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• GRAY MATTER INVOLVEMENT IN MULTIPLE SCLEROSIS
  
  "Most therapeutic, diagnostic, and research efforts have concentrated on the white matter (WM) pathology in multiple sclerosis (MS); yet features including physical disability, seizures, cognitive impairment, and fatigue have also been linked to gray matter (GM) involvement. It has been known since the late 19th century that MS affects both WM and GM. In 1962, a large pathologic case series examined 32 MS brains and concluded that 26% of all brain lesions were located in GM, including 17% at the gray–white junction, 4% in deep GM nuclei, and 5% in the cortical mantle. Because of recent advances in imaging techniques including MRI and PET, GM involvement is again receiving considerable attention. We review the current understanding of MS in light of imaging and neuropathologic data suggesting GM involvement."
  
  Pathologic and imaging studies of GM involment
  
  "Although GM involvement is classically explained as secondary to WM lesions leading to axonal damage, Wallerian degeneration, and neuronal loss, a recent histopathologic study suggested a dissociation between inflammatory demyelination and neurodegeneration. This is further supported by MRI studies suggesting that cortical atrophy appears early in the disease process, and may occur independent of WM pathology and MS relapses. These observations raise the possibility that the earliest pathologic events in MS may in some cases be concentrated in the cortical GM. It is theoretically possible that the inflammatory demyelinating features of MS WM lesions are triggered by this early GM-based process, as seen in some viral models of MS."
  
  "In a 3-year longitudinal study, patients with early RRMS had large decreases in global GM but small increases in global WM brain volume, whereas those with clinically isolated demyelinating syndromes (CISs) had decreases in GM volume but no changes in WM volume. At the same time, both groups had substantial increases in WM lesions, suggesting that WM volume loss was offset by inflammation- and edema-related increases in tissue bulk. This increase in global WM volume may mask ongoing atrophy while the GM is relatively devoid of inflammation. Taken together, these data suggest that GM volume loss may be a more sensitive marker of early disease progression in MS than measures of WM volume loss."
  
  Symptoms related to GM involvement
  
  "Cognitive impairment is related to GM involvement. Imaging data suggest that neuropsychologic impairment in MS is related, in part, to atrophy of GM regions."
  
  "A recently published study suggests that WM volume loss is most closely associated with processing speed and working memory, whereas GM volume is most closely linked to verbal memory, euphoria, and disinhibition."
  
  "Physical disability is related to GM involvement. MRI markers of GM involvement correlate better with measures of physical disability than do conventional MRI WM lesion markers in patients with MS."
  
  Is MS driven by neurodegeneration?
  
  "The extensive cortical damage observed predominantly in progressive forms of MS suggests that GM involvement may be an important pathologic correlate of irreversible disability. Furthermore, early cortical involvement seen on imaging studies raises the intriguing possibility that the GM may represent the primary and initial target of the disease process, leading to axonal degeneration and subsequent demyelination (the “inside-out” model of MS). One of the most important questions regarding GM involvement is whether it is a consequence of WM demyelination with secondary axonal damage leading to neuronal loss in GM structures or whether the GM, in particular neurons, are a direct target of the disease process. Emerging histopathologic and neuroimaging studies support the concept that GM pathology occurs in part independently of WM lesions and may precede WM pathology. It is hotly debated whether a primary neuronal or axonal process could lead to WM demyelination as opposed to WM demyelination leading to secondary axonal and neuronal damage."
  
  ...or by inflammation and neurodegeneration?
  
