Patterns thread: Selective treatment for the four patterns

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Patterns thread: Selective treatment for the four patterns

Post by frodo » Sun Nov 26, 2017 4:04 am

In this post I will try to keep track of the developments in the specific treatment of the four patterns, whose existence was at first disputed, but it seems that now there is overwhelming evidence supporting them.

For the new ones, the main idea is that there are four patterns of MS (one of them, IV very rare and often ignored), and they represent different pathogenic kinds of MS. Probably the most common, pattern II, is related to EBV while the rest are not.

Patterns I and II lesions show perivenous distribution, sharp borders and macrophages/microglia, and are considered typical autoimmune MS lesions. Pattern III and IV do not show macrophages/microglia and probably will be officially excluded from MS at some point.

Image

PS: Image taken from:
Imaging in multiple sclerosis: A new spin on lesions
https://onlinelibrary.wiley.com/doi/ful ... 9485.12498
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Patterns thread: Selective treatment for the four patterns

Post by frodo » Mon Apr 23, 2018 5:47 am

Summary of the research about specific treatments:

- Jan 2019: Immunoadsorption or plasma exchange in steroid‐refractory multiple sclerosis and neuromyelitis optica: They say that immunoadsorption is equally effective than plasma exchange.

- June 2018: Mitoxantrone treatment in a patient with multiple sclerosis and pattern III lesions: They report for the first time a successful Mitoxantrone treatment in a patient with specifically determined pattern III lesions.

- April 2018: Differences in the Reponses to Apheresis of patients with histopathologically classified Patterns of MS: Response to apheresis therapy (plasmapheresis) may be associated with immunopathological patterns and thus with pathological mechanisms of lesion development.

- March 2018: Rescue therapy with alemtuzumab in B cell/antibody-mediated MS They explain that Alemtuzumab works better for pattern II and they identify the B-cells problem with this pattern.

- May 2017: Sublethal oligodendrocyte injury: A reversible condition in multiple sclerosis?: They explain that pattern III MS could be reversed.

- November 2016: Multiple sclerosis: the upward trajectory continues. Pattern III lesions linked to hypoxia and resposive to oxygen therapy: "Whilst these findings, including the reversal of ongoing hypoxia, need to be verified, they suggest a key role for hypoxia in the pattern III lesions". Available as pdf in http://discovery.ucl.ac.uk/1534337/1/Th ... v-2016.pdf

- August 2005: Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. First report about a selective treatment. All patients with pattern II but none with patterns I or III, achieved neurological improvement.
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discriminating the patterns

Post by frodo » Mon Apr 23, 2018 5:57 am

Papers about tests for discriminating the patterns

- April 2018: Tissue Markers for Acute Multiple Sclerosis Treatment Response—A Step Toward Personalized Medicine: Personalized medicine tries to find the right medicine for each patient. Patterns are considered in this article.

- Dec. 2014: Predicting therapeutic efficacy of intravenous immunoglobulin IVIG in RRMS Pattern II, and therefore response to plasmapheresis, can be predicted from the genetic profile of a given patient.

- June 2009: Molecular Changes in White Matter Adjacent to an Active Demyelinating Lesion in Early MS. They say that in Pattern III there is evidence for reactive nitrogen species (RNS)‐mediated damage to oligodendrocytes.

- Nov. 2008: Review: Mitochondria and disease progression in multiple sclerosis. Reports about damage in mitochondria in pattern III MS and Balo's type lesions, where NAA is reduced and lactate is increased.

- Pattern III: Functionally important defects of mitochondrial respiratory chain complex IV are present in Pattern III but not in Pattern II multiple sclerosis lesions.(https://academic.oup.com/brain/article/ ... 722/387831)

- Pattern III: monocytes and microglia are differently activated in pattern II and III MS lesions
https://academic.oup.com/jnen/article/63/3/262/2916610

- Oct. 2013: Isolation of Clostridium perfringens Type B in an Individual at First Clinical Presentation of MS Provides Clues for Environmental Triggers of the Disease. They report a strain of that bacteria in a pattern III lesion at that time known as "nascent lesion".

- Jun. 2003: A new paraclinical CSF marker for hypoxia‐like tissue damage in multiple sclerosis lesions: A monoclonal antibody against "canine distemper virus" detects a cross‐reactive endogenous brain epitope, able to discriminate pattern III.
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Papers about the theoretical research in Patterns

Post by frodo » Mon Apr 23, 2018 6:05 am

Papers about the theoretical research in Patterns

- Feb. 2019: Complement system in MS: A freely available PhD thesis speaking about pattern II (complement mediated) MS.

