How sure are you that you have MS? #ClinicSpeak #NeuroSpeak #MSBlog
Not everything that looks like MS is MS. Did you know that about 1 person in 20 with MS does not have the disease? This won’t come as a surprise to you if you are a regular reader of this blog; I have posted on this issue several times in the past. Today’s post by the MouseDoctor on two patients getting worse with alemtuzumab raises questions about whether or not they had MS to begin with versus the suggestion they developed a second disease on top of MS.
We have know for some time that patients with NMO (neuromyelitis optica) spectrum disorder do very badly on alemtuzumab. Of the 4 cases written up below, 3 of them died post-alemtuzumab from catastrophic ongoing relapses. The one case that did well was subsequently treated with rituximab. These cases of catastrophic relapses post-alemtuzumab raises the question of how good we really are at diagnosing MS? Clearly there many more MS mimics out there that need to identified, defined and treated differently to MS.
Cases 1 to 3:
Azzopardi et al. Alemtuzumab use in neuromyelitis optica spectrum disorders: a brief case series. J Neurol. 2016 Jan;263(1):25-9.
Alemtuzumab is an anti-CD52 monoclonal antibody recently licensed for use in relapsing-remitting multiple sclerosis. Here, we report our experience of its use in neuromyelitis optica (NMO) spectrum disorders. A retrospective case review of patients treated with alemtuzumab in Cambridge, UK, was conducted to identify those who fulfil the criteria for NMO spectrum disorder. Three cases were identified. Case 1, 9-year-old female, presented with transverse myelitis and bilateral optic neuritis,with one lower medullary and several longitudinally extensive cord lesions. Despite immunosuppression including two courses of alemtuzumab, she continued to relapse, was wheelchair bound and registered blind by age 12, and died at age 18. Case 2, 41-year-old female, presented with bilateral optic neuritis and transverse myelitis with longitudinally extensive cervical cord lesions. Despite three courses of alemtuzumab, she had five relapses with visual impairment and new cord lesions. She later developed tumefactive white matter lesions and died aged 51.Case 3, 31-year-old female, presented with transverse myelitis with longitudinally extensive cervical cord lesions and positive aquaporin-4 antibody. After one course of alemtuzumab, she relapsed with 4 episodes of myelitis with new enhancing lesions and accumulating disability. She became relapse free after rituximab and mycophenolate mofetil. From this case series, we conclude that alemtuzumab failed to prevent disabling relapses and poor outcome in NMO. We hypothesise that rituximab is more effective, as in case 3, because it causes much more prolonged B lymphocyte depletion than alemtuzumab. We therefore caution against the use of alemtuzumab in NMO.
Case 4:
Gelfand et al. Massive CNS monocytic infiltration at autopsy in an alemtuzumab-treated patient with NMO. Neurol Neuroimmunol Neuroinflamm. 2014 Oct 9;1(3):e34.
OBJECTIVES: To describe the clinical course and neuropathology at autopsy of a patient with neuromyelitis optica (NMO) treated with alemtuzumab.
METHODS: Case report.
RESULTS: A 61-year-old woman with aquaporin-4 immunoglobulin G antibody seropositive NMO had 10 clinical relapses in 4 years despite treatment with multiple immunosuppressive therapies. Alemtuzumab was administered and was redosed 15 months later. For the first 19 months after the initial alemtuzumab infusion, the patient did not experience discrete clinical relapses or have evidence of abnormally enhancing lesions on brain or spinal cord MRI. However, she experienced insidiously progressive nausea, vomiting, and vision loss, and her brain MRI revealed marked extension of cortical, subcortical, and brainstem T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities. She died 20 months after the initial alemtuzumab infusion. Acute, subacute, and chronic demyelinating lesions were found at autopsy. Many of the lesions showed marked macrophage infiltration with a paucity of lymphocytes.
CONCLUSIONS: Following alemtuzumab treatment, there appeared to be ongoing innate immune activation associated with tissue destruction that correlated with nonenhancing T2/FLAIR hyperintensities on MRI. We interpret the cessation of clinical relapses, absence of contrast-enhancing lesions, and scarcity of lymphocytes at autopsy to be indicative of suppression of adaptive immunity by alemtuzumab. This case illustrates that progressive worsening in NMO can occur as a consequence of tissue injury associated with monocytic infiltration. This observation may be relevant to multiple sclerosis (MS) as well as NMO and might explain why in previous studies of secondary progressive MS alemtuzumab did not seem to inhibit disability progression despite a dramatic decline in contrast-enhancing lesions.
CoI: multiple
When I had my MRI – after about 13 years of slow progression – my neurologist said that they never really reach 100% certainty in diagnosis of MS. After my MRI, the certainty was about 97% with me, I seem to remember him saying. There was a little more certainty after I had some signs of myelin instability ("relapses") later on. This doesn't surprise me because so little seems to be known about MS for sure in terms of its pathology.
Could the other 2 cases have had a form of NMO?
So is it really that people with positive OCBs and all the evolution of lesions in MRI are the ones that really have MS? I ask this because here in Brazil I see several people without positive OCBs having their diagnoses closed to MS (following the McDonald criteria) some of them without checking the anti-aquaporin 4 test to verify if it was MS itself, and unfortunately these people do not seem to respond to any highly DMT effective even, nothing. Now I confess to being very "logical" the hypothesis that the lymphocytes are still trapped for a while in the lymph nodes in fingolimod treatments and are not reached in a Alemtuzumab cycle, because I think we already know a little about how Alemtuzumabe acts.
Just a quick note on the rate of misdiagnosis in multiple sclerosis. Back in 2009, I was examined by the neuroimmunology team at the National Institutes of Health, as part of a study they were doing trying to identify a population of people with clinically definite multiple sclerosis. The reason they were conducting this study was because, retrospectively, the researchers at the NIH had found that 10%-15% of the trial subjects in their clinical MS studies were, in fact, misdiagnosed, and didn't have multiple sclerosis at all. These people had, in effect, corrupted all of the data in these studies.I believe this is a tremendous problem, and is especially prevalent when patients don't have access to MS specialists, but instead rely on general neurologists.Just FYI, after many tests and various pokes and prods (including scanning by a 7T machine), it was determined that I do not have clinically definite multiple sclerosis. In fact, none of the many doctors I've seen has been able to nail down my diagnosis, 14 years since my initial diagnosis. In purely scientific terms, I can unequivocally state in purely scientific terminology that it absolutely sucks to be a mystery patient. When asked, I usually tell people I have "creeping paralysis", a term used in the late 19th and early early 20th centuries to describe what would later be commonly called MS, but which perfectly describes what I am experiencing…
Sorry about the doubling up of "purely scientific", one of the dangers of using voice recognition software and not proofreading…