Clinical Neurology and Neurosurgery 115S (2013) S30–S34
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Challenges in multiple sclerosis; how to define occurence of progression V.V. Brinar a,b,∗ , B. Barun c a b c
School of Medicine, University of Zagreb, Zagreb, Croatia Association for MS Research Zagreb, Zagreb, Croatia University Hospital Center Zagreb, Department of Neurology, Refferal Center for Demyelinating Diseases of the Central Nervous System, Zagreb, Croatia
a r t i c l e
i n f o
Keywords: Multiple sclerosis Pathology Natural history studies MRI in MS brain atrophy Therapy of MS
a b s t r a c t The challenges in MS are related to number of controversies in various aspects of disease but the relationship between relapses and disability progression, or aspects of MS as an inflammatory and/or neurodegenerative disease are extremely important because of its implications on prognosis and therapy of MS. MS was classically regarded as white matter inflammatory disease, while disability progression, brain and spinal cord atrophy were regarded as a consequence of global inflammation of NAWM and secondary involvement of grey matter. More recent histopathology studies, but also new, modern MRI techniques changed this view in MS as a prominent grey and white matter disease. Inflammatory demyelination of grey matter occurs early in MS sometimes even before occurrence of white matter lesions. Inspite of early therapy of MS with immunomodulatory drugs disability progression and neurodegeneration are still important and common part of MS pathogenesis. This indicate that treatment is not adequate to the predicted severity of MS, or perhaps to the basic pathogenetic mechanisms in MS. Beside acute clinical symptoms, conclusions about the severity of the disease are reflection of MRI sensitivity to detect focal WM lesions and insensitivity to detect grey matter lesions which correlate better with clinical symptoms. All presented studies and evaluations point to the necessity of changing the established diagnostic evaluation and treatment in MS. At the earliest stage of MS as well as in follow up of disease it would be necessary to apply a new MRI techniques more available for clinical practice such as DIR brain MR imaging at 3 T because of their sensitivity to detect grey matter lesions. In patient with present cortical lesions even in earliest stages of MS depending on severity of grey matter involvement more efficacious therapy like second or even third line therapy should start. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is inflammatory disease of the central nervous system (CNS), characterized in majority of patient with an unpredictable relapsing–remitting course (RRMS) subsequently leading on to secondary progressive disease (SPMS). Another less common type of multiple sclerosis is primary progressive (PPMS), with or without superimposed relapses characterized with progression from the onset of disease. Relapsing remitting MS is classically regarded as a biphasic disease with relapsing and potentially reversible phase that correlates with inflammatory demyelination, and secondary progressive irreversible phase, that correlates with critical axonal loss and progressive neurological deficit [1]. While relapsing remitting MS phase is characterized
∗ Corresponding author: Tel.: +385 146 14 713/+38598238084; fax: +385 146 14 713/+38512421891. E-mail address: [email protected] (V.V. Brinar). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.017
with clinically variable, heterogeneous manifestations, second phase has almost uniform and devastating clinical manifestation characterized with difficulties in walking [2].Many neuropathology and clinical studies tried to define the mutual relationship between inflammatory and progressive phases of MS. Based on such clinical studies it was shown that early relapses influence the long term disability in MS [3,4]. Other studies also showed that effect of relapses on long term disability do not diminished with the time [5]. Such clinical observations along with neuropathology rediscovery of extensive axonal injury in early acute and in active chronic MS lesions, and low injuries in inactive chronic lesions [6–10] in correlation with neuroimaging studies [11–14] led to the conclusion that axonal pathology in MS is a consequence of inflammation and demyelisation. This led to the concept of myelin related pathogenesis in multiple sclerosis. Epidemiological and natural history studies however showed some limitations of inflammatory influence on disability progression and challenge the concept of myelin related pathology. Dilemma whether MS is inflammatory or primary neurodegenerative disease has prompted numerous debates
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and studies that led to new insights and conclusions with important implications for the treatment of MS.
2. Myelin related concept of MS versus MS as a primary neurodegenerative disease 2.1. Some natural history studies showed limitations or even challenged the myelin related concept of MS Confavreux et al. [15] in natural history study of patients with relapsing remitting multiple sclerosis identified early predictors of disability progression in MS to disability status scale (DSS) 4,0. These early predictors were identified as age, gender, initial symptoms, degree of recovery from the first relapse, interrelapse interval, number of relapses, and time from onset to the second neurological episode. The authors emphasized, that these variables are not predictive for the subsequent disability progression after five years. Another important natural history study conducted by Kremenchutzky et al. [16] focused on progressive course of MS; SPMS PPMS and SAP (single attack progressive MS). It was found that between all three progressive features there was no difference in time to DSS 6,8,10, and that median age at the onset of progressive phase of disease was the same in secondary progressive and in primary or single attack progressive MS. The conclusion was that progressive course of the disease is independent from relapses, suggesting that multiple sclerosis may correspond to a chronic neurodegenerative age-related disease. Similar conclusions were presented by Confavreux and Vukusic [17,18] in their natural history study based on observation that median age at onset of progressive phase was similar in PPMS and SPMS patients. They concluded that multiple sclerosis appears to be at least to some extent, age depended disease not substantially affected by initial course. In 2009 Tremlett et al. [19] published results of their extensive study (they followed up 2477 RRMS pts during more than 20 years with 11,722 post onset relapses). The conclusion based on this study was that an early relapse within 5 year post onset is associated with an increased hazard in disease progression over short term. However, they found that long-term impact of relapses was minimal either for early or later relapses. Conclusion was that relapses occurring >10 years post onset only marginally increase the hazard reaching the EDSS 6 from that time point onward. Results of another two studies [20,21] also pointed to the independence of inflammatory and neurodegenerative phases of RRMS. Leray et al. [20] used data base that included MS patients (2054 pts) registered from 1976 (with average follow up of patients 13, ±9 years). Patients were divided into two phases. Phase 1 included patients with low neurologic deficit from clinical onset to irreversible clinical manifestations (DSS score from 0 to 3), while Phase 2 included patients with irreversible DSS 3 to irreversible DSS 6. Outcome was assessed with five parameters: (1) Phase 1 duration, (2) age at development of DSS 3 (3) time to development DSS 6 from multiple sclerosis onset (4) Phase 2 duration and (5) age at DSS 6. It was found that age at onset, gender, residual deficit after first relapse, relapses during first two years are independent predictors of disability progression to DSS 3 but, only in Phase 1. The results of this study indicated that disability progression during Phase 2 was independent of that during Phase 1, and that median Phase 2 duration was nearly identical from six to nine years irrespective of Phase 1 duration. The authors concluded that in multiple sclerosis disability progression follows two-stage processes, a first stage probably dependent on focal inflammation and second stage probably independent of current focal inflammation. Scalfari et al. [21] also analysed relationships between relapses and disability progression in MS on series of 806 patients with
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relapsing remitting onset multiple sclerosis from the London Ontario natural history cohort. The focus was on period prior to the onset of the progressive course of MS and on the development of high disability levels to DSS 6–8–10. The results of the study didn’t show relationship between relapse frequency for the patients entering the progressive phase of MS with the time to DSS 6, 8 or 10, nor confirm the importance of relapse location or polysymptomatic presentation, except that early relapse frequency and shorter first interattack interval does predict rapid clinical course. Indications that poor outcomes result from the relapse determined accumulation of disability was not found. Neither total number of relapses in RRMS, nor relapses after the second year of disease duration up to onset of progression were found to influence the probability of developing the secondary progressive phase of disease. Surprisingly they found that shorter latency to progressive phase of disease correlate with fewer relapses from year 3. They found that time to DSS 3 highly and independently predicted the time to DSS 6, 8, and 10.
