The Limitation of What We See--Gray Matter and MS
The diagnosis of Multiple Sclerosis is currently made utilizing MRI detection of white matter lesions.  This is because our technology has allowed us to see demyelination of the white matter---those hallmark lesions on MRI.  The diagnosis of MS has been based on what we could see.   But we have not been seeing the FULL story.    What if it is only now-- now that we have more powerful MRI technology which allows us to see what is really going on in the gray matter--that we can understand the true nature of MS?   What if we have been targeting the wrong "bad guy", and it is not the loss of myelin in the white matter, but the atrophy of the gray matter?   Gray matter is named gray matter because that is the color of this neural tissue.  It is primarily made up of cell bodies and dendrites.  Gray matter uses 20% of our body's blood flow and energy, it uses 94% of the brain's oxygen.  Gray matter is 40% of our brain tissue, white matter is the other 60%.   White matter, or myelinated tissue, is made up of nerve cells.    When the EAE model was created by Dr. Rivers in the 1930s, (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212888/) he was attempting to replicate white matter lesions in mice, because that is what he could see.   He did this by injecting a foreign antigen into the mouse brain, and he created an immune reaction which looks like ADEM (Acute Disseminated Encephalomyelitis)  All of the current MS drugs are made to get rid of EAE in mice....but they do not work the same way in people with MS.  Why?   Because MS is not like ADEM or EAE at all....   EAE is primarily a disease of white matter.  It does not involve extensive gray matter atrophy.  It does not look like the MS we can see today.   “Experimental allergic encephalomyelitis  (EAE) is a true autoimmune disorder. It has been accepted as an animal model of multiple sclerosis … However, a false orthodoxy claiming that multiple sclerosis is an autoimmune disorder has developed and formed the present basis of treatment, drug trials and research. The outcome of this misplaced creed has been truly catastrophic.”  http://www.mednat.org/vaccini/sclerosi.pdf   Progressive MS does not have white matter lesions, inflammation, and demyelination, yet disability continues. This has baffled MS researchers.  Why would the disease progress, without the hallmark inflammation that we see in relapsing remitting MS?  What changes when MS becomes progressive?     What if NOTHING changes, and we've simply been monitoring the wrong symptom....the white matter lesions.  I've made the comment many times---MS obviously isn't  only about white matter lesions, or else how could someone like my husband, with over 20 white matter lesions, still be hiking and biking, when our friend, with one lesion and progressive MS, is using a wheelchair?     "Initially, multiple sclerosis was considered primary a white-matter disease," says Weinstock-Guttman, "but today we know that the gray matter may be more affected than white matter." http://www.medicalnewstoday.com/articles/178458.php      Here is recent research utilizing the most highly-powered MRI technology to look at the gray matter in MS brains.  The abstract mentions how lower Tesla MRIs have allowed doctors to see the white matter lesions and make an earlier diagnosis...but now we can see the "underlying pathologic substrates" and "structural and functional brain damage" to the gray matter.     The evidence suggesting a role of extensive cortical demyelization and atrophy in progressive multiple sclerosis is rapidly increasing. Although conventional magnetic resonance imaging has had a huge impact on multiple sclerosis by enabling an earlier diagnosis, and by providing surrogate markers for monitoring disease response to anti-inflammatory/immunomodulatory treatments, it is limited by the low pathological specificity and the low sensitivity to both diffuse damage in normal-appearing white matter and focal and diffuse damage in gray matter. Advanced magnetic resonance imaging techniques can partially overcome these limitations by providing markers more specific to the underlying pathologic substrates and more sensitive to the structural and functional "occult" brain tissue damage in patients with multiple sclerosis. This review describes brain and spinal cord imaging studies of multiple sclerosis with particular emphasis on gray matter imaging in both secondary progressive and primary progressive multiple sclerosis, discusses the clinical implications of gray matter damage, and outlines current magnetic resonance imaging developments at high and ultrahigh magnetic field strength. Mt Sinai J Med 78:258-267, 2011. © 2011 Mount Sinai School of Medicine.   Inglese M, Oesingmann N, Casaccia P, Fleysher L  Mt Sinai J Med 2011 Mar; 78(2):258-67. http://onlinelibrary.wiley.com/doi/10.1002/msj.20247/abstract     Cortical demyelization is loss of gray matter of the brain.  This has been shown to occur INDEPENDENT of white matter demyelination-- Here is a study that looked at white and gray matter damage in MS autopsy brains, and found no correlation between the two.  This is important, because some neurologists claim that the white matter disease comes first, and leads to gray matter loss.  This study says the two are independent of each other--   http://archneur.ama-assn.org/cgi/reprint/64/1/76.pdf   Here is a study using this new imaging technique to see lesions in the gray matter-   Multiple sclerosis (MS) is typically considered to be a chronic inflammatory-demyelinating disease of CNS white matter. In the past decade, however, pathological and MRI studies have shown that lesions are often located in the gray matter, especially in the cerebral cortex. The histopathological characteristics of these cortical lesions differ substantially from lesions located in the white matter, which suggests location-dependent expression of the MS immunopathological process. Double inversion recovery imaging-an MRI technique that selectively images gray matter and lesions-has enabled researchers to image cortical lesions in vivo. Double inversion recovery studies have shown that cortical lesions can be detected at the earliest clinical stages of MS, and cortical lesion burden positively correlates with the severity of physical and cognitive impairments. These gray matter lesions are also independent predictors of subsequent disease evolution. This Review provides a summary of the main histopathological and MRI findings with regard to cortical lesions in MS, and indicates that increasing our understanding of cortical lesions has increased our knowledge of MS pathobiology. http://www.mendeley.com/research/cortical-lesions-in-multiple-sclerosis/     Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system of unknown origin. Since the time of Charcot, a relationship between the cerebral veins and the inflammatory lesions associated with MS has been consistently reported (1,2). Observations have been made that the periventricular lesions of MS seem to extend along cerebral veins and that the cortical lesions occur within territory drained by cortical veins (1,3-5). Additional post-mortem studies have confirmed the relationship between the lesions of MS and the small veins of the CNS (6-8). For example, Fog showed that MS plaques arise from segments of large epiventricular veins and then extend into the cerebral hemispheres along the cerebral veins (6). In addition, Putnam showed plaques lined with gliotic tissue containing large veins, surrounded by hematogenous pigment (7). While these observations imply a connection between the cerebral veins and MS, this connection was felt to be interesting but was largely ignored. http://www.rivascularinstitute.com/medical_conditions/CCSVI/ccsvi_background.html   I've included a picture from Dr. Zamboni's research where he shows how reflux of the deep cerebral veins impacts the gray matter structures of our brains.  http://www.nature.com/jcbfm/journal/v29/n12/fig_tab/jcbfm2009180f6.html     We need to stop the insanity of defining a disease with an 80 year old mouse model that is no longer correct.  We need to see what is truly in front of us.  We need to continue to research jugular venous reflux, gray matter atrophy, iron deposition, and cortical lesions.  We need to do this now.   If pharmaceutical companies try to hold this research back, because they have made their money on the wrong model of MS--we will work around them, bypass them, and fund the researchers who care more about the truth than profits.  Because we can see the new research, with our own eyes.  We have access to the researchers via the internet.  We have each other.  And we are not going away. Joan