Diagnosis – Prof G's MS Blog Archive

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:

The evolving definition of MS based on diagnostic criteria:

Clinical criteria only:

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:

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:

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

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

I look after a patient with MS who is now in her late 60’s. She was diagnosed with MS almost 30 years ago in the early ’90s. She has done very well and has by definition benign MS. Apart from mild unsteadiness of gait, a weak right leg that causes a mild limp when she is tired and back pain, she is fully functional. She was treated with interferon-beta for 14 years and after having no relapses for over 10 years she decided to stop taking interferon-beta. She made the decision to stop interferon-beta treatment when she retired in her early 60s. Her only ‘MS medication’ is 300mg of gabapentin at night; this helps dull the back or myelopathic pain so she can get a good nights sleep.

Despite having MS and a good prognosis she suffers from PTSD (post-traumatic stress disorder) in relation to how her MS was diagnosed by a private neurologist in London. She had a prior history of vertigo and unsteadiness of gait and had developed weakness of her right leg, presumably from a spinal cord attack. This was before the world-wide-web and DMT era so most people in the general population did not know a lot about MS; their knowledge of MS was based on a billboard advertising campaign of the MS society showing young pwMS in wheelchairs. The idea of the MS Society’s campaign at the time was to scare the general public to donate money for research. In addition, to this, the poster child of MS at the time was Jacqueline du Pré, the celebrated British cellist, who had tragically died at the age of 42 from MS. Jacqueline du Pré had died quite recently in 1987 and as her death had been extensively covered on TV and in the newspapers. The general public’s view of MS in the late ‘80s and ‘90s was not a very good one; MS was a disease that struck you down when you were young and invariably caused disability and early death. How things have changed!

The private neurologist who saw my patient was not an MS expert and had not prepared my patient for the diagnosis. When she returned for her follow-up or diagnostic appointment he simply walked up to an old backlight x-ray box on which he had pre-arranged her MRI scans and said without looking at her that she had a large number of white blobs on her MRI, which confirmed his suspicions that she had MS. He then turned around and said that he will write to her GP with the details. And that was the end of the consultation; no time for questions, no information on MS its treatment or prognosis. My patient recalls having to walk out of the consultation with a cold panic enveloping her. Tragically on catching the tube home she ended-up opposite one of the MS Society’s posters of a young person with MS with a zip down their spine; the implication that the damage MS had done to the spinal cord was responsible for causing the disability. My patient recalls this person in the poster, leaning forward in a wheelchair. This is clearly not the kind of poster you would want to see minutes after you have been told that you have MS.

To this day my patient gets regular (almost daily) and intrusive flashbacks of this experience. These flashbacks are associated with a feeling of anxiety or panic, palpitations, hyperventilation, hot flushes, sweating and a feeling of doom. The flashbacks can come on spontaneously, but typically happen when she needs to come to the hospital and particularly when she has an MRI scan. In fact, MRI is such a problem that she has now refused to have repeat MRI studies. The white blobs have become a bogeyman and she imagines them expanding and suffocating her. Her GP has diagnosed her as having PTSD or post-traumatic stress disorder and had prescribed an SSRI (selective serotonin reuptake inhibitor), which did help reduce the frequency and intensity of the flashbacks. However, as the SSRI caused weight gain the patient decided to stop taking it. She has subsequently found CBT (cognitive behavioural therapy) and mindfulness or meditation helpful, but clearly not a cure.

Interestingly, as I make a slow physical recovery from my injuries, I have started to have flashbacks about my recent accident. These are not intrusive and are typically triggered by crossing and traffic intersection or when I hear a motorcycle in the distance. These flashbacks are fleeting and not associated with any systemic symptoms. I, therefore, suspect flashbacks are a normal phenomenon for people who have just suffered a traumatic experience, but simply experiencing them provides a context and a deeper understanding of how traumatic it can be for someone to be diagnosed with MS or for that matter any chronic disabling disease.

My patient above may be an extreme example, but when asked a large number of pwMS tell me the worst part of MS is being told you have MS. In the Italian study below a quarter of pwMS have symptoms of PTSD and more than 1 in 20 have a confirmed diagnosis of PTSD. This is way more common than I expected this phenomenon to be. The question I ask is why are we HCPs so bad at communicating the diagnosis of MS? Is there anything that HCPs can do to improve the experience?

Nowadays most people who turn out to have MS already suspect the diagnosis because they have asked Dr Google. Is this a good or bad thing? Does it cause more or less anxiety going into a consultation suspecting the outcome?

George Pepper, one of the cofounders of shift.ms talks about his diagnostic experience as being a very poor one in that there was no support for people like him. This is why he started shift.ms, to create an online resource centre and supportive community to help people, particularly young people, come to terms with the diagnosis of MS. The Shift.ms YouTube movie Gallop is almost autobiographical and captures some of George’s experiences before and during the diagnostic phase of MS. If you haven’t watched the video before I would recommend it.

What were your experiences like? Have any of you developed PTSD as a result of being diagnosed with MS? Do you have any advice for other people with MS?

Carletto et al. Prevalence of Posttraumatic Stress Disorder in Patients With Multiple Sclerosis. J Nerv Ment Dis. 2018 Feb;206(2):149-151.

Chronic and life-threatening illnesses, such as multiple sclerosis (MS), have been identified as significant stressors potentially triggering posttraumatic stress disorder (PTSD). The study aims to investigate the prevalence of PTSD according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria in a large sample of patients with MS. A total of 988 patients with MS were screened with the Impact of Event Scale-Revised, and then assessed with the PTSD module of the Structured Clinical Interview for DSM-IV and with the Clinician-Administered PTSD Scale to confirm PTSD diagnosis. Posttraumatic symptoms were reported by 25.5% of the sample. A confirmed diagnosis of PTSD was found in 5.7% of patients, but prevalence could reach 8.5%, including also dropout patients. Further studies are needed to evaluate if adjustment disorder could better encompass the frequently encountered subthreshold posttraumatic stress symptoms and how clinicians can deal with these symptoms with appropriate interventions.

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CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211