3. MS is inflammatory or neurodegenerative disease? In interpretation of such epidemiologic results [21] specific neuropathology studies showing lack of correlation between demyelinating lesions and decreased axonal density in CNS in MS were indicated [22–27]. These studies have shown that in MS decreased axonal density and total axonal loss were evident in corticospinal and sensory tracts at all levels of neuroaxis, with significantly lower levels in cervical and upper thoracic parts for sensory tracts, particularly loss of small diameter fibers, comparing with healthy controls. However, substantial loss of axons was found in the areas apparently not affected by demyelination [22–27]. They concluded that inflammation induced demyelination doesn’t determine full extent to which axons are lost, as it was shown in MRI measures [21]. However, many other pathological studies showed that axonal injury developed at the disease onset and correlated with the degree of white matter inflammation [6–10]. Such clinical, pathological and MRI contraversies culminated in two opposite standing; on one side MS is inflammatory demyelinating disease characterized with relapsing–remitting phase progressing in neurodegenerative phase due to relapses; on the other side MS is primarily neurodegenerative disease, independent from inflammatory phase of disease [16–21]. Even the role of early relapses in development of secondary progressive MS was regarded as uncertain, although with explanation that early relapses may trigger a variant immune responses leading to more robust progressive phase. Therefore targeting early relapses in year 1 or 2 would have greater chance to impact the progressive phase of illness [21,28]. The standing that parceling out relapses into “they matter early,” but they “do not matter later” was on the other side regarded as a failure [29]. Such different views have caused numerous debates on basic pathogenesis of multiple sclerosis as an inflammatory or primarily neurodegenerative disorder [28–31].
4. How this dilemma was solved and what were the consequences? The fact that focal demyelinated plaques located in the CNS white matter in MS only partially correlate with neurological deficit and disease progression indicate necessity for some other pathological clarifications such as influence of diffuse injury of normal appearing white matter (NAWM), but also pointed out the importance of grey matter (GM) damage in the pathogenesis of MS [32–34].
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Diffuse injury of NAWM and cortical demyelination, the hallmark of primary and secondary progressive multiple sclerosis were extensively evaluated [32–34]. Although NAWM in MS is characterized with more or less decreased axonal density depending on analysed area it is still not clear whether this reduction in axons is caused by Wallerian degeneration after axonal transection in focal lesions or is an independent process [34,35]. Also it was shown that there is correlation between diffuse NAWM inflammation and extent of cortical lesion, but such correlation was not found between focal white matter lesion load [36]. Although demyelinating lesions were more or less occasionally observed in cerebral cortex in early pathology studies [37], MS was traditionally regarded as primarily white matter disease. Development of new immunohistochemical staining techniques enabled better detection of cortical grey matter pathology in MS [38–40]. Pathological studies showed that cortical GM lesions in MS may be very extensive especially in chronic phase of disease, but also that they may start early in and substantially affects clinico-cognitive functioning of MS patient [41,43]. It was shown that grey matter lesions correlate with irreversible disability, epilepsy and cognitive impairment [44,45]. It was shown that grey matter lesions are not only located in cerebral cortex, but also in deep brain grey matter structures (thalamus, hypothalamus, hippocampus, amygdala, putamen, pallidum, caudatum and substantia nigra), cerebellar cortex and in spinal cord [46–48]. Histopathology studies also have shown that cortical lesions in MS occur in remote areas not connected with white matter demyelinating lesions and without mutual anatomical relations [49]. Although significant neuronal and axonal pathology has been detected in GM MS lesions, inflammation was found to be less pronounced in grey matter than in WM lesions [50]. Grey matter lesions also differ from white matter lesions in rare disruption of blood brain barrier with leakage of plasma proteins, and complement deposition [51–53].The presence and extent of GM lesions has been correlated to meningeal inflammation, and also related to ectopic B cell follicle-like meningeal structures, with subpial and cortical grey matter demyelination [54,55]. Meningeal inflammation as a cause of subpial cortical damage was debated as one of possibilities that may have a prominent role in the pathogenesis of grey matter lesions [42,54–56]. Such clinical and neuropathology findings indicate the need to establish the fundamental dilemma—the pathogenesis of these grey matter lesions is primarily inflammatory or neurodegenerative? Extensive neuropathology study performed with a large number of biopsies showed that cortical demyelination is present and is also common in early MS, and showed inflammatory demyelination. By this they pointed out the important elements in the pathogenesis of grey matter damage in MS [57]. Dilemmas about the pathogenesis of grey matter lesions, whether they occur as a consequences of glutamatergic excitotoxic processes in white matter, disrupted intra-axonal transport or mitochondrial dysfunction that may led to dying-back axonopathy with secondary effect upon the cortex, or already mentioned meningeal inflammation [42,53,54] were solved with biopsied material showing that early cortical lesions are topographically associated with meningeal inflammation [57–59]. Based on such evaluation it was concluded that pathology of early cortical lesions is different from observed pathology in chronic MS. As early cortical lesions were highly inflammatory it suggested that neurodegeneration in MS occurs on an inflammatory background. This also indicated on importance of relationship between cortical demyelination and meningeal inflammation in initiating and perpetuing the disease process in early MS [57–59].
4.1. Role of MRI in detection of grey matter pathology in MS White matters MS lesion in MRI are presented as non-specific focal hyperintensities that resembles to many other types of inflammatory and non inflammatory pathology in CNS. However morphology and location of such focal hyperintensities, as well as postcontrast imbibition of specific lesions in T1 images are quite specific for MS [11–14,60]. Focal cortical lesions are not seen with conventional MRI because this techniques are not sensitive to lesions of grey matter, and if they are detected they present “the tip of the pathological iceberg” [61]. A correlative pathological and MRI studies have shown that T2 or FLAIR weight images detect only 3–5% of total 63 histopathologically proven lesions [62]. However development of new and advanced imaging techniques like magnetisation transfer (MTI), T1 relaxometry, proton magnetic resonance spectroscopy (MRS) are more sensitive not only to detect grey matter lesions but also abnormalities in normal appearing grey matter (NAGM) [63–65]. Introduction of double inversion recovery (DIR), MRI technique that provide good distinction between cerebral cortex and white matter specifically 3D-DIR, and using DIR techniques at higher field strength (3 T) significantly increased detection of intracortical lesion in MS, and confirmed histopathology studies reporting grey matter lesions already present in early phase of MS, even in clinically isolated syndromes (CIS) [66–68]. In longitudinal magnetic resonance imaging study it was shown that although cortical lesions are present already in early, they a more frequent in chronic MS, with relative cortical sparing in benign MS, as it was shown in pathology study [69,70]. Introduction of more advanced techniques, new pulse sequences and (ultra) high-field strength has been proven to be even more advantageous in the visualization of cortical lesions, allowing identification of GM damage location in correlation with pathological findings [71–75]. MRI studies in non-cortical GM damages mostly focus on thalamus because of its extensive reciprocal connections with cortex and subcortical structures, which makes thalamus specifically sensitive to pathological changes. Reduction in thalamic fraction was more pronounced in relapsing remitting compared to SPMS, and similar was found in a longitudinal thalamic study indicating that neural damage in thalamus occurs early in disease course [70,76,77]. 