On the CRAB Drugs
In May 2000, Berlex Laboratories stopped their study on Betaseron’s effectiveness in treating secondary progressive MS because the data had already failed to show any positive effect in the slowing of the progression of disability compared to a placebo. (1.) In January 2003, the clinical trials of Copaxone for primary progressive MS were halted because no benefits were seen. (2.)
A 1995 study from the Mayo Clinic reported, “…neutralizing antibody formation was seen in 38% of patients receiving high dose Betaseron after three years of taking this medication. With the development of these antibodies, there was no longer clinical evidence that the drug remained effective.” And “Of particular interest was the finding that patients receiving low dose Betaseron developed “confirmed treatment failure” sooner than placebo-treated patients, despite a clear treatment benefit on MRI-detected evidence of subclinical disease activity.” (3) Another study , concluding that Betaseron fails to be cost effective, points out a serious flaw in the statistics in relapse rate and drop out bias. “There was a high drop-out rate (154 patients out of 372), 44% of these because of worsening disease …” (4) This same finding is repeated in August 2000: “No single drug used in the treatment of multiple sclerosis has shown to be better than any other drug despite the huge difference in cost, a recent review has found.” The drugs considered are “azathioprine, interferon beta, cladribine, cydophosphamide, glatimer, intravenuous immunoglobulin, methotrexate and mitoxantrone,” with costs ranging from $27 to $10,000 per patient. (5.)
Poor as these reported results are, they may still be called to question if they are accurately measuring relevant changes in the disease condition. Given the current methods and tools used in research, these results may be overly optimistic. For instance, “Conventional MRI measures the density of hydrogen protons and thus is a map of water, which implies edema and thus the presence of a local imflammatory response, but conventional images do not inform on de- or re-myelination, axonal loss or gliosis and correlate poorly with clinical scores. It is concluded that recent MS theraputic trials are subject to important criticism.” (6.)
Yet another study suggests that a better quality of method and control are needed. “There are many promising approaches to this clinical dilemma, but none has been proven to be effective in stopping or retarding progressive MS. More well-designed, controlled, blinded, randomized clinical trials are needed to test these putative therapies. In the meantime, we should avoid subjecting patients to potentially dangerous and unproven regimes.” This statement essentially calls into question all current therapies. (7.)
What is MS?
The studies reflect the confusion about the disease, calling to question all the assumptions made so far.
The search is still on for the smoking gun infectious agent. “Multiple sclerosis (MS) currently defies clinical and scientific definitions, and carries a prognosis that remains practically unchanged despite many years of intensive research. Although the prevailing dogma is that MS is an immune-mediated condition, it fulfills none of the criteria of an autoimmune disease. On the other hand, there is enough significant data to suggest that an infectious agent(s) could be involved in either direct damage to the white matter or induce inflammatory responses that secondarily affect the brain.” (8.) This infectious agent hypothesis is supported in another report: “…recent studies of a few select pathogens suggest that viral or bacterial infections or reactivations may trigger clinical exacerbations in relapsing-remitting MS.” (9.)
Going beyond the search for the one event, another group of researchers suggest: “The concept that two concomitant, but possibly unrelated, inflammatory events, occurring in the CNS and in the periphery, represent the crucial elements sustaining MS, might reveal a more comprehensive view (dual signal hypothesis) of the entire etiopathogenic process underlying this disease.” (10.)
The popular assumption is that the T cells are responsible for the cascading event leading to myelin damage and disability. New studies are casting doubt on that. “The need to ensure an accurate diagnosis and proper treatment for multiple sclerosis patients, considering the various clinical and immunpathological subtypes of the disease, requires the identification of biomarkers that measure disease activity and predict the course of disease development in patients.” (11.) The search for the other factors goes on: “However, recent findings in both experimental autoimmune encephalomyelitis and multiple sclerosis question a simple CD4 T helper type 1 T cell paradigm and provide evidence for the role of various immune cells in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis.” Investigations continue: “In addition, a renewed interest in the possible contributions of B cells to MS immunopathology of MS… focus is given to autoreactive T cells and cytokines as well as B cells and autoantibodies and their role in CNS pathogenesis in MS.” (13.) And, “There is much evidence to implicate B cells, plasma cells, and their products in the pathogenesis of MS.” (14.) It certainly is a daunting task to design a treatment that intervenes in the immune system when the exact mechanism or cellular elements involved are not known.