- Jan 2019: Brain histopathological study and prognosis in MOG antibody‐associated demyelination: They present two cases of anti-MOG encephalomyelitis, not MS, but similar to tumefactive MS, having lesions belonging at the same time to patterns I and II. This could explain some reports about coexistence of patterns.

-June 2018: Multiple sclerosis pathogenesis: missing pieces of an old puzzle: At least two distinct demyelinating processes may be responsible for lesion genesis in MS; in one the primary target of injury are oligodendrocytes and in the other myelin components.

- March 2018: Detailed Characterization of T Cell Receptor Repertoires in Multiple Sclerosis Brain Lesions: Description of the T-cells behaviour in pattern II. Clonal T cell expansions in MS brain lesions allow the identification of T cells that are assumed to be involved in the disease process.

- Jan. 2018: Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. They say that EBV is strongly related to clonally expanded CD4+ and CD8+ T cells, the ones detected in pattern II brain lesions.

- October 2016: Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: The say that microglia is the culprit in pattern I but not in the others patterns: "In acute MS cases with either pattern II or pattern III lesion pathology we found no evidence of microglial clusters or linear deposits of C3d, suggesting that clusters formation is independent of active demyelination".

- Sept 2016: Intrathecal Immunoglobulin Synthesis in MS—A Complete Reappraisal Microarrays discriminate immune signatures in the sera. Interestingly, immune signatures based on IgG and IgM also discriminated pathologic patterns I and II.

- August 2017: Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis: A special test called the MRZ reaction, reported in 60–80% of MS patients was absent in all pattern II or III MS patients tested. Besides Oligoclonal bands were present in nearly all samples from pattern I but only in few samples from patients with patterns II or III.

- Feb. 2016: Patent for diagnosis of the MS subtype, able to discriminate patterns I and II. Methods and kits for diagnosing multiple sclerosis (MS) in a subject. Particularly, the present invention relates to methods and kits for diagnosing a subtype of MS in a subject, the subtype selected from relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and a pathologic sub-type of MS lesions selected from Pattern I and Pattern II MS lesion

- Jan 2016 - Immunology of Multiple Sclerosis. Review. Expression of distinct chemokine receptors of pattern II patients, a more favorable response to therapeutic plasma exchange, and different serum antibody signatures in patients with demyelinating patterns I and II, as well as the more direct evidence that T cells releasing Th2 cytokines and able to provide B-cell help dominate the T-cell infiltrate in pattern II brain lesions, support the existence of different pathological patterns of MS.

- June 2015: Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions: First functional evidence for arole of Th2/Tc2 cells in pattern II MS, supporting the existence of this pathogenic phenotype.

-Nov. 2008: Unique serum immune signatures characterize immunopathogenic mechanisms of MS. Biomarkers in blood can identify the pathological MS pattern.

- September 2006: Multiple sclerosis with and without CSF bands: Clinically indistinguishable but immunogenetically distinct. Genotyping results suggest that OCB-positive and OCB-negative MS are immunogenetically distinct. Not patterns, but it could be related.
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CSF discrimination

Post by frodo » Thu Apr 26, 2018 3:30 am

Reports about discrimination of pathological patterns by CSF analysis

- Feb. 2019: Myelinoclastic diffuse sclerosis (Schilder’s disease) is immunologically distinct from multiple sclerosis: results from retrospective analysis of 92 lumbar punctures. They say that Schilder's has no oligoclonal bands.

- Jan 2018: Baló’s concentric sclerosis is immunologically distinct from multiple sclerosis: They also say that Pattern III MS is a subtype of Balo and not MS: "Pattern III MS is diagnosed ... has only recently been proposed to denote a disease entity distinct from MS based on our observation that those patients are negative for OCB"
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Re: Patterns thread: Selective treatment for the four patter

Post by frodo » Thu May 10, 2018 1:54 am

Other summary. As introduction they say:

"Histopathological studies have demonstrated at least three different lesion patterns [...]. Pattern I show T cell and macrophage infiltration. Pattern II is defined by additional antibody and complement deposition Pattern III is characterized by distal oligodendrogliopathy [...]. These findings raise the possibility that MS, a diagnosis currently based mainly on phenotypical, namely clinical and radiological features, may in fact be a pathologically heterogeneous syndrome rather than a single disease entity. Importantly, two recent studies demonstrated intraindividual homogeneity and persistence of pattern I, II and III lesions over time further corroborating the notion that lesion pathology may rather define pathogenetically distinct entities than reflect stage-dependent processes in the development of lesions"

Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis

https://jneuroinflammation.biomedcentra ... 017-0929-z

Background: The diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. However, histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity.

