Multiple sclerosis (MS) may progress from the outermost layers of the brain to its deep parts, and isn’t always an “inside-out” process as previously thought, reported a new collaborative study from researchers at the Mayo Clinic and the Cleveland Clinic. The traditional understanding is that the disease begins in the white matter that forms the bulk of the brain’s inside, and extends to involve the brain’s superficial layers, the cortex. Study findings support an opposite, outside-in process: from the cerebrospinal fluid-filled subarachnoid space, that cushions the outside of the brain and the cortex, into the white matter. The new findings will guide researchers as they seek to further understand and treat the disease. The study was published in the December 8th, 20011 issue of the New England Journal of Medicine.
In the video below, Dr. Claudia Lucchinetti, M.D., co-lead author of the study describes some of the findings. Short sound/video clips are listed out below.
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Animation:
Short Video/Sound Clips:
(1) Dr. Lucchinetti talk about how this research shifted the thinking about the early stages of MS. Video – Audio
(2) Dr. Lucchinetti points out why MS was thought of as a disease of the white matter. Video – Audio
(3) Dr. Lucchinetti on why this research is unique. Video - Audio
(4) Dr. Lucchinetti describes on how the research was done. Video – Audio
(5) Dr. Lucchinetti describes what this means for patients and for future research.
Video – Audio
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Researchers do not know precisely what causes MS, but it is thought to be an autoimmune disease in which the body’s immune system attacks and destroys its own myelin. This fatty substance surrounds and protects axons, nerve cell projections that carry information, and its damage slows down or blocks messages between the brain and body, leading to MS symptoms, which can include blindness, numbness, paralysis, and thinking and memory problems.
“Our study shows the cortex is involved early in MS and may even be the initial target of disease,” says Claudia F. Lucchinetti, M.D., co-lead author of the study and Mayo Clinic neurologist. “Inflammation in the cortex must be considered when investigating the causes and progression of MS”, she says.
Study authors say current therapeutic options may not even address issues associated with the cortex. Understanding how the cortex is involved, therefore, is critical to creating new therapies for MS. “Measures of cortical damage will enhance enormously the power of clinical trials to determine if new medications address tissue changes of MS in all regions of the brain,” says co-lead author Richard Ransohoff, M.D., a Cleveland Clinic neurologist.
These measures are important because disease accumulates in the cortex over time, and inflammation in the cortex is a sign the disease has progressed.
The research is distinct because it studied brain tissues from patients in the earliest stages of MS. “What’s unique about the study is, and the reason the National MS Society funded this international team of researchers, is that it offers a rare view of MS.” says Timothy Coetzee, Ph.D., Chief Research Officer at the National Multiple Sclerosis Society. “Colloborative studies like this, that deepen our understanding of the sequence of nervous-system-damaging events, should offer new opportunities for stopping MS disease progression and improving quality of life for people with MS.”
The findings support the understanding that MS is primarily a disease of inflammation, not neurodegeneration, as some studies have recently suggested. Co-lead authors Drs. Lucchinetti and Ransohoff conclude that it is “overwhelmingly likely” that MS is fundamentally an inflammatory disease, and not a neurodegenerative Alzheimer-like disease.
How They Did It
The research did not at first focus on the ‘outside-in’ question, says Dr. Lucchinetti. Instead, the team initially wondered what tissue changes in the cortex of MS patients gave rise to indicators of cortical damage. For the last several years, researchers knew from MRI studies that the cortex was damaged very early after onset of MS, and they knew from autopsy studies that the cortex was demyelinated, as was white matter. What researchers were unable to determine, until completion of the present study, was whether findings at autopsy (usually after 30-50 years of disease) accurately reflected the indicators of cortical damage from MRI images taken after only a few months of disease. In autopsy MS tissues, cortical lesions show demyelination, but without inflammation-raising the possibility that MS cortex degenerates due to intrinsic tissue defects. Such a process would not be treatable by current MS therapies and could not be explained by present concepts of the causes of MS.
Drs. Lucchinetti and Ransohoff determined to see if early-MS cortical lesions were, or were not, inflammatory. To do so, they studied the Mayo resource of white-matter biopsies taken largely from patients with suspected tumors, but eventually proving to have MS. About one-fourth of the biopsies also included tiny fragments of cortex, which formed the focus of study. The primary question was quickly answered: cortical demyelinating lesions of early-MS patients resembled those found at autopsy in every way but one — the early lesions were highly inflammatory. These findings reassure back up current research trends and medications derived from the research.
While investigating the cortical changes in the biopsies, researchers were struck by the frequency of cortical demyelinating lesions. In the white matter biopsies, which contained miniscule cortical fragments, about 20% inflammatory demyelination was contained entirely in the cortex.