4.2. Brain atrophy Regional brain atrophy and cortical thinning were shown to be reliable measures and important features of MS pathology, with possible contribution of various pathological substrates [6]. NAWM atrophy most probably indicate diffuse axonal loss caused by Wallerian degeneration of axons damaged by focal plaques in white matter, although axonal loss maybe also independent of focal lesions [36].Grey matter atrophy probably occurs because of neuronal and glial loss [78]. Occurrence of cortical thinning apart from demyelinating lesions where neuronal loss is sparse or absent most probably indicate reduction of synaptic density as a consequence of neuronal connectivity impairment [6,78]. It was shown that although both white and grey matter demyelination are present from the earliest phases of disease, development of GM atrophy correlate more strongly with disability and cognitive impairment than WM atrophy [35,70,79,80]. That grey matter atrophy occurs already in early MS even in clinically isolated syndrome (CIS) was shown in several longitudinal studies in patients with CIS. Decrease in grey matter fractional volume (GMF) was significantly larger in patients who in three year developed MS than in remaining CIS group [81]. No decrease in white matter fractional volumes (WMF) was seen, as it was also reported in other study comparing the development of atrophy between white and grey matter [82]. GMF changes correlate only modestly with the change in T2 lesion volume from baseline to
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year 3 suggesting that progressive grey matter, and not white matter atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis [80–82]. Extensive grey and white matter involvement in multiple sclerosis point to conclusion that MS is an pan demyelinating or pan-degenerative disease, probably caused by an auto-immune inflammatory demyelinating process, although findings of axonal pathology without demyelination and examples of oligodendrocyte and myelin degeneration without immune response may point to the other mechanisms in pathogenesis of multiple sclerosis [36,83]. However, whether the development of brain atrophy may be prevented and stop the progression of the disease is the main issue [84,85]. Inhibition of CNS injury, thereby preventing neurological and cognitive disability is the key goal of the therapy. As measures of whole and grey matter atrophy may provide assessment of that goal there is necessity to move from research to treatment monitoring in order to identify the most effective preventive treatment already in early phase of MS [84,85]. 5. Conclusion Summing up all relevant clinical, neuropathological and MR studies, multiple sclerosis is an inflammatory demyelinating disease of the white and grey matter of CNS. Inflammatory demyelination of grey matter occurs early in MS sometimes even before occurrence of white matter lesions and play a key role in the progression of disability and cognitive impairment. It is important to emphasize that degenerative changes in multiple sclerosis differ in early and secondary stages of the disease. While early stage is associated with acute neuronal damage caused by inflammation which is in some way different in white and in grey matter, later stage develops from secondary neurodegeneration, consequent to the diffuse inflammation of the normal appearing white and grey matter, and probably mainly occurs by Wallerian degeneration. Based on these insights, results of epidemiologic studies are quite understandable, showing that clinical symptoms due to relapses and T2 lesion load in MRI only partially correlate with development of permanent disability, but not because MS is primarily neurodegenerative disease. MS is inflammatory demyelinating disease, but severity of grey matter involvement, mostly hidden by the use of conventional MRI, influence the progressive development of neurodegeneration already in earlier phases of MS. The fact that existing immunomodulatory treatment is not efficacious enough to stop disability progression in MS, indicate that initiation of treatment is too late, too mild or does not correspond to the basic pathogenesis of the disease. Current knowledge on the pathogenesis of multiple sclerosis indicate the need to change established diagnostic evaluation with new MRI techniques which may prove damaging of grey matter in early phase of MS and are more available for clinical practice e.g. DIR brain MR imaging at 3 T and/or others. In patient with present cortical lesions even in earliest stages of MS depending on severity of grey matter involvement more efficacious therapy of second or even third line should start immediately. Author’s contribution Study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and administrative, technical and material support was performed by Brinar and Barun. Conflict of interest statement There is no conflict of interest.
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References [1] Compston A, Coles A. Multiple sclerosis. Lancet 2008;25(372):1502–17. [2] Lassmann H, van Horssen J. The molecular basis of neurodegeneration in multiple sclerosis. FEBS Lett 2011;585:3715–23. [3] Weinschenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study I. Clinical course and disability. Brain 1989;112:133–46. [4] Weinschenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study.2. Predictive value of the early clinical course. Brain 1989;112:133–46. [5] Lublin FD, Baier M, Cutter G. Effect of relapse on development of residual deficit in multiple sclerosis. Neurology 2003;61:1528–32. [6] Trapp BD, Peterson J, Ransohoff RM, Rudick R, et al. Axonal transectionin the lesion of multiple sclerosis. N Engl J Med 1998;338:278–85. [7] Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 1999;12:295–302 . Review. [8] Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393–9. [9] Evangelou N, Konz D, Esiri MM, et al. Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 2000;123:1845–9. [10] Kuhlmann T, Lingfeld G, Bitsch A, et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002;125(Pt 10):2202–12. [11] Filippi M, Paty DW, Kappos L, et al. Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study. Neurology 1995;45(2):255–60. Feb. [12] Filippi M. Non-conventional MR techniques in monitoring MS activity and evolution. Electroencephalogr Clin Neurophysiol Suppl 1999;50:565–9. Review. [13] Filippi M, Bozzali M, Rovaris M. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 2003;126:433–7. [14] Katz D, Taubenberger JK, Cannella B, et al. Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 1993;34:661–9. [15] Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability: an amnestic process. Brain 2003;126(Pt 4): 770–82. [16] Kremenchutzky M, Rice GPA, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of disease. Brain 2006;129:584–94. [17] Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006 a;129:606–16. [18] Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain 2006 b;129:595–605. [19] Tremlett H, Yousefi M, Devonshire V, et al. Impact of multiple sclerosis on progression diminished with time. Neurology 2009;73:1616–23. [20] Leray E, Yaouanq J, Le Page E, et al. Brain 2010;133:1900–13. [21] Scalfari A, Neuhaus A, Degenhardt A, et al. Brain 2010;133:1914–29. [22] Wujek JR, Bjartmar C, Richer E, et al. Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J Neuropathol Exp Neurol 2002;61(1):23–32. [23] Lovas G, Szilágyi N, Majtényi K, et al. Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 2000;123:308–17. Feb. [24] Bjatmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of disease. J Neurol Sci 2003;15(206):165–71. [25] Evangelou N, DeLuca GC, Owens T, et al. Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions. Brain 2005;128:29. [26] DeLuca GC, Ebers GC, Esiri MM. Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain 2004;127:1009–18. [27] DeLuca GC, Williams K, Evangelou N, et al. The contribution of demyelination to axonal loss in multiple sclerosis. Brain 2006;129:1507–16. [28] Casserly C, Ebers G. Relapses do not matter in relation to long-term disability: yes. MSJ 2011;17(12):1412–4. [29] Lublin FD. Relapses do not matter inrelation to long-term disability: no (they do). MSJ 2011;17(12):1415–6. [30] Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008;31:247–69. [31] Lassmann H. Multiple sclerosis: is there neurodegeneration independent frinflammation? J Neurol Sci 2007;259:3–6. [32] Allen IV, McKeown SR. A histochemical and biochemical study of macroscopically normal white matter in multiple sclerosis. J Neurol Sci 1979;41, 81-81. [33] Bjartmar C, Kinkel RP, Kidd G, et al. Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 2001;57:1248–52. [34] Evangelou N, Esiri MM, Smith S, et al. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 2000;47:391–5. [35] Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705–12. [36] Seewann A, Vrenken H, van der Valk P. Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis. Arch Neurol 2009;66:601–9.