  "Imaging and MRS studies have suggested that brain damage in MS may be mediated by two independent events: an inflammatory reaction, which drives the formation of WM lesions, and neurodegeneration, which is responsible for diffuse and progressive brain damage. However, from the pathologic perspective, neurodegeneration is defined as degeneration of nervous system cells (neurons or glia) due to a genetic, metabolic, or toxic effect. Inflammatory diseases are distinguished from neurodegenerative diseases by the fact that inflammation is thought to drive this destruction. In contrast to classic neurodegenerative diseases, all MS lesions, regardless of the stage and type of the disease, are associated with inflammation. The apparent lack of correlation between early clinical or neuroimaging markers of inflammation and subsequent disease progression do not necessarily imply the two processes are completely dissociated. It is likely that the inflammatory response is both qualitatively and quantitatively different during the early vs late phases of the disease as well as within areas of GM and WM damage. However, regardless of the course, phase, or site of the disease, neurodegeneration in MS appears to occur on a background of inflammation. The presence of GM damage does not exclude the possibility that it is mediated by inflammatory processes (e.g., an infectious agent). The focus on the neurodegenerative aspects may underestimate the pathogenic importance of persistent global inflammation in contributing to ongoing tissue injury. Although the inflammatory response is a key feature of MS pathology, what drives the inflammatory response remains to be determined."
  
  ...or by inflammation?
  
  "Focal new WM lesions are associated with blood–brain barrier damage, inflammation, and acute axonal injury both in the lesion and distal to the lesion site due to Wallerian degeneration. This type of injury is likely to be limited by immunomodulatory and immunosuppressant drugs. However, diffuse global brain injury including GM involvement is likely associated with a compartmentalized inflammatory response that occurs typically behind an intact blood–brain barrier in the absence of ongoing focal WM demyelination. The limited benefit of antiinflammatory or immunomodulatory therapy in the chronic slowly progressive phase of MS may in part be explained by the compartmentalization of this inflammatory reaction in the CNS. Additional studies examining mechanisms underlying GM damage are needed to better understand the pathogenesis of disease initiation, evolution, and progression, in the hope of ultimately developing more effective therapeutic strategies."
  
  -Neurology 68 February 27, 2007 p. 634-643

Dr Coles,

I follow MS research closely and much recent research has suggested that in addition to damage to White Matter (myelin) there is also a substantial amount of damage, from the earliest stages of the disease, to Grey Matter. Some research suggests that different mechanisms may be responsible for the damage to White Matter and Grey Matter. Is there any evidence as to whether treatments such as Tysabri or Campath are having an effect in terms of reducing damage to both White Matter and Grey Matter, or are these treatments only having an effect on the damage to White Matter, which is believed to be caused by inflammation?


Thank you for this very informed question.

I would imagine that both Tysabri and Campath-1H reduce grey matter plaques, because I personally think these are also due to inflammation. But I know that this has not been directly studied in the case of people treated with Campath-1H, and I would guess the same is true for people who have had Tysabri.

Alasdair

bromley wrote:The issue of reversible and irreversible disability damage / disability has also been raised in this thread. Given that we can't do anything about the latter (yet) we should concentrate on the former. Hopefully some interesting research relating to reversible disability will be highlighted at the AAN conference at the start of May.

Dr Coles,

I am a recipient of Campath 1-H (last November) and am so far thrilled with the results. I would be grateful for your thoughts on the following:

(i) Campath 1-H appears to offer most advantage early in the disease for those with Relapsing / Remitting MS. How long will it be before any conclusions can be drawn as to whether or not Campath 1-H offers long-term benefits to these patients (as when Campath 1-H was used on those with Secondary Progressive MS, relapses and inflammation were reduced but, over time, the progression of disability continued)?

(ii) Much research is being undertaken into neuro-protective agents, such as minocycline and cannabis extracts. If agents offering neuro-protective benefits are identified, might these offer a sensible add-on therapy to Campath 1-H, given that the latter primarily targets the inflammatory process in MS?

(iii) Some MS researchers have suggested that inflammation is a secondary response rather than the initiating process in MS. Is the research into Campath 1-H going to provide some insights as to whether MS is an inflammatory disease which results in neuro-degeneration, or a neuro-degenerative disease which (for some patients) then leads to an inflammatory response?

