Scientific Commentary |
Establishing preconditions for Baló's concentric sclerosis
Concentric sclerosis is a rare variant of multiple sclerosis, first described by Baló in 1928 (Baló, 1928
). It is characterized by the development of alternating bands of demyelinated and myelinated white matter, forming concentric rings or irregular stripes. In an affected patient these lesions are usually multiple but may be admixed with other, typical plaques. Although often a feature of rapidly progressive disease, Baló's sclerosis is not always fatal and can also occur in chronic multiple sclerosis, as has been well demonstrated by the use of MRI (Bolay et al., 1996; Karaarslan et al., 2001).
The pathogenesis of this histologically striking form of demyelination has long been a puzzle. Although in some cases the bands of myelinated white matter include remyelinated fibres (Moore et al., 1985), the myelin sheaths within the bands are mostly of normal thickness, indicating that they have been preserved from demyelination rather than being a product of remyelination (Moore et al., 2001). There is some loss of oligodendrocytes, but much less so in the preserved white matter than in the intervening bands of demyelination. Similarly, mRNA levels for myelin-related proteins are lowest in demyelinated areas, intermediate in the preserved bands, and highest in the normal-appearing white matter away from the lesions (Yao et al., 1994).
In previous studies of multiple sclerosis, Lassman and colleagues found that the oligodendrocytes in some plaques had similar abnormalities to those produced by ischaemia (Aboul-Enein et al., 2003; Lassmann, 2003). In these so-called type III plaques, oligodendrocytes showed nuclear expression of hypoxia-inducible factor-1
and loss of myelin-associated glycoprotein despite relative preservation of other myelin proteins, such as proteolipid protein and myelin oligodendrocyte glycoprotein. Oligodendrocyte degeneration had morphological features of apoptosis. Within the lesions there was also strong expression of D-110 [a still incompletely characterized epitope that is abundant in white matter after ischaemic injury (Lassmann et al., 2003)].
In the present issue of Brain, the same group draws together these previous findings and some novel observations on autopsy-derived tissue from 14 patients with Baló's sclerosis to propose an explanation for the intriguing pattern of demyelination in this variant of multiple sclerosis (Stadelmann et al., 2005). The authors found that the demyelinated bands of white matter had immunohistochemical features of type III plaques and were associated with the presence of inducible nitric oxide synthase (iNOS) in macrophages and microglia, whereas oligodendrocytes in the preserved white matter expressed hypoxia inducible factor-1 (HIF-1) and heat shock protein 70 (hsp 70). Both HIF-1 and hsp 70 are up-regulated in response to ischaemia and play key roles in ischaemic preconditioning and the induction of tolerance to ischaemia (Liu et al., 1992; Sharp et al., 2001; Sharp et al., 2004; Yang and Lin, 1999). Stadelmann and colleagues propose that the lesions of Baló's sclerosis develop because inflammatory demyelination causes protective preconditioning of oligodendrocytes in a band of im-mediately adjacent white matter, which is therefore preserved from demyelination as the inflammatory process spreads outwards until it reaches the next region with oligodendrocytes that are still susceptible (Stadelmann et al., 2005).
It would probably be wrong to conclude that demyelination in Baló's sclerosis or other type III lesions is ischaemic. The pattern of lesions is not compatible with damage from lack of blood supply. Indeed, concentric sclerosis is sometimes centred on (patent) blood vessels. However, several lines of evidence suggest the involvement of oxidative stress in the development of this type of demyelination. Reactive oxygen and nitrogen species have been shown to be present in actively demyelinating lesions in multiple sclerosis (Oleszak et al., 1998; Smith et al., 1999), and oligodendrocytes are known to be susceptible to glutamate-induced oxidative injury and oxygen-glucose deprivation (Rosin et al., 2004). The presence of abundant iNOS within macrophages and microglia is in keeping with local production of nitric oxide (NO) in the bands of demyelination. These cells are likely to be crucial for the protective preconditioning of adjacent white matter, through the release of mediators of oxidative stress, such as NO (Cho et al., 2005), which stabilizes HIF-1 (Zhou and Brune, 2005; Zhou et al., 2004), and superoxide, which together with NO and other mediators of oxidative stress, causes mitochondrial damage and induces the synthesis of hsp 70 (Mori et al., 2000; Kuzmin et al., 2004). Lassmann and colleagues propose a central role for inflammatory damage to mitochondria (Lassmann, 2003; Aboul-Enein and Lassmann, 2005) and suggest that this produces a type of ‘histotoxic’ hypoxia—analogous to that produced by mitochondrial toxins such as cyanide (Ferraro, 1933; Wilson, 1983) and hydrogen sulphide (Solnyshkova and Shakhlamov, 2002; Solnyshkova, 2003). Of course, demyelination resembling that in multiple sclerosis can also occur in mitochondrial disease: Leber's hereditary optic neuropathy (LHON) caused by the G11778A (Harding et al., 1992, 1995; Olsen et al., 1995) or, less commonly, the T14484C mutation in mitochondrial DNA (Kovacs et al., 2005).
Even if correct, the hypothesis of Stadelmann et al. (2005) still leaves several aspects of Baló's sclerosis unexplained. These include the determinants of the (usually) fulminant disease course and, in particular, what it is about patients with Baló's sclerosis that causes this unusual response to demyelination to manifest fully only in them. Primary and secondary LHON mutations seem not to contribute significantly to genetic susceptibility to most types of multiple sclerosis (Kalman et al., 1995; Leuzzi et al., 1997; Ohlenbusch et al., 1998; Mojon et al., 1999a, b; Penisson-Besnier et al., 2001) but could be relevant in this limited context, as might functional polymorphisms of genes involved in preconditioning.
The finding that proteins involved in ischaemic preconditioning are up-regulated in the preserved intralesional white matter in Baló's sclerosis suggests possible approaches to the treatment of at least some forms of demyelination. Whilst the sort of preconditioning used in animal models of ischaemia is clearly impractical for application in man, agents such as KATP channel openers and adenosine agonists have been shown experimentally to mimic the neuroprotection achieved by ischaemic or hyperthermic preconditioning (Riepe and Ludolph, 1997; Blondeau et al., 2000; Shake et al., 2001) and could conceivably have a role in limiting the progression of demyelination.
Finally, I should note that this study illustrates yet again that careful post-mortem study of human brain tissue remains crucial for continued progress in the understanding of neurological diseases. Whilst the requirements of researchers for post-mortem brain tissue from patients with the commoner neurological diseases will probably continue to be met largely by disease-specific brain banks, it remains to be seen what the effects will be in the UK of the implementation next year of the 2004 Human Tissue Act, and of the impending Amendments to the Coroners' Rules. The concern is that these will severely curtail the retention post mortem, and the availability for research, of brains and brain tissue from patients with rare diseases such as Baló's sclerosis, which are often undiagnosed or misdiagnosed in life.
Department of Neuropathology, University of Bristol Institute of Clinical Neuroscience
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