S34
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[37] Sobel RA, Moore GW. In: Love S, Louis DN, Ellison DW, editors. Demyelinating diseases in Greenfield’s neuropathology, 2, 8th ed. Oxford: University Press; 2008. p. 1608–5013. [38] Brownell B, Hughes JT. The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry 1962;25:315–20. [39] Kid D, Barkhof B, McConnell R, et al. Cortical lesions in multiple sclerosis. Brain 1999;122:7–26. [40] Peterson JW, Bo L, Mork S, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389–400. [41] Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol 2008;7(9):841–51. [42] Bo I, Vedeler CA, Nyland HL, et al. Subpial demyelination in cerebral cortex of multiple sclerosis patients. J Neuropath Exp Neurol 2003;62: 723–32. [43] Vercellino M, Plano F, et VottaB, et al. Gray matter pathology in multiple sclerosis. J Neuropath Exp Neurol 2005;64:1101–7. [44] Spat J, ChaixR, Mamoli B. Epileptic and non-epileptic seizures in multiple sclerosis. J Neurol 2001;248:2–9. [45] Amato MP, BartolozziMI, Zipoli V, et al. Neocortical volume decrease in relapsing remitting MS patients with mild cognitive impairment. Neurology 2004;63:89–93. [46] Kutzelnigg A, Faber-Rod JC, Bauer J, et al. Widespread demyelination in cerebellar cortex in multiple sclerosis. Brain Pathol 2007;17:38–44. [47] Gilmore CP, Donaldson I, Bo L, et al. Regional variations in the extent and pattern of grey matter demyelination in multiple sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter and spinal cord. J Neurol Neurosurg Psychiatry 2009;80(2):182–7. [48] Gilmore CP, DeLuca GC, Bö L. Spinal cord neuronal pathology in multiple sclerosis. Brain Pathol 2009;19(4):642–9. [49] Bö L, Geurts JJ, van der Valk P, et al. Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis. Arch Neurol J 2007;64(1):76–80. [50] Bø L, Vedeler CA, Nyland H, et al. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 2003;9(4):323–31. [51] Brink BP, Veerhuis R, Breij EC, et al. The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J Neuropath Exp Neurol 2005;64:147–55. [52] Van Horsen J, Brink BP, de Vries HE, et al. The blood brain barrier in multiple sclerosis lesions. J Neuropathol Exp Neurol 2007;66:321–8. [53] Lassmann H. A dynamic view of the blood brain barrier in active multiple sclerosis lesions. Ann Neurol 2011;70:1–2. [54] Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007;130:1089–104. [55] Howell OW, Reeves CA, Nicholas R, Carassiti D. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011;134(Pt 9):2755–71. [56] Kooi EJ, Geurts JJ, van Horssen J, et al. Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J Neuropathol Exp Neurol 2009;68(9):1021–8. [57] Lucchinetti C, Popescu F, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011;365(23):2188–97. [58] Popescu B, Bunyan R, Parisi J, et al. A case of multiple sclerosis presenting with inflammatory cortical demyelination. Neurology 2011;76:1705–10. [59] Popescu B, Lucchinetti C. Menigeal and cortical grey matter pathology in multiple sclerosis. BMC Neurol 2012;12:1–8. [60] Cotton F, Weiner HL, Jolesz FA, et al. MRI contrast uptake in new lesions in relapsing–remitting MS followed at weekly intervals. Neurology 2003:606064–146. [61] Seewann A, Vrenken H, Kooi DL, et al. Imaging the tip of the iceberg;visualisation of cortical lesions in multiple sclerosis. Mult Scler 2011.
[62] Geurts JJ, Bo L, Powels P, et al. Cortical lesions in multiple sclerosis presenting combined postmorten MR imaging and histopathology. AJNR—Am J Neurorad 2007;26:572–7. [63] Cercignani M, Bozzali M, Iannucci G, et al. Magnetisation transfer ratio and mean diffusity of normal appearing white and grey matter from patients with multiple sclerosis. J Neurol Neurosurg Psichiatry 2001;70:311–7. [64] Vrenken H, Geurts JJ, Knol DI, et al. Whole brain T1 mapping in multiple sclerosis:global changes of normal-appearing gray and white matter. Radiology 2006;240:811–20. [65] Geurts JJ, Reuling IE, Vrenken H, et al. MR spectroscopic evidence for thalamic and hippocampal but not cortical damage in multiple sclerosis. Magn Reson Med 2006;55:478–83. [66] Simon B, Schmidt S, Lukas C, et al. Improved in vivo detection of cortical lesions in multiple sclerosis using double inversion recovery MR imaging at 3 Tesla. Eur Radiol 2010;20:1675–80. [67] Birgit S, Stephan S, Carsten L, et al. Improved in vivo detection of cortical lesions in multiple sclerosis using double inversion recovery MR imaging at 3 Telsa. Eur Radiol 2010;20(7):1675–80. July. [68] Calabrese M, Fillipi M, Gallo P. Cortical lesions in multiple sclerosis. Nat Rev Neurol 2010;6:438–44. [69] Calabrese M, Fillipi M, Rovaris M, et al. Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study. Mult Scler 2009;15:36–41. [70] Fisher E, Lee JC, Nakamura K, et al. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64:255–65. [71] Mainero CC, Benner T, Radding A, et al. In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI. Neurology 2009;73:941–8. [72] Filippi M, Rocca MA, Horsfield MA. Imaging cortical damage and dysfunction in multiple sclerosis. JAMA Neurol 2013 May;70(5):556–64. [73] Kilsdonk ID, de Graaf WL, Soriano AL, et al. Multicontrast MR imaging at 7 T in multiple sclerosis: highest lesion detection in cortical gray matter with 3DFLAIR. AJNR Am J Neuroradiol 2013;34(4):791–6. [74] Hannoun S, Durand-Dubief F, Confavreux C. Diffusion tensor-MRI evidence for extra-axonal neuronal degeneration in caudate and thalamic nuclei of patients with multiple sclerosis. AJNR Am J Neuroradiol 2012;33(7):1363–8. [75] Hulst HE, Geurts J. Gray matter imaging in multiple sclerosis: what have we learned? BMC Neurol 2011;11:153. [76] Cifelli A, ArridgeM, Jezzard P, et al. Thalamic neurodegeneration in multiple sclerosis. Ann Neurol 2002;53:650–3. [77] Zivadinov R, Bergsland N, Dolezal O. Evolution of cortical and thalamus atrophy and disability progression in early relapsing–remitting MS during 5 years. AJNR—Am J Neuroradiol 2013. [78] Wegner C, Esiri MM, Chance SA. Neocortical, neuronal, synaptic and glial loss in multiple sclerosis. Neurology 2006;67:960–7. [79] Miller DH, Barhof F, Frank JA, et al. Measurement of atrophy in multiple sclerosis; pathological basis, methodological aspets and clinical relevance. Brain 2002;125:1676–95. [80] Geurts JJ, Calabrese M, Fisher E. Measurement and clinical effect of grey matter pathology in multiple sclerosis. Lancet Neurol 2012. [81] Dalton CM, Chardt DT, Davies GR, et al. Early development of multiple asclerosis is associated with progressive gray matter atrophy in patients presenting with clinically isolated syndrome. Brain 2004;127:1101–10. [82] Raz E, Cercignani M, Sbardella E. Gray and white matter changes after 1 year after first clinical episode of multiple sclerosis. Radiology 2010:257448–53. [83] Geurts JJ. The neurologist’s dilemma: MS is a grey matter disease that standard clinical and MRI measures cannot assess adequately: yes. Mult Scler 2012;May 18(5):559–60. [84] Rudick RA, Fisher E. Preventing brain atrophy should be the gold standard of effective therapy in MS (after the first year of treatment): yes. Mult Scler 2013;19(8):1003–4. Jul. [85] Filippi M, Rocca M. Preventing brain atrophy should be the gold standard of effective theraphy in MS (after the first year of treatment): no. Mult Scler 2013;19(8):1005–6. Jul.