Many thanks

Ian


Thank you for your post.

i) As with all drugs in multiple sclerosis, it takes a “long time” to get “long-term” data! But it is this information that is so important. We have already published anecdotal data on people with multiple sclerosis who had Campath-1H up to five years ago. But we only have rigorous clinical trial data for two years of Campath-1H treatment. Later this year we will have three-year data… and so it goes.

ii) I agree. I think the ideal treatment strategy for multiple sclerosis will be drugs that are safe enough to take really early on in the course of multiple sclerosis and that combine both anti-inflammatory and neuroprotective actions.

iii) A good point. I think that the long-term effects of drugs like Campath-1H will tell us whether inflammation is the driving force behind multiple sclerosis (in which case we should see a good outcome) or just a secondary response (in which case there will be no long-term benefit).

Hope that helps

Alasdair

There's not enough clinical evidence of the ability of minocycline to delay the progression of permanent disability, but if it was a novel molecule, I bet there already would be. The first clinical study made with it was published at the AAN conference three years ago, but very little has happened since.

bromley wrote:I contacted one of my neuros (not Dr Coles) following the publication of the research and asked if this meant that very powerful immuno-suppressants were a waste of time in treating MS. His response was:

Not necessarily – it means that we have to treat MS early and not after too much damage has happened. It takes a long time for damage axons and neurons to die, probably months to years. This study just confirms our clinical observation that treating progressive MS aggressively, simply stops the relapses and not the progression. Good thing that you have had your Campath early.

• Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). It is the most common demyelinating disease in young adults. Although Charcot noted axonal loss in demyelinated MS lesions over a century ago, the majority of MS research has focused on the process of demyelination with significantly less attention paid to the neurodegenerative component (Bjartmar and Trapp, 2001; Charcot, 1868). There is little doubt that axonal loss is the main determinant of permanent clinical disability. However, the role of axonal loss early in the disease course or during relapsing–remitting (RR) disease is still unclear, as are the interactions and interdependency of inflammation, demyelination and neurodegeneration.

• "Several hypotheses exist to explain the relationship between inflammation and neurodegeneration in MS. One theory is that the pathogenesis of MS occurs in two distinct phases, an initial inflammatory autoimmune phase with a RR disease course followed by a progressive neurodegenerative phase in which axonal loss and permanent neurological disability occur (Steinman, 2001). Another hypothesis is that the different forms of MS represent different types of pathology with RR disease classified as an inflammatory demyelinating disease and PP disease as a neurodegenerative demyelinating disease."
• "Several possibilities exist for the relationship between inflammation and neurodegeneration: (1) that inflammation induces neurodegeneration; (2) that neurodegeneration causes inflammation; (3) other factors contribute to the development of inflammation and/or neurodegeneration; (4) inflammation and neurodegeneration participate in a cycle or a cascade in which they augment one another; and (5) that inflammation can protect against neurodegeneration. In the context of MS and its animal models these hypotheses are not necessarily mutually exclusive."
• "In MS axonal loss could occur through the toxicity of effectors such as glutamate, direct attack by autoreactive antibodies or cytotoxic T cells or secondary to demyelination due to exposure of naked axons (Owens, 2003)."
• "It is typically thought that demyelination precedes axonal loss; however, evidence from our group and others suggests that in some instances axonal loss precedes demyelination (Tsunoda et al., 2003; Tsunoda and Fujinami, 2002). We have proposed a model for the relationship between inflammation, demyelination and neurodegeneration with regard to axonal loss in which damage can be initiated either from the inside–out or the outside–in. In the inside–out model, the axon is injured by viral infection, direct attack by autoreactive T or B cells, and/or glutamate toxicity, etc., which can lead to the spread of axonal damage through Wallerian degeneration or disruption of the cross-talk between oligodendrocytes and axons. Microglia become activated, and the damage can spread to oligodendrocytes either through disruption of cross-talk, viral spread or induction of apoptosis potentially resulting in demyelination. Damaged myelin, oligodendrocytes and axons are then phagocytosed and both viral and neural antigens can be presented to T and B cells triggering an autoimmune response against myelin, axons or oligodendrocytes inducing demyelination which can lead to secondary axonal damage. Thus axonal damage has come full circle and the cycle can begin again. Alternatively, in the outside–in model demyelination occurs first and leads to secondary axonal injury, which can in turn cause demyelination."