Objective: The aim of this study was to investigate whether patients with pattern I MS differ from patients with pattern II or III MS with regard to cerebrospinal fluid (CSF) findings, especially with reference to intrathecal IgG synthesis, which is found in most patients with MS but is frequently missing in MS mimics such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-IgG-positive encephalomyelitis.

Methods: Findings from 68 lumbar punctures in patients who underwent brain biopsy as part of their diagnostic work-up and who could be unequivocally classified as having pattern I, pattern II or pattern III MS were analysed retrospectively.

Results: Oligoclonal bands (OCBs) were present in 88.2% of samples from pattern I MS patients but in only 27% of samples from patients with pattern II or pattern III MS (P < 0.00004); moreover, OCBs were present only transiently in some of the latter patients. A polyspecific intrathecal IgG response to measles, rubella and/or varicella zoster virus (so-called MRZ reaction) was previously reported in 60–80% of MS patients, but was absent in all pattern II or III MS patients tested (P < 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of blood–CSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (P < 0.002). Accordingly, QAlb values and albumin and total protein levels were higher in pattern II and III MS samples than in pattern I MS samples (P < 0.005, P < 0.009 and P < 0.006, respectively).

Conclusions: Patients with pattern II or pattern III MS differ significantly from patients with pattern I MS as well as from previous, histologically non-classified MS cohorts with regard to both intrathecal IgG synthesis and blood–CSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS.

Other source:



Patterns I and II (specially pattern II) responsive to plasmapheresis. Pattern III unresponsive. This is just the last of several reports in this sense.

Differences in the Reponses to Apheresis Therapy of Patients With 3 Histopathologically Classified Immunopathological Patterns of Multiple Sclerosis

https://jamanetwork.com/journals/jamane ... irect=true

Abstract

Importance Plasma exchange and immunoadsorption are second-line apheresis therapies for patients experiencing multiple sclerosis relapses. Early active multiple sclerosis lesions can be classified into different histopathological patterns of demyelination. Pattern 1 and 2 lesions show T-cell– and macrophage–associated demyelination, and pattern 2 is selectively associated with immunoglobulin and complement deposits, suggesting a humoral immune response. Pattern 3 lesions show signs of oligodendrocyte degeneration. Thus it is possible that pathogenic heterogeneity might predict therapy response.

Objective To evaluate the apheresis response in relation to histopathologically defined immunopathological patterns of multiple sclerosis.

Design, Setting and Participants This single-center cohort study recruited 69 patients nationwide between 2005 and 2016. All included patients had a diagnosis of early active inflammatory demyelination consistent with multiple sclerosis; were classified into patterns 1, 2, or 3 based on brain biopsy analysis; and underwent apheresis treatments. Patients who had concomitant severe disease, neuromyelitis optica, or acute disseminated encephalomyelitis were excluded.

Main Outcomes and Measures The primary therapy outcome was a functionally relevant improvement of the relapse-related neurological deficit. Radiological and Expanded Disability Status Scale changes were secondary outcome parameters.

Results The mean (SD) age of patients was 36.6 (13.3) years; 46 of the 69 participants (67%) were female. Overall, 16 patients (23%) exhibited pattern 1 lesions, 40 (58%) had pattern 2 lesions, and 13 (19%) had pattern 3 lesions. A functional therapy response was observed in 5 of the 16 patients with pattern 1 disease (31%) and 22 of the 40 patients with pattern 2 disease (55%), but none of the 13 patients with pattern 3 disease exhibited improvement (pattern 2 vs 3 P < .001). Radiological improvements were found in 4 (25%), 22 (56%), and 1 (11%) of patients with patterns 1, 2, and 3, respectively. The respective rates of response measured by changes in Expanded Disability Status Scale scores were 25%, 40%, and 0%. Brainstem involvement was a negative predictive factor for the functional therapy response (logarithmic odds ratio [logOR], −1.43; 95% CI, −3.21 to 0.17; P = .03), while immunoadsorption (as compared with plasma exchange) might be a positive predictive factor (logOR, 3.26; 95% CI, 0.75 to 8.13; P = .01).