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Challenges in multiple sclerosis; how to define occurence of progression V.V. Brinar a,b,∗ , B. Barun c a b c
School of Medicine, University of Zagreb, Zagreb, Croatia Association for MS Research Zagreb, Zagreb, Croatia University Hospital Center Zagreb, Department of Neurology, Refferal Center for Demyelinating Diseases of the Central Nervous System, Zagreb, Croatia
a r t i c l e
i n f o
Keywords: Multiple sclerosis Pathology Natural history studies MRI in MS brain atrophy Therapy of MS
a b s t r a c t The challenges in MS are related to number of controversies in various aspects of disease but the relationship between relapses and disability progression, or aspects of MS as an inflammatory and/or neurodegenerative disease are extremely important because of its implications on prognosis and therapy of MS. MS was classically regarded as white matter inflammatory disease, while disability progression, brain and spinal cord atrophy were regarded as a consequence of global inflammation of NAWM and secondary involvement of grey matter. More recent histopathology studies, but also new, modern MRI techniques changed this view in MS as a prominent grey and white matter disease. Inflammatory demyelination of grey matter occurs early in MS sometimes even before occurrence of white matter lesions. Inspite of early therapy of MS with immunomodulatory drugs disability progression and neurodegeneration are still important and common part of MS pathogenesis. This indicate that treatment is not adequate to the predicted severity of MS, or perhaps to the basic pathogenetic mechanisms in MS. Beside acute clinical symptoms, conclusions about the severity of the disease are reflection of MRI sensitivity to detect focal WM lesions and insensitivity to detect grey matter lesions which correlate better with clinical symptoms. All presented studies and evaluations point to the necessity of changing the established diagnostic evaluation and treatment in MS. At the earliest stage of MS as well as in follow up of disease it would be necessary to apply a new MRI techniques more available for clinical practice such as DIR brain MR imaging at 3 T because of their sensitivity to detect grey matter lesions. In patient with present cortical lesions even in earliest stages of MS depending on severity of grey matter involvement more efficacious therapy like second or even third line therapy should start. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is inflammatory disease of the central nervous system (CNS), characterized in majority of patient with an unpredictable relapsing–remitting course (RRMS) subsequently leading on to secondary progressive disease (SPMS). Another less common type of multiple sclerosis is primary progressive (PPMS), with or without superimposed relapses characterized with progression from the onset of disease. Relapsing remitting MS is classically regarded as a biphasic disease with relapsing and potentially reversible phase that correlates with inflammatory demyelination, and secondary progressive irreversible phase, that correlates with critical axonal loss and progressive neurological deficit [1]. While relapsing remitting MS phase is characterized
∗ Corresponding author: Tel.: +385 146 14 713/+38598238084; fax: +385 146 14 713/+38512421891. E-mail address: [email protected] (V.V. Brinar). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.017
with clinically variable, heterogeneous manifestations, second phase has almost uniform and devastating clinical manifestation characterized with difficulties in walking [2].Many neuropathology and clinical studies tried to define the mutual relationship between inflammatory and progressive phases of MS. Based on such clinical studies it was shown that early relapses influence the long term disability in MS [3,4]. Other studies also showed that effect of relapses on long term disability do not diminished with the time [5]. Such clinical observations along with neuropathology rediscovery of extensive axonal injury in early acute and in active chronic MS lesions, and low injuries in inactive chronic lesions [6–10] in correlation with neuroimaging studies [11–14] led to the conclusion that axonal pathology in MS is a consequence of inflammation and demyelisation. This led to the concept of myelin related pathogenesis in multiple sclerosis. Epidemiological and natural history studies however showed some limitations of inflammatory influence on disability progression and challenge the concept of myelin related pathology. Dilemma whether MS is inflammatory or primary neurodegenerative disease has prompted numerous debates
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and studies that led to new insights and conclusions with important implications for the treatment of MS.
2. Myelin related concept of MS versus MS as a primary neurodegenerative disease 2.1. Some natural history studies showed limitations or even challenged the myelin related concept of MS Confavreux et al. [15] in natural history study of patients with relapsing remitting multiple sclerosis identified early predictors of disability progression in MS to disability status scale (DSS) 4,0. These early predictors were identified as age, gender, initial symptoms, degree of recovery from the first relapse, interrelapse interval, number of relapses, and time from onset to the second neurological episode. The authors emphasized, that these variables are not predictive for the subsequent disability progression after five years. Another important natural history study conducted by Kremenchutzky et al. [16] focused on progressive course of MS; SPMS PPMS and SAP (single attack progressive MS). It was found that between all three progressive features there was no difference in time to DSS 6,8,10, and that median age at the onset of progressive phase of disease was the same in secondary progressive and in primary or single attack progressive MS. The conclusion was that progressive course of the disease is independent from relapses, suggesting that multiple sclerosis may correspond to a chronic neurodegenerative age-related disease. Similar conclusions were presented by Confavreux and Vukusic [17,18] in their natural history study based on observation that median age at onset of progressive phase was similar in PPMS and SPMS patients. They concluded that multiple sclerosis appears to be at least to some extent, age depended disease not substantially affected by initial course. In 2009 Tremlett et al. [19] published results of their extensive study (they followed up 2477 RRMS pts during more than 20 years with 11,722 post onset relapses). The conclusion based on this study was that an early relapse within 5 year post onset is associated with an increased hazard in disease progression over short term. However, they found that long-term impact of relapses was minimal either for early or later relapses. Conclusion was that relapses occurring >10 years post onset only marginally increase the hazard reaching the EDSS 6 from that time point onward. Results of another two studies [20,21] also pointed to the independence of inflammatory and neurodegenerative phases of RRMS. Leray et al. [20] used data base that included MS patients (2054 pts) registered from 1976 (with average follow up of patients 13, ±9 years). Patients were divided into two phases. Phase 1 included patients with low neurologic deficit from clinical onset to irreversible clinical manifestations (DSS score from 0 to 3), while Phase 2 included patients with irreversible DSS 3 to irreversible DSS 6. Outcome was assessed with five parameters: (1) Phase 1 duration, (2) age at development of DSS 3 (3) time to development DSS 6 from multiple sclerosis onset (4) Phase 2 duration and (5) age at DSS 6. It was found that age at onset, gender, residual deficit after first relapse, relapses during first two years are independent predictors of disability progression to DSS 3 but, only in Phase 1. The results of this study indicated that disability progression during Phase 2 was independent of that during Phase 1, and that median Phase 2 duration was nearly identical from six to nine years irrespective of Phase 1 duration. The authors concluded that in multiple sclerosis disability progression follows two-stage processes, a first stage probably dependent on focal inflammation and second stage probably independent of current focal inflammation. Scalfari et al. [21] also analysed relationships between relapses and disability progression in MS on series of 806 patients with
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relapsing remitting onset multiple sclerosis from the London Ontario natural history cohort. The focus was on period prior to the onset of the progressive course of MS and on the development of high disability levels to DSS 6–8–10. The results of the study didn’t show relationship between relapse frequency for the patients entering the progressive phase of MS with the time to DSS 6, 8 or 10, nor confirm the importance of relapse location or polysymptomatic presentation, except that early relapse frequency and shorter first interattack interval does predict rapid clinical course. Indications that poor outcomes result from the relapse determined accumulation of disability was not found. Neither total number of relapses in RRMS, nor relapses after the second year of disease duration up to onset of progression were found to influence the probability of developing the secondary progressive phase of disease. Surprisingly they found that shorter latency to progressive phase of disease correlate with fewer relapses from year 3. They found that time to DSS 3 highly and independently predicted the time to DSS 6, 8, and 10.
