St Elsewhere


Barts-MS rose-tinted-odometer: zero ★’s

St Elsewhere is a euphemism in medicine for a fuck-up done under someone else’s watch, i.e. at St Elsewhere’s hospital. In this week’s NEJM there is a tragic case of a 22-year old Pakistani man who was misdiagnosed as having MS at St Elsewhere, started on natalizumab, which was ineffective, before being switched to interferon beta. By the time he was admitted to UCSF he was in extremis. A relatively standard workup revealed this gentleman had a tumour; a CNS germinoma that had spread to the meninges or coverings of the brain and spinal cord. On reviewing his initial presentation there were so many ‘red flags’ it is hard to understand why he was misdiagnosed. Tragically this poor man now has ‘substantial neurologic disability, for which he received assistance with all activities of daily living’. This case is a tragedy because CNS germinomas when caught early and treated have a reasonable prognosis with a 10-year survival rate of about 70%. 

Minter et al. Stalking the Diagnosis. N Engl J Med. 2021 Apr 1;384(13):1262-1267. 

If only this patient had had a lumbar puncture and CSF analysis done as part of his initial diagnostic work-up the correct diagnosis would have been made. The question arises whether or not this gentleman had medical insurance or not? He was a delivery driver and had only recently immigrated to the USA. To be fair to the neurological team looking after him a diagnostic short-cut may have had to be made because he simply didn’t have the financial resources to pay for the diagnostic tests. I suspect the latter is likely to have happened and maybe the title of this post should have been St Poor.

I want to remind you that if you have been diagnosed with MS you may not have MS. In the study below approximately 1 in 5 people diagnosed with MS don’t have MS. This figure is much higher than previous studies. I have always quoted the Danish post-mortem studies that suggest that about 1 in 20 patients are misdiagnosed. Maybe Danish neurologists are simply better at diagnosing MS compared to their American colleagues?

There is no one test that can be done to diagnose MS. MS is diagnosed by combing a set of clinical and MRI findings, electric or neurophysiological investigations and laboratory tests. If these tests fulfil a set of so-called MS diagnostic criteria the Healthcare professional (HCP) or neurologist makes a diagnosis of MS.

The underlying principle of making a diagnosis of MS is showing dissemination of lesions in space and time and excluding other possible diagnoses that can mimic MS. The diagnostic criteria have evolved over time from being based purely on clinical attacks to those including electrical and spinal fluid tests to the modern era in which we use MRI to help confirm dissemination in time and space.

Dissemination in time means at least two attacks or two MS lesions occurring at least 30 days apart. 

Dissemination in space means lesions occurring in different locations, for example, the optic nerve and spinal cord.

The electrical or neurophysiological tests are called evoked potential (EPs) and test electrical conduction in a particular neuronal pathway. They can be useful to show the effects of lesions in pathways that are not evident on neurological examination or seen on MRI. The EPs can also show slow electrical conduction which is one of the hallmarks of diseases that affect myelin, the insulation of nerves that are responsible for speeding up electrical conduction.

The laboratory tests are typically done to exclude other diseases that can mimic MS. One test that is useful in helping to make the diagnosis of MS is examining the spinal fluid for the presence of oligoclonal immunoglobulin G or IgG bands (OCBs), which are the fingerprint of a specific type of immune activation within the central nervous system (CNS). The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context. Please note OCBs can are found in infections of the nervous system and other autoimmune diseases, therefore, the presence of OCBs are not diagnostic on their own. 

When CSF is sent to the laboratory they also measure the protein, glucose, lactose and do a cell count. An often the spins the cells out of the CSF and examine them to make sure they are abnormal. I suspect if this patient had had a CSF examination it may have been abnormal, which would have led the clinicians to the correct diagnosis, which will have allowed him to be treated differently; importantly, treated early and he may not have become profoundly disabled. 

Why is getting the correct diagnosis of MS so important? Firstly, some of the treatments for MS have life-threatening complications; you don’t want to expose people without MS to these complications. Some diseases that mimic MS can be made worse by MS DMTs. This latter is particularly relevant for NMO or neuromyelitis optic. Patients with NMO misdiagnosed as having MS get worse on many of the MS DMTs. Finally, a diagnosis of MS has many psychological, social, financial and economic implications for people. Just having a diagnosis of MS, even if you turn out to have benign MS in the future, has implications for the person concerned. For example, it may affect your life choices and may impact your ability to get insurance cover to name to obvious examples. I would, therefore, advise you to make sure you have MS and not an MS mimic.

The most common MS mimics:

  1. Cerebrovascular disease
  2. Acute disseminated encephalomyelitis or ADEM
  3. Neuromyelitis optica or NMO
  4. Behcet’s syndrome
  5. Migraine
  6. Sarcoidosis
  7. SLE or systemic lupus erythematosus
  8. Antiphospholipid antibody syndrome
  9. Leukodystrophies

The evolving definition of MS based on diagnostic criteria:

Clinical criteria only:

  1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68.

