“I did a follow-up MS clinic yesterday and had a few MSers who returned for decisions after having had annual monitoring MRI scans. Three of them had breakthrough disease on MRI, i.e. new or enhancing lesions, when the current scan was compared to the one from a year ago. All of these MSers thought they were relapse free and stable. How could this be? When I probed them with questions all three of them had had intermittent symptoms that were clearly minor relapses. One had sensory symptoms affecting a leg, another was had an episode of being more unsteady and noticing a deterioration in their walking distance and another had tripped and fell and noticed some transient weakness in their foot. My first insight is that we are simply not capturing all relapses with our current definition. We need a better way of monitoring this clinical activity without being too intrusive on MSers lives; several MSers are not comfortable with a daily diary as it takes too much time and reminds them every day of their MS. Any suggestions?”
“Another insight is that most MSers with subclinical relapses (MRI activity) do not feel right; adjectives used are ‘very tired‘, ‘exhausted‘, ‘fatigued‘, ‘out of sorts‘, ‘I could sleep all day‘, ‘my brain fog is back‘ and ‘I just don’t feel well‘. I am sure these symptoms are compatible with MS-related sickness behaviour. Sickness behaviour is triggered by inflammation; the inflammatory mediators, or messengers, signal to the brain to slow down and sleep. From an evolutionary perspective this behaviour is triggered in sick animals to conserve energy to allow the body to recover. Anyone who has had influenzae will know what sickness behaviour feels like. May be we need a way of measuring this sickness behaviour between annual MRI scans? Any thoughts?”
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| The MS Iceberg |
“Another insight is that all these MSers were on injectable 1st-line therapies. These therapies were probably taking the edge off the relapses, i.e. making them less frequent and clearly less severe. The downside of this is that none of these MSers would be classified as having highly-active or rapidly evolving MS and therefore would not be eligible for the most effective therapies we have to treat MS. They would have to go through intermediate efficacy DMTs. In other words the less effective drugs are creating a large number of MSers with smouldering MS, that is partially under control, but not under control enough when applying the zero-tolerance litmus test. In other words these DMTs do not stop the shredder, they only slow it down. This is why we really need to get biomarkers into clinical practice that measure the hidden disease activity so that we can target the bottom of the MS iceberg and stop the slow burn that results in end-organ damage. At the end of the day our treatment target must be to prevent disability, not to simply slow the rate of its accumulation down. Zero tolerance has to be the goal. Do you agree? Or do you disagree?”
“I am seriously considering cutting down on clinical practice; I simply don’t have enough hours in my day. However, seeing MSers, and managing MS in real life, stimulates thinking and generates ideas. In short, clinical practice is an Idea Factory.”
CoI: multiple
Prof G,Thanks for your post. This is very timely for me. I'm a recipient of a highly effective therapy (alemtuzumab), but 5 years after my second infusion have over the last month noticed some leg weakness, tight feet and ankles. My neuro is excellent and is seeing me next week – he's an advocate of NEDA. Why are you thinking of reducing your clinical work? Your promotion of NEDA and highly effective treatments will have a big positive impact in the future. I hope the Charcot trial has some positive results. While I can see the intellectual challenge of research, there not enough MS specialist neuros.
Re: "Why are you thinking of reducing your clinical work? "I don't have enough time to do everything what is required of me. I am a centre lead, I run a large research group, I am expected to head-up MS@UCLP, I am journal editor, I am expected to write big grants and coordinate some new funding bids, I sit on numerous steering committees, I mentor 4 young academic fellows, I supervise PhD students, and the list goes on. This is before I start discussing my clinical and teaching activities.
Thank you for your hard work. Through your writing here you reach patients who could never see you in person.
Great post – who could possibly disagree with the aim of NEDA? How does the EBV theory fit with what you describe above? Is it that the virus continues to cause damage, but it's impact is reduced by the 1st line DMDs? Is the virus the target of both the adaptive and innate immune systems? I'm confused.
Biomarkers – we could talk all day how to better supervise MS – we need reliable tests – either blood or lumbar or an optimised version of OCT to see how the brain is doing even when a patient feels 'okay'.Investigate more OCT – I think the eye is the answer to the problem (even a test with ca. 90% accuracy is better than none).
Well, it is quite simple to explain – the 1st line DMTs protect only slightly against relapses so smaller relapses are to be expected. I would worry if I were on those super strong DMTs and still having relapes but even then one patient may be a non-responder and the other has NEDA.I think with strong DMTs (which offer 80-100% relapses free) and a neuroprotective agent on top of that MSer will achieve true NEDA but not before.
Great blog. Prof G do you think this will change the mind set of those who decide what drugs are allocated to what people? Are you the only one advoctting the'iceberg' theory?A blog like this leaves me with a hell of a lot more questions than answers. While I think that is a good idea, its gets people thinking it might also make people despair of ever gettig to the NEDA.Finally we need you doing clinics because of your empathy and understanding of the hell that people with MS are going through all the time.
Annual MRIs – now that would be a fine thing. How can I get them, when, having asked, have been refused?
Exactly, this post angered me at first because I suspect I am exactly a smouldering MSer on a first line therapy – although I don't even know!! Routine annual MRI please NHS…
Anonymous Friday, June 20, 2014 10:21:00 am: EBV may not be the target, EBV infects B cells, these infected B cells may be the conductor orchestrating the immune response not the target of the attack. In glandular fever they attract other immune cells to themselves.
GG, is it possible to "stop the shredder" if you don't know the cause of the disease?
Re: "…is it possible to "stop the shredder" if you don't know the cause of the disease?"That depends on your world view and how you define stopping the shredder. My talk last week at our 5th MS Research Day was on this exact topic. http://multiple-sclerosis-research.blogspot.co.uk/2014/06/why-havent-we-cured-ms-yet.htmlAt the moment we don't look for activity at the bottom of the iceberg and hence it is difficult to make a call on this in individual MSers. Hence a call to arms to look more closely at disease activity.
You quote how patients feel out of sorts, fatigued, etc, but it isn't always an MS relapse. It takes quite a while to diagnose the true problem. In my case, the tests took over a year before I had diagnosis of an illness totally unconnected to MS. My GP always looks beyond my MS for these symptoms and in my experience it has always been something more serious. An MRI scan for MS would be of no benefit. Lucky for me my doctors look beyond their own speciality and see me as an individual.
SymTrac is pretty good if you have a smart phone for monitoring..,I suspect small relapses also go undocumented as people are busy. Having to get an appt, take a day off work and visit a relapse clinic for something mild could be improved.I also suspect people do not count some small things in the fear that it is a relapse, trying to desperately stay relapse free..,
I count even the small things and it freaks me out. However, for example, I found out that I have some other minor disease that has been causing many of the things that I automatically associated with MS so it not always has to be MS – check your whole body because some of the symptoms can mimick MS as in my case or make my MS worse. Also the 24h rule is quite sensible – if you are stressed out and your symptoms worsen temporarily than most likely is a pseudo-relapse.
Symtrachttp://multiple-sclerosis-research.blogspot.co.uk/2014/04/novartis-launch-symtrac-ap-to-monitor.html
People kept diaries long before smart phones. Making notes before an appointment works. The point is every patient should not assume the symptoms quoted above by Prof G are MS related.
The neurologist doesn't pay enough attention when I say I'm not feeling well and my symptoms are worse. He does the usual exam and says there is no clinical change. Sometimes he orders an MRI but I'm on a 'super strong DMT' and it never shows fresh activity now.