Researchers also noted inflammation was present in the meninges, the protective membranes that cover the surface of the brain and demarcate the subarachnoid space. Meningeal inflammation and cortical demyelination were highly-associated. The research findings also lend urgency to efforts to use MRI to “see” more deeply into the cortical lesions of MS, particularly given that cortical damage is an important correlate of progressive disability and cognitive dysfunction in MS.
This study was funded by the National MS Society’s MS Lesion Project, led by Dr. Lucchinetti, as well as the National Institutes of Health.
Other Mayo Clinic study authors include: Bogdan Popescu, M.D.; Reem Bunyan, M.D.; Shanu Roemer, M.D.; Joseph Parisi, M.D.; Bernd Scheithauer, M.D.; Caterina Giannini, M.D.; Stephen Weigand, M.S.; Jay Mandrekar, Ph.D.
Additional authors included Hans Lassmann, M.D. from the Center for Brain Research, Medical University of Vienna, Austria; Wolfgang Bruck, M.D. from the Department of Neuropathology, University Medical Center and Institute for MS Research in Gottingen, Germany; and Natalia Moll, M.D, Ph.D. from the Neuroinflammation Research Center and Department of Neurosciences Lerner Research Institute, Cleveland Clinic.
Might cortical inflammation be the cause of the high incidence of headache in MS patients?
We’re checking on an answer to your question.
That is an interesting question, but difficult to answer with our
current study given that headaches are quite a common condition, and can have many varied causes. In our NEJM study the amount of inflammation we observed in the outer portions of the brain (that is…the meninges or protective outer membrane surrounding the brain and the cortex which is the superficial layer of neural tissue of the brain) was very focal and tightly associated with underlying cortical myelin damage. This contrasts with for example, meningitis, in which the amount of meningeal inflammation is quite extensive resulting in irritation of the meninges which are pain sensitive structures that can result in severe headache. I would therefore not expect the very focal amount of meningeal inflammation we observed in our MS study to result in an increased frequency of headaches. Claudia Lucchinetti, M.D.
You certainly are familiar with Prof. Damadian’s recent theory on the involvement of CSF leakages from the subarachnoid space into the cortex tissue in MS (http://www.fonar.com/pdf/PCP41_damadian.pdf). My question is highly speculative – however, might not your study support Prof. Damadian’s findings?
Thank you for your interest. Your question has been passed on. Thanks.
Inflammation is usually caused by an infection of some sort. Do you think that ms is could be caused by a chronic occult infection like several Major University are finding? To name a few Dr.s …Dr. Siriam, Dr.David Wheldon, Dr.Brian Balin, Dr.Charles Stratton ? They as well as many other dr.s have treated and cured many ms patients.
http://www.cpnhelp.org/
http://www.patentstorm.us/patents/6884784/fulltext.html
http://www.davidwheldon.co.uk/ms-treatment.html
http://www.pcom.edu/department_web_pages/dept_path_m_i/Brian_Balin_Ph_D_/brian_balin__ph.d._.html
Thanks for your interest. We have passed your question on.
drs. found and removed a large menengioma,at this time they also found lesions. could these two be associated. It seems so by what your astudy has found
i just reread the article and found my answer. Thank you
thank you for your information.I have got ms ill for 2 years. I just want to say my suggestion about MS. I have had colon problem (for example constipation ) befor have ms. If ı were doctor . I investigate ms ill’s colon.I think that. colon has got special bacteria.It has got specifications that may pass body from colon. Because it has got moleculer structure which has got same miyelin.
For this reason,immune system were triggered by bacteria. Is it possible?
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The observation that early MS begins with inflammation in the outer cortical regions of the brain seems to fit with the physiology of the location of the BBB and the close proximity to microglia cells, an arrangement that suggests something is crossing the BBB to initiate inflammation and vessel infiltrate.
It is also interesting that white matter lesions later on seem to aggregate around or near the central ventricles often with micro-vessel inflammation/infiltrate seen in the ependyma membrane of the ventricles. This also suggests some outside factor is entering from the “Outside-In” through the CSF.
The spirochete hypothesis of sclerosing pathology suggested by myself, suggests that Borrelia (various species) enter through the BBB and inflame the vessels and activate microglia. Some motile bacteria may also enter the subarachnoid space a place spirochetes cannot thrive and then find their way to the ventricles-ependyma and back into blood vessels where spirochetes can find a more favorable environment. Increases in quinolinic acid levels from BBB-junction inflammation may also contribute to white matter destruction without the direct presence of the bacteria in the white matter lesions. (Spirochetes are more often found in the gray-matter)
This is born out by the lack of spirochetes found in white matter lesions, but classical forms when found, are almost always in the gray matter. This can be seen by using silver stains combined with microwave deflation of the fresh brain cells allowing the spirochetes from many levels becoming visible as the metal coated bacteria rise through the collapsed brain tissue.
