Dr Jeanette Lechner-Scott from the University of Newcastle talks about fatigue and cognition. They are symptoms of Multiple Sclerosis which have a tremendous impact on the quality of life.
I will speak about fatigue and cognition, and I think this is very important symptoms of Multiple Sclerosis, and they have a tremendous impact on the quality of life.
Fatigue is a very important symptom of Multiple Sclerosis. It often occurs prior to even being diagnosed, and up to 97% of patients and people with MS do report fatigue. We all know that it is actually something that alerts you to maybe that a relapse is coming. Often patients describe this overwhelming fatigue and then have other symptoms with it.
It is described as presenting symptoms in one third of all MS patients, and it is the one that affects your quality of life and your daily activity most. Its often completely independent of physical disability, and I want to state here that I’m not talking about secondary fatigue, which you can have as much as anyone else; secondary to sleep disorders, or medication, and that’s quite common in MS symptoms. You might have this secondary fatigue together with the binary MS fatigue. Lots of you take antidepressants that make you tired, you might take medication for spasticity which makes you tired, you might have additional thyroid disease, you might be depressed that makes you fatigued.
So there is lots that can contribute, but even if that does not occur, there is an intrinsic fatigue due to MS. And there are three different theories why this fatigue exists. There is the theory of inflammation, and I particularly interested in that and think it is probably the cause of MS fatigue.
Similarly to a viral infection, there’s a lot of circulated cytokines and inflammatory cells, and you feel like a bus has hit you. There is a second theory that it is due to demyelination. So as Michael has explained, with a little macrophage nibbling away your myelin sheath, and if your myelin sheath is gone, then your nerve conduction is a lot slower.
Or it might be due to axonal damage; the more nerves actually degenerated, the more fatigued you are. One of my early studies looked at PET scans, and we know that PET scans do look at metabolism; glucose metabolism in the brain, and things that light up is the ones where the most energy is used in the brain. So we know that MS patients have overall reduced metabolism, compared to healthy controls. And we looked at fatigue patients versus non-fatigue patients and found that here in the frontal areas, and in the basal ganglia, patients with fatigue light up more.
Management of fatigue is a very difficult issue. The best that we can do is probably just give good advice for non pharmacological treatment; to stop smoking, to reduce your caffeine intake because you do have a rebound phenomenon of that, to adjust your sleep pattern; everybody needs eight hours sleep, and make sure that you really are rested and don’t use your computer in the night, I mean what they tell for the youth is true for the adults as well; adjust your daily activity. If you are fatigued, you probably need to recharge your batteries in the afternoon and take a short nap. We always have shown that regular exercise actually doesn’t make you more fatigued, but gives you more energy.
Pharmacological treatment has been disappointing. There’s no good study showing any evidence of any of the drugs. Most of us use amantadine and a third of patients respond and report a good effect of it. Pemoline is another one that in some patients does work. there is one study on 72 patients on single arm trial that showed that modatinil is effective with MS, but you need to be aware that it has a strong tachyphalaxis and you will need to take higher and higher doses.
But a larger study which has only been published early this year, where is was placebo control and is shows over and over again how important it is to have placebo control trials. It shows that there is no effect whatsoever.
How important fatigue and cognition is for multiple sclerosis patients is nicely shown from a study by Glynis Clarke and Bruce Taylor; looked all over New Zealand and collected up to 3000 patients. Typical distribution – predominantly female, predominantly relapsing remitting, and they looked at the self-reported reasons for change in employment status. And fatigue, as you can see here, is the predominant symptom. Lower body motor function, but also cognition. Very important points to keep you all in the working force.
So looking at the percent of age group employed, so the blue ones are male, the pink are female, and they compared MS patients to census data. So the dotted ones are healthy people or the overall generation and people with MS are the ones with the continuous line. And you can see that fairly short after already onset of symptoms, prior to diagnosis, there’s a drop in employment, and this is true also for the median annual income. We all know that multiple sclerosis actually affects predominantly higher income people, and this drops very quickly after the diagnosis. And also no doubt that there is very big gap between male and female, and I don’t think that’s only in New Zealand.
Now to the prevalence of cognitive deficits, this depends very much who’s looking at that. So we as neurologists are actually quite poor in deciding if someone has cognitive difficulties or not. That is probably because you still are trying to impress us with your appearance. So if you though test it, and lots of people have had that; a three hour gruelling neuropsychological testing where they’re given all sorts of stories that you then have to remember again, and you have to remember word lists and all that. Then we will find that actually up to 65% will have difficulties.
We always thought that this was a late stage symptom, but more and more shows that it actually occurs early in the disease. And a very recent study from Otago showed that here 30% already had cognitive deficits, which means that more than three tests failed in the three hour testing, at the first symptom. And this is about what we find in our group as well, that when you’re secondary progressive, then you’re probably up to 80%.