3. MS is inflammatory or neurodegenerative disease? In interpretation of such epidemiologic results [21] specific neuropathology studies showing lack of correlation between demyelinating lesions and decreased axonal density in CNS in MS were indicated [22–27]. These studies have shown that in MS decreased axonal density and total axonal loss were evident in corticospinal and sensory tracts at all levels of neuroaxis, with significantly lower levels in cervical and upper thoracic parts for sensory tracts, particularly loss of small diameter fibers, comparing with healthy controls. However, substantial loss of axons was found in the areas apparently not affected by demyelination [22–27]. They concluded that inflammation induced demyelination doesn’t determine full extent to which axons are lost, as it was shown in MRI measures [21]. However, many other pathological studies showed that axonal injury developed at the disease onset and correlated with the degree of white matter inflammation [6–10]. Such clinical, pathological and MRI contraversies culminated in two opposite standing; on one side MS is inflammatory demyelinating disease characterized with relapsing–remitting phase progressing in neurodegenerative phase due to relapses; on the other side MS is primarily neurodegenerative disease, independent from inflammatory phase of disease [16–21]. Even the role of early relapses in development of secondary progressive MS was regarded as uncertain, although with explanation that early relapses may trigger a variant immune responses leading to more robust progressive phase. Therefore targeting early relapses in year 1 or 2 would have greater chance to impact the progressive phase of illness [21,28]. The standing that parceling out relapses into “they matter early,” but they “do not matter later” was on the other side regarded as a failure [29]. Such different views have caused numerous debates on basic pathogenesis of multiple sclerosis as an inflammatory or primarily neurodegenerative disorder [28–31].
4. How this dilemma was solved and what were the consequences? The fact that focal demyelinated plaques located in the CNS white matter in MS only partially correlate with neurological deficit and disease progression indicate necessity for some other pathological clarifications such as influence of diffuse injury of normal appearing white matter (NAWM), but also pointed out the importance of grey matter (GM) damage in the pathogenesis of MS [32–34].
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Diffuse injury of NAWM and cortical demyelination, the hallmark of primary and secondary progressive multiple sclerosis were extensively evaluated [32–34]. Although NAWM in MS is characterized with more or less decreased axonal density depending on analysed area it is still not clear whether this reduction in axons is caused by Wallerian degeneration after axonal transection in focal lesions or is an independent process [34,35]. Also it was shown that there is correlation between diffuse NAWM inflammation and extent of cortical lesion, but such correlation was not found between focal white matter lesion load [36]. Although demyelinating lesions were more or less occasionally observed in cerebral cortex in early pathology studies [37], MS was traditionally regarded as primarily white matter disease. Development of new immunohistochemical staining techniques enabled better detection of cortical grey matter pathology in MS [38–40]. Pathological studies showed that cortical GM lesions in MS may be very extensive especially in chronic phase of disease, but also that they may start early in and substantially affects clinico-cognitive functioning of MS patient [41,43]. It was shown that grey matter lesions correlate with irreversible disability, epilepsy and cognitive impairment [44,45]. It was shown that grey matter lesions are not only located in cerebral cortex, but also in deep brain grey matter structures (thalamus, hypothalamus, hippocampus, amygdala, putamen, pallidum, caudatum and substantia nigra), cerebellar cortex and in spinal cord [46–48]. Histopathology studies also have shown that cortical lesions in MS occur in remote areas not connected with white matter demyelinating lesions and without mutual anatomical relations [49]. Although significant neuronal and axonal pathology has been detected in GM MS lesions, inflammation was found to be less pronounced in grey matter than in WM lesions [50]. Grey matter lesions also differ from white matter lesions in rare disruption of blood brain barrier with leakage of plasma proteins, and complement deposition [51–53].The presence and extent of GM lesions has been correlated to meningeal inflammation, and also related to ectopic B cell follicle-like meningeal structures, with subpial and cortical grey matter demyelination [54,55]. Meningeal inflammation as a cause of subpial cortical damage was debated as one of possibilities that may have a prominent role in the pathogenesis of grey matter lesions [42,54–56]. Such clinical and neuropathology findings indicate the need to establish the fundamental dilemma—the pathogenesis of these grey matter lesions is primarily inflammatory or neurodegenerative? Extensive neuropathology study performed with a large number of biopsies showed that cortical demyelination is present and is also common in early MS, and showed inflammatory demyelination. By this they pointed out the important elements in the pathogenesis of grey matter damage in MS [57]. Dilemmas about the pathogenesis of grey matter lesions, whether they occur as a consequences of glutamatergic excitotoxic processes in white matter, disrupted intra-axonal transport or mitochondrial dysfunction that may led to dying-back axonopathy with secondary effect upon the cortex, or already mentioned meningeal inflammation [42,53,54] were solved with biopsied material showing that early cortical lesions are topographically associated with meningeal inflammation [57–59]. Based on such evaluation it was concluded that pathology of early cortical lesions is different from observed pathology in chronic MS. As early cortical lesions were highly inflammatory it suggested that neurodegeneration in MS occurs on an inflammatory background. This also indicated on importance of relationship between cortical demyelination and meningeal inflammation in initiating and perpetuing the disease process in early MS [57–59].
4.1. Role of MRI in detection of grey matter pathology in MS White matters MS lesion in MRI are presented as non-specific focal hyperintensities that resembles to many other types of inflammatory and non inflammatory pathology in CNS. However morphology and location of such focal hyperintensities, as well as postcontrast imbibition of specific lesions in T1 images are quite specific for MS [11–14,60]. Focal cortical lesions are not seen with conventional MRI because this techniques are not sensitive to lesions of grey matter, and if they are detected they present “the tip of the pathological iceberg” [61]. A correlative pathological and MRI studies have shown that T2 or FLAIR weight images detect only 3–5% of total 63 histopathologically proven lesions [62]. However development of new and advanced imaging techniques like magnetisation transfer (MTI), T1 relaxometry, proton magnetic resonance spectroscopy (MRS) are more sensitive not only to detect grey matter lesions but also abnormalities in normal appearing grey matter (NAGM) [63–65]. Introduction of double inversion recovery (DIR), MRI technique that provide good distinction between cerebral cortex and white matter specifically 3D-DIR, and using DIR techniques at higher field strength (3 T) significantly increased detection of intracortical lesion in MS, and confirmed histopathology studies reporting grey matter lesions already present in early phase of MS, even in clinically isolated syndromes (CIS) [66–68]. In longitudinal magnetic resonance imaging study it was shown that although cortical lesions are present already in early, they a more frequent in chronic MS, with relative cortical sparing in benign MS, as it was shown in pathology study [69,70]. Introduction of more advanced techniques, new pulse sequences and (ultra) high-field strength has been proven to be even more advantageous in the visualization of cortical lesions, allowing identification of GM damage location in correlation with pathological findings [71–75]. MRI studies in non-cortical GM damages mostly focus on thalamus because of its extensive reciprocal connections with cortex and subcortical structures, which makes thalamus specifically sensitive to pathological changes. Reduction in thalamic fraction was more pronounced in relapsing remitting compared to SPMS, and similar was found in a longitudinal thalamic study indicating that neural damage in thalamus occurs early in disease course [70,76,77]. 