Natalizumab lifts cog-fog #ClinicSpeak #ECTRIMS2017 # SelfMonitoring
Summary: this post highlights the problem of cog-fog in pwMS and describes the science behind the symptom. It also presents the results of a study looking at the effects of natalizumab on cog-fog. The post concludes with an appeal to the community for help in developing a cog-fog-o-meter.
Every now and again a post on this blog catches the imagination of the readers and gives me insights into MS that I haven’t appreciated before. Yesterday’s post on the impact of MS on day-to-day functioning, albeit golf, that occurs at a level too subtle to be detected using our crude assessment tools was a revelation. It is clear this patient had ongoing inflammation, associated with a drop off in physical and cognitive functioning. I recall him complaining to me that he didn’t feel right on fingolimod, in particular, he had cog-fog.
What is cog-fog?
One of the first things I noticed when I started using natalizumab is that patients would come back after 3-4 months feeling better. They would often describe their ‘brain fog’ – now better known as ‘cog-fog’ – lifting, their ‘fatigue evaporating’, ‘having energy’, noting improvements in both ‘mood and anxiety’ and saying ‘I feel normal again’.
Please note this patient felt well on natalizumab and this is not unique to this patient. I often refer to natalizumab as being transformational and use it describe three eras in the management and study of MS:
- The pre-DMT era (before IFNbeta ~1993)
- The pre-natalizumab DMT era (1993-2004)
- The post-natalizumab DMT era (after 2004)
The TYNERGY study below supports my anecdotal clinical observations. When patients with active MS went onto natalizumab a large number of their negative symptoms improved. I don’t think these observations are limited to natalizumab and are also seen with other highly effective therapies, but take longer for the improvements to be seen with the other high-efficacy DMTs. How do you include these effects in the benefit and risk profile of DMTs? A hard to quantify treatment effect.
The question that needs answering is how does an anti-inflammatory DMT such as natalizumab reduce fatigue? I have hypothesised that it works via suppressing inflammation in the brain that drives fatigue. Inflammation is known to cause sickness behaviour, a programmed behavioural response designed to conserve energy and allow the body to recover.
Sickness behaviour goes far back in the evolutionary tree so it must have given our evolutionary ancestors a survival advantage. Two mediators of inflammation, one called interleukin-1 (IL-1) and the other tumour necrosis factor alpha (TNF-alpha), are known triggers of this behavioural response. IL-1 and TNF-alpha cause fatigue, sleepiness (hypersomnolence), reduced appetite (anorexia), a raised body temperature (fever) and low mood (depression) that forces one to lie down, sleep and allow our sick bodies to recover. We all have experienced sickness behaviour before these are the typical symptoms we get when we have a systemic infection similar to how you feel when you have influenza. We know that in MS both IL-1 and TNF-alpha levels are increased in the brains of pwMS. Therefore, I am convinced as DMTs switch off inflammation in the brain and IL-1 and TNF-alpha levels drop fatigue improves as sickness behaviour disappears.
The following is an old slide presentation of mine on fatigue that includes a section on sickness behaviour. Some of the points covered in this slide presentation are quite technical; if they need more explanation please ask and I will do additional posts on this.
Now I need your help. I am giving several presentations at ECTRIMS this year, however, two of the talks are somehow related. The first is a hot topic talk on self-monitoring using web-based apps and the second is a TED-type talk in a satellite symposium on the need for routine cognitive testing in clinical practice. In these talks, I will be making the case for self-monitoring across multiple domains including cognition. However, I am not aware of any outcome measure that specifically captures sickness behaviour or cog-fog in pwMS. Do you think we can measure cog-fog? If yes, how?
To assess cog-fog we need to assess all of the components of sickness behaviour. The Illness Behaviour Questionnaire (IBQ) is a generic tool that has been developed to assess sickness behaviour. In my opinion is a too long to be used daily to track and follow sickness behaviour in pwMS. Any ideas to help develop a cog-fog-o-meter would be much appreciated.
