Stem Cell Therapy for Multiple Sclerosis
A new treatment for MS now exists without altering the immune system, without employing the use of medication, and therefore without exposing the patient to the risk of side effects. That new treatment is stem cell therapy.
Initial trials with stem cell therapy in the treatment of MS have shown great promise. In general, stem cells have been shown to be potent agents of regeneration and re-myelination not only in MS but in all demyelinating diseases, such as cerebral palsy and ALS ("Lou Gehrig's Disease"). Not only have stem cells been found to remyelinate the central nervous system, but they have also been shown to be effective in correcting diseases of an autoimmune nature.
Among the many different types of stem cells, one particular type has been identified as being especially promising in the treatment of MS. Known as "CD34(+)", these are purified multipotent stem cells which are present in embryonic tissue, umbilical cord blood and certain types of adult tissue such as bone marrow. As such, these particular stem cells have the capacity to differentiate into a variety of cells, and they are also known for their "homing" ability in migrating to areas in which damaged tissue needs to be repaired.
Related to the CD34(+) stem cell is the "subset" known as the "CD133" stem cell, which has been shown to balance the immune system and to differentiate into neuroprotective glia as well as the oligodendrocytes and astrocytes which produce myelin. Such characteristics make the CD34(+) stem cells a particularly potent treatment modality not only for immune disorders but also in the remyelination of central nervous system diseases. Since MS falls under both categories, these particular stem cells offer great promise for the treatment of MS.
Stem Cells and Remyelination:
In the relapsing-remitting (RR) pattern of MS, some remyelination has been observed. It has already been established that the adult brain possesses its own capacity to replace cells, and in MS it is believed that something interrupts this process. In a recent study led by Bruce D. Trapp, Ph.D., of the Cleveland Clinic Foundation in Ohio, researchers discovered that the brain does in fact produce its own new cells in an attempt to repair the damage from MS, even years after the first symptoms appear. However, in most cases the cells are unable to complete the repairs, suggesting the presence of an unknown factor which limits or interferes with the natural repair process. According to Dr. Trapp, "The brain is making a serious attempt to repair the damage." The study, which was supported by NINDS, also indicates that some brain lesions in MS are actually repaired during the early years of multiple sclerosis, although most lesions, however, are not repaired, especially as the disease progresses. Dr. Trapp and his colleagues examined brain tissue from autopsies of 10 patients with MS and found that the oligodendrocytes, which make the myelin, were produced by the brain even in the chronic lesions. As the duration of the disease increased, however, the number of lesions containing the oligodendrocytes declined. The new oligodendrocytes were found to have "arms" which extended around the damaged axons, and which produced the proteins needed for the manufacture of myelin; however, in most of the cases, the myelin was not manufactured and the axons were not repaired. Exactly what this "interfering factor" might be is not yet known. (From the New England Journal of Medicine, Vol. 346, No. 3, Jan. 17, 2002, pp. 165 - 173).
This type of spontaneous remyelination, whether partial or complete, is believed by some researchers to be the result of previously quiescent oligodendrocyte progenitor cells rather than mature oligodendrocytes. Platelet-derived growth factor has been found to stimulate the multiplication and growth of these oligodendrocyte progenitor cells, and may therefore be used in combination with stem cell therapy.
In the progressive degeneration patterns (PP, SP and PR, known collectively as "chronic progressive"), oligodendrocytes are destroyed. Implants of oligodendrocyte progenitor cells into MS patients with these patterns have been successful. However, while Schwann cells also promote remyelination, their implantation has a greater risk of fibroblast overgrowth that subsequently can destroy axonal pathways. By contrast, glial cell implants have shown positive results in creating oligodenrocytes.
In an animal study, neural stem cells were transplanted into rats with experimental autoimmune encephalomyelitis (an animal model for MS). The cells migrated into the brain and spinal cord, exclusively into the inflamed white matter but not into adjacent gray matter regions. After two weeks, many transplanted cells had migrated into distant white matter tracts and acquired astroglial and oligodendroglial lineages. The investigators concluded that the inflammatory process may attract the migration of transplanted precursor cells into the brain parenchyma, which is the connective tissue network of the brain.
The effectiveness of stem cells in treating autoimmune diseases was first observed in patients who received allogeneic hematopioetic stem cell transplants for leukemia and aplasia, and who also suffered from severe autoimmune disorders (namely, lupus and rheumatoid arthritis).