More studies illustrate the frustration in indentifying the mechanism of the disease process. “Although inflammation and chronic demyelination are probable causes of axonal transection, little is known about the molecular mechanisms that are involved. The view that MS can also be considered an inflammatory neurodegenerative disease has important clinical implications…” (15.) Another study found: “… we have shown that even completely unrelated peptide sequences may lead to cross-recognition by T cells.”(16). Adding more variables to the mix.
One researcher concludes: “We suggest that the disease process of MS is more complex than previously believed.” (17.) Echoing this the same researcher “the pathogenic heterogeneity of multiple sclerosis suggests that immunomodulatory treatment of this disease may be more complex than previously anticipated.”
There are more scholarly articles and research presented in mainstream medicine’s most revered tomes, all questioning the MS paradigm. I could continue to cite more studies, revealing more flaws and questions about the current theory and practice, but the point has been made. It is clear that despite the hype about the great progress made in understanding MS, little is really known or understood. Nor are there any indications that medicine is even close.
Notes
(1.) NMSS paper—Research/Clinical Update fact sheet, May 2000
(2.) MS Connection, Iowa Chapter of NMSS, January-February 2003
(3.) Noseworthy, JH, “Interferon beta-1b: latest published results, 1995”, Multiple Sclerosis, England, July 1996.
(4.) Richards, Richard G., “Interferon beta in multiple sclerosis: clinical cost
Effectiveness falls at the first hurdle,” British Medical Journal, November 1996.
(5.) Macdonald, Rhona, “Cost effectiveness of multiple sclerosis drugs remain
Unknown,” British Medical Journal, August 12, 2000.
(6.) Pryse-Phillips, W., “Twenty questions about Multiple sclerosis clinical trials
Methodologies.” Neurological Sciences, 22(2):187-93,April 2001.
(7.) Myers, LW, “Immunologic therapy for secondary and primary progressive
Multiple sclerosis,” Current Neurology and Neuroscience Reports, May 2001.
(8.) Steiner, I., Nisipianu, P., Wirguin I., “Infection and the etiology and pathogenesis
of multiple sclerosis.” Current Neurology and Neuroscience Reports, May 2001.
(9.) Granieri, E., Casetta, I., Tola, MR, Ferrara, P., “Multiple Sclerosis: infectious
hypothesis.” Neurological Sciences, April 2001.
(10.) Martino, G., Furlan, R., et al, “Cytokines and immunity in multiple sclerosis:
the dual signal hypothesis.” Journal of Neuroimmunology, September 2000.
(11.)Galboiz, Y., Miller, A., “Immunological indicators of disease activity and
prognosis in multiple sclerosis.” Current Opinion inNeurology, June 2002.
(12.) Hemmer, B., Cepok, S., Nessler, S., Somner, N., “Pathogenesis of multiple
sclerosis: an update on immunology.”, Current Opinion in Neurology, June
2002.
(13.) O’Connor, KC, Bar-Or, A., Hafler, DA, “The neuroimmunology of multiple
sclerosis: possible roles of T and B lymphocytes in immunopathologies.”
Journal of Clinical Immunology, March 2001.
(14.) Cross, AH, Trotter, JL, Lyons, J, “B cells and antibodies in CNS demyelinating
disease.” Journal of Neuroimmunology, January 2001.
(15.) Bjartmar, C., Trapp, BD, “Axonal and neuronal degeneration in multiple
sclerosis: mechanisms and functional consequences.” Current Opinion
In Neurology, January 2001
(16.) Martin, R., Gran, B et al, “Molecular mimicry and antigen specific T cell
responses in multiple sclerosis and chronic Lyme disease.” Journal of
Autoimmunity, May 2001.
