Why do MS lesions with an iron halo continue to expand?
The slowly expanding MS lesion or SEL is where the money or lack of money is. In my post ‘explaining why you are getting worse despite being NEDA‘ I mention SELs as one of the reasons that underlie progressive MS and are largely unresponsive or poorly responsive, to standard DMTs.
Danny Reich’s team at the NIH have convincingly showed how these lesions differ from other lesions that regress over time. The expanding lesions have a rim of macrophages/microglia on their edges that are actively phagocytosing, or eating, myelin. These lesions are characterised by a prolonged rim of Gd-enhancement and dark rim on MRI that occurs due to an accumulation of iron in macrophages/microglia. These lesions are very destructive and leave behind a black-hole on MRI; the so-called Swiss cheese brain.
SELs and black-holes are associated with more axonal loss. The pathological study below shows that these lesions are not found (or rarely found) around remyelinated shadow plaques. Iron rims were due to pro-inflammatory activated microglia/macrophages and only very rarely in astrocytes.
An important observation is that these lesions don’t seem to have prominent lymphocytes infiltrates; it is as if the macrophages/microglia in these lesions have become independent of adaptive (T and B cells) inflammation. Are these microglia dysregulated or are they responding appropriately to something in the surrounding tissue. One of the current hypotheses is that progressive MS is due to ‘hot microglia‘; the chronic expanding lesion may be the substrate for how microglia lead to progressive MS. Could SELs be the real disease?
Some have suggested these microglia are responding to the immunoglobulin that has bound to myelin or other components in the issue. Some have suggested the microglia are activated to clear up myelin that is being damaged by other mechanisms, for example, from viral or toxic factors.
SELs are found very early in the course of MS, even in the asymptomatic phase of MS or RIS (radiologically isolated syndrome) and a SEL forms in a strategic location it can drive worsening of disability in one pathway, such as progressive weakness of one side of the body (hemiplegia).
DMTs reduce the development of new SELs but have minimal impact on established SELs. This is another reason why we need to treat MS early and effectively. Clearly, to address SELs we will need to do a lot more research and develop new CNS-penetrant drugs that target the pathogenic mechanisms that are driving the expansion of these lesions. This may include add-on drugs to scrub the CNS clean of plasma cells, i.e. the cells that are producing the abnormal immunoglobulins, antivirals to switch off the causative virus or drugs that switch off macrophages/microglia. I am a little sceptical about the latter approach; I truly believe the microglia and macrophages are simply doing their jobs and are responding to the cause of the disease.
Dal-Bianco et al. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathol. 2016 Oct 27.
Background: In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions.
Aims: We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims.
Methods: Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages. Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging. In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence.
Results: Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques. Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes. Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible. Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003).
Conclusions: We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003). Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS.