title: Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study Cognitive enhancing effects of modafinil in healthy volunteers Randomised multicentre trial on safety and efficacy of rivastigmine in cognitively impaired multiple sclerosis patients Modafinil for fatigue in MS Cognitive effects of modafinil in patients with multiple sclerosis: A clinical trial. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis Exercise training effects on memory and hippocampal viscoelasticity in multiple sclerosis: a novel application of magnetic resonance elastography The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Effects of single dose mixed amphetamine salts - extended release on processing speed in multiple sclerosis: a double blind placebo controlled study Memantine induces reversible neurologic impairment in patients with MS The effects of l-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial Modafinil effects in multiple sclerosis patients with fatigue Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients L-amphetamine improves memory in MS patients with objective memory impairment Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis Lisdexamfetamine dimesylate improves processing speed and memory in cognitively impaired MS patients: a phase II study Amantadine influences cognitive processing in patients with multiple sclerosis. The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis. Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial Effects of rivastigmine on memory and cognition in multiple sclerosis. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial Impact of Armodafinil on Cognition in Multiple Sclerosis: A Randomized, Double-blind Crossover Pilot Study Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine The effects of 4‐aminopyridine on cognitive function in patients with multiple sclerosis HAGIL (Hamburg Vigil Study): a randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis The effects of rivastigmine on processing speed and brain activation in patients with multiple sclerosis and subjective cognitive fatigue Ginkgo biloba does not improve cognitive function in MS
abstract: Objective : To assess the efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis ( MS ) . Methods : Patients aged 18–65 years with a diagnosis of MS , a stable disability level ≤6 on the Kurtzke extended disability status scale ( EDSS ) , and a mean score > 4 on the fatigue severity scale ( FSS ) were eligible for the 9 week , single blind , phase 2 , two centre study . Exclusion criteria included a diagnosis of narcolepsy , sleep apnoea , or clinical ly significant major systemic disease and recent use of medications affecting fatigue . All patients , who remained blinded for the treatment regimen , received placebo during weeks 1–2 , 200 mg/day modafinil during weeks 3–4 , 400 mg/day modafinil during weeks 5–6 , and placebo during weeks 7–9 . Safety was evaluated by unblinded investigators . Efficacy was evaluated by self rating scales , using the FSS , the modified fatigue impact scale ( MFIS ) , a visual analogue scale for fatigue ( VAS-F ) , and the Epworth sleepiness scale ( ESS ) . Adverse events were recorded . Results : Seventy two patients ( MS type : 74 % relapsing-remitting ; 7 % primary progressive ; 19 % secondary progressive ) received treatment . After treatment with 200 mg/day modafinil for 2 weeks , a significant improvement in fatigue versus placebo run in was demonstrated . Mean scores after treatment with 200 mg/day modafinil were : FSS , 4.7 versus 5.5 for placebo ( p<0.001 ) ; MFIS , 37.7 versus 44.7 ( p<0.001 ) ; and VAS-F , 5.4 versus 4.5 ( p=0.003 ) . Fatigue scores for 400 mg/day modafinil were not significantly improved versus placebo run in . Mean ESS scores were significantly improved ( p<0.001 ) with 200 mg/day modafinil ( 7.2 ) and 400 mg/day ( 7.0 ) versus the score at baseline ( 9.5 ) . Serious adverse events were not found at either dose . The most common adverse events were headache , nausea , and aesthenia . Sixty five patients ( 90 % ) completed the study . Conclusions : These data suggest that 200 mg/day modafinil significantly improves fatigue and is well tolerated in patients with MS Abstract Rationale . Modafinil , a novel wake-promoting agent , has been shown to have a similar clinical profile to that of conventional stimulants such as methylpheni date . We were therefore interested in assessing whether modafinil , with its unique pharmacological mode of action , might offer similar potential as a cognitive enhancer , without the side effects commonly experienced with amphetamine-like drugs . Objectives . The main aim of this study was to evaluate the cognitive enhancing potential of this novel agent using a comprehensive battery of neuropsychological tests . Methods . Sixty healthy young adult male volunteers received either a single oral dose of placebo , or 100 mg or 200 mg modafinil prior to performing a variety of tasks design ed to test memory and attention . A r and omised double-blind , between-subjects design was used . Results . Modafinil significantly enhanced performance on tests of digit span , visual pattern recognition memory , spatial planning and stop-signal reaction time . These performance improvements were complemented by a slowing in latency on three tests : delayed matching to sample , a decision-making task and the spatial planning task . Subjects reported feeling more alert , attentive and energetic on drug . The effects were not clearly dose dependent , except for those seen with the stop-signal paradigm . In contrast to previous findings with methylpheni date , there were no significant effects of drug on spatial memory span , spatial working memory , rapid visual information processing or attentional set-shifting . Additionally , no effects on paired associates learning were identified . Conclusions . These data indicate that modafinil selectively improves neuropsychological task performance . This improvement may be attributable to an enhanced ability to inhibit pre-potent responses . This effect appears to reduce impulsive responding , suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder Background : Cognitive decline has been recognised as a frequent symptom in multiple sclerosis ( MS ) .  