In 1998, Burt and coworkers treated 10 patients suffering from autoimmune disease (6 patients with MS, 2 with Lupus, and 2 with rheumatoid arthritis) with autologous hematopoietic stem cells from bone marrow or mobilized from peripheral blood. CD34(+) stem cells were reinfused after either myelosuppressive conditioning with cyclophosphamide, methylprednisolone and antithymocyte globulin or with myeloablative conditioning with total body irradiation plus methylprednisolone and cyclophosphamide. Results indicated that regimen-related nonhematopoietic toxicity was minimal. All patients improved or had stabilization of the disease for 5-17 months. The author concluded that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating autoimmune disease.
Dr. Ouyang and associates of the Nanjing University School of Medicine in China demonstrated positive results in a patient with progressive multiple sclerosis who received an autologous peripheral blood stem cell transplantation. The patient showed clinical remission and there was no relapse at the 6 month follow-up examination. The authors conclude that autologous peripheral blood stem cell transplantation is effective and safe for progressive multiple sclerosis.
An MRI study of MS patients who received autologous hematopoietic stem cell transplantations (HSCT) revealed the disappearance of enhanced T1 brain lesions as well as a reduction in the T2 lesion load, even 18 months after the transplant. These findings correlate with the clinical stabilization of the patients.
In a multicenter Phase II study by Fassas and coworkers investigating autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis, 85 patients with progressive MS (with a median Extended Disability Status Scale score of 6.5) were treated in 20 European centers. Neurological improvement was seen in 18 patients (21%). Confirmed progression-free survival was seen in 74% of the patients at 3 years. Disease progression was seen in 20%. The authors conclude that autologous HSCT early results are positive and feasible for the management of progressive MS.
In a Phase II report by Carreras and associates, the authors used CD34(+) cell transplantation in 15 Multiple Sclerosis patients. Patients were selected who had advanced secondary-progressive (SP) or relapsing-remitting (RR) MS or who showed worsening of the Extended Disability Status Scale despite interferon and other immunotherapies. They were treated with Cyclophosphamide, granulocyte colony stimulating factor, BCNU, Antithymocyte Globules, Methyl Prednisolone, MESNA, Cipor, Fluconoyol, Acyclovir, Pentomidine, and Trimethoprim Sulfamethoxzaole Immunoglobins. There were a number of complications from this combination of powerful drugs. At 12 months, the Extended Disability Status Scale had improved in three patients, worsened in two and remained stable in nine. Despite withdrawal of all immunosuppressive therapy, only two patients had relapses. The authors conclude that CD34(+) autologous stem cell transplantation using BCNU, Cylophosphamide and Antithymocyte Globules as a conditioning regimen has an acceptable toxicity and clearly reduces the progression of multiple sclerosis.
In each case, however, not only is the particular type of stem cell that is used of great importance, but so is the origin of the cells. In studies in which peripheral blood stem cell mobilization techniques were combined with powerful immune suppressants, antibiotics, antifungals and steroids, a number of side effects were observed, with only marginal effectiveness. One observation is that some of these therapies actually inhibit stem cell growth and proliferation. When compared with the case studies to date of umbilical cord CD34(+) stem cell transplantation given alone without additional medications, the umbilical cord stem cells show much greater success with virtually no side effects.
Depression and Stem Cell Therapy:
One of the most common symptoms of Multiple Sclerosis is depression. A new model of depression is now emerging, which is based upon the inhibition of neural stem cell growth within the hippocampal dentate gyrus. Factors such as stress-related glucocorticoids that inhibit stem cell growth also induce depression.
As previously mentioned, it has been shown in animal studies that corticosterone significantly reduces the proliferation of oligodendrocyte precursors throughout the white and gray matter regions of the brain. Since oligodendrocyte precursors play a major role in remyelination, the use of anti-inflammatory therapies may actually perpetuate depression as well as brain injury. In contrast to the use of steroids for treating MS, stem cell therapies promote the proliferation of new oligodendrocytes, with the secondary benefit of alleviating depression. Generally, depression clears within 30 days following CD34(+) stem cell transplantation.
Methylation and Multiple Sclerosis:
Folate and vitamin B12 deficiencies (methylcobalamin has greater neurological importance than cyanocobalamin) can cause neurologic and psychiatric disturbances, including depression, dementia, and demyelinating myelopathy. In most cases, folate and methylcobalamin injections improve MS symptoms and prevent relapses. Treatment with additional methyl donors such as S-adenosylmethionine, betaine, or methionine can also relieve depression and promote remyelination in patients with inborn errors of folate metabolism.
