Multiple sclerosis as a simultaneous "2 components" disease
•
2 likes•1,164 views
Multiple sclerosis as a simultaneous "2 components" disease
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Viewers also liked (14)
Similar to Multiple sclerosis as a simultaneous "2 components" disease
Similar to Multiple sclerosis as a simultaneous "2 components" disease (20)
Recently uploaded
Recently uploaded (20)
Multiple sclerosis as a simultaneous "2 components" disease
- 1. Multiple sclerosis as a “simultaneous two components” disease Emilie LOMMERS 4th year of the Master in Neurology FRS-FNRSCandidat Spécialiste Doctorant 2014.
- 2. MS as a “two stages” disease : classical view of MS pathology MS as a “two components” disease : emerging view of MS pathology Conclusions and perspectives OVERVIEW • Inflammation and focal damages • Focal damages and disease progression • Limitations of this model • Histopathological point of view • Two distinct pathways • Is neurodegeneration exist in early MS?
- 3. Peripherally activated T cells enter the CNS Episodic relapses due to inflammation MS AS A “TWO STAGES” DISEASE: Inflammation and focal damages References: 1. Markiewicz et al. Acta Neurobiol Exp 2006;66:343-358. 2. Lassmann. Curr op in Neurol 2008;21:242-247. 3. Weiner. J Neurol 2008;255(S1):3-11. 4. Van der Walt et al. Pharmacol and Therapeutics 2010;126:82-93. 5. Stys et al. Nature Rev Neurosc 2012;13:507-514.
- 4. References: 1. De Jager et al. Annu Rev Med. 2007;58:417-32. 2. Lassmann. Curr Opin Neurol. 2008;1:242-7. 3. Markiewicz et al. Acta Neurobiol Exp. 2006;66:343-58. 4. Nair et al. Cell Mol Life Sci. 2008;65:2702-20. 5. Van der Walt et al. Pharmacol Ther. 2010;126:82-93. 6. Weiner. J Neurol. 2008;255 S1:3–11. 7. Zhang et al. Mol Neurobiol. 2010;41:232-41. Proinflammatory Cytokines IL-1β IFN γ Activated T-cell CD4+ Activated Astrocytes Auto-reactive T-cell PERIPHERY INSIDE THE CNS Th1 Th2 B Demylination Axonal injury Macrophage/microglie activation Direct toxicity TNFα, IFN γ RO, NO Complement Mediated injury Actvated T-cell CD8+ Antibodies CLASSICAL VIEW OF MS PERIPHERAL T-CELL MEDIATED PATHWAY
- 5. Peripheral T-cell–mediated inflammation leads to focal lesions visible on conventional MRI MS AS A “TWO STAGES” DISEASE: Focal damages Reference: Bermel & Fox. MRI in multiple sclerosis. Continuum Lifelong Learning Neurol. 2010;16(5):37-57. T2 lesions: Acute and chronic demyelination Overall lesion burden Gadolinium-enhanced T1 lesions: Acute inflammation Blood-brain-barrier dysfunction Hypo-intense T1 lesions (black holes): Permanent axonal loss
- 6. MS AS A “TWO STAGES” DISEASE: Focal damages and disease progression Reference: Compston & Coles. Multiple Sclerosis. Lancet 2002;359:1221–31.
