 Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial ItalyRCT PEDro=10 NInitial=1346, NFinal=1255 |
Population: Ozanimod 1.0mg (n=447): Mean age=34.8yr; Sex: males=164, females=283; Disease course: RRMS=438, PRMS=9; Mean EDSS=2.6; Mean disease duration=3.6yr. Ozanimod 0.5mg (n=451): Mean age=36.0yr; Sex: males=140, females=311; Disease course: RRMS=443, PRMS=5, SPMS=3; Mean EDSS=2.7; Mean disease duration=3.7yr. Interferon beta-1a (n=448): Mean age=35.9yr; Sex: males=148, females=300; Disease course: RRMS=441, PRMS=5, SPMS=2; Mean EDSS=2.6; Mean disease duration=3.7yr. Intervention: Participants were randomized to receive either ozanimod HCl 1.0mg 1x/d, ozanimod HCl 0.5mg 1x/d, or weekly interferon beta-1a 30µg for at least 12mo. Cognitive Outcomes/Outcome Measures: Multiple Sclerosis Functional Composite (MSFC) within which the Symbol Digit Modalities Test (SDMT) was substituted for the Paced Auditory Serial Addition Test (PASAT). |
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Discussion
The results of this phase III trial support that ozanimod may provide greater protection against CI or worsening compared to IFN-β-1a over 12 months. Visual processing speed according to the SDMT trial results align with the relapse rate and MRI trial results in that they all significantly favoured ozanimod. However, not provided are the absolute change scores, and it is unclear whether the SDMT results were clinically meaningful. The Multiple Sclerosis Functional Composite (MSFC) z change scores (within which the SDMT was replaced for the PASAT in this trial) also favoured ozanimod. The SDMT may be a more sensitive outcome of processing speed than the PASAT. However, the MSFC also includes the Timed 25 Foot Walk Test and the upper limb Nine-Hole Peg Test and none of the sub-components of the MSFC were reported separately; therefore, it is unclear to what extent cognition contributed to the MSFC z change scores.
Conclusion
There is level 1b evidence that ozanimod may improve visual processing speed compared to interferon beta 1a over 12 months in relapsing-remitting MS (one randomized controlled trial; Comi et al. 2019).
Ozanimod may protect against worsening cognitive function, based on 12-month data.
3.1.14.5.5 Interferon Beta vs. Fingolimod
Fingolimod was the first oral Health Canada approved drug for the treatment of relapsing-remitting MS, based on the results of the FREEDOMS (Calabresi et al., 2014) and TRANSFORMS (Cohen et al., 2010) phase III trials. Fingolimod is a S1P receptor modulator which binds to S1P1 receptors 1,3,4, and 5 on lymphocytes, preventing lymphocyte egress from lymph nodes and reducing the number of lymphocytes in circulation. For other studies on fingolimod see also sections 3.1.14.5.7, 3.1.14.5.8, and 3.1.14.7.1 of this module.
Table 22. Study Comparing Interferon Beta vs. Fingolimod for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Comi et al. 2017 Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study) ItalyRCT PEDro=5 NInitial=157, NFinal=127 |
Population: Fingolimod (n=80): Mean age=40.23yr; Sex: males=23, females=57; Disease course: RRMS; Mean EDSS=2.78; Mean disease duration=4.97yr. Interferon beta-1b (n=28): Mean age=37.64yr; Sex: males=9, females=19; Disease course: RRMS; Mean EDSS=2.09; Mean disease duration=4.71yr. Intervention: Participants were randomized to receive oral fingolimod (0.5mg/d) or subcutaneous interferon beta-1b (250µg every other day) for 18mo. Outcomes were assessed at screening and at 9 and 18mo. Cognitive Outcomes/Outcome Measures: Rao's Brief Repeatable Battery: Selective Reminding Test (SRT): long-term storage (SRT-LTS), consistent long-term retrieval (SRT-CLTR), delayed recall (SRT-d); 10/36 Spatial Recall Test (10/36 SPART): total correct responses (10/36 SPART-T), delayed recall (SPART-DR); Symbol Digit Modalities Test (SDMT); Paced Auditory Serial Addition Test (PASAT); Word List Generation; Delis-Kaplan Executive Function System (DKEFS) sorting test. |
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Discussion
A study by Comi et al. (2017) examined the changes on a battery of cognitive tests in a randomized, open label study comparing IFN-β-1b and fingolimod. Both groups demonstrated an increase in scores on all cognitive tests over time; there was no significant worsening noted. However, there was no difference in the change in scores based on the treatment group. There were a number of limitations with the study: the fingolimod group had significantly worse baseline disease activity and PASAT and SDMT scores, more participants in the interferon group were lost to follow up (40% compared to 8.5% in the fingolimod group, p≤0.0001), those lost to follow up in the interferon group had worse cognitive scores at baseline, and the study was not powered to evaluate between-group differences on the cognitive outcomes. These limitations significantly impact the ability to compare between-group results in terms of the cognitive outcomes.
Conclusion
There is level 2 evidence that fingolimod or interferon beta 1b may improve cognition on a comprehensive cognitive battery over 18 months in relapsing-remitting MS (one open label randomized controlled trial; Comi et. al. 2017).
Preliminary evidence supports that there is no difference in cognitive outcomes between treatment with interferon beta 1b or fingolimod over an 18-month period in relapsing-remitting MS.