4.2. Brain atrophy Regional brain atrophy and cortical thinning were shown to be reliable measures and important features of MS pathology, with possible contribution of various pathological substrates [6]. NAWM atrophy most probably indicate diffuse axonal loss caused by Wallerian degeneration of axons damaged by focal plaques in white matter, although axonal loss maybe also independent of focal lesions [36].Grey matter atrophy probably occurs because of neuronal and glial loss [78]. Occurrence of cortical thinning apart from demyelinating lesions where neuronal loss is sparse or absent most probably indicate reduction of synaptic density as a consequence of neuronal connectivity impairment [6,78]. It was shown that although both white and grey matter demyelination are present from the earliest phases of disease, development of GM atrophy correlate more strongly with disability and cognitive impairment than WM atrophy [35,70,79,80]. That grey matter atrophy occurs already in early MS even in clinically isolated syndrome (CIS) was shown in several longitudinal studies in patients with CIS. Decrease in grey matter fractional volume (GMF) was significantly larger in patients who in three year developed MS than in remaining CIS group [81]. No decrease in white matter fractional volumes (WMF) was seen, as it was also reported in other study comparing the development of atrophy between white and grey matter [82]. GMF changes correlate only modestly with the change in T2 lesion volume from baseline to
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year 3 suggesting that progressive grey matter, and not white matter atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis [80–82]. Extensive grey and white matter involvement in multiple sclerosis point to conclusion that MS is an pan demyelinating or pan-degenerative disease, probably caused by an auto-immune inflammatory demyelinating process, although findings of axonal pathology without demyelination and examples of oligodendrocyte and myelin degeneration without immune response may point to the other mechanisms in pathogenesis of multiple sclerosis [36,83]. However, whether the development of brain atrophy may be prevented and stop the progression of the disease is the main issue [84,85]. Inhibition of CNS injury, thereby preventing neurological and cognitive disability is the key goal of the therapy. As measures of whole and grey matter atrophy may provide assessment of that goal there is necessity to move from research to treatment monitoring in order to identify the most effective preventive treatment already in early phase of MS [84,85]. 5. Conclusion Summing up all relevant clinical, neuropathological and MR studies, multiple sclerosis is an inflammatory demyelinating disease of the white and grey matter of CNS. Inflammatory demyelination of grey matter occurs early in MS sometimes even before occurrence of white matter lesions and play a key role in the progression of disability and cognitive impairment. It is important to emphasize that degenerative changes in multiple sclerosis differ in early and secondary stages of the disease. While early stage is associated with acute neuronal damage caused by inflammation which is in some way different in white and in grey matter, later stage develops from secondary neurodegeneration, consequent to the diffuse inflammation of the normal appearing white and grey matter, and probably mainly occurs by Wallerian degeneration. Based on these insights, results of epidemiologic studies are quite understandable, showing that clinical symptoms due to relapses and T2 lesion load in MRI only partially correlate with development of permanent disability, but not because MS is primarily neurodegenerative disease. MS is inflammatory demyelinating disease, but severity of grey matter involvement, mostly hidden by the use of conventional MRI, influence the progressive development of neurodegeneration already in earlier phases of MS. The fact that existing immunomodulatory treatment is not efficacious enough to stop disability progression in MS, indicate that initiation of treatment is too late, too mild or does not correspond to the basic pathogenesis of the disease. Current knowledge on the pathogenesis of multiple sclerosis indicate the need to change established diagnostic evaluation with new MRI techniques which may prove damaging of grey matter in early phase of MS and are more available for clinical practice e.g. DIR brain MR imaging at 3 T and/or others. In patient with present cortical lesions even in earliest stages of MS depending on severity of grey matter involvement more efficacious therapy of second or even third line should start immediately. Author’s contribution Study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and administrative, technical and material support was performed by Brinar and Barun. Conflict of interest statement There is no conflict of interest.
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References [1] Compston A, Coles A. Multiple sclerosis. Lancet 2008;25(372):1502–17. [2] Lassmann H, van Horssen J. The molecular basis of neurodegeneration in multiple sclerosis. FEBS Lett 2011;585:3715–23. [3] Weinschenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study I. Clinical course and disability. Brain 1989;112:133–46. [4] Weinschenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study.2. Predictive value of the early clinical course. Brain 1989;112:133–46. [5] Lublin FD, Baier M, Cutter G. Effect of relapse on development of residual deficit in multiple sclerosis. Neurology 2003;61:1528–32. [6] Trapp BD, Peterson J, Ransohoff RM, Rudick R, et al. Axonal transectionin the lesion of multiple sclerosis. N Engl J Med 1998;338:278–85. [7] Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 1999;12:295–302 . Review. [8] Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393–9. [9] Evangelou N, Konz D, Esiri MM, et al. Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 2000;123:1845–9. [10] Kuhlmann T, Lingfeld G, Bitsch A, et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002;125(Pt 10):2202–12. [11] Filippi M, Paty DW, Kappos L, et al. Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study. Neurology 1995;45(2):255–60. Feb. [12] Filippi M. Non-conventional MR techniques in monitoring MS activity and evolution. Electroencephalogr Clin Neurophysiol Suppl 1999;50:565–9. Review. [13] Filippi M, Bozzali M, Rovaris M. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 2003;126:433–7. [14] Katz D, Taubenberger JK, Cannella B, et al. Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 1993;34:661–9. [15] Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability: an amnestic process. Brain 2003;126(Pt 4): 770–82. [16] Kremenchutzky M, Rice GPA, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of disease. Brain 2006;129:584–94. [17] Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006 a;129:606–16. [18] Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain 2006 b;129:595–605. [19] Tremlett H, Yousefi M, Devonshire V, et al. Impact of multiple sclerosis on progression diminished with time. Neurology 2009;73:1616–23. [20] Leray E, Yaouanq J, Le Page E, et al. Brain 2010;133:1900–13. [21] Scalfari A, Neuhaus A, Degenhardt A, et al. Brain 2010;133:1914–29. [22] Wujek JR, Bjartmar C, Richer E, et al. Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J Neuropathol Exp Neurol 2002;61(1):23–32. [23] Lovas G, Szilágyi N, Majtényi K, et al. Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 2000;123:308–17. Feb. [24] Bjatmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of disease. J Neurol Sci 2003;15(206):165–71. [25] Evangelou N, DeLuca GC, Owens T, et al. Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions. Brain 2005;128:29. [26] DeLuca GC, Ebers GC, Esiri MM. Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain 2004;127:1009–18. [27] DeLuca GC, Williams K, Evangelou N, et al. The contribution of demyelination to axonal loss in multiple sclerosis. Brain 2006;129:1507–16. [28] Casserly C, Ebers G. Relapses do not matter in relation to long-term disability: yes. MSJ 2011;17(12):1412–4. [29] Lublin FD. Relapses do not matter inrelation to long-term disability: no (they do). MSJ 2011;17(12):1415–6. [30] Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008;31:247–69. [31] Lassmann H. Multiple sclerosis: is there neurodegeneration independent frinflammation? J Neurol Sci 2007;259:3–6. [32] Allen IV, McKeown SR. A histochemical and biochemical study of macroscopically normal white matter in multiple sclerosis. J Neurol Sci 1979;41, 81-81. [33] Bjartmar C, Kinkel RP, Kidd G, et al. Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 2001;57:1248–52. [34] Evangelou N, Esiri MM, Smith S, et al. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 2000;47:391–5. [35] Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705–12. [36] Seewann A, Vrenken H, van der Valk P. Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis. Arch Neurol 2009;66:601–9.