A Comprehensive Program for MS:
Stem cells seem to have the ability to assist greatly in regenerating the glial cells that are injured and destroyed in MS. Other holistic approaches which incorporate anti-virals, growth factors, antioxidants, nutritional therapies, and heavy metal detoxification should be helpful as well. Such a program could include stem cell injections while inflammation is present in the CNS (but not in other organs), followed by anti-virals, growth factors, antioxidants and nutrients to continue protecting the oligodendrocytes and axons from oxidative stress. Care must be taken for several months after stem cell administration to avoid products that inhibit neurogenesis and stem cell proliferation. Such products include cortisone, alcohol, and monosodium glutamate. Physical and emotional stress increases glucocosteroid release, and should also be avoided as much as possible.
Autoimmune Disease and Patterns of Relapsing-Remitting Episodes
The Myelin Sheath:
Myelin sheaths are formed around axons by spiraling plasma membranes of Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. Glycoproteins are prominent components of the plasma membranes and include protein zero and peripheral myelin protein-22 in peripheral nervous system myelin, as well as myelin-associated glycoprotein which is located on the inside of the sheaths in both the PNS and CNS and which functions in glia-axon interactions, and also myelin-oligodendrocyte glycoprotein (MOG) which is located on the outside of CNS myelin sheaths. MOG appears to be an important target antigen in multiple sclerosis.
Autoimmune T-cell responses to myelin components are being investigated for their role in initiating and/or maintaining inflammatory responses that result in myelin destruction. T cells, so named because they are made by the thymus, have been found to play an important role in MS. Myelin oligodendrocyte glycoprotein (MOG) is a myelin protein which was found in one study to elicit greater anti-MOG B-cell responses in MS patient samples, while in another study it was found to elicit similar T cell responses in MS patient samples and controls, but with different cytokine activity. The MS samples elicited increased levels of TNF-alpha upon stimulation when compared to the control samples. Tejada-Simon and associates found that MOG samples from MS patients elicited anti-MOG antibodies which reacted predominantly to the extracellular 1-60 region, while control samples elicited anti-MOG antibody reactions to the transmembrane/cytoplasmic domains.
Autoimmune reactions to cardiolipin (which is important in heart and brain mitochondrial function) have also been seen in MS patients.
Patterns Resembling Virus and Toxin-induced Immune Responses
Mercury Toxicity:
Mercuric chloride is toxic at low concentrations to oligodendroglial cells, resulting in cell death through apoptosis. Symptoms of mercury toxicity include chronic fatigue, depression, poor memory and cognitive function, emotional instability, peripheral numbness or tingling, decreased sensations of touch, hearing or vision, hypersensitivity and allergies, persistent infections including chronic yeast overgrowth, compromised immune function and cardiovascular disease. Mercury levels are often elevated in MS patients, and may result from a variety of sources.
- Dental Amalgams. Though research findings are contradictory, Huggins found a change in cerebrospinal fluid proteins following dental intervention, using CSF photolabeling. Changes were seen in ceruloplasmin, transferrin, IgG heavy and light chains, Apo E, transthyretin and other proteins. Additional markers that can be used to monitor MS include CSF, S100B and Glial-Fibrillary Acidic Protein (GFAP). S100 B was found to be a good marker for relapsing MS and GFAP correlated with Disability Scales and may therefore be a marker for neurological damage.
- Mercury contamination in fish and soil. Mercury is a major environmental concern, traditionally in freshwater fish and more recently because of the toxic effects on soil microorganisms. Those patients living near mercury emission sources are at greater risk of mercury contamination. Shark and swordfish are reported to have the highest methyl mercury levels, and shrimp, scallops and salmon the lowest concentrations in ocean fish. Farmed fish may not be any safer than ocean fish, as fish farms may be producing fish that contain higher concentrations of pesticide and mercury due to the use of contaminated feed sources.
- Elevated insulin levels allow the cellular entry of heavy metals. Insulin is elevated by large meals, high sugar and refined carbohydrate diets, and oxidative stress. Antioxidants can help protect the cells from heavy metal toxicity.
- Leaky Gut Syndrome can be caused by Candida endotoxins, nutritional deficiencies and excessive alcohol use, all of which allow heavy metals and macromolecules to enter the bloodstream, thereby causing immune and autoimmune responses, free radicals, and cellular injury or cellular death. In an animal study conducted by Keshavarzian and associates, results demonstrated that supplementation with oats prevented gut leakiness and endotoxin-induced liver damage.