It has a tremendous impact on your life, and cognitive impaired people with MS retire independent from their physical ability. They’re more likely to be dependent on other people. They’re more likely to have fewer social contacts. More likely to have accidents and that’s why you’re required to report your disease to RTA. And unfortunately and that’s particularly bad, less likely to adhere to medication, and I’ll tell you why in a minute.
As I said, neurologists are not very good in picking up cognitive deficits. This is because when you sit in our rooms and we talk to you, your language is not affected, communication is still happening even if there’s quite tremendous deficits. But its information processing, memory, problem solving which is the problem here, and which is required when you work, when you’re explained your task and it takes you longer to understand it and you need it to be repeated. And this makes work really difficult.
Why is that so? These are functional imaging studies, and I find them fascinating. So PET is one idea to do and see where the activity in the brain is happening. Functional MRI does it similarly. So it lights up where the brain is currently working. So people, as you can see, people that have a right arm weakness and are asked to move the right arm, use the left hemisphere as well, whereas control subjects don’t.
So you do need to require more brain if you have a deficit. And similarly, in a cognitive deficit, so the top line is control subjects, and these are mildly impaired MS patients, and these are severely cognitive impaired patients. These people probably function quite well in the workforce, but they need a lot more brain activity, and probably are very tired at the end of the day of working time. And achieve to achieve the same goal as these ones, because they don’t use as much energy.
Here, when you’re secondary progressive and have obvious cognitive deficits, your brain doesn’t use that much energy anymore because you just can’t, and the deficits are adverse. But these are the ones that are clinically isolated symptoms that do need more energy to do the same job as they’ve done before.
It’s not all doom and gloom. Already, in 2000, the first Avonex trial; a pivotal trial; they have tested the patients with a brief preforbedetal battery. And all patients over the study period did decline, but you can see the ones which were on placebo, declined more so than the ones that were on Avonex. So this first study is sort of repeated, but unfortunately none of the other pivotal trials have used full cognitive screening, so this is the five year Beta-interferon trial, and this is just looking at the Pasart, which is, many of you might have done that, this is a terrible test where you have to add the last heard number to the new one that you hear, but you cant keep adding, you need to always add the new on to the last one heard. So you need to be quite attentive for a long period of time, and its fifty numbers that you are told, and it’s hard.
In the Benefit trial, you see the ones that were started early on treatment improved more. Both groups improved, that’s probably practice effect, but both improved but more so when you were started early on treatment.
And similarly, in a natalizumab study, the ones that were on natalizumab significantly better than the ones that were on control, improved in the study period, which again I think is only reflecting practice effect. But it has a positive effect.
Unfortunately, the same can’t be said for Glatiramer-acetate. They have done a full study with brief, repeatable battery in their pivotal trial, tests after 12 and 24 months and couldn’t find any significant difference. And then the follow up study, when they looked at 10 year follow up, was always criticised because they only succeeded in getting 42% of their patients back for review. And they have published in saying that there’s good news that nobody really deteriorates over ten years. But if you, maybe not tremendously, the overall cognitive function doesn’t deteriorate significantly, but if you look at the single tests, they all showed significant worsening, and there was only minimal difference between the ones that were originally; they were all on treatment after the two years, so any effect will then always be diluted.
Symptomatic treatment. Acetylcholine-esterase-inhibitors are used for Alzheimer’s and improve or slow down their progression of cognitive deficits in Alzheimer, but they have been disappointing in MS. So Nematine was studied, and that study was stopped fairly early because 9 patients reported worsening of their MS symptoms. Revastigmine was studied only over three months, but didn’t show any affect. There was an early study on Donepezil, from Lauren Krupp, and she could show some difference in the single digit modality test, but not in Pasart. And unfortunately, again, this year’s study from the 120 placebo controlled again, the placebo controlled, bigger trial, didn’t show any benefit.
What about cognitive rehabilitation? There is a lot of small studies out there. We were one of the first to develop a computer training program, where our patients did improve, but we didn’t have a control allowance, so the study was always criticised. This is the recent Italian study where they looked at 150 patients. 20 of them were more than one and a half standard deviations below the expected age and education norm. And 10 of them went into treatment, which meant an interactive program three hours per week for three months, and the other 10 didn’t. And lots of the subjects improved. But again, a larger study, this time only a single arm, did not show any benefit.
So there is lots more to do, how we can improve cognitive deficits. And the best what I can suggest so far, is to go to the MS Society UK website. They have a very nice information sheet for you; how to manage best your difficulties in life, and what to do to overcome them; to still have a good life.
So in summary, fatigue and cognitive impairments occur early on in the disease. They have major impact on your quality of life; employment, income. They’re often insufficiently tested for. Unfortunately symptomatic treatment has so far shown not to be effective, but disease modifying treatment seem to have a positive effect. And we’re about to publish data that really it does in the clinical setting; people that are on treatment and remain on treatment do do better than the ones that are not on treatment.
And therefore I find it essential to monitor for these symptoms, to monitor for fatigue and to monitor for cognition. And I can only do that because I’ve got a very good and nice team that supports me in testing my patients all the time. Thank you.