(17.) Lassmann, H., “The pathology of multiple sclerosis and its evolution.”
Biological Sciences transcript of the Royal Society of London, Oct., 1999.
Section 2 - Research Update 2005-2007
A review of the research articles published 2005-2007, as listed in MedLine, mark some advances in basic science, but little by way of answers. Some old “truisms” that have been held about MS are discredited, casting more doubt on the existing theory and treatments. Given the lack of true understanding, most research is still descriptive; delineating what cells or what chemicals are present in the tissue or blood of people with MS, but there is no context or explanation of the exact disease process. It has become accepted that MS has two disease paths; the demyelination resulting from inflammation leaving lesions, which has been the main focus of study and drug development, and the second pathway is the more crucial axonal destruction under normal appearing white or gray matter that causes the disability. This second disease process is not at all understood. The existing drug treatments were geared to reducing the lesion load and were measured by the number and size of the lesions in an MRI—all of which does not address the true disabling disease path.
Progress in understanding the lack of understanding
“However, recent clinical and neuroradiological studies on the evolution of the disease and its brain lesions, as well as ongoing attempts to define the genetic basis of the disease, indicate that our current pathogenic concepts may be too simple and that essential aspects of MS pathology have to be redefined”[1]. “Indeed, we know now that MS is not purely a demyelinating disease but a ‘whole brain disease’”. The vastness of pathology in MS and the fact that several pathogenic mechanisms work in concert have made a ‘cure’ for MS as yet unattainable”[2]. At this point the definitions include many questions such as this statement from a researcher at the University of Cambridge; “My expectation is that when all is finally known, people who develop multiple sclerosis will be shown to have a (genetically determined) diathesis that does indeed predispose to neurodegeneration, and hence disease progression, quite possibly in a specific pathway, but the exposure of that vulnerability requires an inflammatory insult without which the degenerative component does not manifest. Since this interplay is likely to depend on a number of additional variables influencing either component, the impact of which may differ between individuals, a strict relationship between inflammation and degeneration (or relapse activity and progression) is not to be expected.” This researcher goes on to say that this relationship may change with time and change in character[3].
Specifically, “There is now overwhelming evidence supporting the following statements: MS causes widespread tissue damage in the normal appearing white matter of the brain and spinal cord, whose extent and severity is more strictly associated to the clinical manifestations of the disease than the extent of focal pathology. Discrete, macroscopic lesions are just the tip of the iceberg of MS pathology. Grey matter damage is a consistent feature of all MS phenotypes, which is progressive from the start of the relapsing-remitting phase of the disease.”[4].
With this discovery that neurodegeneration is the critical disease process and that though the lesion load is somehow connected it is not the main factor in disease progression. This new insight is forcing allopathic medicine to rethink not only their theories, but also their treatments. “In view of the small effects of immunomodulating and immunosuppressive treatments in preventing the transition to secondary progressive, the development of treatments promoting neuroaxonal repair remains an important goal in this disease”[5]. Not only is there the unknown degenerative process, but lesions have now been classified into 4 types, “However, except in a few specific forms, most MS patients cannot be assigned to one of these lesion subtypes by means of clinical and paraclinical parameters.”[6]. There is also controversy about when this degenerative process starts—as a result of the inflammation as suggested in a quote above or, “Neurodegeneration in MS, long considered as a late process following recurrent episodes of demyelination, is now accepted as an early and major trigger of MS pathogenesis on which research should focus”[7]. MS was thought to be a disease of white matter only, then gray matter was included and now: “these findings suggest that gray matter loss is related to other aspects of brain pathology and has more clinical relevance than white matter atrophy in MS” [8].
Old “truisms” fall
The MRI’s image of lesions was the basis of measuring the disease and the drug treatment’s effectiveness. Now it is understood that axonal destruction in normal appearing grey and white matter (cortical) is the critical disease process. “Current magnetic resonance imaging (MRI) methods are not sensitive to purely cortical lesions”[9]. Further, “Many evaluations of the accuracy of magnetic resonance imaging for the early detection of multiple sclerosis have produced inflated estimates of test performance owing to methodological weaknesses”[10].
