Alternative Therapies for Multiple Sclerosis

8/8/2019 Alternative Therapies for Multiple Sclerosis

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Alternative Therapies for Multiple

Sclerosis

By David Steenblock, M.S., D.O. and Lyn Darnell

This review is for educational purposes only and is not intended to be a substitute foryour physician's advice.

Multiple Sclerosis (MS) is an inflammatory, autoimmune, demyelinating disease of the central nervous systemthat destroys myelin, oligodendrocytes, and axons (14). Oligodendrocytes are white matter cells that produce

myelin for the myelin sheath, a protective covering around nerve fibers that speeds neural transmission. Axons

are nerve fibers that conduct nerve impulses away from a neuron. Between 250,000 - 350,000 people in theUnited States suffer from Multiple Sclerosis. The name relates to the multiple hardened (sclerotic) lesions and

scars in the brain and spinal cord. Initial symptoms may include extreme fatigue, vertigo, optic neuritis, andnumbness in the extremities. Most patients experience relapsing-remitting episodes that over time can lead to

progressive neurological deterioration.

MS lesions are found in various stages in MS, from new, active lesions to old but inactive lesions. Lucchinetti

and associates analyzed MS tissues from human biopsies and autopsies and found four distinct lesion patterns

Therefore, four distinct causes may be involved in MS.

Pattern I showed autoimmune destruction mediated by T-cells and antibodies. Lesion edges were sharply

demarcated and located around veins. Active demyelination was associated with inflammation but also present

was remyelination and the preservation of oligodendrocytes. In the injured myelin sheaths, all myelin proteins

were lost at the same rate.

Pattern II lesions were the same as Pattern I but with the addition of IgG deposition and activated complement.

Pattern III lesions were similar to viral or toxin-induced oligodendroycte dystrophy. Lesions were not around

veins and lesion borders were diffuse and irregular. Lymphocytes and activated myeloid cells were detected but

activated complements of IgG were not. The myelin sheaths showed a loss of Myelin Oligodendrocyte

Glycoprotein (MOG). Oligodendrocyte death from apoptosis was prominent.

Pattern IV lesions were similar to those of Pattern III, except oligodendrocyte death appeared necrotic.

In the 83 cases analyzed, pattern II lesions were most common and characteristic of relapsing, remitting disease.Pattern IV lesions were found in patients with primary progressive disease and pattern III lesions were seen as"starter" lesions capable of converting to another pattern. Brain regions unaffected by inflammation and neurons

with intact myelin sheaths also showed axonal damage (13).

In the central nervous system, microglia are tissue macrophages (immune cells) which have the ability to

regulate and be regulated by immune cells (lymphocytes, macrophages, B cells) and stromal cells (neurons and

glia). Microglia are found throughout the central nervous system and participate in the onset and progression of


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CNS inflammatory responses. Microglia, when activated, are highly damaging to CNS function through theirproduction of neurotoxins, inflammatory cells (Inflammatory Protein-10, Macrophage Inflammatory Protein-1

Macrophage Inflammatory Protein-2, C-C Chemokine Ligand 19, Monocyte Chemoattractant Protein-1

Monocyte Chemoattractant Protein-2) and immune cells that produce antibodies. Microglia direct inflammatoryresponses that can result in the brain and spinal cord being infiltrated with immune cells against foreign

invaders as well as T-cells that destroy myelin proteins.

Microglia also limit inflammation by producing neuroprotectants and immunosuppressive factors. Whetheractivated microglia produce growth factors or neurotoxins such as nitric oxide and excess glutamate depends on

the signals received from neurons, T cells, glia and macrophages (13). The destruction may be further enhanced

by the presence of heavy metals, viruses and endotoxins. These factors contribute to a downward cycle of local

inflammation, demyelination and axonal damage, which results in further inflammation, demyelination and

axonal damage.

Current therapies for MS are designed to delay disease progression by immuno-modulation or

immunosuppression. Until recently, the persisting neurological damage has remained mostly irreversible

Today, there is increased optimism about slowing and perhaps reversing the disease with a comprehensiveprogram that includes therapies that improve blood circulation, myelin regeneration, cell energy production, gut

normalization, and dietary, anti-inflammatory, antimicrobial, immune-modulating and antioxidant factors.