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[37] Sobel RA, Moore GW. In: Love S, Louis DN, Ellison DW, editors. Demyelinating diseases in Greenfield’s neuropathology, 2, 8th ed. Oxford: University Press; 2008. p. 1608–5013. [38] Brownell B, Hughes JT. The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry 1962;25:315–20. [39] Kid D, Barkhof B, McConnell R, et al. Cortical lesions in multiple sclerosis. Brain 1999;122:7–26. [40] Peterson JW, Bo L, Mork S, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389–400. [41] Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol 2008;7(9):841–51. [42] Bo I, Vedeler CA, Nyland HL, et al. Subpial demyelination in cerebral cortex of multiple sclerosis patients. J Neuropath Exp Neurol 2003;62: 723–32. [43] Vercellino M, Plano F, et VottaB, et al. Gray matter pathology in multiple sclerosis. J Neuropath Exp Neurol 2005;64:1101–7. [44] Spat J, ChaixR, Mamoli B. Epileptic and non-epileptic seizures in multiple sclerosis. J Neurol 2001;248:2–9. [45] Amato MP, BartolozziMI, Zipoli V, et al. Neocortical volume decrease in relapsing remitting MS patients with mild cognitive impairment. Neurology 2004;63:89–93. [46] Kutzelnigg A, Faber-Rod JC, Bauer J, et al. Widespread demyelination in cerebellar cortex in multiple sclerosis. Brain Pathol 2007;17:38–44. [47] Gilmore CP, Donaldson I, Bo L, et al. Regional variations in the extent and pattern of grey matter demyelination in multiple sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter and spinal cord. J Neurol Neurosurg Psychiatry 2009;80(2):182–7. [48] Gilmore CP, DeLuca GC, Bö L. Spinal cord neuronal pathology in multiple sclerosis. Brain Pathol 2009;19(4):642–9. [49] Bö L, Geurts JJ, van der Valk P, et al. Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis. Arch Neurol J 2007;64(1):76–80. [50] Bø L, Vedeler CA, Nyland H, et al. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 2003;9(4):323–31. [51] Brink BP, Veerhuis R, Breij EC, et al. The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J Neuropath Exp Neurol 2005;64:147–55. [52] Van Horsen J, Brink BP, de Vries HE, et al. The blood brain barrier in multiple sclerosis lesions. J Neuropathol Exp Neurol 2007;66:321–8. [53] Lassmann H. A dynamic view of the blood brain barrier in active multiple sclerosis lesions. Ann Neurol 2011;70:1–2. [54] Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007;130:1089–104. [55] Howell OW, Reeves CA, Nicholas R, Carassiti D. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011;134(Pt 9):2755–71. [56] Kooi EJ, Geurts JJ, van Horssen J, et al. Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J Neuropathol Exp Neurol 2009;68(9):1021–8. [57] Lucchinetti C, Popescu F, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011;365(23):2188–97. [58] Popescu B, Bunyan R, Parisi J, et al. A case of multiple sclerosis presenting with inflammatory cortical demyelination. Neurology 2011;76:1705–10. [59] Popescu B, Lucchinetti C. Menigeal and cortical grey matter pathology in multiple sclerosis. BMC Neurol 2012;12:1–8. [60] Cotton F, Weiner HL, Jolesz FA, et al. MRI contrast uptake in new lesions in relapsing–remitting MS followed at weekly intervals. Neurology 2003:606064–146. [61] Seewann A, Vrenken H, Kooi DL, et al. Imaging the tip of the iceberg;visualisation of cortical lesions in multiple sclerosis. Mult Scler 2011.
[62] Geurts JJ, Bo L, Powels P, et al. Cortical lesions in multiple sclerosis presenting combined postmorten MR imaging and histopathology. AJNR—Am J Neurorad 2007;26:572–7. [63] Cercignani M, Bozzali M, Iannucci G, et al. Magnetisation transfer ratio and mean diffusity of normal appearing white and grey matter from patients with multiple sclerosis. J Neurol Neurosurg Psichiatry 2001;70:311–7. [64] Vrenken H, Geurts JJ, Knol DI, et al. Whole brain T1 mapping in multiple sclerosis:global changes of normal-appearing gray and white matter. Radiology 2006;240:811–20. [65] Geurts JJ, Reuling IE, Vrenken H, et al. MR spectroscopic evidence for thalamic and hippocampal but not cortical damage in multiple sclerosis. Magn Reson Med 2006;55:478–83. [66] Simon B, Schmidt S, Lukas C, et al. Improved in vivo detection of cortical lesions in multiple sclerosis using double inversion recovery MR imaging at 3 Tesla. Eur Radiol 2010;20:1675–80. [67] Birgit S, Stephan S, Carsten L, et al. Improved in vivo detection of cortical lesions in multiple sclerosis using double inversion recovery MR imaging at 3 Telsa. Eur Radiol 2010;20(7):1675–80. July. [68] Calabrese M, Fillipi M, Gallo P. Cortical lesions in multiple sclerosis. Nat Rev Neurol 2010;6:438–44. [69] Calabrese M, Fillipi M, Rovaris M, et al. Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study. Mult Scler 2009;15:36–41. [70] Fisher E, Lee JC, Nakamura K, et al. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64:255–65. [71] Mainero CC, Benner T, Radding A, et al. In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI. Neurology 2009;73:941–8. [72] Filippi M, Rocca MA, Horsfield MA. Imaging cortical damage and dysfunction in multiple sclerosis. JAMA Neurol 2013 May;70(5):556–64. [73] Kilsdonk ID, de Graaf WL, Soriano AL, et al. Multicontrast MR imaging at 7 T in multiple sclerosis: highest lesion detection in cortical gray matter with 3DFLAIR. AJNR Am J Neuroradiol 2013;34(4):791–6. [74] Hannoun S, Durand-Dubief F, Confavreux C. Diffusion tensor-MRI evidence for extra-axonal neuronal degeneration in caudate and thalamic nuclei of patients with multiple sclerosis. AJNR Am J Neuroradiol 2012;33(7):1363–8. [75] Hulst HE, Geurts J. Gray matter imaging in multiple sclerosis: what have we learned? BMC Neurol 2011;11:153. [76] Cifelli A, ArridgeM, Jezzard P, et al. Thalamic neurodegeneration in multiple sclerosis. Ann Neurol 2002;53:650–3. [77] Zivadinov R, Bergsland N, Dolezal O. Evolution of cortical and thalamus atrophy and disability progression in early relapsing–remitting MS during 5 years. AJNR—Am J Neuroradiol 2013. [78] Wegner C, Esiri MM, Chance SA. Neocortical, neuronal, synaptic and glial loss in multiple sclerosis. Neurology 2006;67:960–7. [79] Miller DH, Barhof F, Frank JA, et al. Measurement of atrophy in multiple sclerosis; pathological basis, methodological aspets and clinical relevance. Brain 2002;125:1676–95. [80] Geurts JJ, Calabrese M, Fisher E. Measurement and clinical effect of grey matter pathology in multiple sclerosis. Lancet Neurol 2012. [81] Dalton CM, Chardt DT, Davies GR, et al. Early development of multiple asclerosis is associated with progressive gray matter atrophy in patients presenting with clinically isolated syndrome. Brain 2004;127:1101–10. [82] Raz E, Cercignani M, Sbardella E. Gray and white matter changes after 1 year after first clinical episode of multiple sclerosis. Radiology 2010:257448–53. [83] Geurts JJ. The neurologist’s dilemma: MS is a grey matter disease that standard clinical and MRI measures cannot assess adequately: yes. Mult Scler 2012;May 18(5):559–60. [84] Rudick RA, Fisher E. Preventing brain atrophy should be the gold standard of effective therapy in MS (after the first year of treatment): yes. Mult Scler 2013;19(8):1003–4. Jul. [85] Filippi M, Rocca M. Preventing brain atrophy should be the gold standard of effective theraphy in MS (after the first year of treatment): no. Mult Scler 2013;19(8):1005–6. Jul.
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