Cholinesterase inhibitors ( ChEIs ) are employed for the treatment of Alzheimer ’s disease , but there is some evidence that ChEIs might also be effective in MS patients with cognitive deficits , particularly deficits of memory function . Objective : The aim of this study was to evaluate efficacy on memory function and safety of the ChEI rivastigmine in MS patients with cognitive deficits as measured by the change from baseline of the total recall score of the selective reminding test ( SRT ) after 16 weeks of treatment . Methods : Efficacy and safety of rivastigmine were analysed in a 16-week , multicentre , double-blind , r and omised , placebo-controlled study , followed by an optional one-year open-label treatment phase . Effects of rivastigmine and placebo were compared by an analysis of covariance . Results : In total , 86 patients were enrolled . Patients who received rivastigmine ( n = 43 ) showed a non-significant increase in total recall score ( sum of all words immediately recalled over all six trials ) over placebo ( n = 38 ) after 16 weeks of treatment ( p = 0.2576 ) . Other outcome measures provided no evidence supporting benefits of rivastigmine . Treatment with rivastigmine was well tolerated . Conclusions : With the results of this study , the need for an effective therapy in cognitively impaired MS patients is still required . Thus , intensive and continued clinical research is required to explore therapeutic options for cognitive deficits in MS patients Objective : To assess whether modafinil , a wakefulness-promoting agent , is useful for fatigue in patients with multiple sclerosis ( MS ) . Methods : Patients with MS with stable disability , and a baseline score of 45 or more on the Modified Fatigue Impact Scale ( MFIS ) , were eligible for the 5-week r and omized , double-blind , placebo-controlled , parallel group study . The initial daily dose of modafinil was 200 mg for 1 week . Depending on tolerance , the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35 . The primary outcome variable was the change of MFIS score at day 35 . Results : A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis . The mean MFIS score at baseline was 63 ± 9 in the placebo group and 63 ± 10 in the modafinil group . MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups , but no significant difference was detected between the two groups . There was no major safety concern . Conclusions : There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale PURPOSE / OBJECTIVE To assess the efficacy of modafinil for the treatment of new learning and memory deficits and fatigue in multiple sclerosis . Only 1 previous study in the literature , to our knowledge , examined the effect of modafinil on cognition specifically in persons with multiple sclerosis . RESEARCH METHOD / DESIGN Sixteen patients with a diagnosis of multiple sclerosis ( MS ) and documented new learning impairment completed the study . In a 5-week r and omized , double-blinded , crossover design , participants received either a single daily oral dose of modafinil ( 200 mg ) or placebo for 2 weeks . A 1-week washout period was included between study arms . RESULTS No effect of modafinil was noted on learning and memory performance . Participants taking 200 mg of modafinil showed improvement in 1 of the 2 working memory measures administered , the Wechsler Adult Intelligence Scale-III ( WAIS-III ) Letter-Number Sequencing task , as compared with those on placebo . Treatment with modafinil did not have a beneficial effect in reducing self-reported fatigue . No changes were noted on the Modified Fatigue Impact Scale or the Fatigue Severity Scale with the treatment of modafinil , as compared with placebo . CONCLUSIONS / IMPLICATION S Findings indicate that 200 mg of modafinil has the potential to improve working memory in persons with MS . These findings suggest that modafinil may enhance aspects of cognition in persons with MS and may be an effective adjunct to clinical rehabilitation interventions Objectives : The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter , double-blind , r and omized clinical trial ( RCT ) . Methods : Donepezil 10 mg daily was compared to placebo to treat memory impairment . Eligibility criteria included the following : age 18–59 years , clinical ly definite multiple sclerosis ( MS ) , and performance ≤½ SD below published norms on the Rey Auditory Verbal Learning Test ( RAVLT ) .  Neuropsychological assessment s were performed at baseline and 24 weeks . Primary outcomes were change on the Selective Reminding Test ( SRT ) of verbal memory and the participant 's impression of memory change . Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician 's impression of memory change . Results : A total of 120 participants were enrolled and r and omized to either donepezil or placebo . No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes . A trend was noted for the clinician 's impression of memory change in favor of donepezil ( 37.7 % ) vs placebo ( 23.7 % ) ( p = 0.097 ) . No serious or unanticipated adverse events attributed to study medication developed . Conclusions : Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study . Classification of evidence : This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average Introduction Cognitive impairment is common and debilitating among persons with multiple sclerosis ( MS ) and might be managed with exercise training . However , the effects of exercise training on viscoelastic brain properties in this population are unknown . The present pilot study adopted a single-blind r and omized controlled trial ( RCT ) design and is the first to examine the effect of an aerobic exercise training intervention on learning and memory and hippocampal viscoelasticity using magnetic resonance elastography ( MRE ) in persons with MS . Methods Eight fully ambulatory females with MS were r and omly assigned into exercise training intervention or waitlist control conditions . The intervention condition involved 12 weeks of supervised , progressive treadmill walking exercise training . All participants underwent measures of learning and memory ( i.e. , California Verbal Learning Test-II ; CVLT-II ) and further underwent MRE scans for measurement of shear stiffness ( μ ) and damping ratio ( ξ ) of the hippocampus before and after the 12-week period . Results Overall , there were small-to-moderate intervention effects on CVLT-II performance ( d = 0.34 ) and large intervention effects on hippocampal μ ( d = 0.94 ) and hippocampal ξ ( d = −1.20 ) . Change in CVLT-II scores was strongly associated with change in μ ( r = 0.93 , p < 0.01 ) and ξ ( r = −.96 , p < 0.01 ) of the hippocampus . Conclusion This small pilot RCT provides exciting proof-of-concept data supporting progressive treadmill walking exercise training for potentially improving learning and memory and underlying hippocampal viscoelastic properties in persons with MS . This is important given the high prevalence and burden of MS-related memory impairment Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Rationale Multiple sclerosis ( MS ) commonly affects cognitive function , most frequently presenting as impaired processing speed ( PS ) . There are currently no approved treatments for PS in this population , but previous studies suggest amphetamines may be beneficial . Objective The objective of this study is to determine if mixed amphetamine salts , extended release ( MAS-XR ) has the potential to improve impaired PS in MS patients in a r and omized controlled pre- and post-dose testing study . Methods Fifty-two MS patients demonstrating PS impairment on either the  Symbol Digit Modalities Test ( SDMT ) or  Paced Auditory Serial Addition Test ( PASAT ) were r and omized to a single dose of 5 mg MAS-XR ( n = 18 ) , 10 mg MAS-XR ( n = 20 ) , or placebo ( n = 14 ) . Subjects were evaluated a second time , after taking the blinded medication . ANOVA was used to compare the change on the SDMT and PASAT in each of the treatment groups compared to the placebo . Cohen ’s d was used to calculate effect size . Results At baseline , the mean SDMT score was 43.3 ± 7.2 and the mean PASAT was 34.8 ± 13.4 , with 47 ( 90.4 % ) and 25 ( 48.1 % ) categorized as impaired on the SDMT and PASAT , respectively . The change in SDMT scores from baseline to post-treatment demonstrated significant improvement for the MAS-XR 10-mg dose compared to placebo , increasing by 5.2 ± 4.5 vs. 0.6 ± 4.4 points ( p = 0.043 ) , with a medium effect size of 0.47 . Change on the PASAT was not significantly different in either treatment group . Conclusions This study supports MAS-XR 10 mg as a potential treatment for MS patients with demonstrated PS impairment , warranting a larger longitudinal study Background : Cognitive dysfunction is very common in multiple sclerosis ( MS ) and it severely impairs patients ’ quality of life . Thus , we explored whether memantine might improve cognitive performance in patients with MS . Methods : We conducted a pilot trial with memantine ( 30 mg/day ) in patients with MS with cognitive impairment . The trial was design ed as a 1-year , r and omized , double-blind , crossover study comparing memantine against a placebo in 60 patients with MS and cognitive impairment . Cognitive impairment was defined as the performance 1.5 st and ard deviations below the normative data in at least two tests of two cognitive domains in the Brief Repeatable Battery – Neuropsychology . The primary endpoint was improvement of verbal memory and the secondary endpoints were safety and improvements in the other cognitive domains , disability and quality of life . The trial was registered at www . clinical trials.org : NCT00638833 . Results : Although 19 patients had been included , the trial was halted after nine patients reported a worsening of their neurologic symptoms that deteriorated their quality of life . Seven of the nine patients in the memantine arm had blurred vision , fatigue , severe headache , increased muscle weakness , walking difficulties , or unstable gait . Only two patients in the placebo group reported neurologic symptoms and in both cases they were related with changes in their disease-modifying therapy . The adverse events only occurred on reaching the maximum dose ( 30 mg/day ) . After stopping medication , the