- 7. MS AS A “TWO STAGES” DISEASE: CLASSICAL VIEW DOES NOT FULLY EXPLAIN LONG TERM DISABILITY No or weak correlation between frequency of relapses and accumulation of irreversible disability 2,4. Reference: Shirani, et al. JAMA. 2012;308:247-256 Time to EDSS 6 Percentageofpatients
- 8. Dissociation between therapeutic effects on relapse frequency versus effect on disability progression 2,5. Once EDSS 4.0 reached, the rate of disability progression seems to be independant of the preceding disease course and unaffected by relapses during the progressive phase 4. References: 1. Scalfari, et al. Brain. 2010;133:1914-1929. 2. Shirani, et al. JAMA. 2012;308:247-256. 3. Confavreux & Vukusic. Brain. 2006. 4. Kurtzke, et al. Neurology; 1983;33:1444-52. 5. Confavreux et al., Clinical neurology and neurosurgery. 2006; 327-332 MS AS A “TWO STAGES” DISEASE: CLASSICAL VIEW DOES NOT FULLY EXPLAIN LONG TERM DISABILITY
- 9. References: 1. Zivadinov et al., J Neuroimaging 2005;15:10S-21S. 2. Kirov, et al. J Neurol Neurosurg Psychiatry. 2009;80(12): 1330-1336. Weak correlation between number of T1 Gd-enhanced lesions and long term disability. Modest correlation between T2 lesion load and disability progression Stronger relationship between brain atrophy and disability progression but: – Focal lesions occupy less than 3% of the total brain volume in MS patients – Total brain atrophy is weakly correlated to T2 lesion load Relapses / focal lesions are NOT sufficient predictors of long-term disability MS AS A “TWO STAGES” DISEASE: CLASSICAL VIEW DOES NOT FULLY EXPLAIN LONG TERM DISABILITY
- 10. MS as a “two stages” disease : classical view of MS pathology MS as a “two components” disease : emerging view of MS pathology Conclusions and perspectives OVERVIEW • Inflammation and focal damages • Focal damages and disease progression • Limitations of this model • Histopathological point of view • Two distinct pathways • Is neurodegeneration exist in early MS?
- 11. MS AS A “TWO COMPONENTS” DISEASE: Histopathological point of view Reference: Kutzelnigg et al., Brain 2005, 128, 2705–2712. Focal demyelinated plaques in WM Demyelinated lesions in cortex and deep GM Dark dots: diffuse inflammation in WM
- 12. There are two distinct pathways contributing to neurodegeneration and subsequent disability. Diffuse neurodegenerative processes are partially independent of the inflammatory immune response originating from the periphery1 Neurodegeneration is correlated with diffuse pathology1,3,4 Diffuse pathology – Occurs both in grey matter and in normal-appearing white matter (NAWM)5,6 – Predominant in PP-SPMS but begins in the early stages of MS – Plays an important in brain atrophy and long-term disability9-11 MS AS A “TWO COMPONENTS” DISEASE: Two distinct pathways References: 1. Charil & Filippi. J Neurol Sci. 2007;259:7-15. 2. Bo, et al. Mult. Scler. 2003;9:323–31. 3. De Stefano, et al. Neurology. 2010;74:1868. 4. Martola, et al. Neuroradiology. 2010;52:109-117. 5. Markiewicz & Lukomska. Acta Neurobiol Exp (Wars). 2006;66(4):343-358. 6. Cambron, et al. J Cereb Blood Flow Metab. 2012; 32:413-424. 7. De Stefano, et al. Arch Neurol. 2002;59:1565-1571. 8. Rovaris, et al. Brain. 2003;126:2323-2332. 9. Kirov, et al. J Neurol Neurosurg Psychiatry. 2009;80(12):1330-1336. 10. Li, et al. Neurology. 2006;66(9):1384-1389. 11. Fisher, et al. Neurology. 2002;59:1412-1420.