The neutralizing antibodies (NAbs) were not at first considered when treating an MS patient with the immunmodulating drugs. New studies are showing more negative impact: “The induction of NAbs in IFN-beta (Avonex, Beta Seron, Rebif) treated patients reduce clinical effect and accelerate disease progression”[11]. Copaxone (Glatiramer acetate) does not fare any better in the research: “We noticed a higher level of systemic adverse events in our patients than in reports in the literature”[12]. More, the body’s inflammatory reaction may also have a beneficial effect in the disease process, again reflecting the intricate complications of this disease. “However, it should be stressed that inflammation does not only have a detrimental effect in MS. In fact, parts of the inflammatory events are crucial for the control and conclusion of the acute phase of damage and it is probable that they actually favor regeneration and recovery. Due to the above, several trials with immunosuppressant drugs failed or were suspended because of unexpected worsening of the course of MS”[13].
Of more concern, children who are increasingly diagnosed with MS are being administered these same drugs “There has been no controlled clinical trial in children with disease modifying therapies approved for adult MS due to the limited number of patients under 18 years compared with the adult contingent. As a result, children are receiving adult therapies in an arbitrary manner and our understanding of pediatric treatment effect and tolerability is limited”[14].
“It is difficult to prove long-term benefit of therapy in chronic diseases characterized by individual variability and unpredictability and there exists no study that convincingly establishes a long-term improvement over natural history for any MS therapy,” conclude doctors from the Mayo Clinic[15].
Mice aren’t people
For years science have conducted experiments on mice giving them experimental autoimmune encephalomyelitis (EAE) which was thought to replicate MS in people. Much of the theory and drug development was based on this assumption, which is now being rethought. “Seventy years after the first description of EAE and the publication of over 7000 articles, we are aware of the obvious limitation of EAE as a model of multiple sclerosis, but feel strongly that when used appropriately it will continue to provide a crucial tool for improving our understanding and treatment of this devastating disease” [16]. Old icons die hard. Logically, one would think that given the time and number, it would be obvious that the answer does not lie in that direction.
$$$$
In the United States, “total average costs are estimated at $47,215 per patient and year” [17]. Moreover, the lifetime cost per patient is $2.2 million.
Symptoms and Symptom Management
Given that there is no really effective treatment in allopathic medicine’s arsenal, it follows that symptom management would be a major focus. Physical symptoms are more measurable and apparent to the medical profession, which has been slow to acknowledge the huge impact of the more subtle and hard to define symptoms of pain, fatigue and loss of cognitive functions.
Some studies are addressing this. “The frequency of pain-related symptoms is high and clinical treatment guidelines are lacking, perhaps due to the fact that the mechanisms of pain in MS have yet to be understood. The absence of controlled, clinical trials should encourage this to be the focus of future work”[18].
And, the same can be said for fatigue in MS. Acknowledging first there is little understanding of the pathophysiology or even agreement on the definition of MS fatigue, it follows that an effective treatment for MS fatigue also eludes medicine. “Medications are partially beneficial, and with the exception of amantadine, their efficacy has not been confirmed by randomized double-blind trials”[19]. With little understanding of the true nature of this paralyzing phenomena, researchers are conducting studies to measure the possible benefit of exercise, with titles like “Fatigability evaluation of multiple sclerosis patients by using a hand held dynamometer”[20].
Cognitive loss has been scrutinized with many studies describing loss of function and even quantifying it. “Evidence has established that between 40% and 60% of MS patients suffer cognitive impairment of a significant magnitude”[21]. Most of the studies are descriptive and offer no real solutions.
Depression is also addressed in studies, citing an incidence rate of 40%. It is not known if it is the result of the physiological disease process or the psychological and sociological fact of having the disease.
Current Directions in Research
Without a good understanding and with the disappointment in the CRAB drugs, the research field is wide open and looking for a solution in all sorts of places.
