Rebranding the MS prodrome: Missed MS?

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A prodrome is an early symptom or set of symptoms that indicates the onset of a disease before more diagnostically specific signs develop. One of the most typical examples is a migrainous aura (i.e. flickerings in your visual field) half an hour before you develop a throbbing migrainous headache. However, very often prodromal symptoms are very unspecific. Clouds could be a prodrome of a storm, but – as Charlie Mackesy illustrated – could also just hide the sun.

Over the preceding years, several studies have reported about the existence of an ‘MS prodrome’. This is a period covering about 5-10 years before the official diagnosis of MS during which pwMS have more physician and hospital encounters for various reasons. Before diagnosis, pwMS were more likely to present with mood/mental health disorders and migraine for example, and reported more urinary, musculoskeletal or skin-related conditions. If a prodrome exists, it is important to characterise it as early recognition might open the window to early treatment. However, …

Gasperi et al. analysed the symptoms and diagnoses 5 years before official MS diagnosis registered in the medical records from 10,262 pwMS living in Bavaria (Germany), and compared them with the symptoms registered for people diagnosed with psoriasis, Crohn’s disease and healthy controls (HC). In a first analysis, they found that 43 symptoms were more frequent among pwMS such as visual disturbance, dizziness, motor impairment, disorders of the urinary system, abnormal skin sensation, …. When people with psoriasis or Crohn’s disease were used as controls, 35/43 and 19/43 symptoms were still more common among pwMS, respectively. As many of these 43 symptoms could be caused by a demyelinating event, the authors performed a more stringent analysis in which they excluded all patients with symptoms that could flag a demyelinating event (e.g. blurry vision > optic neuritis). In this second analysis, none of the remaining 20/43 symptoms/disorders were significantly associated with MS.

This study thus questions the presence of an MS prodrome, and suggests that all symptoms preceding the official MS diagnosis are potential unrecognised demyelinating events. On the MD side, one of the contributing factors might be that most symptoms before diagnosis were recorded by GP’s who potentially do not always recognise the ‘neurology’ in the symptom. On the pwMS and MD side, there is always a tendency to minimise the importance of symptoms that are transitory. In MS, we should all fear the “postdromal” silence after the storm. People’s brain tend to interpret transient symptoms as benign, which is a good rule of thumb for many other non-neurological symptoms. 

Hence, we need to rethink the MS prodrome terminology because it suggests that the 5 years before MS are different from what comes after. In addition, it gives too much credit to neurologists for determining the onset of the disease. Timing of diagnosis is a moment on which all pieces of the puzzle come together rather than a biologically defined moment in the MS disease course. How do you think we should rebrand the prodrome? Let us know by filling out the survey! 

Twitter: @SmetsIde

Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Neurology 2021 Apr 26;10.1212/WNL.0000000000012074.

Systematic Assessment of Medical Diagnoses Preceding the First Diagnosis of Multiple Sclerosis

Christiane Gasperi 1, Alexander Hapfelmeier 2 3, Tanja Daltrozzo 4, Antonius Schneider 3, Ewan Donnachie 5, Bernhard Hemmer 6 7

  • PMID: 33903190
  • DOI: 10.1212/WNL.0000000000012074

Abstract

Objective: To explore the occurrence of diseases and symptoms in the five years prior to diagnosis in patients with multiple sclerosis (MS) in a case-control study. Methods: Using ambulatory claims data we systematically assessed differences in the occurrence of diseases and symptoms in the five years prior to first diagnosis in patients with MS (n=10,262) as compared to patients with two other autoimmune diseases – Crohn’s disease (n=15,502) and psoriasis (n=98,432) – and individuals without these diseases (n=73,430). Results: Forty-three ICD-10 codes were recorded more frequently for patients with MS before diagnosis as compared to controls without autoimmune disease. Many of these findings were confirmed in a comparison to the other control groups. A high proportion of these ICD-10 codes represent symptoms suggestive of demyelinating events or other neurological diagnoses. In a sensitivity analysis excluding patients with such recordings prior to first diagnosis, no association remained significant. Seven ICD-10 codes were associated with lower odds ratios of MS, four of which represented upper respiratory tract infections. Here, the relations with MS were even more pronounced in the sensitivity analysis. Conclusions: Our analyses suggest that patients with MS are frequently not diagnosed at their first demyelinating event but often years later. Symptoms and physician encounters before MS diagnosis seem to be related to already ongoing disease rather than a prodrome. The observed association of upper respiratory tract infections with lower ORs of MS diagnosis suggests a link between protection from infection and MS that however needs to be validated and further investigated.

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Ide Smets

25 comments

  • Things have progressed since 1988. but if transitory, wouldn’t it be the case that with a transitory event a GP wouldn’t necessarily associate such a symptom with MS. It suggests the need for a very robust sort of diagnostic tree of symptoms against which a GP could compare a symptom. Seems a bit of a pipe dream as medics and systems are overstretched the world over.