Improved Blood Circulation

Reduced oxygen levels are found in MS patients and those patients with advanced cerebral atrophy havesignificantly reduced cerebral blood circulation and oxygen concentrations.(114) Increased ischemia (lack of

blood flow) and hypoxia (lack of oxygen) can contribute to a vulnerable blood-brain barrier, allowing the entry

of pathogens and toxins.

Hyperbaric (high pressure) oxygen improves the delivery of oxygen to damaged tissues in the brain and speedstheir repair. Pressurized oxygen offers the following benefits:

1. Increases oxygen delivery to injured cells and tissues.

2. Reduces swelling and inflammation.

3. Increases the formation of new blood vessels to injured tissue.

4. Improves wound healing.

5. Improves the body's resistance to infections.

6. Renews damaged neurons and their axons and dendrites.

7. Speeds the elimination of toxins.

Most trials using hyperbaric oxygen for MS are for a month with higher pressures (1.75 - 2.5 ATA) but longer

treatments at low pressures (1.2-1.5 ATA) may be more effective in reducing hypoxia and ischemia while


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reducing the risk of free radical generation caused by higher pressures. Long term HBOT within a

comprehensive program that includes antioxidants may show more promise in promoting remission.(46)

With hyperbaric oxygen therapy, the patient is placed in a chamber and breathes 100% oxygen by mask while

the pressure in the chamber is increased to 1.5 - 2.0 times the normal atmospheric pressure. This therapy

provides a significant increase in oxygen delivery to the brain compared with that received by breathing air atnormal pressure. Damaged brain tissue, either from immune attacks, infections, or toxins, is also hypoxic tissue

(lacking oxygen). Hyperbaric oxygen pushes oxygen into the plasma (the liquid portion of the blood) and fromthe plasma, the oxygen diffuses into the white and grey matter of the brain, fights infection, reduces

inflammation and speeds wound healing. Oxygen may also be beneficial for myelin production at low pressures

of 1.5 ATA or 1.5 times the atmospheric pressure at sea level by supporting neural stem cell differentiation and

the production of oligodendrocytes. We would like to see more research done in this area, especially in

combination with ECP.

External Counterpulsation (ECP) is a fairly new non-invasive alternative to heart surgery for some conditions of

heart disease. ECP is FDA approved for the treatment of angina and congestive heart failure. The device pumps

blood from the legs back to the heart. In the process, ECP also increases the blood supply (and thereforeincreased oxygen and nutrients and the removal of waste products) to other organs such as the brain, liver and

kidneys. (112,115) It has been our experience that ECP, in combination with hyperbaric oxygen, improves brain

function in patients with stroke and brain injuries and may also prove to be beneficial in MS cases as well.

Stem cell therapies show great promise as a treatment for MS. However, the causes of myelin degenerationneed to be addressed before the stem cells are given to maximize stem cell growth, migration, differentiation

and renewed function.

Stem Cells and Multiple Sclerosis

CD34+

CD34 refers to an adhesion structure expressed on embryonic fibroblasts and nervous tissue. CD34+ stem cellsare primitive, undifferentiated cells of the embryo, bone marrow, umbilical cord blood and adult tissue that have

the capacity to differentiate into hemopoietic cells as well as a variety of other cells, including neurons and glial

cells.

The "First Cell" (fertilized egg) at the beginning of life is "totipotent," capable of generating every other cell of

the body. When this First Cell divides into three embryonic layers (the ectoderm, mesoderm and endoderm), the

daughter cells become "multipotent", able to transform into a variety of cell types, but unable to make an entire

individual. CD34 (+) is a purified multipotent stem cell found in bone marrow and umbilical cord blood. These

stem cells are capable of "homing" to an injured area where they move into the tissue and proliferate into thespecific cells needed to repair the tissue. CD34(+) cells, and especially its CD133 subset, are capable of

balancing the immune system as well as transforming into neuroprotective glia and myelin-producingoligodendrocytes and astrocytes. Such potency makes CD34+ stem cells a valuable treatment modality in

immune disorders of the central nervous system such as Multiple Sclerosis.