The exact gene or cluster of genes that determine a predisposition for MS has not been located. “Because of the relative failure of linkage analysis in multiple sclerosis, despite the investigation of more than 700 affected relative pairs, we have applied four alternative strategies to identify genes that confer susceptibility to the disease.” The results—eighty genes showed evidence of importance in three isolated populations that could be traced back to common ancestry [22]. In another study, “In consequence, we did not find further evidence for apoptosis-related genes as predisposition factors in MS” [23].
Demographic studies validate the rising incidence around the world, sadly now with child onset MS[24]. “The substantial increase in the female to male sex ratio in Canada seems to result from a disproportional increase in the incidence of multiple sclerosis in women. This rapid change must have environmental origins even if it is associated with a gene environment interaction, and implies that a large proportion of multiple sclerosis cases may be preventable in situ”[25]. Supporting the environmental impact, the cluster studies support regional difference, but do cite any understanding of why[26].
New, or recycled drug treatments that are being studied are: Donepezil (Alzheimer Drug) for cognitive difficulties.27, the Statins with thoughts that there would be some vascular protection, cancer drugs (immunosuppressants), stem cells, and intravenous Immunoglobiin28. Of note Dr. Roy Swank used the precursor—plasma exchange—decades ago, and found good results, but gave it up due to lack of funding. Other treatments being considered are cannabinoids (marijuana) and surgery.
Descriptive studies of differences in people with MS include: saliva, dopamine, nitric oxide, aluminum and iron elevated, P wave is different in cardio functioning, and gut metabolism abnormalities. Also the cervical lymph nodes have been found to play some role, making MS a whole body disease either in the disease process or in the recruitment to fight the disease. However, what that means, or how this information can be used is unknown. Without a context, this only shows how profoundly this disease affects the body.
Fitting into the Recovery Diet Understanding of MS
Echoing Swank, several studies are focused on MS as partly a vascular disease. “MS has traditionally been viewed and researched as an immune-mediated disease with principal emphasis on the role of activated inflammatory cells, oligodendrocytes and astrocytes in its pathogenesis…..A deeper understanding of endothelial pathophysiology in MS may help develop effective treatments through stabilization of endothelial (cells that line the blood vessels) function, translating into delay or arrest of MS disease onset and disability in MS patients”[29]. Again, the disease process is not so simple: “This study shows for the first time that in MS brain changes in the vasculature take place not only in focal lesions but also in DAWM (diffusely abnormal white matter) as detected by post mortem MRI”[30].
Swank found in the 1950s that fat intake was a factor in the progression of MS and based his popular treatment program on reduction of high saturated fats and the increased ingestion of low saturated fats. Conventional medicine is coming around to this conclusion now as evidenced in a research paper entitled “Low dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients”. The conclusion is that omega-3 fatty acid supplementation is beneficial to those people with MS.[31.]
The Recovery Diet and Ashton Embry have advocated Vitamin D as an aide in prevention and treatment of MS for years now. Allopathic medicine is catching on. “Vitamin D supplementation may help prevent the development of MS symptoms and may be a useful addition to therapy”[32].
The same is true for the concept of molecular mimicry: now a study states “Overall, this virus-induced molecular mimicry model has provided critical information regarding the mechanisms by which infection-induced molecular mimicry can induce autoimmune diseases”[33]. One article proposes a connection between molecular mimicry and abnormalities in the digestive track, two contentions of the Recovery Diet. “It is suggested that a microorganism responsible for autoimmune activity in MS could be a normally occurring gut bacterium. This would explain many of the peculiar MS epidemiological data and why no infective agent has been identified for MS and supports recently found MS gut metabolism abnormalities”[34].
Not Getting It
One researcher wrote “Perceived treatment failure is a significant factor for about 50% of patients who stop therapy”[35]. It would seem that the patients are the ones who can best judge whether a treatment is working or not, rather than a physician, especially in a disease like MS with such active, obvious and even florid symptoms.
More is mentioned in the literature about needing individualized treatments—the MS Recovery Diet is already there.