3.1.14.5.6 Interferon Beta and/vs. Natalizumab
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Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Weinstock-Guttman et al. 2012 Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS USANot specified |
Population: SENTINEL: Natalizumab + interferon beta (IFNβ)-1a group: Disease course: RRMS. Placebo + IFNβ-1a group: Disease course: RRMS. No further information provided. Intervention: In the SENTINEL trial participants were randomized to natalizumab 300mg or placebo once monthly plus IFNβ-1a. Cognitive Outcomes/Outcome Measures: Time to confirmed progression of cognitive deficit (0.5 SD worsening on PASAT-3 sustained for 12wks, and percentage of patients with cognitive progression at 2yr). |
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Sundgren et al. 2016 Cognitive function did not improve after initiation of natalizumab treatment in relapsing-remitting multiple sclerosis. A prospective one-year dual control group study SwedenPCT NInitial=42, NFinal=42 |
Population: MS-Natalizumab (NZ) group (n=15): Mean age=34.6yr; Sex: males=2, females=13; Disease course: RRMS; Mean EDSS=2.9; Mean disease duration=5.7yr. MS-Control (MS-C) group (n=15): Mean age=36.1yr; Sex: males=3, females=12; Disease course: RRMS; Mean EDSS=1.5; Mean disease duration=4.6yr. Healthy control (HC) group (n=12): Mean age=32.1yr; Sex: males=3, females=9. Intervention: Patients received either NZ or were in the control condition (MS-C) comprising interferon beta therapy, for 1yr. A HC group was also analyzed. Cognitive Outcomes/Outcome Measures: Benton Visual Retention Test; Rey Auditory Verbal Learning Test; Vocabulary Test; Controlled Oral Word Association Test; Digit Span forward, backward, total; Trail Making Test 1-3 & 5; Color-Word Interference Test 1-4; Block Design Test; Symbol Search Test; Digit Symbol Coding Test; Global score (all tests and subtests). |
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Portaccio et al. 2013 Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis: a prospective, non-randomized pilot study ItalyPCT NInitial=26, NFinal=26 |
Population: Natalizumab group (n=12): Mean age=37.3yr; Sex: males=3, females=9; Disease course: RRMS; Mean EDSS=3.5; Mean disease duration=8.1yr. IFNB group (n=14): Mean age=39.0yr; Sex: males=3, females=11; Disease course: RRMS; Mean EDSS=1.3; Mean disease duration=8.6yr. Intervention: Patients received natalizumab or interferon beta (IFNB) therapy. Assessments were performed at baseline and after 18mo of treatment. Cognitive Outcomes/Outcome Measures: Selective Reminding Test (SRT) long-term storage (SRT-LTS), consistent long-term retrieval (SRT-CLTR), delayed (SRTD); Spatial Recall Test (SPART); SPART delayed (SPARTD); Symbol Digit Modalities Test (SDMT); Paced Auditory Serial Addition Test (PASAT); Word List Generation (WLG). |
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Discussion
The multi-centre SENTINEL RCT compared natalizumab plus IFN-β-1a group versus IFN-β-1a group alone (Rudick et al. 2006). There were no between-group differences on the PASAT-3 outcome. Natalizumab is a higher efficacy MS disease drug for controlling MS disease activity (relapses and new MRI lesions) than IFN-β-1a. It is possible that early intervention in younger patients is important for detecting a response to higher efficacy treatment, or that natalizumab is not superior to IFN-β-1a on cognitive processing speed outcomes. The SENTINEL study participants were older with longer disease duration at the time they started the trial (mean age 38.9 years, SD ±7.7, disease duration median 7 years) compared to the participants in the AFFIRM trial (mean age 36 years, SD± 8.3, disease duration 5 years). The AFFIRM trial compared natalizumab to placebo and reported improvement on the PASAT-3.
Sundgren et al. (2016), in a small prospective non-randomized one-year study, compared three conditions: natalizumab treated; IFN-β treated; and healthy controls without an MS diagnosis. The global cognitive z score improved with no significant between-group differences. Importantly, the healthy controls and treated MS group z scores both improved. However, when examining specific cognitive domains (i.e., executive function, verbal ability, etc.) there were some differences between groups. This trial design with a healthy control group emphasizes the need to consider practice effects and the baseline CI level in the specific cognitive domains of interest when evaluating interventions for CI in MS.
Portaccio et al. (2013) compared participants with RRMS who were receiving either natalizumab or IFN-β in a small non-randomized study over a mean of 1.5 years (follow-up was not standardized). All participants in the natalizumab group had been treated with either IFN-β or glatiramer acetate prior to starting natalizumab. At baseline, the two groups were well-matched on the cognitive measures. Over time, the participants in the natalizumab group deteriorated on fewer tests compared to the IFN-β group (0.7 ± 0.7 vs. 1.7 ± 1.4, respectively; p=0.031). Although statistically significant, the clinical significance is not clear due to the non-continuous nature of the number of tests. For other studies on natalizumab see also sections 3.1.14.5.7, 3.1.14.7, 3.1.14.7.1, and 3.1.14.7.2 of this module.
Conclusion
There is level 1b evidence that natalizumab in combination with interferon beta 1a may not be superior to interferon beta 1a alone over 2 years for delaying a decline in auditory processing speed in persons with relapsing-remitting MS (one randomized controlled trial; Weinstock-Guttman et al. 2012; Rudick et al. 2006).
There is level 2 evidence that natalizumab may not be superior to interferon beta at 1 year for improving a global assessment summary score of cognitive tests in persons with relapsing-remitting MS (one prospective controlled trial; Sundgren et al. 2016).
There is level 2 evidence that natalizumab may be more effective for reducing cognitive deterioration compared to interferon beta after a mean of 1.5 years in persons with relapsing-remitting MS (one prospective controlled trial; Portaccio et al. 2013).
Natalizumab as monotherapy or as combination therapy with interferon beta 1a may not be superior to interferon beta 1a alone for improving cognitive function but may be superior in terms of delaying cognitive decline in relapsing-remitting MS.