Chelating factors in various foods can prevent mercury absorption, including citric acid, tartaric acid, cysteine, selenium, garlic, chlorella (also an anti-inflammatory), and cilantro. Methyl mercury can bind with L-cysteine and be transported across the blood brain barrier; L-leucine inhibits this transport. A balanced leucine/cysteine ratio is found in whey protein. Calcium and magnesium are also protective against mercury and methyl mercury toxicity. EDTA oral and intravenous chelation methods are currently being promoted for the removal of mercury and methylmercury as well as other heavy metals. Since heavy metals can inhibit stem cell growth, chelation is advised before stem cell therapy. Oral DMSA has been proven to be a generally safe and effective method for removing mercury and lead.
Anti-virals
Multiple Sclerosis is associated with viral infections, including Herpesvirus 6, Epstein-Barr virus, herpes simplex, infectious mononucleosis, measles and mumps (especially after 15 years of age), Chlamydia, Mycoplasma pneumoniae, Varicella zoster, retroviruses, and nidoviruses.
Medicinal Plants:
Ecinacea purpurea and Panax ginseng significantly enhance Natural Killer activity and antibody-dependent cellular immunity against human herpesvirus 6 infected cells.
Reticulosa:
Reticulosa is a peptide-nucleic acid immunomodulator that boosts immune system activity in virally-infected patients. It has broad-spectrum antiviral activity that includes the stimulation of gamma interferon, interleukin-1, interleukin-6 and Tissue Necrosis Factor-alpha. In general, it appears free of side effects, is reasonably priced and often effective.
Acyclovir:
The antiviral drug acyclovir inhibits herpesvirus-6 infection and markedly reduces the frequency of disease exacerbations in patients with MS.
Sea Cucumber:
Sea cucumber (Cucumaria japonica) and coumarins from lemon peels have been shown to have an inhibitory effect on Epstein-Barr virus.
Palm Oil:
Gamma- and delta-tocotrienols derived from palm oil exhibit a strong activity against Epstein-Barr virus expression and may be of benefit to MS patients.
Factors that Promote Remyelination
The Ciliary Neurotrophic Family:
CNTF, leukemia inhibitory factor, cardiotrophin-1, and oncostatin M have been shown to induce a strong promyelinating effect by promoting oligodendrocyte maturation, mediated through the 130 kDa glycoprotein receptor to the CNTF family.
Thyroid:
T4 administration to experimental allergic encephalomyelitis animals resulted in an up-regulation of oligodendrocyte progenitors and mature oligodendrocytes in the spinal cord, ofactory bulb, and subventricular zone.
Thymus:
Ikehara, et al. report that the success rate of bone marrow transplants in patients over 45 years of age is low, due to the aging of the thymus. BMT plus embryonal thymus grafts can be used to treat late-onset autoimmune disease in mice and can be a valuable strategy for treating older patients with various intractable diseases, including autoimmune diseases. NatCell Thymus, a thymus extract providing a broad spectrum of thymic peptides (available from Atrium Biotechnologies) is being used successfully to restore immune balance in patients with autoimmune disease who are not on immunosuppressants.
Adrenal Support:
Krenn, et al. present a case of Adrenoleukodystrophy that mimics the symptoms of multiple sclerosis. Both conditions include lesions of the white matter which may be alleviated with adrenal support. Adrenal insufficiency is present in 85% of the childhood cerebral forms and in about 70% of the adult forms of adrenoleukodystrophy and may contribute to white matter lesions in multiple sclerosis as well. Since adrenal extracts may also promote corticosteroid-induced stem cell injury, products such the Atrium adrenal extracts should be used several weeks before stem cell therapy to strengthen the adrenal glands.
Interleukin-1:
Mason writes that interleukin-1 beta promotes remyelination and CNS repair through inducing astrocyte and microglia-macrophage-derived insulin-like growth factor-1.
Interleukin-10:
Interleukin-10 was found to protect against oligodendroglial death evoked by lipopolysaccharide and interferon-gamma. IL-10 downregulates the function of inflammatory cells and promotes survival of progenitors and differentiated oligodendrocytes.
Immunoglobulin Therapy:
High-dose intravenous immunoglobulin (IVIg) treatment is being used for inflammatory demyelinating disease. The treatment protects oligodendrocyte precursor cells and oligodendrocytes by inhibiting inflammatory mechanisms. Unfortunately, it has a high cost, needs to be given every three weeks and does not result in remissions.