- 13. No BBB dysfunction, no peripheral inflammation1 Activation of astrocytes and microglia leading to pro-inflammatory cytokines production2,3 . Astrocyte activation appears prominently in normal appearing white matter2 MS AS A “TWO COMPONENTS” DISEASE Diffuse pathology References: 1. Trapp & Nave. Ann Rev Neurosci. 2008;31:247-269. 2. Filippi, et al. Lancet Neurol. 2012;11:349-360. 3. Markiewicz & Lukomska. Acta Neurobiol Exp (Wars). 2006;66(4):343-358. 4. Cambron, et al. J Cereb Blood Flow Metab. 2012; 32:413-424. 5. Sofroniew. Trends Neurosci. 2009;32(12):638-647. 6. Bjartmar, et al. Neurology. 2001;57:1248–1252. 7. Evangelou, et al. Ann Neurol. 2000;47:391-395. 8. Watzlawik, et al. Expert Rev Neurother. 2010;10:441–457. 9. Imitola, et al. Arch Neurol. 2006;63:25-33. 10. Nair, et al. Cell Mol Life Sci. 2008;65:2702–2720. Axonal density in normal-appearing white matter is decreased by 12% to 45% , which is partly explain by Wallerian degeneration after transection 2,6,7 Results in demyelination1,8, axonal loss1,8, glial scarring9,10 and loss of oligodendrocytes8, partly correlated with cortical lesions but not with T2 lesion load
- 14. References: 1. Lassmann. Curr Opin Neurol. 2008;1:242-7. 2. Markiewicz, et al. Acta Neurobiol Exp. 2006;66:343-58. 3. Nair, et al. Cell Mol Life Sci. 2008;65:2702-20. 4. Van der Walt, et al. Pharmacol Ther. 2010;126:82-93. 5. Weiner. J Neurol. 2008;255 S1:3–11. 6. Zhang, et al. Mol Neurobiol. 2010;41:232-41. THE CNS-RESIDENT-CELL PATHWAY Proinflammatory Cytokines Oligodendrocyte Oligodendrocyte Damage/Apoptosis Astrocyte Activated Astrocytes Myelin Residue AXONAL DAMAGE TNF-α, NO, O2 INSIDE THE CNS Degenerative Trigger Glial Scar Formation Activated Microglia
- 15. MS AS A “TWO COMPONENTS” DISEASE Is neurodegeneration exist in early MS? Reference: Lassman et al., Nature reviews Neurology, 2012; 8, 647-656. Focal lesions Peripheral T-cell mediated pathway Diffuse pathology CNS-resident-cells pathway
- 16. Brain atrophy measures Uniform longitudinal decrease in brain volume during short and long follow-up 1,2 Atrophy progression rate is very similar in the different MS subtypes1,2 MS AS A “TWO COMPONENTS” DISEASE Is neurodegeneration exist in early MS? References: 1. De Stefano, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010;74:1868. 2. Martola, et al. A longitudinal observational study of brain atrophy rate reflecting four decades of multiple sclerosis: a comparison of serial 1D, 2D, and volumetric measurements from MRI images. Neuroradiology. 2010;52:109-117.
- 17. Proton magnetic resonance spectroscopy • N-acetylaspartate (tNAA) is a surrogate marker for axonal integrity. • Myo-inositol (Ins) is a potential marker for increase of activity or number of glial and inflammatory cells, as well as migroglia activity. • Choline (Cho) et Creatine (Cr) may be accounted for an increase in cell turnover or metabolism, which might be expected to occur with inflammatory or glial reactive features CIS population • Reduce whole brain NAA in CIS with DIT criteria • Increased Ins and Cr in NAWM • Partly correlated to T2 lesion load References: 1. Charil et al., J Neurol Science, 2007; 259, 7-15. 2. Filippi et al., Brain, 2004; 126: 433-7. 3. Fernando et al., Brain, 2004; 127, 1361-9. MS AS A “TWO COMPONENTS” DISEASE Is neurodegeneration exist in early MS?
