Case study:
Prof G, I am contacting you as I think I am having a relapse. I have just been diagnosed with COVID-19 after being exposed at Christmas to my niece who developed symptoms late Christmas day. I have a typical cold and a sore throat with a temperature of 38.2C. When I woke up this morning I had a numb and clumsy left arm and I noticed my left foot was dragging when I went to the toilet. My wife googled my symptoms and Dr Google says I may be having a stroke. Am I having a relapse or a stroke? Do I need an MRI? Do I need steroids? What do you advise?
Prof G’s opinion:
Am I having a relapse or not? This question comes up several times a year if you are someone living with MS. Our MS clinical nurse specialists have to deal with this question on a daily basis and often call me when they are not sure. The answer is not black or white and is made much more difficult by how we define an MS relapse.
Firstly, you do not have to have an active MRI scan to tell if you are having a relapse. Please note the current definition of what is a relapse does not require an MRI to make and/or confirm the diagnosis. Many relapses are due to lesions that are small and below the threshold of detection of the current MRI scanners, which is about 3-4mm in size. Relapse can also be due to disease activity in the grey matter, which are areas of the brain and spinal cord that are not well visualised using current diagnostic scanners and standard MRI protocols.
Therefore in a person with established MS who presents with a possible relapse, you don’t necessarily need an MRI. I would argue that in the majority of cases, you don’t need an MRI to make a diagnosis of relapse. The question that needs to be asked is how is the result of the MRI going to change your management? Will the results of the MRI change the decision to use steroids or not? The use of steroids to treat a relapse should be based on the clinical severity of the relapse and whether or not it is associated with severe pain and not whether there is a culpable lesion on MRI.
Will the results of the MRI change the diagnosis from a relapse to a pseudorelapse? If the answer to the latter question is yes then you need to ask what is the sensitivity and specificity of MRI in this situation is. I am not aware of any studies that have been done to address this specific question. I suspect if there is no offending active lesion seen on MRI in the appropriate pathway the odds are the relapse may be a pseudorelapse, but as I have stated above the offending lesion could be too small to be detected on MRI.
Will the results of the MRI affect the decision around your treatment? Possibly. In the NHS to switch to many of the more effective treatments that are licensed for highly active MS (fingolimod, cladribine, alemtuzumab) or rapidly evolving severe MS (natalizumab, HSCT) require you to also have objective evidence of recent MRI activity (Gd-enhancing and/or new or enlarging T2 lesions). The latter is the most common reason for doing an MRI in the NHS and is why the MRI is not urgent in response to a relapse. Clearly, if an alternative diagnosis needs to be excluded, for example, PML, then an urgent diagnostic MRI is required.
Yes new neurological symptoms in someone with MS could be due to another condition and is not necessarily due to MS. The commonest relapse mimics after pseudorelapses is migraine aura, vascular lesions or strokes, focal seizures, brain tumours and infectious complications of immunosuppression, in particular, progressive multifocal leukoencephalopathy (PML). Obviously, if your neurologist expects an alternative diagnosis you may need an MRI and additional investigations for these other diseases.
What is a relapse and what is a pseudorelapse?
I think I know what causes pseudorelapes, but I have difficulty defining it as a specific clinical entity. Are they simply relapses that don’t fulfil our current definition of a relapse? Now that we are doing annual MRI studies on all of our patients on DMTs, too many patients with transient or intermittent, symptoms have evidence of active disease on MRI in the last 12 months. Therefore, we shouldn’t dismiss transient symptoms as being insignificant and that our current definition of what is a relapse is far too restrictive.
At present we define relapse as ‘the appearance of new symptoms, or the return of old symptoms, for a period of 24 hours or more – in the absence of a change in core body temperature or infection’. This definition does not allow us to make a diagnosis of relapse in patients presenting with new symptoms, that are not associated with focal neurological signs, for example, cognitive issues, fatigue, sleep disorders (e.g. narcolepsy), Lhermitte’s sign (shooting electric-shock like sensation down your back when you bend your neck), flexor muscle spasms, trigeminal neuralgia, etc. In clinical trial protocols, the definition of what is a relapse is even more restrictive and typically requires patients to deteriorate on the expanded disability status score (EDSS) and/or one of the neurological functional systems (FS) that are assessed before calculating the EDSS. Typically the score in one FS has to increase by at least 2 points or the score in two FS by 1 point. This explains why when you read the results of trials we often discuss protocol and non-protocol defined relapses; the former fulfils a strict definition based on metrics and the second is based on the assessment of the treating physician. Who do you believe? I think we need to reassess our definition of what is a relapse and seriously think about how we define pseudorelapses in MS.
Is your MS temperature sensitive?
In my experience the vast majority of pwMS are affected by changes in body temperature; it is either hot or cold temperatures that trigger changes in central nerve conduction velocity that brings on old symptoms. For example. one of my patients reports becoming paralysed if he sits outdoors in the sunshine for as little as 30 minutes in the middle of summer. Others report worsening of their cognitive fatigue with relatively minor changes in temperature. Women post-ovulation raise their body temperatures by about 0.5࿁C; in some women, this is enough to incapacitate them. I call this catamenial temperature-related fatigue and it often responds to non-steroidal anti-inflammatories and maybe the reason why aspirin has been shown to improve MS-related fatigue.
