Do you suffer from cog-fog, fatigue or sickness behaviour?

Sickness behaviour, fatigue and cog-fog raise the question of whether or not you can have a relapse that is defined by these symptoms.

Did you know that MS-related fatigue could be caused by sickness behaviour?

Photo by Kinga Cichewicz on Unsplash

Sickness behaviour is a coordinated set of behavioural changes that occur in response to inflammation and/or infection, which includes fatigue or lethargy, depressed mood & motivation, reduced social exploration, loss of appetite, sleepiness, reduced concentration & attention and brain fog.

Many pwMS complain of periods of increased fatigue and sickness-like behaviour, which can be associated with a rise in inflammatory markers in their peripheral blood and new active (gadolinium-enhancing) lesions on MRI. One of the symptoms pwMS refer to is cog-fog or cognitive fog. This term is now embedded in the general public’s medical lexicon as it is one of the symptoms of long-COVID and other post-viral fatigue syndromes. 

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 or cog-fog lifting, their fatigue evaporating and having a burst of newfound energy. In parallel, they would often notice an improvement in physical functioning and their MS activity on MRI would go into remission (NEDA).

My clinical observations have been supported by formal studies in pwMS on natalizumab ( Penner et al. Front Neurol. 2015 Feb 23;6:18.). 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, in particular with ocrelizumab. People on ocrelizumab describe feeling ‘crap’ in the few weeks leading up to their next infusion. I have also seen this phenomenon in patients on other high-efficacy DMTs, but less frequently. I suspect what is happen is that there is immune reconstitution occurring with trafficking of pro-inflammatory cells into the central nervous system that may be causing fatigue and sickness behaviour.  

Sickness behaviour

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 we feel when we have influenza. We know that both IL-1 and TNF-alpha levels are increased in the brains of pwMS. Therefore, I am convinced that anti-inflammatory DMTs switch off inflammation in the brain and as IL-1 and TNF-alpha levels drop fatigue improves as sickness behaviour disappears. 

The following is an illustration of mine on the causes of MS-related fatigue that includes a section on sickness behaviour. The Illness Behaviour Questionnaire (IBQ) is a generic tool that has been developed to quantify sickness behaviour. In my opinion, is too long to be used daily to track and follow sickness behaviour in pwMS, but it gives you an idea of some of the associated symptoms. 

Sickness behaviour, fatigue and cog-fog raise the question of whether or not you can have a relapse that is defined by these symptoms. I have been to many a meeting where this issue has been debated and the consensus is that a relapse should be defined as worsening of old or the appearance of new focal neurological signs. I don’t agree with this as this feeds into the clinical definition of MS. I think a relapse should be defined biologically as the recurrence of focal inflammation and the latter could be detected using MRI and/or biochemically with biomarkers. Why can’t someone have a relapse without neurological symptoms?

The reason why I take a biological view of MS is simply that asymptomatic disease activity, i.e. without focal neurological symptoms, can be as damaging as lesions that cause symptoms. If we want to maximise the outcomes of pwMS how can we only focus on the tip of the iceberg and ignore all the other inflammatory activity occurring beneath the surface? This is why our treatment target in MS is NEDA (no evident disease activity) and beyond (preventing end-organ damage).

I would be interested to know how many of you have had intermittent cog-fog or episodes of unexplained fatigue and what you have done about it. In addition, do any of you suffer from the wearing-off phenomenon before your next infusion of natalizumab or ocrelizumab?

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.