|
|
| View previous topic :: View next topic |
| Author |
Message |
agate
Site Admin
Joined: 17 May 2006
Posts: 5694
Location: Oregon
|
 Posted: Wed Feb 20, 2013 12:18 pm Post subject: Controversies in MS: Do RRMS & PPMS have the same cause? |
 |
|
Under the heading "Controversies in MS," two neuropathologists give their views about whether RRMS and PPMS have the same cause, followed by a commentary by a consultant neuropathologist. Actually, they are also discussing SPMS.
From Multiple Sclerosis Journal, February 20, 2013 [references omitted]:
| Quote: |
Relapsing–remitting and primary progressive MS have the same cause(s) – the neuropathologist’s view: 1
Hans Lassmann
Medical University of Vienna, Austria
Hans Lassmann, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Wien, Austria. Email: hans.lassmann@meduniwien.ac.at
Multiple sclerosis (MS) presents with different clinical manifestations, including acute MS, relapsing–remitting (RRMS), secondary progressive (SPMS) and primary progressive MS (PPMS). The clinical manifestations in these different forms of MS as well as the response to anti-inflammatory treatment of patients vary profoundly, and therefore the question has been proposed whether the cause and disease mechanisms are the same or differ between patient subgroups or stages of the disease. However, the pathology of the disease in the different forms does not support this concept.
The pathology of MS is defined by a spectrum of tissue alterations in the central nervous system. This includes plaques of primary demyelination and astrocytic scar formation in the white and gray matter that when active arise around inflamed veins. In addition diffuse inflammation, microglia activation, axonal and neuronal loss and reactive gliosis affect the normal-appearing white and gray matter. These changes finally result in profound tissue loss, reflected by brain atrophy. All these features are essential criteria for the pathological diagnosis of MS and are, thus, seen in all patients, irrespective of their clinical course. However, their extent and relative contribution to the global pathology seen in a given MS patient is variable, and this variability in quantitative terms also reflects different clinical disease courses.1
Inflammation is a key element of MS pathology. Inflammatory infiltrates mainly consist of T-lymphocytes and a much lower number of B-cells and plasma cells. Activation of microglia cells and macrophages is associated with active demyelination and neurodegeneration. The inflammatory reaction is most intense in patients at early disease stages and declines with patient age and disease duration.2 Thus, in comparison to early (acute or RR) MS, the extent of inflammation is lower in patients with secondary progressive MS (SPMS) and even lower in PPMS.3 However, active demyelination and neurodegeneration is invariably associated with inflammation. In patients in whom inflammation has declined to levels seen in age-matched controls, active demyelination is absent and axonal injury too has declined to levels seen in the respective controls.2 Furthermore, persistent meningeal inflammation is associated with active demyelination and neurodegeneration in the cortex not only in the early stages of MS,4 but also in patients with SPMS or PPMS.5,6 The inflammatory response in part is fuelled by a new influx of inflammatory cells from the circulation, and this process is associated with blood-brain barrier injury, reflected by gadolinium (Gd)-enhancement in magnetic resonance imaging (MRI). Part of the inflammatory response, however, occurs in the brain parenchyme and around blood vessels in the absence of blood-brain barrier disruption.7 While inflammation, which is associated with blood-brain barrier damage, is mainly present in patients with acute and RRMS, it becomes rare in patients who have entered the progressive phase of the disease.
The opposite is seen with inflammation, which is compartmentalized behind a normal (repaired) blood-brain barrier. This is more pronounced in patients with progressive compared to those with early MS. A similar shift is also seen in the quantitative relation of different types of tissue injury between early relapsing and late progressive MS.8 New focal white matter lesions are frequent in the early stages of MS, but become rare in patients with progressive disease. In contrast, slowly expanding focal white matter lesions, the number and size of cortical lesions and the extent of diffuse injury in the normal-appearing white and gray matter increase with age and disease duration. Thus, the differences in the pathology between RRMS, SPMS and PPMS are of quantitative, but not of qualitative nature.
Recent data suggest that oxidative injury and subsequent mitochondrial damage may play an important role in driving demyelination and neurodegeneration in the MS brain.9 Oxidative injury can be induced by inflammation, resulting in oxdidative burst, and can further be amplified by various mechanisms that are related to brain aging and preexisting neurodegeneration.
Thus, it is proposed that MS starts with the invasion of inflammatory cells from the peripheral immune system, which results in tissue injury through different immunological mechanisms, including the induction of oxidative burst in microglia and macrophages. With increasing disease duration, the intensity of this inflammatory response declines.
Thus, in the progressive stage of the disease inflammation and microglia activation is still required for the propagation of demyelination and neurodegeneration, but it becomes amplified by additional mechanisms related to brain aging and the accumulation of brain damage. Potential amplification factors are an age-dependent decrease of neuroprotective or repair mechanisms and age-dependent iron accumulation in the human brain, which is released from oligodendrocytes within active lesions and may amplify oxidative injury.