patients reverted to their baseline disability within a few days . Conclusions : Memantine at a dose of 30 mg/day may induce transient worsening of neurologic symptoms of multiple sclerosis Defects in processing speed and memory are common in multiple sclerosis ( MS ) patients . In other population s , amphetamines have been shown to enhance cognition , but their use is limited by adverse behavioral effects . The l-isomer may have equivalent cognition enhancement with less adverse effects due to decreased potency in subcortical areas . The aim of this study was to assess the safety and efficacy of l-amphetamine sulfate in the treatment of cognitive dysfunction in MS . This was a 2:1 r and omized , placebo-controlled , double-blind trial , involving 33 MS clinics across the USA . One hundred and fifty-one clinical ly definite MS patients with documented cognitive dysfunction who were relapse free for ≥90 days , with an Exp and ed Disability Status Scale ( EDSS ) ≤6.5 , and with no other medical/psychiatric condition that may cause psychological dysfunction were r and omized to 30 mg of oral l-amphetamine sulfate or placebo for 29 days , including a dose escalation period . A history of cardiac disease , uncontrolled hypertension or electrocardiograph abnormalities result ed in exclusion . The primary outcomes were the Subject Global Assessment of Change and Symbol Digit Modalities Test ( SDMT ) . Secondary outcomes were the results from the California Verbal Learning Test , second edition ( CVLT2 ) , Brief Visual Memory Test-Revised ( BVMTR ) , and Paced Auditory Serial Addition Test ( PASAT ) . One hundred and thirty-six subjects completed the study . No differences were found at baseline in demographics or in the results of the neuropsychological tests . After treatment , the active group performed significantly better for total learning ( P = 0.041 ) and delayed recall ( P < 0.01 ) on the BVMTR , and for delayed recall ( P = 0.012 ) on the CVLT2 . Five patients ( four from the treatment group , one placebo ) withdrew due to intolerable adverse events . l-amphetamine sulfate was associated with improved learning and memory and was well tolerated in this study . However , because the positive findings were observed on secondary outcome measures , the study requires replication before l-amphetamine sulfate can be recommended for the treatment of cognitive impairment in MS Background To investigate the effects of Modafinil on focused attention , motor function and motor excitability in patients with multiple sclerosis ( MS ) and fatigue . Methods 21 MS patients with fatigue were enrolled in this double-blind placebo-controlled study . Modafinil ( MOD ) or placebo ( PL ) was administered for 8 weeks . The d2 alertness test , the Nine Hole Peg Test ( 9HPT ) and several transcranial magnetic stimulation ( TMS ) techniques were applied prior to and after the first drug ingestion and well as after 8 weeks of drug intake . Results Prior to the first drug intake , the two groups were comparable . After the first drug ingestion , fatigue as measured by the Fatigue Severity Scale ( FSS ) , performance of the d2 test and the 9HPT improved significantly in the MOD group and remained better than in the PL group after 8 weeks of treatment . Patients in the MOD group made fewer mistakes in the D2 test without being slower . They completed the 9HPT faster . Motor evoked potential amplitudes produced by paired pulse TMS were larger in the MOD group than the PL group . Motor thresholds and silent period duration s remained unchanged . Conclusions Compared to PL , MOD improved fatigue , focused attention and dexterity and enhanced motor cortex excitability in this group of patients . MOD may be helpful in MS patients with fatigue to improve cognitive and motor abilities To examine the efficacy and toxicity of oral 3,4 diaminopyridine ( DAP ) in dosages up to 100 mg/day , 36 patients with multiple sclerosis ( MS ) enrolled in a r and omized , double-blind , placebo-controlled , crossover trial . The primary outcome measure was improvement of a prospect ively defined neurologic deficit , which was leg weakness in 34 patients . Secondary outcome measures included the patient 's subjective response , scored manual motor testing ( MMT ) of leg strength , scored leg strength from videotaped motor testing ( VMT ) , quadriceps and hamstrings strength ( QMT ) measured by isometric dynamometry , neuropsychological testing ( NPT ) , ambulation index ( AI ) , and Exp and ed Disability Status Scale ( EDSS ) score . Paresthesias and abdominal pain were common and were dose limiting in eight patients . Three patients had episodes of confusion , and one patient had a seizure while on DAP . Eight patients withdrew from the study , leaving 28 evaluable patients for the efficacy analysis . The prospect ively defined neurologic deficit improved in 24 patients -22 on DAP and 2 on placebo ( p = 0.0005 ) . All improvements were in leg weakness . Subjective response and measures of leg strength and function ( MMT , VMT , QMT , and AI ) improved on DAP compared with placebo . Neither NPT nor EDSS scores improved . DAP treatment can induce improvements in leg strength in MS patients , but toxicity is limiting in many patients . NEUROLOGY 1996;47 : 1457 - Background : Memory impairment is prevalent in multiple sclerosis ( MS ) , but no drugs are approved to treat these memory problems . Objective : The objective of the study was to examine the effect of l-amphetamine versus placebo on auditory/verbal memory and