  • Very nice post. I think missed MS refers to a missed medical opportunity, i.e. the HCP ignores the symptoms. Unrecognised MS is the better term because the patient and/or the HCP identifies and acknowledges symptoms and/or signs but does link them to MS and the patient is not put through a diagnostic pathway.

    Undiagnosed MS will include patients when the symptoms/signs have been identified and the possibility of a neurological condition considered, but they have yet to be diagnosed.

    I agree that prodromal MS does quite cut the mustard it implies that it is not MS. I think MS is a biological disease and we should be able to diagnose it in the asymptomatic stages. MS is not a clinicoradiological construct which is how we define it at present.

  • Ide….is it standard practice for nuerologists to check previous medical records, including minor episodes reported at the GP. I ask because when diagnosed with CIS, there were a few events that were suggestive of nuerological disfunction such as a ‘stone in the shoe’ sensation 6 months prior and what i thought was acid reflux that ended up with a referal to ENT and a uvleaechtomy. I have often wondered whether these were the first signs and if so, by the time i reached the nuerologist with a spinal lesion, they should have surely spotted the previous activity? i imagine that i am not alone

    • Hi! I don’t think it’s standard practice to actually go and check GP records. However, many neurologists will enquire about previous symptoms. But the questions asked during clinics might be too generic for patients to understand what kind of symptoms might be related to demyelination

      • It is 35 years since the following study using general practice records was published as a leading article in the Lancet. A small confirmatory letter appeared in the Lancet, in the following year.

        Gay D et al Multiple Sclerosis associated with sinusitis. A case controlled study in general practice. Lancet 1986,i,815-9.

        Callaghan T. Multiple Sclerosis and sinusitis. Lancet 1986, ii, 160.

        There followed a number of letters and papers criticising or failing to support the Lancet data, but not a single attempt to test the general practice data using the same methods has ever appeared.

        It was conventional wisdom, when I was taught science, that observations should be tested using the original methods, to confirm or refute.

  • Nice post.

    My first noticeable symptoms (year before diagnosis) were lack of thigh sensation when running – when the thighs touched (wearing shorts) there was a lack of sensation in the skin. At the same time I had a chest infection and the GP sent me for an x-ray and blood tests. I went back to the GP every month (for the next four months) with odd symptoms eg desensitised hand (shaving was tricky) and tightness around waist – GP though a trapped nerve. Eventually I saw an older GP who asked me to stand with my eyes shut and arms arms held out. She referred me to the neuro.

    I don’t blame my GPs as they were thorough and did a range of tests. They probably see few cases of MS and many more cases of sciatica etc. It’s probably easier to spot early MS if the symptoms start with the eyes eg blurred vision / loss of vision eg in a young patient. In an ideal world a blood test might pick up MS or doing regular MRIs on the children (eg from age 18 onwards) who have a parent with MS. But this will be costly and take up precious MRI time. Many early symptoms of MS are mild and patients (who have no knowledge of MS) will assume they will pass eg like a slight muscle pull.

  • Now make sense having problems and blaming the car accident when could been a CIS 3 years before got ms. Thank you

  • Yep its right there is no proof off earlier muscles, problems.. May not wrk. Its difficult to difference btw ppl experiences. Most obvious are sudden optic neru.. Eye and give away and Nerve problems.

    The main problems we have here is big pharmaceutical lobbing gene therapies.. 🤔 Well they all do most in pocks off good consultants.. Having given the choice i know most would treat there love ones to this this.

    In fairness these no pre _ signs i suppose doe blood dna testing count?

    I ve heard many yrs ago we all hv these time bombs in us.. However its the timing is hard to pin point.

  • I am a professional marketing and branding expert. “Early ms” is not bad but no option IMO adequately expressed the need for u for the doctor to find and treat. For example in strokes the “golden hour” refers to that window you have to alter the course of the event and it’s impact on a person if you identify and act quickly.
    We need something that both suggests you’re getting clues this person has ms AND a golden opportunity to find it and treat it before permanent damage and disability is too late. What do you call that? The “ms window?” Something else? What do you think?

    • I agree the golden hour sounds way more catchy than early MS. The window is interesting, but is also very often used to advocate for early treatment after MS diagnosis, so will maybe be misinterpreted. what do you think about SIMS : symptom isolated MS? as opposed to the RIMS radiologically isolated MS

  • I always assumed the prodromal phase was after smoldering MS began but before there were any visible lesions on MRI. How could one even make the MS diagnosis at that point? Every neurologist seems to insist that without lesions one doesn’t have MS.

    • These people probably have already lesions, but no MRI is requested based on their symptoms. Because the symptoms are most likely not recognised as coming from the CNS

    • Spot on.

      And don’t forget that symptoms without obvious causes MUST be labeled with something and the low-hanging fruits of psychosomatic and stress are the top contenders.