3.1.14.5.7 Interferon vs. Fingolimod or Natalizumab
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Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
|
Utz et al. 2016 Cognitive functions over the course of 1 year in multiple sclerosis patients treated with disease modifying therapies GermanyPCT NInitial=73, NFinal=41 |
Population: Fingolimod (n=22): Median age=35yr; Sex: males=8, females=14; Disease course: RRMS; Median EDSS=2.5; Median disease duration=68mo. Natalizumab (n=11): Median age=35yr; Sex: males=4, females=7; Disease course: RRMS; Mean EDSS=2.5; Median disease duration=28mo. Interferon (n=7): Median age=29yr; Sex: males=3, females=4; Disease course: RRMS; Median EDSS=1.0; Median disease duration=24mo. Intervention: Patients received disease-modifying therapies (fingolimod, natalizumab, or interferon) over a 1yr period. Assessments were performed at baseline, and at 6 and 12mo follow-ups. Cognitive Outcomes/Outcome Measures: Paced Auditory Serial Addition Test-3 (PASAT-3); 10/36 Spatial Recall Test (SPART); SPART delayed recall (SPARTDR); Digit span forward, backward; Spatial span forward, backward; Logical memory I; Go/Nogo; Divided attention; Visual search: reaction time (RT), movement time (MT). |
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Discussion
Utz et al. (2016), in a non-randomized study, examined cognitive function at baseline, and six and 12 months after treatment in participants who were being treated with either interferon, fingolimod, or natalizumab. Overall, approximately 75% remained relatively stable over time, with improvements noted due to practice effects in 12-30%, depending on the measure used. There were no associations between treatments and declining or stable cognitive function at six or 12 months. The study did not include an untreated control group. For other studies on fingolimod and natalizumab see also sections 3.1.14.5.5, 3.1.14.5.6, 3.1.14.5.8, 3.1.14.7, 3.1.14.7.1, and 3.1.14.7.2 of this module.
Conclusion
There is level 2 evidence that fingolimod, natalizumab, and interferon may not be more effective compared to one another for cognitive stability in persons with relapsing-remitting MS (one prospective controlled trial; Utz et al. 2016).
Preliminary evidence supports that fingolimod, natalizumab, or interferon are not more effective compared to one another for maintaining cognition over one year in persons with relapsing-remitting MS.
3.1.14.5.8 Interferon vs. Fingolimod or Glatiramer Acetate
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Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
|
Cree et al. 2018 Phase IV study of retention on fingolimod versus injectable multiple sclerosis therapies: a randomized clinical trial USARCT PEDro=6 NInitial=875, NFinal=713 |
Population: Fingolimod (n=436): Mean age=41.5yr; Sex: males=125, females=311; Disease course: RRMS; Median EDSS=2.0; Mean disease duration=4.42yr. Injectable disease modifying therapies (iDMT; n=439): Mean age=41.9yr; Sex: males=110, females=329; Disease course: RRMS; Median EDSS=2.0; Mean disease duration=4.21yr. Intervention: Participants were randomized to fingolimod 0.5mg/d or to an iDMT (interferon beta-1a, interferon beta-1b, glatiramer acetate) for 48wks. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT). |
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Discussion
An RCT by Cree et al. (2018) included both the oral and written version of the SDMT in relapsing MS participants randomized to fingolimod or an injectable DMT (either glatiramer acetate or IFN-β). It is important to note that only the oral version is validated in the MS population and only the oral version has normative data for MS. It is also difficult to come to any conclusions for between-group differences on the oral SDMT in this study since there were low retention rates in the injectable DMT group. For other studies on fingolimod and glatiramer acetate see also sections 3.1.14.4, 3.1.14.5.2, 3.1.14.5.5, 3.1.14.5.7, 3.1.14.7.1, and 3.1.14.7.2 of this module.
Conclusion
There is level 1b evidence that fingolimod or injectable disease modifying therapies may maintain verbal processing speed at 48 weeks (one open label randomized controlled trial; Cree et al. 2018).
Fingolimod or injectable disease modifying therapies may maintain verbal processing speed at 48 weeks.
Mitoxantrone is a synthetic antineoplastic anthracenedione that was approved by the Food and Drug Administration for the treatment of worsening relapsing MS and progressive MS (Hartung et al., 2002). It is a small molecule that can cross the blood brain barrier, but also accumulates in several other organ tissues. It has rarely been used within the last two decades due to the high risk of cardiac toxicity (systolic dysfunction and heart failure) and leukemia (Marriott et al., 2010).
Table 26. Study Examining Mitoxantrone for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
|
Schröder et al. 2011 Stability of cognitive functions under mitoxantrone therapy in patients with progressive multiple sclerosis: a pilot analysis GermanyCohort NInitial=26, NFinal=26 |
Population: Treatment group (n=20): Mean age=44.7yr; Sex: males=9, females=11; Disease course: SPMS=17, PPMS=1, PRMS=2; Mean EDSS=5.3; Mean disease duration: unspecified. Control group (n=6). No further information provided. Intervention: Participants received mitoxantrone (MX) therapy 10-12mg/m2 in 3-4 monthly intervals for a total mean dose of 42mg/m2. Assessments were performed at baseline and after 24mo. A small subset of 6 patients who did not receive MX therapy was used as a control group. Cognitive Outcomes/Outcome Measures: Leistungspruefsystem subtest 7; Regensburger Word Fluency Test; California Verbal Learning Test (CVLT); Wechsler Memory Scale (WMS-R): visual reproduction, digit span forward, digit span backward. |
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Discussion
Only one study was found which examined the effect of mitoxantrone on CI in PwMS (Schröder et al., 2011). It was a small pilot study that included PPMS, SPMS, and progressive relapsing MS participants, as well as participants with MS not receiving mitoxantrone. After 24 months, there was stability, but no significant change or improvement, in cognitive measures from baseline to 24 months in the mitoxantrone group. In contrast, the group of six untreated participants declined in their performance over the same time period, although data was only available for verbal short-term memory and cognitive flexibility outcomes in this group.
