Article of interest: inflammation the brain shredder

How do you feel about having a shredder in your brain? #MSBlog #MSResearch

"A lot of readers don't like me using the analogy of a paper shredder when referring to the effects of inflammation on the brain of someone with MS. The classic paper of Bruce Trapp and colleagues explains using beautiful pictures and hard data how damaging focal inflammation is in the brain of someone with MS. In each cubic millimeter of an actively inflammed MS lesions over 11,000 axons were transected or shredded compared to less than 1 axon in a control subject. 11,000 to 1 that is the ratio you need to keep in your head. This is why it is so important to suppress inflammation in the brains of MSers to stop the inflammation from shredding your axons. The problem is that once these axons are shredded they very little chance of recovering. Now you need to scale  this damage up several orders of magnitude as most MS lesions are larger than 1 cubic millimeter, i.e. in the order of 1 cubic centimeter or 1000 cubic millimeters, to get a sense of the magnitude of the shredding that is occurring in MSers with active disease. This is why I am such an active proponent of anti-inflammatories in MS, this includes RRMS and progressive MS; and is why in the PROXIMUS trial we are adding neuroprotective drugs on top of existing anti-inflammatories. I would go as far as stating that I doubt an a pure neuroprotective drug will work in MS unless it has anti-inflammatory properties or is added on top of an existing anti-inflammatory drug. Don't let anyone fool you into believing that progressive MS is non-inflammatory; the brains of progressive MSers, both SPMS and PPMS, are stuffed full of inflammatory cells."

Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278-85.

BACKGROUND: MS is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most MSers have progressive neurologic deterioration that may reflect axonal loss. Bruce Trapp and colleagues conducted pathological studies of brain tissues to define the changes in axons in MSers.

METHODS: Brain tissue was obtained at autopsy from 11 MSers and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions.

RESULTS: Transected axons were a consistent feature of the lesions of MS, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains.

CONCLUSIONS: Transected axons are common in the lesions of MS, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.

This picture is embedded from
A picture tells a thousand words: 
  1. The axonal structure is green in this image and represents neurofilaments the scaffolding that supports axons. 
  2. In panels B & C red indicates myelin. 
  3. When green and red are overlaid you get yellow and this indicates myelinated axons. 
  4. In panels D and E red stains macrophages or microglia the cells that clear up the myelin debris; the so called garbage collectors. 
  5. Panels A and D show the centers of active lesions. 
  6. Panels B, C, and E show the edges of active lesions. 
  7. Panel A shows green bulbs or terminal axonal ovoids with single axonal connections (arrows), an axonal ovoid with dual axonal connections (arrowhead), and many normal-appearing axons. 
  8. Panel B shows three large, green (neurofilament–positive) axons undergoing active demyelination (arrowheads). One axon ends in a large terminal ovoid (arrow). 
  9. Panel C shows some axons (green) terminating at the ends of normal-appearing myelin internodes (arrow), and many axons that express neurofilaments surrounded by normal-appearing myelin (arrowheads). 
  10. In Panels D and E, macrophages (red in Panel D) and microglia (red in Panel E) surround and engulf terminal axonal swellings (large arrows) but have no consistent association with normal-appearing axons (arrowheads) or swellings in nontransected axons (Panel E, small arrow).

"Can I suggest we have a vote on the shredding analogy to describe the effects of inflammation on the brains of MSers? I want to reiterate  that I did not coin the term it came from the script of The West Wing, the popular TV series." 

Abbey Bartlet: We had a deal!

President Josiah "Jed" Bartlet: Yes, we had a deal.

Abbey Bartlet: Yes, Jed. Look at me! Do you get that you have M.S.?

President Josiah "Jed" Bartlet: Abbey...

Abbey Bartlet: Do you get that your own immune system is shredding your brain? And I can't tell you why. Do you have any idea how good a doctor I am and that I can't tell you why?

President Josiah "Jed" Bartlet: I've had one episode in two years.

Abbey Bartlet: Yes, but relapsing-remitting M.S. can turn into secondary-progressive M.S. oftentimes ten years after the initial diagnosis which is exactly where we'll be in two years! Do you know what that's going to look like if it happens?

Abbey Bartlet: Memory lapses, loss of cognitive function, failure to reason, failure to think clearly. And I can't tell you if it's going to happen. I don't know if it's going to get better, I don't know if it's going to get worse. But we had a deal. And that deal is how you justified keeping it a secret from the world. It's how you justified it to God... It's how you justified it to me.

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