Growth Factors
Glial Growth Factor:
Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of oligodendrocytes. Mice with experimental autoimmune encephalomyelitis were treated with recombinant human GGF2 during both acute and relapsing phases leading to increased remyelination, decreased symptom severity and statistically significant reductions in relapse rate.
Granulocyte Colony-Stimulating Factor and Stem Cells:
Telomere length decreases with cell divisions and age, and at a crucial length is associated with chromosomal instability and cell senescence (death). Telomerase is a reverse transcriptase enzyme that adds nucleotides to chromosomal ends. Resting hematopoietic stem cells retain low levels of telomerase and long telomeres. Chemotherapy and stem cell transplantation may lead to the accelerated shortening of telomere length. Szyper-Kravitz and associates found that granulocyte colony-stimulating factor upregulates telomerase activity in CD34(+) hematopoietic cells (thereby lengthening the telemeres) and prevents telomere attrition after chemotherapy.
Uric Acid:
Uric acid suppresses the MS animal model of experimental autoimmune encephalomyelitis. In a study involving humans, the MS patients were found to have lower average serum uric acid levels than the controls. Scott and associates have shown that uric acid selectively inhibits peroxynitrite-mediated activity in multiple sclerosis and improves experimental autoimmune encephalomyelitis in mice.
Glatiramer acetate has been approved by the FDA for use in the relapsing-remitting (RR) form of MS, and may improve clinical symptoms by increasing uric acid levels. However, the drug can have adverse effects. Chlorella and/or inosine may also be effective but with fewer side effects. High copper levels induce low levels of uric acid while also having a pro-inflammatory effect. Thus a low copper diet may be indicated. Vitamin B2 is a cofactor for xanthine oxidase, whose deficiency can also contribute to low uric acid levels.
Inosine:
Inosine is a precursor of uric acid. High levels of inosine given to 11 MS patients stopped the progression of disease in all of the patients and improved clinical symptoms in 3 of the patients.
Chen and associates found that the administration of inosine to rat models for experimental stroke resulted in significant axonal rewiring and improved motor function and may therefore also improve axonal growth in MS patients. Further work concluded that the mode by which inosine is effective in experimental allergic encephalomyelitis is via its metabolic conversion to uric acid.
Chlorella:
This single-cell fresh water detoxifying algae raises uric acid levels safely and consistently and should be considered by any person with MS.
Creatine:
Phosphocreatine increases ATP regeneration which is important in supporting remyelination by oligodendrocytes.
Vitamin B12 Injections (Methylcobalamin rather than cyanocobalamin):
Cyanocobalamin activates glutamate receptors and promotes inflammation. Methylation is important in remyelination. Methyl donors include folate, betaine, methione and S-adenosylmethionine. Vitamin B12 deficiencies are associated with demyelination and axonal degeneration. Methylcobalamin also improves evoked potentials and nerve regeneration.
Ginseng:
Ginseng increases Nerve Growth Factor which stimulates the growth of new oligodendrocytes.
Gingko biloba:
Gingko biloba contains factors that stimulate Glial Cell Line-derived Neurotropic Factor in astrocytes. However, Gingko may also inhibit cytochrome P450 metabolism of other medications.
Vitamin A:
Retinol levels for untreated relapsing-remitting (RR) MS patients was found to be lower than for patients with noninflammatory neurological disease. All-trans-retinoic acid (in cod liver oil) increases Ciliary Neurotrophic Factor, which is important in oligodendrocyte maturation and myelin production. Retinoic acid also promotes myelin immune defense.
Moderate sunshine/vitamin D:
Vitamin D is associated with alleviating autoimmune disorders. Vitamin D stimulates Brain-Derived Neurotropic Factor which protects thymocyte precursors and regulatory feedback mechanisms involved in thymocyte differentation and immune function.
Recapitulation
Among their tools for evaluating the progression of MS, scientists are increasing the number and specificity of identifiable biomarkers, especially those derived from blood and cerebrospinal fluid. A greater understanding of the precise mechanisms governing inflammation, demyelination, oxidative stress, axonal damage, and remyelination will improve not only the treatment and management of the disease but also the diagnostics and stratification of subcategories of MS, and of their various stages.
In 2001, the National Institute of Medicine, which serves as the federal technical and scientific advisory agency, published a strategic review of MS research, entitled, "Multiple Sclerosis: Current Status and Strategies for the Future (2001)". In this report, the complexity of the disease is addressed in detail, and may be succinctly summarized herein as follows:
"Several pathophysiological processes such as inflammation, demyelination, axonal damage and repair mechanisms contribute to the complex manifestation of MS. These processes are not uniformly represented across patient populations and can selectively predominate in individual patients."
