Tag: misdiagnosis

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

Not diagnosing MS

Last night when I got home I was emotionally burnt-out. I had done an all-day clinic and saw many difficult and challenging patients with MS, both new and follow-up patients. My wife asked me if I had a good day. I replied that it had been exhausting and that I felt numb. She said there must have been something rewarding in my day’s activities? On reflection, there were a lot of small moments that made me feel I was doing something worthwhile. This is highly relevant because my clinical director has recently recommended I stop seeing patients so that I can focus on research for the last decade of my academic career. The question is am I ready to auction off my vintage patella hammer and ophthalmoscope and not see another patient?

The most satisfied patient I saw yesterday was a young woman in whom I was able to not make the diagnosis of MS. Her white matter lesions were non-specific, her CSF was clear (no oligoclonal IgG bands and normal neurofilament levels), she had a full set of evoked potentials, which were normal, and her neurological examination was entirely normal. She has a positive family history with her mother and aunt having died of the MS-related complications. After presenting with visual and sensory symptoms her previous neurologist had been influenced by the family history and raised the possibility of her having MS. The non-specific white matter lesions on MRI had cemented the possibility in both the referring neurologist’s and the patient’s minds. 

The tragedy of this case is that this patient has been living with the possibility of having MS for the last 6 months. Her anxiety levels were sky-high and she had already internalised the diagnosis and had started to behave like someone with a chronic disease. She developed ‘MS-fatigue’, which on reflection was due to anxiety and depression and had tragically turned down a promotion at work that required her to transfer to her company’s office in New York. On reflection, her symptoms were almost certainly due to migraine aura. She was not the only patient to cry in clinic yesterday, the only difference was that her tears were tears of joy. 

Not diagnosing MS is easier than undiagnosing MS, which is a topic I teach on frequently. There are many reasons why people are misdiagnosed as having MS, but it is much commoner than you realise. I am not sure if you are aware that if you have MS there is a 1 in 20 chance that you have another disease; if you are interested I have already covered this issue in a previous blog post. 

What, I don’t have MS?

In the study below approximately 1 in 5 people diagnosed with MS don’t have MS. This is so much higher than previous studies. I have always quoted the Danish post-mortem studies that sugget only 1 in 20 MSers 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 to attacks or 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 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.

I have spent some time explaining this all to you as we neurologists get the diagnosis wrong in approximately 5% of the time and if this paper below is correct may be in even a higher number of patients. In other words, at least 1 in 20 people who have a diagnosis of MS in life don’t have MS when their brains are studied at postmortem.

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 disease, has implications for the person concerned. For example, it may affect your life choices and may impact on 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 fulfill contemporary McDonald Criteria and had a more likely alternate diagnosis.