Conclusion
There is level 2 evidence that mitoxantrone compared to no treatment may be more effective for cognitive stability (one cohort study; Schröder et al. 2011).
Preliminary evidence supports that mitoxantrone may have stabilizing effects on cognitive functions in persons with MS.
Natalizumab is a DMT for MS administered as an infusion medication. It is a monoclonal antibody, selective adhesion molecule inhibitor blocking α4 integrin and preventing T cell entry into the CNS. For other studies on natalizumab see also sections 3.1.14.5.6, 3.1.14.5.7, 3.1.14.7.1, and 3.1.14.7.2 of this module.
Table 27. Studies Examining Natalizumab for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
|
Perumal et al. 2019 Outcomes of natalizumab treatment within 3 years of relapsing-remitting multiple sclerosis diagnosis: a prespecified 2-year interim analysis of STRIVE USAPre-Post NInitial=231, NFinal=177 |
Population: Mean age=34.0yr; Sex: males=61, females=161; Disease course: RRMS; Median EDSS=2.0; Mean disease duration=1.6yr. Intervention: Participants received natalizumab 300mg intravenously every 4wks for 2yr. Outcomes were assessed at baseline and after 1 and 2yr of treatment. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT). |
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|
Gudesblatt et al. 2018 Improvement in cognitive function as measured by NeuroTrax in patients with relapsing multiple sclerosis treated with natalizumab: a 2-year retrospective analysis USACase Series NInitial=52, NFinal=52 |
Population: Mean age=45.9yr; Sex: males=13, females=39; Disease course: RRMS; Median EDSS=2; Mean disease duration: 0-5yr=22, 6-10yr=14, 11-15yr=13, ≥16yr=3. Intervention: Participants received natalizumab 300mg intravenously every 4wks for ≥2yr. Outcomes were assessed at baseline and after 1 and 2yr of treatment. Cognitive Outcomes/Outcome Measures: Mindstreams Global Assessment Battery (NeuroTraxTM): global cognitive score (GCS), memory, executive function, visual-spatial processing, verbal function, attention, information processing speed, motor function. |
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Planche et al. 2017 Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: a 3-year follow-up multicentric study FrancePre-Post NInitial=48, NFinal=36 |
Population: Mean age=41.1yr; Sex: males=11, females=37; Disease course: RRMS; Median EDSS=3.0; Mean disease duration=8.0yr. Intervention: Participants received natalizumab 300mg intravenously every 4wks for 3yr. Outcomes were assessed at baseline, 18mo, and 36mo. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT); Paced Auditory Serial Addition Test (PASAT); forward and backward digit span subtest of Wechsler Adult Intelligence Scale-III; Selective Reminding Test (SRT); Stroop Test; Multiple Errands Test. |
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Talmage et al. 2017 Natalizumab stabilizes physical, cognitive, MRI, and OCT markers of disease activity: a prospective, non-randomized pilot study USAPre-Post NInitial=20, NFinal=15 |
Population: Mean age=39yr; Sex: males=2, females=13; Disease course: RRMS; Median EDSS=3; Median disease duration=3yr. Intervention: Participants received natalizumab 300mg intravenously every 4wks for 96wks. Outcomes were assessed at baseline, 48wks, and 96wks. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT). |
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Weinstock-Guttman et al. 2012 Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS USANot specified |
Population: AFFIRM: Natalizumab group: Disease course: RRMS. Placebo group: Disease course: RRMS. No further information provided. Intervention: In the AFFIRM trial participants were randomized to natalizumab treatment at 300mg or placebo once monthly. Cognitive Outcomes/Outcome Measures: Time to confirmed progression of cognitive deficit (0.5 SD worsening on PASAT-3 sustained for 12wks, and percentage of patients with cognitive progression at 2yr). |
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Jacques et al. 2016 Cognitive evolution in natalizumab-treated multiple sclerosis patients CanadaPre-Post NInitial=63, NFinal=62 |
Population: ≤2yr treatment group (n=34): Mean age=43.56yr; Sex: unspecified; Disease course: unspecified; Mean EDSS=3.09; Mean disease duration=11.65yr. >2yr treatment group (n=28): Mean age=46.14yr; Sex: unspecified; Disease course: unspecified; Mean EDSS=2.88; Mean disease duration=14.46yr. Intervention: All patients received further natalizumab treatment and were divided into 2 groups based on natalizumab treatment duration at baseline: ≤2yr or >2yr (mean treatment duration of 0.35yr and 3.6yr, respectively). Assessments were performed prospectively every 4wks for 2yr. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test; Cogstate battery test: International Shopping List Test, Groton Maze Learning Test, One Back, Detection, Identification. |
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Sundgren et al. 2016 Cognitive function did not improve after initiation of natalizumab treatment in relapsing-remitting multiple sclerosis. A prospective one-year dual control group study SwedenPCT NInitial=42, NFinal=42 |
Population: MS-Natalizumab (NZ) group (n=15): Mean age=34.6yr; Sex: males=2, females=13; Disease course: RRMS; Mean EDSS=2.9; Mean disease duration=5.7yr. MS-Control (MS-C) group (n=15): Mean age=36.1yr; Sex: males=3, females=12; Disease course: RRMS; Mean EDSS=1.5; Mean disease duration=4.6yr. Healthy control (HC) group (n=12): Mean age=32.1yr; Sex: males=3, females=9. Intervention: Patients received either NZ or were in the control condition (MS-C) comprising interferon beta therapy, for 1yr. A HC group was also analyzed. Cognitive Outcomes/Outcome Measures: Benton Visual Retention Test; Rey Auditory Verbal Learning Test; Vocabulary Test; Controlled Oral Word Association Test; Digit Span forward, backward, total; Trail Making Test 1-3 & 5; Color-Word Interference Test 1-4; Block Design Test; Symbol Search Test; Digit Symbol Coding Test; Global score (all tests and subtests). |