• "The term “protective autoimmunity” was originally coined to describe the protective effect of MBP-specific T cells on injured RGCs in a rat optical nerve crush model (Moalem et al., 1999). It was also found that adoptive transfer of the same MBP-specific T cells into rats with spinal cord contusion injuries improved the recovery of hind limb motor activity (Hauben et al., 2000). In addition, overexpression of an MBP-specific T cell receptor in mice subjected to optical nerve crush was found to be neuroprotective (Yoles et al., 2001). - - - Therefore, the autoimmune response to MBP as well as other myelin antigens is complex and caution should be used in designing therapeutic treatments which induce autoimmunity.
• "Protective autoimmunity induced by antibodies has also been reported. - - - Interestingly, MS patients have been found to have higher levels of natural autoantibodies in their CSF compared to both healthy controls and patients with other neurological diseases (Matsiota et al., 1988). - - - antibodies against myelin may be capable of exerting a more direct effect in neuroprotection or neurodegeneration (Peterson et al., in press). The cause of neurodegeneration is largely unknown. - - - Therefore, although particular myelin antibodies may have a beneficial role in neuroprotection, it is generally accepted that myelin antibodies are involved in demyelination and disease pathogenesis in MS. This should be considered in designing therapies involving antibodies specific for myelin antigens."

• "Several hypotheses exist to explain the relationship between inflammation and neurodegeneration in MS. Examples exist in which inflammation causes neurodegeneration, neurodegeneration causes inflammation, inflammation and neurodegeneration appear to occur independently of one another and in which inflammation protects against neurodegeneration. Further studies need to focus on the relevance of these hypotheses to MS in general, or with respect to different disease courses in MS, as well as whether the hypotheses are mutually exclusive or interdependent."
• "Differences in whether pathogenesis is initiated by axonal loss or demyelination and in the ratios of inflammation, demyelination, remyelination and neurodegeneration in individual patients could explain the different disease courses observed. Future development of treatments for MS should focus on strategies for ending/breaking the cycle of demyelination and neurodegeneration, and it is likely that successful treatments will include a combination of agents that prevent further demyelination and axonal loss.

In the inside–out model, the axon is injured by viral infection, direct attack by autoreactive T or B cells, and/or glutamate toxicity, etc.,

Autoreactive T and B cells are regular components of the healthy immune system. It has been proposed that some of these cells might have a protective function. Recent studies support this notion by demonstrating that a) myelin-autoreactive T cells show neuroprotective effects in vivo, and b) activated antigen-specific human T cells and other immune cells produce bioactive brain-derived neurotrophic factor (BDNF) and other neurotrophic factors in vitro.

"The whole system is like a giant feedback loop. The nervous system controls inflammation and can even initiate inflammation without activation of the immune system. The immune system, in turn, communicates with the nervous system through its own chemical messengers. With a constant two-way communication between the nervous system and the immune system, inflammation can be escalated unless the endless loop communicating the need for inflammation is broken.

Three possible causes for the increase in asthma and rhinosinusitis are being investigated: the chemical hypothesis, which holds that air pollution is responsible; the viral hypothesis, which claims that viral infections might be to blame; and the hygiene hypothesis, which proposes that our high standards of cleanliness are doing us in.

Shayk wrote:I accidentally happened across an abstract that seems to suggest that autoreactive T or B cells might in fact be protective. It seems to be consistent with the idea that inflammation may be neuroprotective.

Shayk wrote:I'm definitely not in the auto-immune camp. ;-) And, if you come across more info from Tsunoda and Fujinami I do hope you'll post it.

Shayk wrote:(btw-- My interest is really in BDNF since some researchers seem to be hard at work trying to figure out how to deliver it to our brains and spinal cords for neuroprotection and to prevent neurodegeneration.)

Well, this is a consensus autoimmune board now, and I try not to corrupt the spirit by posting more here But if I find something really interesting, I promise I'll make an exception and share it.