What I am looking for is a simple self-monitoring tool for cog-fog.
Penner et al. Improvement in Fatigue during Natalizumab Treatment is Linked to Improvement in Depression and Day-Time Sleepiness. Front Neurol. 2015 ;6:18. doi: 10.3389/fneur.2015.00018. eCollection 2015
BACKGROUND: Fatigue is a frequent symptom in multiple sclerosis (MS) and often interrelated with depression and sleep disorders making symptomatic treatment decisions difficult. In the single-arm, observational phase IV TYNERGY study, relapsing-remitting MSers showed a clinically meaningful decrease in fatigue over 1 year of treatment with natalizumab.
OBJECTIVE: To evaluate whether fatigue improvement might be directly linked to improved depression and day-time sleepiness.
METHODS: MSers were assessed regarding fatigue, depression, and day-time sleepiness. The relation between changes of the two latter symptoms and changes in fatigue was analyzed.
RESULTS: After 1 year of natalizumab treatment, the majority of MSers (>92%) remained stable or improved in total, motor, and cognitive fatigue. Proportion of MSers without depression increased by 17% while proportions of mildly depressed MSers or MSers with potential major depression decreased by 5 and 12%, respectively. Proportion of MSers classified as not being sleepy increased by 13% while proportions of sleepy and very sleepy MSers decreased by 11 and 2%, respectively. Most importantly, improved depression and sleepiness were significantly related to improved fatigue.
CONCLUSION: Our findings highlight the importance of patient-reported outcomes in identifying potential benefits of drug treatment beyond its well-established effects on disease activity and disability progression.
CoI: multiple
I think there is a difficulty with the term 'sickness behaviour'. I certainly understand it in terms of being protective and when you have flu then our body makes you rest.However there are other pejorative connotations to 'sickness behaviour' which overlap with malingering, hypocondriasis, seconadary gain etc. The very long questionnaire that you have included really looks more at sickness behaviour in those terms rather than MS fatigue and cog-fog and only a few of the questions seem relevant.I have such mixed feelings about monitoring this. Cognitive decline is one of my great fears and every time I forget something or feel I am not thinking straight I go into a mini-panic. On one level I want to know how I am affected but I never say anything about this to my neurologist as I do not want anything in my notes that could possibly be used against me in terms of my cognition and functioning.
Sickness or illness behaviour is a term that is well established in the scientific literature and has nothing to do with malingering, etc. The phenomenon has been studied in animals including fish. I think we need to educate the community about this. The reason why MSers feel 'shit' a lot of the time is that they have ongoing inflammation in their brains that is driving this. Switch off the inflammation and they feel better. Another bit of dogma that needs challenging is that cognitive impairment is fixed and irreversible. It is not. I seen a large number of patients with so called fixed-deficits improve. You can either put your head in the sand and ignore it or you measure it and do something about it.
How about using a simple Lickert scale from 0 to 7 to describe cog-fog. 0 – nil1 – very mild – only aware of it, but able to function normally (don't avoid tasks)2 – mild – able to function normally but avoid a few tasks3 – mild to moderate – able to function, but have to avoid several tasks4 – moderate, able to function but have to limit activities to the essential5 – severe – avoid many tasks with an impact on social and occupational functioning6 – very severe – manage to activities of daily living, but can't function socially or occupationally7 – extremely severe – incapacitated
I find this scale very useful. I have not been a 0 or 1 for a long time. I'm not sure what normal is anymore but due to MS and Anxiety i could from 3-6 . The unpredicability
Not sure whether this is a useful comment or not, as I don’t really think of myself as a cog-fog person, and generally my MS is all quite gentle. I weightlift and graph my progress in terms of what I can lift in the 3 compound lifts (deadlift, squat, benchpress) on an excel spreadsheet. It is hugely reflective of what is going on with my health, and I maintain it because I find it genuinely interesting. I find it is a nice way to quantify the rewards of your hard work. You can have a copy if you want it. In terms of your PROM, brevity is important, but the more important issue is that answering that questionnaire makes me feel very negatively about my condition. I really don’t want to fill that in, in my spare time. The likert scale, is probably an improvement, but I am still not sure I could be bothered to fill it in.I use my gym tracker because I find it empowering (same could be said for MFP and STRAVA), and I think that is what you need to capture…. Maybe Fitbits would be an interesting PROM, walking is a very objective measure to both clinicians and patients, and if you remember to wear it, it requires no input from the patient other than an interim check… Many people have them already, so it could be cost neutral (ish) as a scoping exercise… Not sure how relevant it is to cog-fog, because I am not sure I have cogfog; but when I feel unwell I walk less, and I don't think MS has ever directly effected my walking ability either, so there is something.
I struggle to make use of J's remark (SPMS, EDSS 8.5, 9HPT-too long ago to say) as the ambulation presumption does not fit for me. Dare I suggest that J is "walkist"?I also struggle with the SlideShare platform which does not appear to let me download, and therefore use, the IBQ.Having grumbled I'd add that the quest for a self monitoring tool seems valuable and exciting. Being me, I'd suggest it be smart phone based (i freely admit to "'smartphoneism") band in some way collate possible phone activity into a cognition index
PS I like the Lickert scale. Perhaps a vanity as I'm a zero
Let me start off by saying that I have been on Tysabri for more than eight years. After my infusion I experience both an improvement in my walking – speed and fluidity – and in cognitive sharpness.However I still have days when fatigue wipes me out. It can be just physical fatigue – body feels like I’m trying to move through treacle, just cognitive fatigue – I feel like a zombie, or worst of all both types. There sometimes obvious causes such as an infection or in the days following a busy or stressful time but at other times I cannot link it to anything specific.My cog-fog includes aphasia and word-retrieval issues, inability to concentrate and assimilate new information as well as short-term memory problems. Cognitive symptoms are the ones that embarrass and scare me the most. It feels like the essence of myself is being eroded. I like the Likert scale – and a phone app would be a great way to enter the data- but suggest it should include a way to note if the fatigue is physical, cognitive or both and record its duration. Recording suggested reasons for the fatigue may also be helpful.
The Lickert scale, seems to me to be very straightforward and I expect, easy to use for the majority. However, I'd rather add more relevant details: as suggested the duration and manner in which it manifests, as in my experience it can be loll on sofa or crash out and sleep. In your presentation slides there's one 'Which of the following affect your sleep' Something similar might allow for more detailed information gathering.
I really like this Lickert Scale. It would work for monitoring any type of chronic problem or disability. What struck me was that it would be a good way to report the effects of depression and anxiety.About sickness behaviour: every now and then, maybe a few times a year, I have spells of feeling ill that are not related to a cold or anything else. Body temperature is normal, there's no body ache, cog fog is sort of normal too – but I feel ill (can't describe it any better). There may be some UTI type symptoms too. Panadol works to get rid of this feeling. So I usually take one tablet on waking up and repeat as necessary during the day.I've been wondering if these could be below-the-surface relapses. Succesive MRIs show new lesions, no enhancing lesions. Perhaps the new lesions form during these spells
Cog-fog is a lived with experience and consequently very difficult to measure compare with my state say 12 months ago. I know my ability to do Sudoku has not diminished but other mental processes have taken a bit of a knock. The obvious ones to me are word recall and memory. I have definitely have lower reserves of energy and every thing takes longer.To my mind self monitoring is not easy. As the problems slowly get worse I slowly adapt and might not even notice the changes until I look back and say to my self 'A couple of years ago I could do ….'. I do think physically the progression is speeding up and that worries the hell out of me. I have progressive MS, I don't think the problem is related to how I feel and I do not take any DMT. I know the problems are there and they are slowly getting worse.
Benefit of this post reflected in reply from a friend: "MS is a complex and difficult to understand illness and I really appreciate that you are happy to help us all understand more with things like this Bart's article. Glad reading it has helped how you're feeling emotionally' 👍😊 Thanks yet again.