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Kunkel et al. 2015 Impact of natalizumab treatment on fatigue, mood, and aspects of cognition in relapsing-remitting multiple sclerosis GermanyPre-Post NInitial=51, NFinal=31 |
Population: Year 1 completers (n=51): Mean age=33.9yr; Sex: males=11, females=40; Disease course: RRMS; Mean EDSS=4.0; Mean disease duration=5.3yr. Year 2 completers (n=31): Mean age: unspecified; Sex: males=7, females=24; Disease course: RRMS; Mean EDSS=3.9; Disease duration: unspecified. Intervention: Patients were treated with natalizumab for up to 2yr. Patients were analyzed depending on length of treatment (1 or 2yr). Assessments were performed at baseline and after 1 and 2yr of treatment. Cognitive Outcomes/Outcome Measures: Attention Test Battery (TAP): alertness (reaction time, reaction time cued), divided attention (reaction time visual, reaction time auditory, errors, omissions), flexibility (reaction time, errors, performance index), Symbol Digit Modalities Test (SDMT). |
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Mattioli et al. 2015 Natalizumab significantly improves cognitive impairment over three years in MS: pattern of disability progression and preliminary MRI findings ItalyPre-Post NInitial=24, NFinal=24 |
Population: Mean age=36.8yr; Sex: males=11, females=13; Disease course: RRMS; Mean EDSS=4.52; Mean disease duration=12.15yr. Intervention: Patients received natalizumab for 3yr. Assessments were performed at baseline and yearly for 3yr. Cognitive Outcomes/Outcome Measures: Number of failed cognitive tests (i.e., a score of < -2.0 z-score below corresponding control mean): Raven's Colored Progressive Matrices (CPM Raven); Digit Span forward; Short Tale; Corsi block tapping test; Rey-Osterrieth Complex Figure Test (ROCFT); Paced Auditory Serial Addition Test 2,3 (PASAT 2, 3); Wisconsin Card Sorting Test (WCST): total errors (TE), perseverative responses (PR), perseverative errors (PE); Controlled Word Association Test (COWA). |
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Iaffaldano et al. 2014 The improvement of cognitive functions is associated with a decrease of plasma Osteopontin levels in Natalizumab treated relapsing multiple sclerosis ItalyPre-Post NInitial=49, NFinal=49 |
Population: MS Treatment group (n=49): Mean age=34.23yr; Sex: males=12, females=37; Disease course: RRMS; Mean EDSS=3.5; Mean disease duration=10.54yr.
MS Treatment Naïve group (n=24): Mean age=35.8yr; Sex: males=7, females=17; Disease course: RRMS; Mean EDSS=2.0; Mean disease duration=5.58yr. Healthy controls (n=22): Mean age=39.18yr; Sex: males=10, females=12. Intervention: Patients received natalizumab treatment for at least 1yr. Assessments were performed at baseline and every 12mo. Cognitive Outcomes/Outcome Measures: Cognitive impairment (i.e., impaired cognitive function on ≥3 cognitive tests from Rao's Brief Repeatable Battery and the Stroop Test): Paced Auditory Serial Addition Test 2, 3 seconds (PASAT-2, -3); Symbol Digit Modalities Test (SDMT); 10/36 Spatial Recall Test (SPART); Selective Reminding Test (SRT); Word List Generation (WLG)); Cognitive Impairment Index (CII); plasma osteopontin levels. |
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Wilken et al. 2013 Changes in fatigue and cognition in patients with relapsing forms of multiple sclerosis treated with Natalizumab: The ENER-G study USAPre-Post NInitial=89, NFinal=89 |
Population: Mean age=41.3yr; Sex: males=10, females=81; Disease course: unspecified; Median EDSS=3.0; Median disease duration=8yr. Intervention: Patients received natalizumab treatment over 12mo. Natalizumab was given intravenously at a dose of 300mg every 4wks. Assessments were performed at baseline and 4, 8, 12, 24 and 48wks after treatment initiation. Cognitive Outcomes/Outcome Measures: Index of Cognitive Efficiency (ICE); Procedural Reaction Time (PRO); Code Substitution Delayed Memory (CDD). |
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Edwards et al. 2012 Improvement of neuropsychological function in cognitively impaired multiple sclerosis patients treated with natalizumab: a preliminary study USACase Series NInitial=40, NFinal=40 |
Population: Mean age=48.5yr; Sex: males=9, females=31; Disease course: RRMS; Mean EDSS=4.59; Mean disease duration: unspecified. Intervention: Patients received natalizumab 300mg every 4wks. Assessments were performed at baseline and after 6mo of treatment. Cognitive Outcomes/Outcome Measures: Neuropsychological Impairment Index calculated based on the results of nine cognitive tests: Digit Span subtest of the Wechsler Adult Intelligence Scale-IV; Stroop Color-Word Test; Letter Number Sequencing Test of the Wechsler Adult Intelligence Scale-IV; Paced Auditory Serial Addition Test-Revised; California Verbal Learning Test-II; Logical Memory subtest of the Wechsler Memory Scale-IV; Controlled Oral Word Association Test; North American Adult Reading Test-Revised; Symbol Digit Modalities Test. |
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Iaffaldano et al. 2012 Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study ItalyPre-Post NInitial=100, NFinal=53 |
Population: 1yr treatment (n=100): Mean age=34.55yr; Sex: males=28, females=72; Disease course: RRMS; Mean EDSS=3.66; Mean disease duration=11.09yr. 2yr treatment (n=53): Mean age=33.41yr; Sex: males=16, females=37; Disease course: RRMS; Mean EDSS=3.58; Mean disease duration=9.67yr. Intervention: Patients received natalizumab treatment for 2yr. Assessments were performed at baseline and every 12mo. Cognitive Outcomes/Outcome Measures: Cognitive impairment (i.e., impaired cognitive function on ≥3 cognitive tests from Rao's Brief Repeatable Battery and the Stroop Test): Paced Auditory Serial Addition Test 2, 3 seconds (PASAT-2, -3); Symbol Digit Modalities Test (SDMT); 10/36 Spatial Recall Test (SPART); Selective Reminding Test (SRT); Word List Generation (WLG)); Cognitive Impairment Index (CII). |