Conclusions and Relevance This cohort study provides evidence that the response to apheresis treatment is associated with immunopathological patterns. Patients with both patterns 1 and 2 improved clinically after apheresis treatment, but pattern 2 patients who showed signs of a humoral immune response benefited most. Apheresis appears unlikely to benefit patients with pattern 3 lesions.
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Pattern II: T-cells description

Post by frodo » Thu May 10, 2018 2:07 am

Pattern II: Description of the T-cells behaviour:

Detailed Characterization of T Cell Receptor Repertoires in Multiple Sclerosis Brain Lesions

https://www.frontiersin.org/articles/10 ... 00509/full

Extracts:

[...] three demyelinating lesions that had different location and inflammatory activity, were obtained from a secondary progressive (SP)MS patient with pattern II demyelinating lesions (22), for whom we had the unique opportunity to have access to peripheral blood mononuclear cells (PBMCs) and CSF cells prior to death and also autopsy brain tissue[...]

Clonal T cell expansions in MS brain lesions allow the identification of T cells that are assumed to be involved in the disease process [...]

It is important to note that the three demyelinating brain lesions analyzed in this study were from a single SPMS patient with pattern II demyelinating lesions (22), and therefore, one may not be able to extrapolate our results to patients with other clinical forms of MS or other demyelinating patterns[...]

Pattern II demyelination is associated with macrophages and T cell inflammation, as well as prominent deposition of antibody/complement complexes at sites of active myelin destruction

[...]and the ability of several of these CSF-TCCs to release Th2 cytokines and help B cells in pattern II demyelination (22), strongly support their pathogenic role and also underline the value of cDNA TRBV-seq of active lesions to identify pathogenic cells.

In conclusion, MS brain lesions, at least in a SPMS patient with pattern II demyelination, independently of their proximity or inflammatory activity, contain CD4+ and CD8+ clonally expanded clonotypes that may play a role in disease pathogenesis.

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Re: Pattern II: T-cells description

Post by frodo » Thu May 10, 2018 2:18 am

Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease

https://onlinelibrary.wiley.com/doi/ful ... glia.23090

[...]White matter lesions of cases with acute MS were classified into patterns I–IV, as previously described (Lucchinetti et al., 2000). Of the 10 acute MS cases included in the present study, 5 showed active lesions resembling the hypoxia‐like pattern III lesions, and 5 showed active lesions with pattern II pathology (Table 1). Evidence of complement activation in and around the lesions has been previously shown for the MS cases with pattern II pathology[...]

[...]In acute MS cases with either pattern II or pattern III lesion pathology we found no evidence of microglial clusters or linear deposits of C3d, suggesting that clusters formation is independent of active demyelination. In the periplaque white matter, microglia showed a sparse distribution and a resting morphology, as indicated by the thin appearance of IBA‐1+ ramifications and the low immunoreactivity for CD68[...]

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Re: Pattern II: T-cells description

Post by frodo » Thu May 10, 2018 2:23 am

About a pattern III experimental model:

Normobaric hyperoxia protects against demyelination in an experimental model of pattern III multiple sclerosis lesions

http://discovery.ucl.ac.uk/1465736/

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Re: Pattern III separation proposal

Post by frodo » Tue May 29, 2018 12:00 am

Pattern III MS proposed to be set appart from classical MS:

"Pattern III MS is diagnosed on the basis of histopathological features, some of which suggest ischemia-mediated tissue damage, and has only recently been proposed to denote a disease entity distinct from classical MS based on our observation that patients with ‘pattern III’ lesions are typically negative for OCB (oligoclonal bands)".

"While probably overrepresented in biopsy/autopsy samples, ‘pattern III MS’ must be a rare disease in the general MS population given that OCB are highly frequent in MS"

Source:

Baló’s concentric sclerosis is immunologically distinct from multiple sclerosis: results from retrospective analysis of almost 150 lumbar punctures


https://jneuroinflammation.biomedcentra ... 017-1043-y

Finally, at least some patients with BCS may suffer from what has been called ‘pattern III’ MS. ‘Pattern III’ MS is diagnosed on the basis of histopathological features, some of which suggest ischemia-mediated tissue damage, and has only recently been proposed to denote a disease entity distinct from classical MS based on our observation that patients with ‘pattern III’ lesions are typically negative for OCB [9]. While probably overrepresented in biopsy/autopsy samples, ‘pattern III MS’ must be a rare disease in the general MS population given that OCB are highly frequent in MS. So far, lesions showing the typical histopathological characteristics of ‘pattern III’ lesions have been reported in 12 patients with ‘concentric demyelination’ [30].