visual/spatial memory in MS patients with and without baseline memory impairment . Methods : We conducted a re- analysis of a previously published clinical trial in which MS patients were r and omly assigned to treatment ( 30 mg l-amphetamine , N = 99 ) or placebo ( N = 37 ) in a four-week , double-blind , parallel-group , dose titration trial . Auditory/verbal memory ( CVLT-II : Long Delay Free Recall ) and visual/spatial memory ( BVMT-R : Delayed Recall ) were assessed at baseline and follow-up across subgroups of patients with intact baseline memory ( mean = 50th percentile ) or impaired baseline memory ( mean = 2nd percentile ) . Primary analyses : 2 ( l-amphetamine , placebo ) × 2 ( baseline , follow-up ) , × 2 ( baseline memory intact , baseline memory impaired ) ANOVAs performed separately for auditory/verbal and visual/spatial memory . Results : For both auditory/verbal and visual/spatial memory , we observed significant 2 × 2 × 2 interactions whereby l-amphetamine  improved memory more than placebo , and this effect was specific to patients with baseline memory impairment . Conclusions : Among memory-impaired patients  , memory improved about 48.5 % for those on l-amphetamine , but only 1.0 % on placebo . Treatment with l-amphetamine produced large memory gains among memory-impaired MS patients Objectives To determine if Ginkgo biloba ( GB ) improves the cognitive performance of subjects with multiple sclerosis ( MS ) . Methods R and omized , double-blind , placebo-controlled trial of GB , 120 mg twice a day or placebo for 12 weeks . The primary outcomes were : the long delay free recall from the California Verbal Learning Test-II ; the Paced Auditory Serial Addition Test ; the Controlled Oral Word Association Test ; the Symbol Digit Modalities Test ; Useful Field of View Test ; and the color-word interference condition from the Stroop Color and Word Test . Results On completion , the GB group ( n=20 ) was 4.5 seconds ( 95 % confidence interval ( CI ) ( 7.6 , 0.9 ) , P=0.015 ) faster than the placebo group ( n=18 ) on the color-word interference condition of the Stroop test . Subjects who were more impaired at baseline experienced more improvement with GB ( treatment*baseline interaction , F=8.10 , P=0.008 ) . We found no differences on the other neuropsychological tests . Subjects on GB reported fewer cognitive difficulties in the Retrospective Memory Scale of the Perceived Deficits Question naire than subjects on placebo ( 1.5 points , 95 % CI ( 2.6 , 0.3 ) , P=0.016 ) . No serious drug related side-effects occurred and GB did not alter platelet function assays . Conclusion Overall , GB did not show a statistically significant improvement in cognitive function . A treatment effect trend , limited to the Stroop test , suggests that GB may have an effect on cognitive domains assessed by this test , such as susceptibility to interference and mental flexibility . Multiple Sclerosis 2007 ; 13 : 376 - 385 . Multiple sclerosis ( MS ) causes cognitive impairment including slowed processing speed and problems with learning and memory . Stimulants are attractive c and i date s for improving mental speed but carry risk of addiction and other adverse behavioral effects . Lisdexamfetamine dimesylate ( LDX ) is a d-amphetamine prodrug currently approved for attention deficit ( hyperactivity ) disorder with the potential to be better tolerated due to its prolonged clinical effect . This phase II placebo-controlled , double-blind study aim ed to assess the safety and efficacy of LDX in cognitively impaired MS patients . Subjects were patients with clinical ly definite MS , aged 18–56 years , and impaired on either of two primary outcomes : the Symbol Digit Modalities Test ( SDMT ) or the  Paced Auditory Serial Addition Test ( PASAT ) . Both SDMT and PASAT are measures of cognitive processing speed . Of 174 MS patients screened , 63 were r and omized to 30 mg of LDX or placebo in a 2:1 fashion ; the dose was increased as tolerated to 70 mg over 4 weeks and then maintained for another 4 weeks . Secondary outcomes were the Brief Visuospatial Memory Test Revised ( BVMTR ) , the California Verbal Learning Test 2nd edition ( CVLT2 ) , both measures of episodic memory , and the Behavioral Rating Inventory of Executive Function for adults ( BRIEF-A ) , a self-report measure of executive function . Fatigue and depression were also evaluated . There was significant improvement in the SDMT score ( + 4.6 vs. + 1.3 ) and CVLT2 score ( + 4.7 vs. −0.9 ) in the LDX group compared with the placebo group among the 49 completers . There was no change on the other outcomes . A high proportion of both LDX-treated and placebo-treated subjects reported adverse events ( 73.5 % vs. 68.4 % ) . However , there were no serious adverse events noted in the study . These preliminary data indicate that LDX has the potential to be an efficacious treatment for MS patients with cognitive impairment We investigated the effect of amantadine on cognitive processing in patients with multiple sclerosis ( MS ) and fatigue with objective electrophysiological measures . Behavioral methods ( Reaction Time , RT ) and two different Event Related Potential ( ERP ) components measuring i ) stimulus selection ( Selection Negativity , SN ) and ii ) response selection ( Lateralized Readiness Potential , LRP ) were employed . Twenty-four patients with clinical definite MS ( 10 relapsing remitting and 14 secondary progressive ) and confirmed fatigue in the past three months ( Fatigue Severity Scale ( FSS ) > 4 ) were