About 3 years ago I launched a campaign to rebrand MS a 'Preventable Dementia'; I took a lot of stick for this campaign because it was considered stigmatising. However, the truth of the matter is that cognitive impairment, and progressive cognitive impairment, is what happens in MS. The study below by Ruano and colleagues, in over a 1,000 Italian MSers, confirms what we already know:
"The overall prevalence of cognitive impairment was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP MS."
The severity of cognitive impairment was greatest in MSers with progressive disease and was related to age and level of disability. What can be done about it? The message is simple; you have to try and prevent yourself from becoming disabled, in other words early effective treatments are needed as well as a brain healthy lifestyle (please see our Brain Health challenge). There is now convincing data that cognitive impairment is strongly associated with progressive brain atrophy and disability. If your MS is getting worse you need to ask the question can anything be done about it? The answer is yes.
Some good news in a sub-study of MS-STAT phase 2 trial showed that high-dose simvastatin signficantly slowed down progressive cognitive impairment in SPMSers. How simvastatin is doing this I can't tell, but it makes a compelling case for doing a definitive phase 3 trial of simvastatin in progressive MS. Please watch this space we have a grant application currently being reviewed by the NIHR (research arm of the NHS) to do this; the PI on the trial is Jeremy Chataway for UCL.
Should all progressive MSers be taking simvastatin now? No. The dose used in this trial is very high and will almost certainly cause adverse effects. The findings in this MS-STAT trial could be a type 1 error, or a false positive result. We therefore have to confirm it in a larger study and show that the benefits of high-dose simvastatin outweigh the risks of the treatment (adverse events) and for the NHS show that the treatment is cost-effective. I suspect the last point is not really an issue with simvastatin as it is off-patent and there are very cheap generics available; I am talking a few pence per day.
BNF price: Tablets, simvastatin 10 mg, net price 28-tab pack = 84p, 20 mg, 28-tab pack = 94p; 40 mg, 28-tab pack = £1.12; 80 mg, 28-tab pack = £2.02.
The current price of simvastatin (7.2 p/day) raises and important point about pharmaceutical innovation; the price of pharmaceuticals eventually come down so much that they become quite insignificant in the scheme of things. I can remember when I had just finished medical school (1987), and simvastatin had just been launched, there was a major debate going on about would society afford the costs of statins and that MSD was being mercenary charging so much for the drug. Now look at the price. We have to assume that the same rule will apply to current high-cost drugs, including the biologicals. In time and with further innovation in making biosimilars cheaply, future generations will reap the benefits. What we have sort out, however, is there a better model that the current one for repurposing off-patent drugs. We need away to monetise off-patent drugs so that Pharma take-up the challenge of doing the necessary trials and regulatory work to get off-patent drugs licensed. We find ourselves in a very difficult position; academia really doesn't have the resources (money) and expertise (regulatory machinery) to license drugs.
D Chan, S Binks, J Nicholas, A Alsanousi, N Fox… - 2016. Effect of high-dose simvastatin on cognition in secondary progressive multiple sclerosis (MS-STAT cognitive): a randomised, placebo-controlled, phase 2 trial
Background: Cognitive impairment is a major contributor to disability and reduced quality of life in secondary progressive MS (SPMS). In the 24 month MS-STAT phase 2 trial we showed that high dose simvastatin significantly reduced the rate of whole brain atrophy, as well demonstrating effects on clinician and patient observed outcome measures. We describe here results of the MS-STAT sub-study, evaluating treatment effect on cognitive and neuropsychiatric outcome measures.
Objectives: 140 patients with SPMS, with Expanded Disability Severity Scales (EDSS) scores between 4 and 6.5, were randomised to receive simvastatin (n=70) or placebo (n=70). Full cognitive and neuropsychiatric testing was undertaken at study entry, 12 and 24 months.