      And why exactly, one must wonder, is “re-branding” of MS prodrome into some other verbiage, SO important? Will that re-branding significantly impact how MS is diagnosed and treated? Color me doubtful that it will. I seem to recall that MS has a pretty specific diagnostic criteria that does not include the several doctors of a patient all squinting really hard together to see the faint outlines of a really gauzy zebra.

      I’m thinking back to myself, with several of the prodrome symptoms (abnormal skin sensations, severe headaches, fibromyalgia, and let’s just add olfactory symptoms for good measure) in the 5 years leading to dx. A few of them I even asked about – asked a GP and a back doctor. Both of them attributed my symptoms to something else and treated (or tried to treat) those symptoms with meds specific to those symptoms. So my experience with siloed medicine is that nobody is talking to each other, they don’t even read the information that you fill out in the waiting room let alone ask for more, and that neither of those symptoms alone would have been enough to cause a twitch in their minds about MS. If I had gone in suggesting it was MS – which I did not, ignorance back then was bliss – I would have most likely been labeled psychosomatic or having anxiety.

      When I was finally diagnosed using the McDonald Criteria, I had 3 and only 3 active lesions. They found no healed ones, so if some doc had actually thought possible MS and had put me in the MRI, I would not have had genuine MS per their own criteria prior to that time.

      • I especially think we need to get rid of the term prodrome, because this suggests that it was not MS yet and could not have been recognised as such.

        • I hate the term prodrome. It’s just:

          “signs or symptoms of MS prior to a formal diagnosis.”

          Some patients seek medical advice at the slightest signs or symptoms (of a disease) while others wait in the hope that the signs or symptoms will go away. So this pre-diagnosis phase could be weeks, months, years or decades.

  • That’s an interesting thought but doesn’t quite IMO communicate the urgency and opportunity together. You need something that says “hey doc this body is giving you a clue that something neurological is going on – don’t dismiss if it spontaneously resolved as that is also another clue that ms is giving you and finding now will drastically alter the course of their lives amd is the closest thing we can do to curing it?”. Lol. Any copy experts want to put that into 2-3 words?

    I would have greatly benefitted from this message! Referred to a neuro in my 30s complaining of hands feeling funny shaking them awake and feeling like they won’t wake up. 35 yr old female with family history of ms. Referred to psychiatrist rather than immediate mri. Resolved of course only to get a diagnosis 5 years later.

    Some ideas:
    Hidden MS onset
    Early stage Modifiable Ms
    Undiagnosed curable stage ms
    Curable stage ms? (I imagine legal experts will have a field day with this)
    MS magic window

    Maybe something in there works or sparks a better idea.

    • “Referred to psychiatrist rather than immediate mri”. Ha. See above (after I pass moderation)

      Doctor bias on full display. That low-hanging fruit. And here’s a hint: He probably wouldn’t have referred you to the shrink right away if you’d been male. But in his world I suppose it got what he assumed was an eye-roll worthy GOMER out as of his hair as quickly as possible.

      So if full on neuros are doing that fairly often – and they DO – it doesn’t matter what what you call a thing, if they won’t even acknowledge the possibility of that thing. I think that’s why these MS Blog constant agonies over the perfectly narrowly defined and impactful verbiage strike me as a distraction and a total waste of brain power. Nobody is really listening anyway.

      • Male here, also initially told I needed psychiatric help. I was stupid enough to disclose that I had been on meds for anxiety and depression in the past and thus the doctor decided my symptoms were just anxiety. My conclusion is that you should never mention an anxiety diagnosis to a doctor if you ever want your problems to be taken seriously.

      • Male here.

        Took me 7 years and more than7 doctors (three of them neuros!!!) to get a diagnosis – on a gold standard insurance plan, no less. Paresthesia? We ruled out carpal tunnel so must be pinched nerve. Have some physiotherapy. Fatigue? Depression and anxiety. Workout (which I already did), cheer up, see a shrink (which I did at two points in my life, useless for me) or have some SSRI (and some rather more out there ideas I am not going to get into). Erectile dysfunction? Must be in your head, but have some Viagra anyhow.

        Only when balance problems came obvious a neuro finally did the whole work.

  • I was convinced for more than a decade that the problems I had in my right hand were RSI. Turns out it was actually my first MS relapse. Took 11 years for me to have another noticeable relapse which led to diagnosis (around 7 brain lesions on MRI), but looking back there were definitely odd things here and there.

  • My MS was missed for 15 years! First MRI aged 35 was because of chronic vertigo/balance problems, buzzing in legs. ‘Something’ was seen on brain MRI which was later dismissed as nothing of concern and my neurologist advised me to stop dwelling on symptoms, go away and get on with life. Needless to say, all symptoms recurred a couple of times a year and my balance never felt right. 15 years later, creeping numbness in right foot and leg led to brain and spinal MRI where several lesions showed up. Hard not to feel let down by my first neurologist!

    • Thanks for sharing, and such a diagnostic delay is obviously a huge missed opportunity for your MS to be treated and must have been very difficult on a personal level.

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