(From: http://newton.nap.edu/books/0309072859/html/17.html. A copy of the report may be downloaded at this website).
Indeed, the heterogeneity in phenotypic expression of this disease contributes to the difficulty of prognosis, and to the lack of consistency among patients in therapeutic response, and to the lack of reliability of conventional therapies. Further development is needed in the use of non-imaging biomarkers such as gene expression and fluctuations in biomolecules that include radicals, lipids and peptides. Longitudinal as well as cross-sectional studies must continue to investigate and dissect the myriad cellular mechanisms involved in MS, such as the numerous antigens and cytokines and their many roles in the progress of the disease. Additionally, scientists must continue to develop new, more precise diagnostic tools, such as those that would combine MRI with genomics and proteomics - which is the large-scale, 3-dimensional study of proteins, and in particular of how protein function is determined by form, and how characteristics such as folding and helical properties influence interactions with other molecules. From studies in genomics it is now understood that protein expression cannot be characterized by gene analysis alone, since there exist significantly fewer protein-encoding genes in the human genome than there are proteins in the human proteome, by approximately a factor of 5; and therefore proteomics is increasingly seen as an essential analytical tool in understanding health and disease.
The Institute of Medicine report further recommends continued investigation into the precise relationship of axonal injury and demyelination to inflammation, to the various cytokines, and to the role of cell- and antibody-mediated immune mechanisms. The roles of T cells and B lymphocytes, and the autoantigen known as "myelin basic protein" (MBP), also require further understanding. Recommendations also encourage research toward the "delineation of the detailed nature of the secondary injury cascade that underlies calcium-mediated damage of axons within white matter, and improved understanding of the molecular mechanisms underlying restoration of conduction in demyelinated axons, with particular attention to identification of the sodium channel subtype(s)." (From: http://newton.nap.edu/books/0309072859/html/17.html.
Regarding the combination and improvement of diagnostic technologies, magnetic resonance imaging (MRI) is often used to detect the lesions of MS, although other modes of imaging are being explored. "Magnetization transfer imaging" (MTI) may be used to detect white matter abnormalities, such as damaged and demyelinated nerves, before the resulting lesions are visible on MRI scans. Similarly, "diffusion-tensor magnetic resonance imaging" (DT-MRI or DTI) measures the random motion and diffusion of water molecules in 3-dimensional images, and changes in the behavior of water within brain tissue can be measured and correlated with the progression of MS. "Functional MRI" (fMRI) uses radio waves in combination with the strong magnetic field of MRI to measure physical changes in the brain, such as blood flow, and to correlate these changes with various mental functions as they are exhibited during the performance of specific cognitive tasks. The recording of "visual evoked potential" (VEP), in which the speed of the brain's response to visual stimuli is measured, has been found to be relevant to MS diagnosis, although auditory and sensory evoked potentials are no longer considered relevant. Even VEPS, in and of themselves, are inconclusive in the diagnosis of MS, and are only useful when combined with other tests.
Despite the complexity of diagnosing and understanding MS, however, one of the central questions in the treatment of MS remains the same: namely, how to promote myelin repair.
In this regard, stem cell therapy offers a safe and effective treatment of a disease which previously has had no such options.
Multiple Sclerosis Overview
According to the website of the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health (NIH), multiple sclerosis is defined as follows:
"An unpredictable disease of the central nervous system, multiple sclerosis (MS) can range from relatively benign to somewhat disabling to devastating, as communication between the brain and other parts of the body is disrupted. Many investigators believe MS to be an autoimmune disease - one in which the body, through its immune system, launches a defense attack against its own tissues. In the case of MS, it is the nerve-insulating myelin that comes under assault. Such assaults may be linked to an unknown environmental trigger, perhaps a virus."
(From the website of the National Institute of Neurological Disorders and Stroke).
As the website also states, "There is as yet no cure for MS," and "there is no universally effective treatment."
The exact causes of MS have also not yet been discovered. The name itself, "multiple sclerosis", describes the numerous "sclerotic", or hardened, lesions and scars that form in the brain and spinal cord as a result of the destruction of myelin, oligodendrocytes and axons throughout the central nervous system. As an inflammatory, autoimmune, and demyelinating disease of the body's primary communication pathway, namely, the central nervous system, MS has typically been one of the most difficult diseases to treat and to understand.