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Lang et al. 2012 Natalizumab may improve cognition and mood in multiple sclerosis GermanyPre-Post NInitial=29, NFinal=29 |
Population: Mean age=33.7yr; Sex: males=5, females=24; Disease course: unspecified; Mean EDSS=3.5; Mean disease duration=10.5yr. Intervention: Patients underwent natalizumab therapy for 6mo. Assessments were performed at baseline and after 3 and 6mo of treatment. Cognitive Outcomes/Outcome Measures: Non-Verbal Learning Test (NVLT): correct, false, difference; Attention Test Battery (TAP); Auditory Verbal Learning Test (AVLT) trials 1-3, recognition; Paced Auditory Serial Addition Test (PASAT); Verbal Learning Test (VLT): false, difference. |
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Stephenson et al. 2012 Impact of natalizumab on patient-reported outcomes in multiple sclerosis: a longitudinal study USAPre-Post NInitial=1275, NFinal=333 |
Population: Mean age=46.8yr; Sex: males=73, females=260; Disease course: unspecified; Disease severity: unspecified; Mean disease duration=10.6yr. Intervention: Patients received natalizumab therapy for 12mo in monthly intravenous infusions of 300mg. Assessments were performed at baseline and after 3, 6, 9, and 12mo. Cognitive Outcomes/Outcome Measures: Medical Outcomes Scale-Cognitive Functioning (MOS-Cog). |
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Mattioli et al. 2011 Natalizumab efficacy on cognitive impairment in MS ItalyPre-Post NInitial=39, NFinal=11 |
Population: Mean age=36.6yr; Sex: males=19, females=20; Disease course: RRMS; Mean EDSS=4.1; Mean disease duration=11.3yr. Intervention: Patients received natalizumab therapy at a dose of 300mg monthly for 1yr. A subset of 11 patients continued the treatment for an additional year. Assessments were performed at baseline, and after 1 and 2yr of treatment. Cognitive Outcomes/Outcome Measures: Paced Auditory Serial Addition Test (PASAT); Wisconsin Card Sorting Test (WCST): total errors (TE), perseverative responses (PR), perseverative errors (PE); Controlled Oral Word Association Test (COWA); Short Tale Test; Selective Reminding Test (SRT); Rey Figure Test; 10/36 Spatial Recall Test (SPART); Raven's Colored Progressive Matrices (CPM Raven). |
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Discussion
The effect of natalizumab as monotherapy compared to placebo on cognitive function in MS is reported in the AFFIRM multi-centre randomized trial (Polman et al. 2006). The PASAT-3 AFFIRM study results are detailed in a separate report by Weinstock-Guttman et al. (2012). The remaining natalizumab studies are pre-post or case series designs.
In the AFFIRM trial, time to clinically meaningful worsening on the PASAT-3 of 0.5SD was delayed significantly for the natalizumab treatment group compared to the placebo group (HR 0.57, 95% CI 0.37, 0.89, p=0.013). In addition, the percentage of patients with worsening on the PASAT-3 over the two years was higher in the placebo group (12%) compared to the natalizumab treatment group (7%). The AFFIRM trial results support a protective effect on auditory processing speed with natalizumab compared to placebo.
In the pre-post and case series studies, cognition also improved compared to baseline in one or more cognitive domain. The most consistent improvements were in the domains of attention and processing speed. Improved cognition occurred among those with and without CI at baseline and as early as four weeks after treatment start. One study reported that just over half of the study sample improved on the cognitive testing, 30% were stable and 17.5% worsened over six months on natalizumab treatment (Edwards et al. 2012). These results support individual differences in the treatment response and the course of cognitive decline. Factors associated with cognitive decline and response to treatment, such as age and disease duration, warrant further research.
Other potential confounders on cognitive testing include fatigue and mood symptoms. These symptoms may negatively affect the treatment response (Planche et al. 2017; Kunkel et al. 2015; Wilken et al. 2013; Iaffaldano et al. 2012; Lang et al. 2012; Stephenson et al. 2012). Only one study reported on the patient's experience of cognitive symptoms in real world settings (Stephenson et al. 2012). Up to 69% of patients reported stabilization or improvement in their cognitive functioning.
Two small studies followed participants treated with natalizumab for three years (Planche et al. (2017) (n=48) and Mattioli et al. (2015) (n=24)). In the Mattioli et al. study, CI in the domains of memory, attention, and executive function improved within the first year. After the first year, cognitive outcomes stabilized, with the exception of verbal memory. Verbal memory continued to improve at two years and three years (p=0.07). After three years, preliminary MRI data supported an increase in the mean cortical volume of the dorsolateral prefrontal cortex and the parahippocampus regions. Planche et al. (2017) also found that verbal learning and memory continued to improve at three years, supporting a possible specific longer-term treatment effect in this cognitive domain. These results also suggest that when the rate of new MRI lesion formation decreases with treatment, it is possible for cognitive gains to occur over the longer term. Future imaging and functional imaging research may improve our understanding of the mechanism of treatment on cognitive function.
