Wednesday, 28 January 2015

Nerve loss in childhood MS

Why is paediatric MS so much worse than adult MS? #MSBlog #MSResearch

"The pathology study below suggests that acute MS lesions in children with MS are more damaging that those that are found in adults. The number of transected, cut or shredded, axons (nerve processes) was 50% greater in inflammed MS lesions from children compared to lesions from adults. This may explain why children with MS are more likely to manifest with cognitive problems than adults. We have always put down the cognitive problems in paediatric MS to the fact that paediatric brain is not fully developed, or mature, therefore it can't deal with the damage. This study suggests that there may be something different about the inflammatory response in children that is more damaging than that which occurs in adults. The latter is something that needs to be looked into; may be a young immune system has more robust and primed inflammatory mechanisms than an older immune system. The other explanation is that this study is biased by MSer selection. The children who had died of MS or needed biopsies were sicker, or had more active disease, compared to the adults MSers studied."


"Whatever the explanation is this is another study that confirms that focal MS lesions are not good for the brain and spinal cord. This is why we try and suppress their development and is what underpins our zero tolerance (ZeTo) strategy with regard to NEDA. Not all neurologists buy into ZeTo; they state that if we target complete suppression of new lesion formation on MRI then most MSers will end-up on the most effective therapies. They don't think is right, because what do you have to offer them if their disease gets really active. They prefer to keep the big guns for a rainy day. My counterargument is that if most MSer end-up on highly effective therapies it indicates that most MSers need to be on the most effective therapies. ZeTo is based on a scientific principle that focal lesions are bad for you, therefore any evidence of ongoing inflammation needs to be suppressed."


"Just to make you aware that there are large number of neurologists who don't support the concept of NEDA (no evident disease activity), but prefer to target MEDA (minimal evident disease activity) and still others who don't think we should be monitoring a response, or lack of a response, to therapy with MRI at all. I cover these issues in my a recent commentary I have just written." 

Giovannoni G. Any evident MRI T2-lesion activity should guide change of therapy in multiple sclerosis - Yes. Mult Scler. 2015 Jan 26. pii: 1352458514566261.

Excerpt (concluding paragraph):

Critics claim that a zero-tolerance strategy would result in the majority of MS patients ending up on so-called highly effective, and potentially more risky, therapies. My response to this criticism is that if they have ongoing inflammation they probably need to be on highly effective therapies. A good analogy is the treat-to-target strategy adopted by rheumatologists to manage rheumatoid arthritis; their treatment algorithms are designed to suppress joint inflammation as much as possible and induce long-term remission with the aim of preventing end-organ, or permanent joint, damage. I don’t understand why MS neurologists would want to manage MS any differently. At least rheumatologists have the option of replacing joints when their treatment strategies fail. Unfortunately, MSologists do not have the luxury of being able to replace the brain and spinal cord; sadly, walking sticks, wheelchairs, beds and coffins await the victims of therapeutic nihilism. Will the non-adoption of a zero-tolerance strategy to focal inflammatory events in MS be viewed as a form of subliminal therapeutic nihilism by the next generation of MS neurologists and patients?

Epub: Pfeifenbring et al. Extensive acute axonal damage in paediatric multiple sclerosis lesions. Ann Neurol. 2015 Jan . doi: 10.1002/ana.24364.

Objective: Axonal damage occurs early in multiple sclerosis (MS) and contributes to the degree of clinical disability. Children with MS more often show disabling and polyfocal neurological symptoms at disease onset than adults with MS. Thus, axonal damage may differ between paediatric and adult MSers. 


Methods: We analyzed axonal pathology in archival brain biopsy and autopsy samples from 19 children with early MS. Lesions were classified according to demyelinating activity and presence of remyelination. Axonal density and extent of acute axonal damage were assessed using Bielschowsky's silver impregnation (axon stain) and immunohistochemistry for amyloid precursor protein (APP) respectively. Axonal injury was correlated with the inflammatory infiltrate as well as clinical characteristics. Results were compared with data from adult MSers.

Results: Acute axonal damage was most extensive in early active demyelinating (EA) lesions of paediatric MSers and correlated positively with the Expanded Disability Status Scale at attack leading to biopsy/autopsy. Comparison with 12 adult MSers showed a 50% increase in the extent of acute axonal damage in EA lesions from children compared to adults, with the highest number of APP-positive spheroids found prior to puberty. The extent of acute axonal damage correlated positively with the number of lesional macrophages. Axonal density was reduced in paediatric lesions irrespective of the demyelinating activity or the presence of remyelination. Axonal reduction was similar between children and adults. 

Interpretation: Our results provide evidence for more pronounced acute axonal damage in inflammatory demyelinating lesions from children compared to adults.

CoI: multiple

B cells and their role in relapse

Hohmann C, Milles B, Schinke M, Schroeter M, Ulzheimer J, Kraft P, Kleinschnitz C, Lehmann PV, Kuerten S. Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood.
Acta Neuropathol Commun. 2014 ;2(1):138.


INTRODUCTION:B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) taken directly from the blood  and after 96 h of stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS).
RESULTS:Nine patients displayed B cells in the blood producing brain-specific antibodies. Six patients were classified as B cell positive donors only after B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly from the blood and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77).
CONCLUSIONS:Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.

This data indicate actively ongoing B cell-mediated immunity against brain antigens in a small subset of people with MS and they appear around the time of relapse whether this causative, is up for debate but will particularly interesting in those sceientists looking at B cell autoimmunity




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"If you wanted to design a disease that is a charlatan’s dream, you could not do better than MS. It is a chronic illness with long periods of remission and occasional relapses. The cause is un- known and the treatment is far from satisfactory. Therefore, if you happen to give somebody an alternative therapy just as the disease goes into remission, he or she will attribute the recovery to that treatment. If the treatment goes badly, you can blame the person for not using enough or the right type of your potion or diet, and proceed to the next level of “treatment.” Since the cause of the disease is unknown, even the most ludicrous theory can be given a surface plausibility by the glib."

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