Another research article is entitled “Complementary and alternative medicine (CAM): is there a role in multiple sclerosis?” The conclusion is “The research on CAM therapies is still exploratory, but considering peoples’ interest and common use of these therapies, further research in this area is clearly warranted”[36].
1. Lassmann, Hans. “Multiple Sclerosis pathology: evolution of pathogenic concepts” Brain Pathology VOl 15(3): 217-222, July 2005
2. Minagar, Alireze. “Multiple Sclerosis: current knowledge and future directions”.Neurological Research Volume 28, April 2006.
3. Compston, Alastair. “Making progress on the natural history of multiple sclerosis.” Brain, Volume 129, number 3, pp 561-563. 2006.
4. Filippi, Massimo. Rocca, Maria Assunta. “MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system.” Journal of Neurolgy 252 Suppl 5:v16-24, November 2005.
5. Rovaris, Marco. Confavreux, Christian, et al. “Secondary progressive multiple sclerosis: current knowledge and future challenges.” Lancet Neurology. 5940:343-54. April 2006.
6. Trebst, C. Wiendl, H. Stangel, M. “Concepts in lesion development in multiple sclerosis.” Nervenarzt. 77(2):158, 160-164. February 2006.
7. Lalive, P.H. Schluep, M. chofflon, M. Du Pasquier, R., “Immunity and neurodegeneration: new concepts in multiple sclerosis.” Revue Medicale Suisse. 2(64)1168-70. May 3, 2006.
8. Sanfilipo, Michael P., Benedict, Ralph H., B. Sharma, Jitendra, Weinstock-Guttman, Bianca. Bakshi, Rohit. “the relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized gray vs. white matter with misclassification correction.” Neuroimage 26(4):1068-77. July 15, 2005.
9. Bo, L. Geurts, JJG. Mork, SJ van der Valk, P. “Gray matter pathology in multiple sclerosis.” Acta Neurologica Scandinavica. 183:48-50. 2006.
10. Whiting, Penny. Harbord, Roger, Main, Caroline, Deeks, Jonathon J. Filippini, Graziella. Egger, Matthias. Sterne, Jonathon A. c. “Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systemic review.”
BMJ 332(7546) April 15, 2006. Also found in Clinical Otolaryngology 31(4):319. August 2006.
1. Namaka, Mike, Pollitt-smith, Merinda, Gupta, Aneri, KLowak, Meghann, Vasconcelos, Marcus, Turcotte, Dana, Gong, Yuewen, Melanson, Maria. “The clinical importance of neutralizing antibodies in relapsing-remitting multiple sclerosis.” Current Medical Research and Opinion. 22(20:223-39 February 2006.
2. Fiore, Ana Patricia Perez, Fragoso, Yara Dadalti. “Tlerability, adverse events and compliance to glatiramer acetate in 28 patinets with multiple sclerosis using the drug continuously for at least 6 months.” Arquivos de Neuro-Psiquiatra. 63(3B0:738-40. September 2005.
3. Cavaletti, Guido. “Current status and future prospective of immunointervention in multiple sclerosis. Current Medicinal Chemistry. 13(19): 2329-43. 2006
4. Chabas, Dorothee, Green, Ari J., Waubant, Emmanuelle. “Pediatric multiple sclerosis.” NeuroRx. 3(2):264-75. April 2006.
5. Kantarci, Orhun and Wingerchuk, Dean. “Epidemiology and natural history in multiple sclerosis: new insights.” Current Opinion in Neurolgy 19:248-54. 2006.
6. Gold, Ralf, Linington, Christopher. Lassmann, Hans. “Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research.: Brain 129)PT8) 1953-71. August 2006.
7. Kobelt, G. Berg, J. Atherly, D. Hadjimichael, O. “Costs and quality of life in multiple sclerosis” a cross-sectional study in the United States.” Neurology. 66(11):1696-702. June 13, 2006.
8. Solaro, C. “Epidemiology and treatment of pain in multiple sclerosis subjects.”
Neurological Sciences 27 Suppl 4:s291-93. September 2006.