The studies of natalizumab treatment discussed in this section include people with relapsing-remitting MS with mean disease durations ranging from 1.6 years (Perumal et al. 2019) to 14.5 years (Jacques et al. 2016). The potential positive effects of natalizumab on cognitive function are promising; however, patient selection may be important.
Conclusion
There is level 1b evidence that natalizumab treatment over 2 years compared to placebo may delay a decline in auditory processing speed in persons with relapsing-remitting MS (one randomized controlled trial; Weinstock-Guttman et al. 2012; Polman et al. 2006).
There is level 4 evidence that natalizumab may stabilize or improve attention and processing speed after 2 years of treatment in persons with relapsing-remitting MS (seven pre-post studies; Perumal et al. 2019; Talmage et al. 2017; Jacques et. al 2016; Kunkel et al. 2015; Mattioli et al. 2015; Iaffaldano et al. 2012; Mattioli et. al. 2011).
There is conflicting evidence that improvements in attention and processing speed after starting natalizumab treatment may be sustained at 3 years in persons with relapsing-remitting MS (two pre-post studies; Planche et al. 2017; Mattioli et al. 2013).
There is level 4 evidence that natalizumab treatment may improve attention and processing speed within 4 weeks to six months of starting treatment in persons with relapsing-remitting MS (three pre-post studies; Wilken et al. 2013; Edwards et al. 2012; Lang et al. 2012).
There is conflicting evidence regarding whether natalizumab improves or maintains cognition consistently across multiple cognitive domains in persons with relapsing-remitting MS (one prospective controlled study; Sundgren et al. 2016; ten pre-post studies; Planche et al. 2017; Jacques et. al 2016; Kunkel et al. 2015; Mattioli et al. 2015; Iaffaldano et. al. 2014; Wilken et al. 2013; Iaffaldano et al. 2012; Edwards et al. 2012; Lang et al. 2012; Mattioli et. al. 2011; one case series; Gudesblatt et al. 2018).
There is level 4 evidence that natalizumab treatment improves or maintains patient reported cognitive function on the Medical Outcomes Scale - Cognitive functioning in persons with relapsing-remitting MS (one pre-post study; Stephenson et al. 2012).
There is level 4 evidence that a decrease in serum osteopontin levels correlates with a globally improved cognitive index score in patients treated with natalizumab for at least one year in persons with relapsing-remitting MS (one pre-post study; Iaffaldano et al. 2014).
Natalizumab may delay a decline in processing speed at two years in relapsing-remitting MS.
Preliminary evidence suggests that improvement in processing speed after natalizumab treatment may be observed as early as four weeks post treatment.
There are conflicting results for the effects of natalizumab on maintaining processing speed at three years.
The effects of natalizumab on maintaining or improving function in different cognitive domains are inconsistent.
3.1.14.7.1 Natalizumab vs. Fingolimod
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Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
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Preziosa et al. 2020 Effects of natalizumab and fingolimod on clinical, cognitive, and magnetic resonance imaging measures in multiple sclerosis ItalyCohort NInitial=63, NFinal=55 |
Population: Fingolimod (n=25): Mean age=37.5yr; Sex: males=10, females=15; Disease course: RRMS; Mean EDSS=2.63; Mean disease duration=11.1yr. Natalizumab (n=30): Mean age=36.8yr; Sex: males=12, females=18; Disease course: RRMS; Mean EDSS=2.36; Mean disease duration=9.5yr. Healthy control (n=15). Intervention: Participants with MS who started natalizumab or fingolimod were followed for 2yr. Outcomes were assessed at baseline, 12mo, and 24mo. Cognitive Outcomes/Outcome Measures: Cognitive performance (i.e., ≥2 abnormal test scores from the Brief Repeatable Battery of Neuropsychological Tests indicated cognitive impairment). |
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Discussion
One cohort study reported that cognitive performance significantly improved at two years in both the natalizumab and fingolimod groups, with no between-group differences. A small healthy control group was also included in the study with MRI brain atrophy outcomes. The rate of brain atrophy progression was similar between the MS treated groups, but higher than that observed in the healthy control group. Cognitive improvement in both MS treated groups trended towards improvement at one year but did not reach statistical significance. A limitation of this study is that the authors do not report the magnitude of the cognitive performance improvement, the specific cognitive domains affected, or the healthy control group cognitive performance scores. However, the authors do suggest that the improved cognitive performance had a positive impact on MS fatigue and depression outcomes. For other studies on fingolimod see also sections 3.1.14.5.5, 3.1.14.5.7, and 3.1.14.5.8 of this module.
Conclusion
There is level 2 evidence that global cognitive performance on the Brief Repeatable Battery improves similarly with natalizumab or fingolimod treatment at two years in persons with relapsing-remitting MS (one cohort study; Preziosa et al. 2020).
Preliminary evidence supports that fingolimod or natalizumab similarly improve global cognitive performance at two years in persons with relapsing-remitting MS.