Mesenchymal Stromal/Stem Cells


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Mesenchymal stem cells are also multipotent cells,found in the bone marrow and umbilical cord blood. Theyare able to differentiate into adipocytes, condrocytes, osteocytes and neuronal/glial cells when specific growth

factors are used. Mesenchymal stem cells help M.S. by releasing growth factors that protect the nerves and

stimulate the growth of new neurons. Mesenchymal stem cells help support the matrix that supports neurons

and they also reduce inflammation.

Dr. Ramirez is treating patients with umbilical cord blood derived CD34+ and mesenchymal stem cells in

Tijuana, Mexico. To date, these treatments twice a year have been able to slow the progression of M.S. and help

people continue to work and be active.

Dr. Steenblock is now providing bone marrow treatments where a person's own CD34+ and mesenchymal stemcells are used for brain repair. Bone marrow blood is extracted from the leg and then transfused into the arm and

bloodstream. Several patients with M.S. have benefited from this procedure and one has not. It is important thatheavy metals, pesticides, viruses, etc. be eliminated before this treatment or any treatment to maximize the

benefits of the circulating stem cells.

Remyelination Studies

Since 1965, scientists have observed spontaneous myelin repair. However, the many factors involved in

promoting a more profound repair than what occurs naturally and maintaining that repair are still being

investigated.

In the relapsing-remitting pattern, some remyelination is observed. Spontaneous remyelination is thought to be

caused by 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.

In the progressive degeneration pattern, oligodendrocytes are destroyed. Implants of oligodendrocyte progenitorcells into MS patients have been successful. However, while Schwann cells also promote remyelination, their

implants have a greater risk of fibroblast overgrowth that subsequently can destroy axonal pathways. Glial cell

implants have had good results in creating oligodenrocytes (6).

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 or spinal cord, exclusively intothe 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 authors

conclude that the inflammatory process may attract the migration of transplanted precursor cells into the

brain parenchyma (connective tissue network) (5).

The effectiveness of stem cells in treating autoimmune disease was observed in patients who received

hematopioetic stem cell transplants for leukemia and aplasia who also suffered from severe autoimmune

disorders (lupus and rheumatoid arthritis).

In 1998, Burt and coworkers treated 10 patients having 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. CD 34+ stem cells were reinfused after either myelosuppressive conditioning with


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cyclophosphamide, methylprednisolone and antithymocyte globulin or myeloablative conditioning with totalbody irradiation, methylprednisolone and cyclophosphamide. Regimen-related nonhema-topoietic toxicity was

minimal. All patients improved or had stabilization of 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 (10).

Dr. Ouyang and associates of Nanjing University School of Medicine, China demonstrated positive results in a

patient with progressive multiple sclerosis who received an autologous peripheral blood stem celltransplantation. The patient showed clinical remission and there was no relapse at the 6 month follow-up. The

authors conclude that auto-Peripheral Blood Stem Cell Transplantation is effective and safe for progressive

multiple sclerosis (73).

An MRI study of MS patients who received hematopoietic stem cell transplantations showed disappearance ofbrain lesions 18 months after the transplant. These findings correlated with clinical stabilization in the patients

(83).

In a multicenter Phase II study by Fassas and coworkers investigating autologous hematopoietic stem celltransplantation 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 18patients (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 (25).

In a Phase II report by Fassas and associates, the authors used CD34+ cell transplantation in 15 Multiple

Sclerosis patients. Patients were selected who had advanced secondary progressive or relapsing-remitting 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, and Acyclovir, Pentomidine, and TrimethoprimSulfamethoxzaole 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 andremained 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 conditioning regimen can be viewed as having an acceptable toxicity and

effectiveness in reducing the progression of Multiple Sclerosis (12).

Umbilical Cord Derived Stem Cells

These results using peripheral blood stem cell mobilization techniques with powerful immune suppressantsantibiotics, antifungals and steroids had a number of side effects with only marginal effectiveness. One factor is

that some of these medications actually inhibit stem cell growth and proliferation. When compared with the

case studies to date of umbilical cord CD34+ stem cell transplantation given without additional medications, the

umbilical cord stem cells show much greater success with virtually no side effects. Immune defenses in theblood of a fetus have to be compatible with the mother, so immune defenses are suppressed. Stem cells from

umbilical cord blood have the advantage of having little or no antigens to cause immune reactions in the

recipients and are therefore the safest stem cell for transplantation (if tested by American Association of Blood

Banks standards).