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Personalized medicine and patterns

Post by frodo » Tue May 29, 2018 3:39 am

Personalized medicine: At present, treatment of multiple sclerosis (MS) relapses is far from personalized medicine: most patients receive 1 or 2 courses of corticosteroids, with treatment of unresponsive relapses escalating to apheresis (either plasma exchange or immunoabsorption).1,2 Predictors of response to either corticosteroids or plasma exchange are limited.

Tissue Markers for Acute Multiple Sclerosis Treatment Response—A Step Toward Personalized Medicine

https://jamanetwork.com/journals/jamane ... ct/2670431

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Mitoxantrone effective in pattern III

Post by frodo » Mon Jun 11, 2018 10:56 pm

Mitoxantrone treatment in a patient with multiple sclerosis and pattern III lesions

https://onlinelibrary.wiley.com/doi/abs ... cen3.12466

Abstract
Background


Brain biopsies of multiple sclerosis patients identified three intraindividually stable lesion patterns. Apart from beneficial effects of plasma exchange in patients with type II lesions, little is known about how multiple sclerosis lesion histology could guide therapeutic decisions.

Case presentation

Here, we report on a 53‐year‐old male patient with polysymptomatic cerebral syndrome as the first episode of multiple sclerosis. Brain biopsy showed an inflammatory demyelinating lesion with apoptotic oligodendrocytes and a loss of myelin‐associated glycoprotein, pathological features typical for pattern III lesions. High‐dose steroids and immunosuppressive treatment with mitoxantrone led to a substantial improvement of disability and long‐term clinical stability.

Conclusion

Mitoxantrone therapy along with steroid pulses could potentially be considered as a therapeutic option for pattern III lesions.

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Re: Mitoxantrone effective in pattern III

Post by NHE » Mon Jun 11, 2018 11:09 pm

frodo wrote:Conclusion

Mitoxantrone therapy along with steroid pulses could potentially be considered as a therapeutic option for pattern III lesions.
Mitoxantrone's cardiotoxicity limits its usefulness.

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Pattern II related to the new discovery of GDP-L-fucose synt

Post by frodo » Mon Oct 22, 2018 7:39 am

We can see what the team that found the new auto-antibody (GDP-L-fucose synthase) was doing when they found it. It is related to the four "luccchinetti patterns". They had just focused in the pattern II, which it was clearly autoimmune for them. Therefore it seems that this discovery only applies to them (they speak about HLA DRB3 immunocompatibility, or DRB3*02:02 Multiple Sclerosis Patients)

https://www.multiplesclerosis.uzh.ch/en ... pedra.html

Autoantigens and disease heterogeneity

Our research aims are:

The identification of the antigen specificity and functional phenotype of autoreactive CD8+ T cells that are clonally expanded in the brains of MS patients with distinct phenotypes, e.g. 'Lucchinetti/Brück/Lassmann type 2' disease, which is characterized by T cell infiltration, antibody- and complement deposition
Addressing in a larger number of patients if the antigens identified under aim above are related to specific MS phenotypes.

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Pattern III due to mitochondria problems

Post by frodo » Mon Feb 18, 2019 1:47 am

Mitochondrial defects in acute multiple sclerosis lesions.

https://www.ncbi.nlm.nih.gov/pubmed/18515320

Multiple sclerosis is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the CNS. The structural and immunopathological patterns of demyelination suggest that different immune mechanisms may be involved in tissue damage. In a subtype of lesions, which are mainly found in patients with acute fulminant multiple sclerosis with Balo's type concentric sclerosis and in a subset of early relapsing remitting multiple sclerosis, the initial myelin changes closely resemble those seen in white matter stroke (WMS), suggesting a hypoxia-like tissue injury. Since mitochondrial injury may be involved in the pathogenesis of such lesions, we analysed a number of mitochondrial respiratory chain proteins in active lesions from acute multiple sclerosis and from WMS using immunohistochemistry.

Functionally important defects of mitochondrial respiratory chain complex IV [cytochrome c oxidase (COX)] including its catalytic component (COX-I) are present in Pattern III but not in Pattern II multiple sclerosis lesions. The lack of immunohistochemically detected COX-I is apparent in oligodendrocytes, hypertrophied astrocytes and axons, but not in microglia.

The profile of immunohistochemically detected mitochondrial respiratory chain complex subunits differs between multiple sclerosis and WMS. The findings suggest that hypoxia-like tissue injury in Pattern III multiple sclerosis lesions may be due to mitochondrial impairment.

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