- 18. Magnetization transfer imaging Reduced MTR in NAWM occurs early in MS1 Reduced MTR in NAWM and NAGM in CIS patients2 • 6 months after CIS • Partly independent from T2 lesion load • More evident for patients who are known to have the highest risk of converting to CDM (those with T2 lesions and those who satisfy the McDonald criteria) Reference: 1. De Stefano, et al. Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch Neurol. 2002;59:1565-1571. 2. Fernando et al., Brain 2005; 128: 2911-25. MS AS A “TWO COMPONENTS” DISEASE Is neurodegeneration exist in early MS? Healthy controls RRMS patients 3 1 -1 -3 ZScore P<.001 RRMS patients with short disease duration (<3 years) P<.005 P<.05 RRMS patients with low volume (<2 cm3) of cerebral T2 lesions MTR
- 19. Diffusion Tensor Imaging Widespread pattern of significant reduction in FA value in NAWM: CIS vs HS1 Higher average NAWM MD, lower average NAWM FA: CIS vs HS2 MS AS A “TWO COMPONENTS” DISEASE Is neurodegeneration exist in early MS? References: 1. Raze et al., Radiology, 2010; 254:227-234. 2. Gallo et al., Arch Neuro, 2005; 62: 803-8
- 20. MS as a “two stages” disease : classical view of MS pathology MS as a “two components” disease : emerging view of MS pathology Conclusions and perspectives OVERVIEW • Inflammation and focal damages • Focal damages and disease progression • Limitations of this model • Histopathological point of view • Two distinct pathways • Is neurodegeneration exist in early MS?
- 21. Peripheral T-cell–mediated pathway Peripherally activated T cells enter the CNS Episodic relapses due to inflammation Visible by conventional MRI CONCLUSIONS: MS as a “two components” disease References: 1. Markiewicz et al. Acta Neurobiol Exp 2006;66:343-358. 2. Lassmann. Curr op in Neurol 2008;21:242-247. 3. Weiner. J Neurol 2008;255(S1):3-11. 4. Van der Walt et al. Pharmacol and Therapeutics 2010;126:82-93. 5. Stys et al. Nature Rev Neurosc 2012;13:507-514. CNS-resident-cell pathway Involving activated astrocytes and microglia, endogenous cells in CNS Results in demyelination and axonal loss, glial scar formation, loss of oligodendrocytes Detectable on non-conventional MRI Focal lesions (acute disability) Diffuse pathology (long-term disability) Both contribute to neurodegeneration ultimately leading to disability
Editor's Notes
- Traditionnellement, la sclérose en plaques est considérée comme une maladie AI qui se caractérise par l’accumulation de plaques inflammatoires démyélinisantes. Certaines de ces plaques peuvent être responsable de poussées clinique. Ces lésions sont associées à une infiltration massive de cellules et médiateurs du système immunitaire périphérique, responsable d’une démyélinisation et d’une dysfonction axonale, voire d’une transection axonale. Dans les SEP RR, le patient présente une rémission plus ou moins complète de la symptomatologie neurologique, à mettre en relation avec une remyélinisation partielle et une compensation de la perte axonale par les mécanismes de plasticité cérébrale. In Panel C (Luxol fast blue), a section of an acute lesion has an indistinct margin and numerous perivascular infiltrate. L’étendue de la remyélinisation (plaque fantome), depend de la survie des oligodendrocytes au niveau de la plaques, ainsi que de la présence de cellules précurseur et d’un mileu de croissance adéquat
- Astrocytes promote demyelination by enhancing the immune response - Astrocytes modulate remyelination by acting on both axon regeneration and oligodendrocyte progenitor cells (OPCs) Ajouter référence astrocytes
- L’IRM conventionnelle est un outils précieux dans le diagnostic et le suivi des patients sclérosés en plaques car elle permet de visualiser les lésions focales et d’en apprécier le degré d’inflammation. ON verra tout à l’heure quelle sont ses limitations.
- Dans le modèle physiopathologique actuel, l’atteinte inflammatoire est une caractéristiques prédominantes des stades précoces de la maladie. La progression clinique est elle la conséquence de l’ accumulation de dommages irréversibles (perte axonale et neuronale) secondaire à l’accumulation de lésions inflammatoires focales, à un échec des mécanismes de réparation et une perte de plasticité cérébrale. On a donc un modèle où la phase inflammatoire fait place à la phase neurodégénerative, l’une entrainant l’autre.