Although the first formal diagnosis of MS appeared in 1849, other possible cases of MS were documented in Holland as early as the 14th century. It is estimated that between 250,000 and 350,000 people in the U.S. currently suffer from multiple sclerosis. A more exact number is difficult to calculate with certainty since many cases often go either undiagnosed or misdiagnosed for years. As described on the NINDS website for multiple sclerosis, "...doctors may not be able to readily identify the cause of the symptoms, leading to years of uncertainty and multiple diagnoses punctuated by baffling symptoms that mysteriously wax and wane."
(From the website of the National Institute of Neurological Disorders and Stroke).
There is no single test with which to detect the disease. This lack of a single, reliable, test-specific diagnostic tool also makes verification of MS difficult. A valid diagnosis of MS is usually possible only after changes in the brain are visibly detectable by scanning methods, and even then, the lesions that are visible could be indications of other diseases instead of MS.
In the U.S. alone, approximately 200 new cases of MS are diagnosed each week. The disease usually strikes people between the ages of 20 and 40, with the first symptoms often manifesting as vision problems, such as blurred or double vision, red-green color distortion, or even blindness in one eye. Other initial symptoms may include muscle weakness in the extremities, extreme general fatigue and problems with balance and coordination, which worsen over time. Walking and standing may be impaired, and in its more severe forms MS may result in partial or complete paralysis. Various types of pain or paresthesia, such as numbness or the sensation of "pins and needles", are also not uncommon, along with speech impediments, tremors, vertigo or dizziness. Hearing loss is an occasional occurrence, and approximately half of all people with MS experience some form of cognitive impairment such as difficulties with concentration, attention, memory, or poor judgment. Depression is common among people with MS.
Both environmental factors and genetics are believed to play strong roles in the development of the disease. Regarding environmental factors, scientists periodically receive reports of MS "clusters", in which unusually large numbers of people within the same region develop MS within the same general time frame. As described on the NINDS website for MS,
"The most famous of these MS 'epidemics' occurred in the Faeroe Islands north of Scotland in the years following the arrival of British troops during World War II. Despite intense study of this and other clusters, however, no direct environmental factors have been identified."
Regarding possible genetic factors, the NINDS website on MS reports that,
"Some populations, such as Gypsies, Eskimos and Bantus, never get MS. Native Indians of North and South America, the Japanese, and other Asian peoples have very low incidence rates. It is unclear whether this is due mostly to genetic or environmental factors."
(From the website of the National Institute of Neurological Disorders and Stroke).
Perhaps one of the most significant factors related to MS, however, is economic. In all but the most extreme cases, MS does not significantly alter life expectancy; consequently the medical, social and economic costs associated with the disease can be significant. In the U.S. alone, the annual cost of MS, not only in terms of medical expenses but also in terms of lost work incurred by those who suffer from MS, has been estimated in the billions of dollars.
Most people who have been diagnosed with MS experience "relapsing-remitting" (RR) episodes of their symptoms, which worsen over time as the neurological deterioration underlying the symptoms also worsens. Other people experience a more progressive degeneration of the disease, known as "primary-progressive" (PP), which lacks distinct periods of remission although there may be some temporary plateaus. A "secondary-progressive" (SP) form begins as relapsing-remitting (RR) and develops into primary-progressive (PP). A more rare form of the disease, known as "progressive-relapsing" (PR) is characterized by progressive worsening of the disease punctuated by acute attacks. PP, SP and PR are sometimes lumped together as "chronic progressive" MS.
Regardless of the particular type of MS, conventional therapies typically focus on an alleviation of symptoms through immuno-modulation or immunosuppression. Until very recently, however, the characteristic scarring and "sclerosis" have usually remained irreversible.
In MS, inflammation is found in "plaques" that appear to be scattered randomly throughout the white matter of the central nervous system. These plaques are associated with the destruction of myelin, which is the fatty covering that insulates nerve cell fibers in the brain and the spinal cord, and which serves as the electrical conductor for the electrochemical messages that flow between the brain, the spinal cord and the rest of the body. When this myelin is damaged, the high-speed transmission of these neurological messages may be slowed or interrupted completely, leading either to diminished or lost function.
As with other neurologically pathological conditions, such as cerebral palsy and stroke, the National Institute of Neurological Disorders and Stroke (NINDS) is a primary funder of research into MS. Along with other institutes at the National Institutes of Health (NIH), NINDS conducts research in their own laboratories at NIH while also supporting additional research through grants that they bestow to major medical institutions and to research organizations throughout the United States.
