#NeuroSpeak & #ClinicSpeak: Is MS many diseases or one disease?

A new MS-mimic may explain the cerebellar phenotype #NeuroSpeak #ClinicSpeak #MSResearch

When I was at medical school I learnt that for a disease to be regarded as an autoimmune disease it needed to answer to Witebsky’s postulates (first formulated by Ernst Witebsky in 1957): 

  1. Direct evidence from transfer of pathogenic antibody or pathogenic T cells
  2. Indirect evidence based on reproduction of the autoimmune disease in experimental animals
  3. Circumstantial evidence from clinical clues
The following paper below describing a new auto-antibody syndrome, targeting the inositol 1,4,5-triphosphate receptor 1 (IP3R1), in three patients presenting with a progressive cerebellar syndrome. These patients presented with unsteadiness of gait, slow movements, in-coordination, difficulty judging distances, an intention tremor, slurred speech and jerky eye movements. Importantly, one patient was eventually diagnosed with primary progressive multiple sclerosis. The question that needs to be asked is does this particular patient have MS or another disease? 

It will be interesting to screen a large group of pwMS for auto-antibodies against the IP3R1 and to see if they correlate with cerebellar signs. There is a group of pwMS that have a predominantly cerebellar phenotype; could a specific auto-antibody identify these as being unique? 

As you have gathered patients presenting with anti-IP3R1 may or may not have an autoimmune disease. What needs to be done is show that these anti-IP3R1 are pathogenic. If we transfer them into an animal, or cell culture of cerebellar cells, do they induce changes in function that could be interpreted as them being pathogenic? Do they kill the cerebellar cells or do they cause them to misfire? Similarly, if we innoculate and animal with IP3R1 and induce the production of anti-IP3R1 antibodies can we induce a disease with similarities to the human disease described below? In addition, if we suppress the production of anti-IP3R1, using immunosuppressive drugs, or remove the anti-IP3R1 antibodies from the blood of patients using plasma exchange, do they improve, or stabilise, clinically?  If we answer these questions we may be able to start labelling these patients as having a new autoimmune disease. 

In summary, the investigator’s have some work to do to show that patients with anti-IP3R1 antibodies have a autoimmune disease.  The paper below is a start and who knows it may yet show that some people diagnosed with MS, who have a predominantly cerebellar-type onset and progression, may in fact have another disease. 

Don’t be alarmed by this paper when we finally find the cause of MS there will be people with MS who turn-out not to have the disease (misdiagnosed at present) and there will be people who don’t have MS at present who will be diagnosed with MS (undiagnosed at present). There are many examples of this in other disease areas. 

Fouka et al. Antibodies to inositol 1,4,5-triphosphate receptor 1 in patients with cerebellar disease. Neurol Neuroimmunol Neuroinflamm. 2016 Dec 5;4(1):e306. eCollection 2017.

OBJECTIVE: To describe newly identified autoantibodies associated with cerebellar disorders.

DESIGN/METHODS: We first screened the sera of 15 patients with cerebellar ataxia, without any known associated autoantibodies, with immunocytochemistry on mouse brain. After characterization and validation of a newly identified antibody, 85 additional patients with suspected autoimmune cerebellar disease were screened using a cell-based assay.

RESULTS: Immunoglobulin G from one of the first 15 patients demonstrated a distinct staining pattern on Purkinje neurons. This autoantibody, as characterized further by immunoprecipitation and mass spectrometry, was binding inositol 1,4,5-triphosphate receptor 1 (IP3R1), an intracellular channel that mediates the release of Ca2+ from intracellular stores. Anti-IP3R1 specificity was then validated with a cell-based assay. On this basis, screening of 85 other patients with cerebellar disease revealed 2 additional IP3R1-positive patients. All 3 patients presented with cerebellar ataxia; the first was eventually diagnosed with primary progressive multiple sclerosis, the second had a homozygous CAG insertion at the gene TBP, and the third was thought to have a neurodegenerative disease.

CONCLUSIONS: We independently identified an autoantibody against IP3R1, a protein highly expressed in Purkinje neurons, confirming an earlier report. Because a mouse knockout model for IP3R1 exhibits ataxia and epilepsy, this autoantibody may have a functional role. The heterogeneity of the antibody-positive patients suggests that this antibody may either have a direct involvement in disease pathogenesis or it is a surrogate marker secondary to cerebellar injury. Anti-IP3R1 antibodies should be further explored in various ataxic and epileptic syndromes as they may denote a marker of response to immunotherapies.

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.

1 comment

  • I know MSers who say that have as a symptom of epileptic seizures, some fainting, but often reports of their outbreaks of eplepsy.
    Neurologists say, as far as I know, to be a rare, very unusual symptom. I always wondered if we would be talking about the same MS disease, or would it be another neuroimmunological disease that is confused with multiple sclerosis. Including a brazilian actress, who has MS and had epileptic seizures, followed by fainting as symptoms of MS outbreaks, main symptoms.
    She got to natalizumab and recently did the transplant.

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