included . Patients were r and omized in a double-blind , placebo-controlled cross-over design . We found a difference between the two treatments for ERP measures to stimuli with relevant colour starting at about 200 ms . This negativity had a higher amplitude during amantadine treatment regardless of treatment order . The RT did not differ significantly between the treated and untreated groups . Additional analysis indicated that patients with a disease duration of less than 7 years had a significant test position ( practice effect ) , but no treatment effect , while patients with a longer MS duration showed no practice effect , but rather an improved reaction speed and increased ERP amplitude effects when treated with amantadine . The present findings suggest that amantadine exerts beneficial effects on early cognitive processes in patients with MS , but appears to be limited to subjects with a longer duration of the disease BACKGROUND Amantadine hydrochloride and pemoline , both frequently used to treat the fatigue of multiple sclerosis ( MS ) , may also improve attention and other cognitive functions in MS . To our knowledge , these agents have never been compared in a placebo-controlled trial of patients with MS . OBJECTIVE To evaluate the effects of amantadine and pemoline on cognitive functioning in MS . METHODS A total of 45 ambulatory patients with MS and severe fatigue were treated for 6 weeks with amantadine , pemoline , or placebo using a parallel group design . They underwent comprehensive neuropsychological testing to determine treatment effects on cognitive functioning . Primary outcome measures were tests of attention ( Digit Span , Trail Making Test , and Symbol Digit Modalities Test ) , verbal memory ( Selective Reminding Test ) , nonverbal memory ( Benton Visual Retention Test ) , and motor speed ( Finger Tapping Test ) . RESULTS Fatigue did not significantly correlate with any of the neuropsychological outcome measures at baseline or after treatment . All three treatment groups improved on tests of attention ( P < .003 ) , verbal memory ( P < .001 ) , and motor speed ( P < .002 ) . There were no significant differences between amantadine , pemoline , and placebo . CONCLUSIONS Cognitive functioning in MS is independent of fatigue . Neither amantadine nor pemoline enhances cognitive performance in MS compared with placebo Background : Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis ( MS ) .  Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans . It may , therefore , be particularly useful for MS patients with pronounced neurodegeneration . Objective : To investigate the potential of st and ardized exercise as a therapeutic intervention for progressive MS , in a r and omized-controlled pilot trial . Methods : Patients with progressive MS and moderate disability ( Exp and ed Disability Status Scale ( EDSS ) of 4–6 ) were r and omized to one of three exercise interventions ( arm ergometry , rowing , bicycle ergometry ) for 8–10 weeks or a waitlist control group . We analyzed the drop-out rate as a measure of feasibility . The primary endpoint of the study was aerobic fitness . Secondary endpoints were walking ability , cognitive function as measured by a neuropsychological test battery , depression and fatigue . Results : A total of 42 patients completed the trial ( 10.6 % drop-out rate ) . Significant improvements were seen in aerobic fitness . In addition , exercise improved walking ability , depressive symptoms , fatigue and several domains of cognitive function . Conclusion : This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS . Larger exercise studies are needed to confirm the effect on cognition . Trial Registration : IS RCT N ( trial number 76467492 ) http://is rct BACKGROUND Cognitive dysfunction is one of the common clinical symptoms in multiple sclerosis ( MS ) , but there is no effective treatment for it . OBJECTIVE The aim of this study was to evaluate the effect of rivastigmine in treating memory and cognitive dysfunction in MS . METHODS A single-center double-blind placebo-controlled r and omized clinical trial conducted from October 2005 to February 2007 . Sixty definite MS patients with cognitive impairment age 16 to 54 years were r and omly allocated to receive a 12-week treatment course of either rivastigmine ( 1.5 mg once a day increment over 4 weeks to 3 mg twice daily ) or placebo . Response to treatment was assessed by the Wechsler Memory Scale ( WMS ) at baseline and 12 weeks after start of therapy . RESULTS A slight , but significant memory improvement occurred in both groups . Of the 30 patients treated with rivastigmine , the mean ( SD ) WMS general memory score increased from 60.3 ( 4.2 ) at baseline to 64.9 ( 5.3 ) at the end of study period ( P<0.001 ) . Correspondingly , in the 30 patients treated with placebo , the mean ( SD ) WMS general memory score increased from 60.5 ( 4.9 ) to 64.5 ( 3.7 ) ( P < 0.001 ) . The average WMS general memory score at the end of trial did not changed between rivastigmine and placebo group ( mean difference , 0.4 ; 95 % CI , -2.0 , 2.8 ) . CONCLUSION No significant differences were seen between rivastigmine and placebo on the mean ( SD ) WMS general memory score . A larger multicenter study of rivastigmine in MS is warranted in order to more definitely assess the efficacy of this intervention Background : Memantine , an NMDA antagonist , is effective for moderate to severe Alzheimer ’s disease . Objective : Determine whether memantine improves cognitive performance ( CP ) among subjects with multiple sclerosis ( MS ) and cognitive impairment ( CI ) . Methods : This double-blind , r and omized , placebo-controlled trial ( Clinical trials.gov NCT00300716 ) compared memantine 10 mg twice a day ( 4 week titration followed by 12 weeks on the highest tolerated dose ) with placebo . The primary outcome was the change from baseline to exit on the  Paced Auditory Serial Addition Test ( PASAT ) and the California Verbal Learning Test-II ( CVLT-II ) Long Delay Free Recall ( LDFR ) . Secondary outcomes included additional neuropsychological tests ; self-report measures of quality of life , fatigue , and depression ; and family/caregiver reports of subjects ’ CI and neuropsychiatric symptoms . Results : The differences between the groups on the change on the PASAT  ( placebo — memantine = 0.0 correct responses , 95 % CI 3.4 , 3.4 ; p = 0.9 ) and on CVLT-II LDFR  ( placebo — memantine = —0.6 words , 95 % CI —2.1 , 0.8 ; p = 0.4 ) as well as on the other cognitive tests were not significant . Subjects on memantine had no serious adverse events ( AEs ) but had more fatigue and neurological AEs as well as , per family members ’ reports , less cognitive improvement and greater neuropsychiatric symptoms than subjects on placebo . Conclusion : Memantine 10 mg twice a day does not improve CP  in subjects with MS , ages 18—65 , without major depression , who have subjective cognitive complaints and perform worse than one SD below the mean on the PASAT or on the California Verbal Learning Test-II  ( total recall or delayed free recall ) Objective : Examine the efficacy of armodafinil in improving cognition in patients with multiple sclerosis ( MS ) . Background : Many patients with MS experience cognitive difficulties .  Armodafinil has shown promise as a cognitive enhancer in other patient population s. No studies have examined whether armodafinil improves cognition in patients with MS . Methods : We conducted a double-blind , placebo-controlled , crossover study testing the efficacy of armodafinil in reducing cognitive problems in patients with MS . We r and omized 17 patients to receive a dose of  lactose placebo  about 2 hours before they underwent a neuropsychological testing session . After a week-long washout period , we gave them a single 250-mg dose of armodafinil about 2 hours before testing them a second time . We r and omized another 16 patients to receive the active drug first , then the placebo .  We excluded 3 of the participants before analyzing the data . Results : After correcting for multiple comparisons of the 8 neuropsychological dependent measures , we found that the patients had significantly improved delayed memory on a list-learning task after they took armodafinil ( P=0.0005 ) , but no improvement on measures of executive function , visual memory , processing speed , or self-reported fatigue . Conclusions : Results provide preliminary evidence that armodafinil may improve delayed verbal recall in patients with MS . A larger trial showing enhanced memory among patients taking long-term armodafinil  could serve as a foundation for its possible clinical use as a memory enhancer in patients with MS Previous studies suggest that aminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis . Although the mechanism underlying the beneficial effect on fatigue remains unclear , it has been proposed that aminopyridines may help to improve conduction in demyelinated central pathways , implicating both axonal and synaptic mechanisms . The objective of the present study is to determine whether 4-AP decreases daily-living fatigue in progressive multiple sclerosis . The effect of 4-AP on other neurophysiological and neuropsychological parameters was also considered . A ` double-blind ' , r and omized , ` placebo-controlled ' , crossover trial was conducted on 54 patients with progressive multiple sclerosis . All patients received treatment with placebo and 32 mg per day of 4-AP , each for 6 months . The main outcome measure was the Fatigue Severity Scale . Secondary measures were EDSS , cognitive functions and neurophysiological parameters .  Forty-nine patients ( 91 % ) completed the study .  Changes in fatigue scores , EDSS and cognitive functions were not significantly different between 4-AP and placebo . However , when patients treated with 4-AP were divided into two groups according to the serum level of 4-AP , a significant effect on fatigue compared with placebo was observed in the ` high level ' ( 430 ng/ml ) group ( P=0.05 ) . Synchronization of motor evoked potentials improved during 4-AP with respect to placebo ( P=0.019 ) and this correlated positively with fatigue reduction ( P=0.010 ) . No relevant side effects were observed 4 Aminopyridine ( 4-AP ) has a favorable effect on the disability of certain patients with MS . We investigated the effect of 4-AP on neuropsychological performance in 20 MS patients using a r and omized , double-blind , placebo-controlled , crossover design . Although there was a trend for improved performance with 4-AP for two of the tests , we could not demonstrate significant effects of 4-AP on cognitive function Objective : To reassess the effect of modafinil , a wakefulness-promoting artificial psychostimulant , on fatigue and neuropsychological measures in patients with multiple sclerosis . Methods : Multiple sclerosis ( MS ) patients with a baseline score of ≥4 on the Fatigue Severity Scale ( FSS ) and an Exp and ed Disability Status Scale score < 7 were eligible for the 8-week r and omized , double-blind , placebo-controlled study . Modafinil was dosed up to 200 mg/day within 1 week . Assessment s were performed at baseline and after 4 and 8 weeks . The primary outcome parameter was the mean change of the FSS mean score . Secondary outcome variables were other question naires covering fatigue , daytime sleepiness and sleep quality . Cognitive impairment was assessed by the oral version of the Symbol Digit Modalities Test ( SDMT ) and the Paced Auditory Serial Addition Test ( PASAT ) . Results : The study included 121 MS patients . Dropout rate was 9 % . Both treatment groups showed improvements through time . While mean FSS at 8 weeks showed a trend difference between groups in the intention-to-treat analysis , the primary endpoint was not met . Assessment of cognitive impairment by SDMT and PASAT showed contradictory results . All other secondary endpoints were not met . There was no major safety concern . Conclusions : In general , the study does not support modafinil as an effective treatment for MS fatigue . However , the study shows the need for new study design s and endpoints in MS fatigue studies Background : Cognitive decline and fatigue are typical in multiple sclerosis ( MS ) . However , there is no official medication for either of these symptoms . Objective : The purpose of this study was to estimate the effects of a single dose of rivastigmine on processing speed and associated brain activity in patients with MS and subjective cognitive fatigue . Methods : Fifteen patients with MS and subjective cognitive fatigue and 13 healthy controls ( HCs ) matched for age , gender and education performed a neuropsychological assessment and functional (f)MRI . A modified version of the Paced Visual Serial Addition Test ( mPVSAT ) was used as the behavioural task during fMRIs . After the first scanning session , both groups were r and omly divided into two subgroups receiving either rivastigmine or placebo . A single dose of rivastigmine or placebo was administrated double-blindly and 2.5 hours later the scanning was repeated . Results : At baseline , the patients with MS showed slower processing speed in mPVSAT compared with the HCs . They also demonstrated stronger bilateral frontal activation after sustained cognitive effort than the HCs . Performance improvement and a further activation increase in the left anterior frontal cortex and additional activation in the right cerebellum were observed in patients who received rivastigmine but not in patients on placebo , or in HCs with placebo or rivastigmine . Conclusion : These preliminary findings suggest that rivastigmine may improve cognitive processing speed by enhancing compensatory brain activation in patients with MS Objective : To determine whether Ginkgo biloba extract ( ginkgo ) improves cognitive function in persons with multiple sclerosis ( MS ) . Methods : Persons with MS from the Seattle and Portl and VA clinics and adjacent communities who scored 1 SD or more below the mean on one of 4 neuropsychological tests ( Stroop Test , California Verbal Learning Test II [ CVLT-II ] , Controlled Oral Word Association Test [ COWAT ] , and Paced Auditory Serial Addition Task [ PASAT ] )  were r and omly assigned to receive either one 120-mg tablet of ginkgo ( EGb-761 ; Willmar Schwabe GmbH & Co , Germany ) or one placebo tablet twice a day for 12 weeks . As the primary outcome , we compared the performance of the 2 groups on the 4 tests at exit after adjusting for baseline performance . Results : Fifty-nine subjects received placebo  and 61 received ginkgo ; 1 participant receiving placebo and 3 receiving ginkgo were lost to follow-up . Two serious adverse events ( AEs ) ( myocardial infa rct ion and severe depression ) believed to be unrelated to the treatment occurred in the ginkgo group ; otherwise , there were no significant differences in AEs . The differences ( ginkgo − placebo ) at exit in the z scores for the cognitive tests were as follows : PASAT −0.2 ( 95 % confidence interval [ CI ] −0.5 to 0.1 ) ; Stroop Test −0.5 ( 95 % CI −0.9 to −0.1 ) ; COWAT 0.0 ( 95 % CI −0.2 to 0.3 ) ; and CVLT-II 0.0 ( 95 % CI −0.3 to 0.3 ) ; none was statistically significant . Conclusions : Treatment with ginkgo 120 mg twice a day did not improve cognitive performance in persons with MS . Classification of evidence : This study provides Class I evidence that treatment with ginkgo 120 mg twice a day for 12 weeks does not improve cognitive performance in people with MS
target: Whilst there was only a limited pool of relatively small trials and a number of different compounds , we found that collectively , both AChEIs ( donepezil and rivastigmine ) and stimulants ( methylpheni date , modafinil , l‐amphetamine sulfate and lisdexamfetamine dimesylate ) offered no significant benefits over placebo on measures of processing speed , working memory , verbal fluency , verbal memory , visuospatial memory or executive functioning
background: HighlightsCognitive deficits are present in up to 70 % of people with multiple sclerosis (MS).There are no approved treatments for these difficulties .
  We examined whether adjunctive pharmacotherapies can improve cognition in MS.Acetylcholinesterase inhibitors offered no significant benefits over placebo .
  Stimulant‐based medications offered no significant benefits over placebo .
  & NA ; We sought to examine the effectiveness of acetylcholinesterase inhibitors ( AChEIs ) and stimulant‐based medications for improving cognitive performance in patients with multiple sclerosis ( MS ) .