Thus far, drug therapy has typically been the only available form of treatment for MS, and most of the research that is funded by NINDS is directed toward the development of new, more effective drugs.
It has been found that interferons, which are naturally occurring antiviral proteins, are somewhat helpful in reducing the severity of the symptoms of multiple sclerosis, although the course of the disease itself remains unchanged. Beta interferon in particular has been shown to reduced the frequency of recurrence of the symptoms in the relapsing-remitting form, and there is some evidence to indicate that it may also slow the disease's progression. Currently there are three forms of beta interferon - Avonex, Betaseron, and Rebif - which have been approved by the Food and Drug Administration (FDA) for treatment of the relapsing- remitting form of MS. The FDA has also approved a synthetic form of "myelin basic protein", known as "copolymer I" (Copaxone), which is also used in the treatment of relapsing-remitting cases of MS. For treatment of the more advanced and chronic MS cases, an immunosuppressant treatment, Novantrone (mitoxantrone), has been approved by the FDA. Alpha interferon is also being studied as a possible treatment for MS, although a number of side effects have been observed.
Spasticity, which may accompany the chronic and advanced forms of MS, is typically treated with muscle relaxants and tranquilizers such as baclofen (Lioresal), tizanide (Zanaflex), diazepam (Valium), clonazepan (Klonopin), and dantrolene (Dantrium).
Amantadine (Symmetrel), pemoline (Cylert) and aminopyridine, the latter of which is still in the experimental stage, have been found to reduce fatigue in some, but not in all, patients. The optic neuritis that accompanies MS is usually treated with methyl-prednisolone (Solu-Medrol) and oral steroids. For pain, MS patients are prescribed aspirin or acetaminophen, antidepressants, and codeine. Cases of trigeminal neuralgia are treated with Carbamazapine and other anticonvulsants. Sexual dysfunction in male MS patients is treated with papaverine injections. Since psychological problems such as depression, apathy and mental fatigue are common among those suffering from MS, antidepressant medication is frequently prescribed in combination with other forms of drug therapy to alleviate these symptoms.
Therapies that are still in the experimental stages include cyclosporine (Sandimmune), cyclophosphamide (Cytoxan), azathioprine (Imuran), cladribine (Leustatin), methotrexate and "total lymphoid irradiation" - a process by which the lymph nodes of the MS patient are irradiated with x-rays in small doses over several weeks, with the intent of destroying lymphatic tissue.
It is believed that people with MS should avoid excessive activity and heat, although a carefully designed physical therapy regimen is often helpful in preserving whatever remaining physical function the individual may have. Some patients may find that physical aids such as canes, walkers and foot braces may also be useful.
Conventional medical treatments for MS may often include the use of steroids, which are believed to reduce the severity and duration of episodic symptoms in some patients. However, it has been demonstrated in animal studies that corticosterone significantly reduces the proliferation of oligodendrocyte precursors throughout the white and gray matter regions of the brain. Since oligodendrocyte precursors play a major role in remyelination, the use of anti-inflammatory therapies may actually perpetuate and exacerbate brain injury in MS. (Please see the section on "Depression and Stem Cell Therapy", below). Nevertheless, corticosteroids are often prescribed for MS patients with depression, and oral steroids accompanied by methylprednisolone (Solu-Medrol) are often prescribed for the treatment of the visual problems, such as optic neuritis, which frequently accompany MS.
None of these drugs, however, have been able to stop or reverse the sclerotic lesions and scars that form throughout the nervous system as a result of MS. Despite that fact, additional drugs are continually being formulated and tested in animal models, and as of 2006 there are more than a dozen clinical trials underway in the U.S. in which even more newly developed drug therapies are being tested on MS patients.
As with all forms of prescribed drugs, side effects and contraindicating factors are important considerations. As stated on the NINDS website for multiple sclerosis, "many medications have serious side effects and some carry significant risks." (From the website of the National Institute of Neurological Disorders and Stroke). Additionally, while immuno-modulating and immunosuppressing drugs may alleviate some of the symptoms in any disease, the mere process of modulating or suppressing the immune system in and of itself has often been found to cause other problems. Especially with autoimmune disorders in general, any treatment that is employed must be prescribed with extra consideration for immunological integrity, and with extra caution toward compromising the immune system any further than it already is. In the case of MS, a regenerative treatment, and one which enhances rather than suppresses the immune system, is urgently needed.
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