Global warming is also having an impact on pwMS. Short-term exposure to wide diurnal temperature ranges (DTRs), which is now more common as a result of climate change, is associated with an increased risk of visits to A&E (emergency departments) for pwMS. I have little doubt that many exacerbations triggered by hot weather may prove to be pseudo-relapses.
In our centre, we have started a study to see if raised neurofilament levels in the blood can help differentiate true relapses from pseudorelapses. With a significant relapse, you would expect some damage to nerves and their processes, which should release their contents, including neurofilaments, into the peripheral blood. We have good data already that raised spinal fluid and/or blood levels are strongly associated with both relapses and disease activity on MRI.
I personally have a small collection of patients with what I call biochemical relapses. These patients all have new transient symptoms with no changes in their neurological examinations and no new lesions on MRI, but they have raised spinal fluid neurofilament levels. Clearly, these patients have new disease activity that is only detectable biochemically. This is why the definition of what is a relapse and what is a pseudorelapse is in flux, at least in my head, and will change with time.
I predict that a major use of the emerging serum neurofilament assays will be to differentiate relapses from pseudorelapses. Sorting out this old problem may prevent unnecessary MRI scans and more importantly reduce the use of steroids used for the treatment of possible relapses. Yes, avoid the use of steroids. Please note the effectiveness of steroids in treating relapses is marginal and they come with many side effects so as a general rule I try not to prescribe them. Steroids don’t affect the final outcome of relapse all they do is speed up the recovery time by about two weeks. However, they come with potentially severe and irreversible adverse effects (see boxed warning below), which is why you need to think twice about having steroids or not.
Please be aware that it is not only the ambient temperature that is important, fever can also result in worsening of symptoms. During the COVID-19 pandemic, we have had many patients contact us with symptoms of a probable pseudorelapse in response to having COVID-19 or shortly after their COVID-19 vaccinations. A useful clue is that if the symptoms feel familiar to you, i.e. the symptoms are similar to ones you had with a previous relapse, and you have a raised body temperature then the most likely diagnosis is a pseudorelapse. Please note this is another self-monitoring prompt; you may want to invest in a good thermometer to measure your own body temperature. The best thermometers are the digital tympanic membrane one, but a good old fashioned oral, under the tongue thermometer does the job just as well provided you know how to use it properly. Please note you can also get digital oral thermometers. Please don’t use the axillae or armpit for temperature assessments this site is notoriously unreliable.
Please be aware that even new symptoms, not experienced by you before, could be a pseudorelapse. The lesion in the pathway concerned may have been subclinical and a result of smouldering processes has gradually caused more damage over time. What then brings the lesions to your attention is temperature-dependent conduction block and apparently, new symptoms in response to an infection, exercise or raised environmental temperatures. This is why our current definition of a relapse excluded new symptoms as being a relapse if they occur in the context of infection and/or a raised body temperature or pyrexia. It may interest you that is common for people with primary progressive MS to notice their first neurological symptoms in this context, usually weakness or dragging of a leg in response to an exercice-induced rise in body temperature.
So getting back to the case above.
Am I having a relapse or a stroke? I suspect neither, but I will need to examine you. At the moment the most likely diagnosis is a pseudorelapse.
Do I need an MRI? Not to diagnose a relapse, but maybe to exclude other potential alternative diagnoses and to see if you are eligible for switching to higher efficacy DMTs. The decision to do an MRI will depend on your neurological examination and how your symptoms evolve over the next few days and weeks.
Do I need steroids? Not at present, but this may change if your symptoms and signs deteriorate over the next few days.
I would be interested to hear your stories about relapses, pseudorelapses and temperature sensitivity. I am sure this newsletter is only scratching the surface of how these problems are dealt with in clinical practice.
Boxed warning: Potential side effects of high-dose steroids
The following is a list of the more common side effects of high-dose pulsed steroids:
Increased appetite, weight gain
Water retention with leg swelling or a swollen, “puffy” face
Nervousness, restlessness
Insomnia
Sudden mood swings (happiness and sadness)
Hypomania (persistent euphoria or extreme happiness) and rarely acute psychosis
Avascular necrosis of the hip and other bones
Thrombosis or clots
Allergic reactions; this is not an allergic reaction to steroids, but to the incipients in the solution. If you are allergic to the IV formulation you can still take high-dose oral steroids.
With more prolonged administration:
Muscle weakness
Blurred vision
Increased growth of body hair
Easy bruising
Lower resistance to infection
Acne
Osteoporosis (bone thinning)
Diabetes or worsening of diabetes
High blood pressure
Stomach irritation
Cataracts or glaucoma
Avascular necrosis and psychosis are the side effects that worry me the most. As with all treatments, there is a risk:benefit ratio and in my opinion the risks of steroids outweigh the benefits for mild and sometimes moderate attacks. Obviously, if your relapse is preventing you from functioning normally then speeding up the recovery is worthwhile. Similarly, severe pain that can occur for example with optic neuritis or one of the neuralgias may be an indication for using steroids to treat a relapse.
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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.
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