This spirochete sclerosing model addresses
1) cortical gray-matter inflammation,
2) rise of an inflammatory toxin of demyelination Quinolinic Acid
3) a mechanism that explains periventricular inflammation and lesions secondary to BBB breakdown and gray-matter inflammation.
4) A possible reason for heterogeneous plagues prevailing
5) The increased incidence of MS in Lyme endemic areas
6) Intracellular infection in neurons explains lack of positive serology tests and patient relapses after antibiotics.
It seems that if spirochetes play a role in forming some plaques similar to MS plaques, then in order to get good data for treatment research we must consider trying to separate the Spirochete Sclerosing componant from the rest of the data.
For example an immune modulating drug might help true MS but if the data is mixed with patients from Lyme endemic areas that have not been separated in these trials, then treatment may have brief improvement and then a worsening without knowing which patients have an infectious component.
In the hundreds of biopsies used in this study were any also stained with anti-Borrelia antibody fluorescent stains or silver stains? If not we can make no conclusions that spirochetes did not play a role in the gray-matter pathologies.
Tom Grier (A survivor a primary progressive MS)
I think you have it right. I was able to reverse damage to the right and left caudate nuclei, left thalmus, and the visual-perception injuries by the use of oral antibiotics for treatment of Borrelia and Babesia. The “Before” and “After” (1 year) SPECT scans demonstrated recovery.
That was 1996 to 1997. Relapses do occur, but resolve with the combination of Minocin, Flagyl, and Benicar (not for hypertension, but the immunological side effect. Moderation of the Herxheimer is accomplished with Cholestyramine mitigate re-absorbtion and accumulation of endotoxins.
I have avoided steroidal and NSAIDS that might mask symptoms that are diagnostic.
I haven’t bothered with anti-malarials for some time, but keep Larium in stock.
For what it is worth….
I agree with your conclusions but your missing one large area that might be the root cause of the BBB crossing .
that is in my opinion through the roots of your teeth or your back molers a simple root canal could be the doorway
This is exactly what I have been trying to figure out! I knew there was a connection with the BBB! I was diagnosed with MS in 2003 because I had an episode of optic neuritis and a lesion on my brain. I didn’t think i had MS and fought it. I had recently received cervical manipulations by a Chiropractor for the first time in my life and believed that something entered into by brain and caused the problem (tested neg for Lyme) So I stayed away from the Chiro for 5 years and then went to the chiro again. Bam!!Within 3 months, just like last time I got a huge lesion on my brain and had terrible neurologic problems. (this time I tested positive for Lyme) I believe the the cervical manipulations somehow caused a breach of the BBB, allowing the Lyme bacteria to enter my brain. This is so important to find out the transmission pathways and to discern between the people who have MS and the people that really have Lyme Disease. Please continue studying this,I believe it will be a benefit to many people!!
In response to Thomas Grier’s post, I am wondering- What does this mean for a person with unexplained symptoms coming to Mayo for an appointment? I have an appointment in several weeks and have had several people tell me that if I have Lyme, I will not get it diagnosed at Mayo. But I cannot get any of the LLMDs (who take insurance) in my area to take me on for evaluation. They have all stopped taking patients or I need to know the secret code word to get an appointment. It’s so frustrating. I might have to go see an LLMD out of network. Are any of the Mayo doctors good to see for a chronic Lyme evaluation? I keep hoping so.
We appreciate your concern. Each patient and their treatment plans are unique and without the benefit of an evaluation we cannot predict how we would proceed. If you want your symptoms evaluated, we would encourage you to keep your appointment.
Any treatment of Lyme’s Disease is done so at the discretion of the physician you will be consulting with.
Man has living since big bag. For this reason, Man is very strong.I think so , If ı were doctor I look ms ill’s colon.(because colon has got many nervous cell) Besides, Human is circuit. Evey part has got action potential for example eyes, hand, etc. If action potential is broken, ms, etc ill bring out. İf action potential is broken, Part of body has got very high current, for that reason out of nervous cell in brain burn.
İs it possible?. I just want to write my suggestion.
OK, so this latest study shows inflammation in the Cortex. WHY is the cortex inflamed? When you find out the WHY of this disease MS would be easier to treat. Also, please look at the MS death map and the Lyme Disease death map. They overlap! I want to see studies within the medical community that answer WHY, WHY, WHY?!?!