Methods: The following cognitive domains were tested: premorbid IQ; general intellectual functioning; verbal and nonverbal memory; semantic memory; visual perceptual function; attention, speed of information processing, and working memory (PASAT-3); frontal lobe function (frontal assessement battery, FAB). Neuropsychiatric symptoms were assessed using the Hamilton Depression Scale and the Neuropsychiatric Inventory Questionnaire. Linear mixed models were used to examine how cognitive and neuropsychiatric scores changed between baseline, 12 and 24 months and to evaluate the difference in score between the placebo and simvastatin group at 12 and 24 months.
Results: Baseline assessment revealed that nearly half of patients showed impairment on frontal lobe function (45%) and on the PASAT-3 (46%). There were also significant numbers of patients (up to 33%) with impairment on tests of verbal and nonverbal memory. Over the entire trial, the cohort as a whole declined on tests of verbal and non-verbal memory. At 24 months, there was a significant difference in FAB scores between the two treatment groups, with a 0.24 point increase in the mean FAB score observed in the simvastatin-treated group, compared with a decline of 0.92 points in the placebo group: a difference of 1.08 ( 95% CI 0.09 to 2.14). No significant treatment effect was observed on any other cognitive or neuropsychiatric measures.
Conclusion: This represents the largest SPMS published cohort to have been studied with longitudinal cognitive and neuropsychiatric assessments. Frequent cognitive impairment was observed at study entry, with decline at 24 months observed primarily in episodic memory. Although results must be interpreted carefully because of the many variables examined, we found that high dose simvastatin significantly improves frontal lobe function, adding to our previous observation of a positive treatment effect on brain atrophy rates. These results highlight the importance of including detailed cognitive outcome measures within progressive MS therapeutic trials.
Ruano et al. Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes. Mult Scler. 2016 Oct 13. pii: 1352458516674367. [Epub ahead of print]
BACKGROUND: There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS).
Objectives: 140 patients with SPMS, with Expanded Disability Severity Scales (EDSS) scores between 4 and 6.5, were randomised to receive simvastatin (n=70) or placebo (n=70). Full cognitive and neuropsychiatric testing was undertaken at study entry, 12 and 24 months.
Methods: The following cognitive domains were tested: premorbid IQ; general intellectual functioning; verbal and nonverbal memory; semantic memory; visual perceptual function; attention, speed of information processing, and working memory (PASAT-3); frontal lobe function (frontal assessement battery, FAB). Neuropsychiatric symptoms were assessed using the Hamilton Depression Scale and the Neuropsychiatric Inventory Questionnaire. Linear mixed models were used to examine how cognitive and neuropsychiatric scores changed between baseline, 12 and 24 months and to evaluate the difference in score between the placebo and simvastatin group at 12 and 24 months.
Results: Baseline assessment revealed that nearly half of patients showed impairment on frontal lobe function (45%) and on the PASAT-3 (46%). There were also significant numbers of patients (up to 33%) with impairment on tests of verbal and nonverbal memory. Over the entire trial, the cohort as a whole declined on tests of verbal and non-verbal memory. At 24 months, there was a significant difference in FAB scores between the two treatment groups, with a 0.24 point increase in the mean FAB score observed in the simvastatin-treated group, compared with a decline of 0.92 points in the placebo group: a difference of 1.08 ( 95% CI 0.09 to 2.14). No significant treatment effect was observed on any other cognitive or neuropsychiatric measures.
Conclusion: This represents the largest SPMS published cohort to have been studied with longitudinal cognitive and neuropsychiatric assessments. Frequent cognitive impairment was observed at study entry, with decline at 24 months observed primarily in episodic memory. Although results must be interpreted carefully because of the many variables examined, we found that high dose simvastatin significantly improves frontal lobe function, adding to our previous observation of a positive treatment effect on brain atrophy rates. These results highlight the importance of including detailed cognitive outcome measures within progressive MS therapeutic trials.
Ruano et al. Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes. Mult Scler. 2016 Oct 13. pii: 1352458516674367. [Epub ahead of print]
BACKGROUND: There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS).
OBJECTIVE: The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants.
METHODS: Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in ⩾ 2 cognitive domains.
RESULTS: A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age.
CONCLUSION: CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.