1. Bethoux, F. “Fatigue and multiple sclerosis.” Annales de Readaption et de Medecine Physique. 49(6):265-71, 355-60. July 2006.
2. Pavan, K. Schmidt, K. Ambriosio, Arica T. Mendes, MF, Tilbery, CP, Lianza, S. “Fatigability evaluation onmultiple sclerosis patients by using hand held dynamometer.” Arquivos de Neuro-psiquiatria. 62(2A):283-6. June 2006.
3. Thornton, Allen E. Raz, Naftali. “Memory Impairment in Multiple Sclerosis: A Quantitative Review.” Neuropsycholog Vol.11, No. 3, 357-366. 1997
4. Hillert, J. “Multiple sclerosis: “Postlinkage genetics.” Clinical Neurology & Neurosurgery 108(3):220-02. March 2006.
5. Godde, R. Brune, S. Jagiello, P. Sindern, E. Haupts, M. Schimrigk, S. Muller, N. Epplen, JT “An extended association screen in multiple screen using 202 microsatellite markers targeting apoptosis-related genes does not reveal new predisposing factors.” Journal of Negative Results in Biomedicine 4:7 September 5, 2005.
6. Waldman, A. O’Connor, E. Tennekoon, G. “Childhood multiple sclerosis: a review.” Mental Retardation & Developmental Disabilities Research Reviews. 12(2):147-56. 2006.
7. Orton, SM, Herrera, BM. Yee, IM. Valdar, W, Ramagopalan, SV, Sadovnick AD, Ebers, GC. “Sex ration of multiple sclerosis in Canada: a longitudinal study.” Lancet Neurology 5(11):932-6. November 2006.
8. Williamson, DM. “Studies of multiple sclerosis in communities concerned about environmental exposures.” Journal of Women’s Health 15(7):810-4. September 2006.
9. Christodoulou, Christopher, Melville, Patricia, Scherl, William f. MacAllister, William S., Elkins, Leigh E., Krupp, Lauren B. “Effects of donepezil on memory and cognition in multiple sclerosis.” Journal of Neurological Sciences 245:127-36. 2006.
10. Katz, U. Kishner, I. Magalashvili D., Schoenfeld Y., Achiron, A. “Long term safety of IVIg therapy in multiple sclerosis: 10 years experience.” Autoimmunity. 39(6):513-7, September 2006.
11. Minagar, Alireza. Jy, Wenche, Jimenez, J.J., Alexander, J Steven. “ Multiple sclerosis as a vascular disease.” Neurological research. 28(3): 230-5. April 2006.
12. Vos, CM. Geurts, JJ. Montagne,L. van Haastert, ES. Bo, L. van der Valk, P. Barkhof, F. de Vries, HE. “Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis.” Neurobiology of Disease 20(3):953-60. December 2005.
13. Weinstock-Guttman, B. Baier, M. Park, Y. Feichert, J Lee Kwan, P. Gallagher, E. Venkatraman, J. Meksawan, K. Deinhert, S. Pendergast, D. Awad, AB Ramanathan, M. Munschauer, F. Rudick, R. “Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients.” Protaglandins, Leuktrienes & Essential Fatty Acids 73(5):397-404. November 2005.
14. Brown, Sherrill J. “The role of vitamin D in multiple sclerosis.” Annals of Pharacotherapy 40(6):1158-61. June 2006.
15. Olson, JK Ercolini, AM Miller, SD. “A virus-induced molecular model of multiple sclerosis.” Current Topics in Microbiology & Immunology. 296:39-53. 2005.
16. Westall, Fred C. “Molecular mimicry revisited: gut bacteria and multiple sclerosis.” Journal of Clinical Microbiology 44(6):2099-104. June 2006.
35. Freedman, Mark S. “Disease-modifying drugs for multiple sclerosis: current and future aspects.” Expert Opinion Pharmacotherapy 7 Suppl 11. 2006.
36. Yadav, V. Bourdette, Dennis. “Complementary and alternative medicine: is there a role in multiple sclerosis?” Current Neurology & Neuroscience Reports. 6(3):259-67. May 2006.