- Ce modèle classique ne permet toutefois pas d’expliquer parfaitement la progression du handicap. Les observations épidémilogiques montrent que
- Additional arguments are derived from the use of disease-modifying drugs. Treatment with β-interferons results in a 30% reduction of the relapse rate, and to a more than 50% reduction in conventional MRI activity. Despite this strong effect on inflammation, the influence of interferons on long term disability and brain atrophy is only marginal. The use of potent immunosuppressive agents has also proven to be instructive: Alemtuzumab; its use in MS patients with a high relapse rate, rapid accumulation of disability and high MRI activity resulted in a profound and prolonged lymphopenia, and the suppression of clinical and MRI activity, but clinical disability and cerebral atrophy still progressed [54]. Similar conclusions can be drawn from the use of mitoxantrone and cyclophosphamide as well as cladribine
- En conclusion ,les poussées et les lésions focales ne sont pas suffisante pour prédire la handicap à long terme, même si elle participe en partie au phénomène neurodégénératif observés. Pour les CIS, la charge lésionnelle est un prédicteur de la progression vers une SEP cliniquement définie
- La notion que la SEP est une maladie purement inflammatoire démyélinisante de la substance blanche est actuellement remise en question
- From the histopathological point of view, focal plaques of demyelination are present all three types of MS, but inflammation within the plaques and their rate of accumulation is higher in RRMS. SP-PPMS are characterized by a mild but diffuse inflammatory reaction in the normal appearing white matter (NAWM), which leads to progressive neurono-axonal degeneration. Moreover, we recently learnt that demyelination can occur in the cerebral cortex and deep GM. This is mainly observed in patients with progressive forms of the disease.
- Whether this reduction in axons is attributable to Wallerian degeneration after axonal tran sections in focal lesions or is an independent process has not been clarifi ed. defective axonal metabolism might be secondary to astrocyte dysfunction.
- Initial malfunction within the CNS Include innate immune system Où est le commencement? Trigger dégénératif ou trigger inflammatoire périphérique?
- Scan 1 et scan 2 à 14 mois d’intervalle. There was heterogeneity of PBVC/y (Percent brain volume change par année) across MS subtypes, with higher PBVC/y in SP patients than in patients with CIS. As expected, baseline NBV (Normalized Brain volume) was different across MS subtypes. Interestingly, when PBVC/y values were corrected for the baseline NBV, the heterogeneity of PBVC/y across MS subtypes disappeared (surtout évident quand on étude le volume au cours de courts intervalles de temps) problems interpreting results [12]. Several factors may affect atrophy evaluation in MS and opponent processes can be present at the same time. Brain volume reduction is caused by axonal loss, decrease of edema, resolution of inflammation, scarring, demyelination, dehydration, and normal aging [26]. On the contrary, brain volume increases can be caused by inflammation, edema, gliosis (tissue bulk), and remyelination [26].
- The application of non conventional MRI techniques to the study of patients with a CIS has enhanced the early neurogeneration. Proton magnetic resonance spectroscopy (1 H-MRS) is a non-invasive technique that enables the in vivo investigation of metabolic alterations associated with brain pathology, and provides a quantitative tool for investigating the abnormalities in the NAWM. La méthodologie est assez difficile est les résultats obtenus sont souvent difficilement reproductible. Toutefois, on peut dégager certains grands résultats.
- MT provides information about the magnetization exchange between protons in tissue water (relatively free) and those bound to macromolecules. Considering the fact that MT reflects mainly the macromolecular content of tissue, it is widely accepted that axon and myelin contribute to measured MT in the brain. The MT ratio reflect the efficiency of this exange. Low MTR values reflects a reduced capacity of macromolecules to exange magnetization with surrounding water molecules.
- Technique différentes, résulatts différents! TBSS voxelwhise, ROIs,… Therefore, we decided to restrict our analysis to the NAWM by removing from analysis all voxels in which at least 10% of the patient population had a lesion (based on the mean lesion mask). These regions are located in bilateral WM tracts, particularly in the corticospinal tracts, corpus callosum, superior longitudinal fasciculi, and inferior longitudinal fasciculi. The overlay of the signifi cant map clusters on the mean lesion mask shows that most of the abnormalities highlighted by TBSS were located in the NAWM and not merely within lesions.