3.1.14.7.2 Natalizumab vs. Interferon Beta, Glatiramer Acetate, or Dimethyl Fumarate
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Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
|
Rorsman et al. 2018 Cognitive functioning following one-year natalizumab treatment: a non-randomized clinical trial SwedenPCT NInitial=34, NFinal=30 |
Population: Natalizumab (n=21): Median age=41yr; Sex: males=7, females=14; Disease course: RRMS; Median EDSS=2; Median disease duration=4yr. Control (n=13): Median age=46yr; Sex: males=1, females=12; Disease course: RRMS; Median EDSS=2; Median disease duration=18yr. Intervention: Participants initiating natalizumab were recruited and compared to a quasi-control group treated with first-line disease modifying therapies (e.g., interferon beta, glatiramer acetate, dimethyl fumarate). Outcomes were assessed at baseline and at 12mo follow-up. Cognitive Outcomes/Outcome Measures: Claeson-Dahl Verbal Learning Test (C-D); Brief Visuospatial Memory Test (BVMT-R); Judgement of Line Orientation (JLO); Symbol Digit Modalities Test (SDMT); Delis-Kaplan Executive Function System Sorting Test (D-KEFS); Controlled Oral Word Association Test (COWAT); Paced Auditory Serial Addition Test (PASAT-3, -2). |
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Discussion
One prospective controlled study by Rorsman et al. 2018 compared natalizumab with a second group which included participants on either interferon, glatiramer acetate, or dimethyl fumarate. The percentage of participants on each of the other first line DMTs in this second group, and the SDMT between group change scores were not reported. There were greater improvements in the natalizumab group at 12 months on the PASAT compared to the control group. However, more participants in the natalizumab group had experienced a relapse in the last 6 months. At baseline, the natalizumab group also had significantly worse scores on the SDMT compared to the control group. For other studies on natalizumab, glatiramer acetate, and dimethyl fumarate see also sections 3.1.14.3, 3.1.14.4, 3.1.14.5.2, 3.1.14.5.6, 3.1.14.5.7, 3.1.14.5.8, 3.1.14.7, and 3.1.14.7.1 of this module.
Conclusion
There is level 2 evidence that natalizumab is associated with greater improvements in auditory processing speed compared to interferon beta, glatiramer acetate, or dimethyl fumarate in relapsing-remitting MS (one prospective controlled trial; Rorsman et al. 2018).
Preliminary evidence supports that natalizumab may improve auditory processing speed more than other first line disease modifying therapies.
Rituximab is a monoclonal antibody targeting the CD20 surface antigen and mediating B-cell and B-lymphocyte lysis and depletion. B-cells are believed to play an important role in the pathogenesis of MS ("Drug monograph: Rituximab," 2021).
Table 30. Study Examining Rituximab for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
|
de Flon et al. 2017 Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS SwedenPre-Post NInitial=75, NFinal=72 |
Population: Mean age=41.1yr; Sex: males=25, females=52; Disease course: RRMS; Median EDSS=1.5; Mean disease duration=9.5yr. Intervention: Participants switched from injection therapy to rituximab (2 doses of 1000mg administered intravenously 2wks apart). Outcomes were assessed at baseline and at 12 and 24mo thereafter. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT). |
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Discussion
One study by de Flon et al. (2017) involved a secondary analysis of data from a previous trial (de Flon et al. 2016). The effect of switching from first-line injectable treatment to rituximab was evaluated in a cohort of clinically stable participants with RRMS. There was a significant improvement in visual processing speed mean SDMT scores at 12 months compared to baseline (p<0.001), which remained unchanged or stable at 24 months. The lack of a control group is a limitation for interpreting the effect of rituximab on cognitive function in this study.
Conclusion
There is level 4 evidence that rituximab may improve visual processing speed in persons with relapsing-remitting MS (one pre-post study; de Flon et al. 2017).
Preliminary evidence suggests that rituximab may improve visual processing speed in persons with relapsing-remitting MS.
Teriflunomide is an oral immunomodulator which inhibits dihydroorotate dehydrogenase, leading to a reduced concentration of activated T- and B-lymphocytes in the CNS. This may in turn reduce the inflammatory demyelination that occurs in MS.
Table 31. Study Examining Teriflunomide for Cognitive Impairment in Multiple Sclerosis|
Author Year Title Country Research Design PEDro Sample Size |
Methods | Results |
|---|---|---|
|
Coyle et al. 2018 Patient-reported outcomes in patients with relapsing forms of MS switching to teriflunomide from other disease-modifying therapies: results from the global phase 4 Teri-PRO study in routine clinical practice USAPre-Post NInitial=594, NFinal=594 |
Population: Mean age=47.5yr; Sex: males=23.6%, females=76.4%; Disease course: relapsing forms of MS; Mean EDSS=3.1; Mean disease duration=13.8yr. Intervention: Participants who were receiving another disease modifying therapy within the 6mo prior to study start were prescribed teriflunomide (14mg or 7mg 1x/d) for 48wks. Outcomes were assessed at baseline and at wk 48. Cognitive Outcomes/Outcome Measures: Symbol Digit Modalities Test (SDMT); Multiple Sclerosis Performance Scale (MSPS) cognitive subscale. |
|
Discussion
One study by Coyle et al. (2018) conducted a secondary analysis of a previous phase IV trial (Coyle et al. 2017) to examine the effect of switching to teriflunomide from other DMTs on cognitive function in PwMS. Participants with relapsing forms of MS received teriflunomide for 48 weeks. Cognitive function was included as a secondary endpoint with the SDMT as well as the cognitive subscale of the patient-reported Multiple Sclerosis Performance Scale. Mean scores on the SDMT remained stable at 48 weeks compared to baseline (p=0.8074). The cognitive subscale of the Multiple Sclerosis Performance Scale also remained stable.
Conclusion
There is level 4 evidence that teriflunomide may have stabilizing effects on cognition (one pre-post study; Coyle et al. 2018).
Preliminary evidence suggests that teriflunomide may have stabilizing effects on clinical and subjective measures of cognitive function in persons with MS.