In addition, accumulation of brain damage may lead to chronic microglia activation through anterograde or retrograde neurodegeneration as well as to further amplification of mitochondrial injury.10 Thus it is likely that the threshold of the central nervous system for neurodegeneration becomes lower with increasing age and disease duration compared to that seen at early disease stages. This together with the compartmentalization of the inflammatory response within the brain may explain the lack of success of anti-inflammatory treatment in patients with progressive MS. On the basis of this concept, the differences between RRMS and PPMS may be related to a shift in the balance between inflammation and the susceptibility of the nervous tissue for neurodegeneration, but not to essential differences in pathogenetic mechanisms.
Conflict of interest: None declared.
Funding:
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors
|
| Quote: |
Relapsing–remitting and primary progressive MS have the same cause(s)- the neuropathologist’s view: 2
Tanja Kuhlmann
Institute of Neuropathology, University Hospital Münster, Germany
Tanja Kuhlmann, Institute of Neuropathology, University Hospital Münster, Domagkstr. 19, 48149 Münster, Germany. Email: tanja.kuhlmann@ukmuenster.de
Multiple sclerosis (MS) is a heterogeneous disease with respect to clinical symptoms, neuroradiological findings and treatment responses. The obvious differences in disease courses between patients led to the classification of MS as either relapsing–remitting (RRMS), secondary progressive (SPMS) or primary progressive MS (PPMS). The majority of patients starts with a relapsing–remitting disease course characterized by acute exacerbation followed by partial or total recovery; whereas PPMS is associated with a continuous worsening of symptoms and is only observed in about 10–15% of the patients. However, even the clinical presentation does not always allow clear separation between RRMS or PPMS, since some MS patients start with a progressive disease course after a single or few relapses or suffer from a progressive disease from the beginning superimposed by few relapses. The subsequent rate of disease progression is comparable in SPMS and PPMS and is not affected by relapses as soon as a certain Expanded Disability Status Scale (EDSS) score is reached.1 Only about 50% of siblings with MS show an identical disease course. The recently identified susceptibility genes, each of which each contributes less than 1% of disease risk, are comparably distributed in RRMS and PPMS.2 These epidemiological findings suggest that the different disease courses represent different ends of a disease spectrum rather than different diseases or disease etiologies. This point of view is supported by histopathological and imaging studies that describe quantitative rather than qualitative differences between different clinical courses. Although no fundamental differences have been identified between patients with either RRMS/SPMS or PPMS, this does not mean that the same pathomechansims are responsible for clinical symptoms in all MS patients. The histopathological hallmarks of MS change with disease duration. Whereas the development of new focal inflammatory demyelinating lesions in grey and white matter dominate the pathology at the beginning of the disease, the progressive disease phase is characterized by diffuse white matter abnormalities, accumulation of axonal loss in demyelinated as well as normal-appearing white matter and limited remyelination.
The relapses are believed to be the consequences of focal inflammatory lesions whereas recovery may be induced by resolution of inflammation and edema, increased plasticity and endogenous repair mechanisms such as remyelination. RRMS patients develop numerous contrast-enhancing lesions which presumably represent actively demyelinating lesions and the number of newly developing lesions decrease with disease duration.3
This point of view is supported by histological studies which demonstrate a higher number of actively demyelinating lesions in RRMS than in SPMS.
Patients with PPMS also develop contrast-enhancing lesions and this is associated with a more rapid progression of disease.4 Not surprisingly, actively demyelinating lesions can also be found in patients with PPMS.3 These highly inflammatory lesions, observed in the early disease stages, are heterogeneous with respect to composition of inflammation and extent of initial oligodendroglial cell death, suggesting that different pathomechanisms may lead to demyelination. However, these different histological patterns described by Lucchinetti et al. are not predictive for the clinical disease course.5 Due to the accumulation of new lesions, the extent of demyelination increases with disease duration: histopathological and imaging studies show that patients with PPMS tend to have comparable lesion loads to RRMS or SPMS patients but that the lesions tend to have formed over much longer intervals.3,6
Demyelination is not limited to the white matter, it is also observed in the cortex and other grey matter areas, even in early disease stages.7 Similarly to white matter, the lesion load of grey matter increases over time and is associated with inflammation that decreases in SPMS.3 Meningeal inflammation is also present in PPMS and a greater degree of meningeal inflammation is associated with more extensive cortical demyelination as well as neuronal pathology in this patient cohort.8 In the progressive disease phase the pathology shifts from the formation of new focal lesions to diffuse pathological changes in the periplaque white and gray matter. These diffuse changes include sparse perivascular T-cell infiltrates, microglial activation, mild demyelination and minor ongoing acute axonal damage, and these changes are present in comparable levels in PPMS as well as in SPMS.3 Interestingly, the extent of diffuse white matter abnormalities correlated with cortical but not white matter lesion load. This is in line with a recent combined magnetic resonance imaging (MRI) and histopathological study which found a correlation between diffuse neurodegeneration within distinct thalamo-cortical tracts suggesting that anatomical connections influences the spread of pathological changes via Wallerian or trans-synaptic degeneration.9,10 Extent of axonal loss in corticospinal tracts is comparable in patients with PPMS and SPMS11 and acute axonal damage as a measure for recent axonal injury is similar in lesions from patients with either RRMS, SPMS and PPMS when lesions with comparable demyelinating and inflammatory activity were analyzed.12
In summary, RRMS/SPMS and PPMS share many similarities; the observed differences are more of a quantitative rather than a qualitative difference, most likely modulated by individual genetic predisposition and environmental influences. The vast majority of epidemiological, imaging or histopathological studies do not provide evidence for fundamentally different causes of RRMS/SPMS or PPMS. The lack of treatment responsiveness of SPMS or PPMS to immunosuppressive or immunomodulatory agents together with imaging and histopathological findings indicates that neurodegeneration instead of inflammation dominates the disease process in the progressive disease phase. The identification of the yet unknown pathways responsible for the lack of remyelination and accumulation of axonal injury and loss and underlying clinical progression are prerequisite for the development of new treatment options.