Clinical, EPs and CSF analysis:

  1. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31.

Clinical, EPs, CSF analysis and MRI:

  1. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.
  2. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840-6.
  3. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.
  4. Thompson et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173.

Kaisey et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019 May;30:51-56.

BACKGROUND: Multiple Sclerosis (MS) specialists routinely evaluate misdiagnosed patients, or patients incorrectly assigned a diagnosis of MS. Misdiagnosis has significant implications for patient morbidity and healthcare costs, yet its contemporary incidence is unknown. We examined the incidence of MS misdiagnosis in new patients referred to two academic MS referral centers, their most common alternate diagnoses, and factors associated with misdiagnosis.

METHODS: Demographic data, comorbidities, neurological examination findings, radiographic and laboratory results, a determination of 2010 McDonald Criteria fulfillment, and final diagnoses were collected from all new patient evaluations completed at the Cedars-Sinai Medical Center and the University of California, Los Angeles MS clinics over twelve months.

RESULTS: Of the 241 new patients referred with an established diagnosis of MS, 17% at Cedars-Sinai and 19% at UCLA were identified as having been misdiagnosed. The most common alternative diagnoses were migraine (16%), radiologically isolated syndrome (9%), spondylopathy (7%), and neuropathy (7%). Clinical syndromes and radiographic findings atypical for MS were both associated with misdiagnosis. The misdiagnosed group received approximately 110 patient-years of unnecessary MS disease-modifying therapy.

CONCLUSION: MS misdiagnosis is common; in our combined cohort, almost 1 in 5 patients who carried an established diagnosis of MS did not fulfil contemporary McDonald Criteria and had a more likely alternate diagnosis.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


    • Possibly. If finance was the underlying issue with this patient this would not have been an issue under the NHS. In the UK healthcare and access to healthcare is a basic human right and this patient would have had a free diagnostic work-up and his treatment would have also been free. Whether or not the neurologist would have misdiagnosed him is difficult to say, but if an LP was done as part of the work-up unlikely.

  • Putting the misdiagnoses aside, how do you change someone from Natalizumab to Inteferon Beta…thay makes no sense surely?

    • I suspect both natalizumab and interferon-beta were being provided free as part of a DMT access scheme for uninsured patients. Therefore, you treat patients with what you can get for free. This is why I suspect this case is not about St Elsewhere but St Poor.

  • IME getting diagnosed after being rushed to hospital as an emergency (in the UK) can leave you in shock but I suppose the benefits are that the diagnostic tests to rule out certain things are done and also done more quickly than they would be if you went to your GP with a few strange symptoms … And thank goodness for the NHS.

  • What about our old friend vitamin B12 deficiency? I’ve always understood that is supposed to be one of the MS mimics which needs to be ruled out as part of the MS diagnostic pathway. Apparently, with the increasing numbers of people going vegetarian or vegan without learning enough about nutrition and consequently missing out on sources of B12, the incidence of significant B12 deficiencies is on the rise.

  • Honestly, the McDonald’s criteria is a bit vague on the differential diagnosis part. There’s a lot of focus on the brain damage part but not on the what could cause the brain damage.

  • Even worse, some neurologist still do not believe spinal lesions have an impact on disease severity or prognosis. Spinal MRIs should be performed with the same frequency as brain MRIs, particularly when there is a history of spinal lesions.

    LPs are necessary, yet can be traumatizing. I had some overly confident resident try the LP on me without a fluoroscope. It was one of the most painful experiences (only rivaled by my reoccurring TN). Just because one has a low BMI and looks in shape does not mean they can tolerate a big ass needle being repeatedly stabbed into their spine, while bent over the side of the hospital bed!!!

    • “Even worse, some neurologist still do not believe spinal lesions have an impact on disease severity or prognosis”…..then some neurologists are fools.
      Spinal MRI are technically more challenging due to movement effects from breathing and this is why they are not always routine….
      LP hope they were using an atraumatic needle rather than a cutting needle

      • The overly confident medical resident was unsuccessful after about 6-7 attempts. So, the following day, a real doctor used the fluoroscope and, yes, atraumatic needle. I know because I could feel the spinal fluid bubbling out each time the angled opening on the tip of the needle pierced my spine. Ouch!!!!

  • “The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context.”
    What if I have OCBs, but negative evoked potentials, non specific brain lesions, symptoms attributed to ‘central sensitivity’ not MS, and most other common MS mimics not considered or discounted?
    I did once pay privately to get a second opinion. As I entered the consultation, the neurologist shared his opinion with me having read only my referral letter (not my notes) and prior to any examination. He did however concede that he might as well examine me at that point, since I was there!
    So PLEASE advise me, where do I find a ‘curious’ neurologist who will even entertain the possibility that I may have been misdiagnosed, and keeps an open mind after reading a referral letter?

    • I dont know sorry….I thought most neuros don’t read as they never seem to know my papers:-(.

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