Funding:
TK is funded by the German Research Foundation and the Interdisciplinary Clinical Research Center in Münster.
Conflicts of interest:
TK has received honoraria from Novartis, Sanofi-Aventis, Bayer-Schering, Merck Serono and Teva.
|
| Quote: |
Relapsing–remitting and primary progressive MS have the same cause(s) - the neuropathologist’s view: Commentary
Michael Farrell
Consultant Neuropathologist, Beaumont Hospital, Dublin 9, Ireland
Dr. Michael Farrell, Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland Email: michaelfarrell@beaumont.ie
Both MS experts have stood by the view that any differences between primary progressive multiple sclerosis (PPMS) and relapsing remitting - secondary progressive sclerosis (RRMS-SPMS) are attributable to variations in degrees of inflammation, demyelination and axonal loss. Accepting that the cause[s] of MS is [are] unknown, it would have been surprising had either neuropathologist adopted a view contrary to classic teaching on MS pathology i.e. an orderly sequence of events beginning with inflammation which results in demyelination and which in some individuals leads to unusually early axonal degeneration with clinical disease progression – so called PPMS.
Had the editor challenged the experts neuropathologists to account for differences between progressive-onset and relapsing-onset MS the task might have been a little more difficult. Progressive-onset MS with little evidence of blood-brain barrier disruption and scanty evidence of active hemispheric white matter demyelination, but in which critically located spinal pathology is frequently encountered, defies many of the explanations for progression in MS. Such patients are difficult to diagnose as MS and of course in a few instances may have aquaporin-4 related disease.
Both experts agree that these patients may have ongoing diffuse white matter inflammation occurring inside an intact blood-brain barrier i.e. so-called compartmentalised inflammation. The problem with compartmentalised inflammation is that it is difficult to demonstrate both radiologically and pathologically. Nevertheless it remains an attractive explanation for tract specific neurodegeneration that may well underpin PPMS. It also provides an escape mechanism for the supporters of inflammation-driven neurodegeneration who will argue that the occurrence of inflammation behind the closed blood-brain barrier is reason enough to explain the poor response of PPMS patients to immunomodulatory therapy i.e. the inflammatory process is hidden and inaccessible. But perhaps inflammation behind closed doors has a different trigger - it ought to have if the blood brain barrier is firmly closed!
There is increasing recognition that low-grade on-going inflammation in NAWM is a major contributor to axonal loss. So-called NAWM may in fact be diffusely abnormal [DAWM] and there is emerging evidence that DAWM may underpin significant neurodegeneration in MS. Some have gone further to suggest that DAWM represents ongoing white matter inflammation which has been triggered by the presence of a primary lipid abnormality in normal white matter i.e. the myelin was never completely normal!1
Any additional role played by ageing in MS-related neurodegeneration and progression remains to be determined but it is notable SPMS and PPMS tend to occur at roughly the same older age and thereafter to run the same clinical course. If both SPMS and PPMS have the same pathologic basis then it must be argued that PPMS patients have had ongoing chronic “below the radar” subclinical inflammation occurring diffusely throughout white matter prior to onset of progressive symptoms. But as indicated this type of inflammation may be different [from] the classical inflammation in MS.
It is the view of this non-expert neuropathologist that progression in MS may occur independently of radiologically visible lesion load and independently of classic peripheral T-cell-dependent macrophage mediated demyelination developing instead as a consequence of central microglial mediated axonal destruction that may in part be triggered by diffuse white matter lipid abnormalities.
Over time this alternative pathway in MS pathology may be recognised as separate from and different to the classic MS inflammatory pathway and perhaps more akin to that seen in a progressive neurodegenerative disorder such as PPMS!
|
|
|
| Back to top |
|
 |
|
|
You can post new topics in this forum
You can reply to topics in this forum
You can edit your posts in this forum
You can delete your posts in this forum
You cannot vote in polls in this forum
|
|
|