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The Steenblock Research Institute has followed several MS patients who were given umbilical cord stem celltreatments by Dr. Fernando Ramirez in Mexico. No side effects were reported. At first, the patients were given

1.5 million CD34+/CD133+ stem/progenitor cells. Improvements were seen in several patients but only for

about four months and then another treatment was needed. Since then Dr. Ramirez has been using larger dosesof cord stem cells and with additional combinations. New combinations have included mesenchymal cells from

umbilical cord blood and cord stem cells with a fyn gene. The fyn gene increases the production of myelin baseprotein for the remyelination of axons. Better results have also been seen with catheter delivery of the cells

more directly into the brain.

Jim Haverlock has been struggling with multiple sclerosis for over twenty years. In 2003, his quest for more

effective treatments led to cord stem cells. His story is available now in the book "Challenging the Dragon,"

available at Amazon.com.

A Comprehensive Stem Cell Program for MS

Stem cells seem to have the ability to greatly assist in regenerating the glial cells injured and destroyed in MS

Care must be taken for several months after stem cell administration to avoid products that inhibit stem cellgrowth and differentiation to neural progenitors. Such products include cortisone, alcohol, cigarettes, cocaine,

air pollution, pesticides, and monosodium glutamate. Physical and emotional stress also indirectly increaseglutamate, which is toxic to neural stem cells and can damage neurons in the hippocampus, the area of learning

and memory.

Depression and Stem Cell Therapy

One of the symptoms of Multiple Sclerosis is depression. A new model of depression is emerging that relates

the consequences of stress to the inhibition of neural stem cell growth in the hippocampal dentate gyrus, an area

of learning and memory as well as stem cell production in the brain (43). Factors such as stress-related adrenal

hormones (glucocorticoids) that inhibit stem cell growth also seem to induce depression. The glucocorticoidsstimulate corticosterone, an immune suppressant, that stimulates the production of glutamate which is toxic to

neural progenitor cells.

In animals studies, corticosterone significantly reduces the proliferation of oligodendrocyte precursorsthroughout the white and gray matter regions of the brain (2). Since oligodendrocytes play a major role in

remyelination, the use of immune-suppressive therapies may actually perpetuate depression as well as brain

lesions. In contrast to the use of steroids for treating MS, stem cell therapies promote the proliferation of newoligodendrocytes, with the secondary benefit of alleviating depression. Generally, depression clears within 30

days after umbilical cord stem cell treatments.

Cell Energy Production

The mitochondria are the energy factories of the cell. Providing sufficient amounts of the precursors for ATP

(adenosine 5'-triphosphate) will help the cell defend itself against toxic injury. Nutritional support for themitochondria include acetyl-L-carnitine, lipoic acid, creatine, magnesium, coenzyme Q10, vitamin C, vitamin E

succinate, biotin, thiamin (vitamin B1), riboflavin (B2), niacinamide (amide of B3) and pantothenic acid (B5).

Spices that can reduce Complex I activity include cloves and cinnamon. Biochemical defects in Complex I may

be a factor in multiple sclerosis.


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There are several pathways that can trigger programmed cell death. The first is the mitochondria being depletedof ATP and being overrun with free radicals. Free radical damage leads to increased glutamate which stimulates

its NMDA receptors to open its channels to calcium influx. The calcium influx then initiates programmed cell

death, where proteases destroy the cell protein bonds, breaking up the cell in small enough pieces to be engulfed

by immune cells called phagocytes. Antioxidants can help prevent free radical damage in the mitochondria.

The second is injury to the extracellular matrix that supports the neurons. Elevated levels of MMP-2 and MMP-

9 can reflect increases in matrix degradation and subsequent apoptosis or programmed cell death of the neuronsNutrients that support the extracellular matrix include vitamin C, zinc metallothionine, alpha-ketoglutarate

glycine, proline and hydroxyproline.

NMDA receptors on the myelin sheath can promote cell injury to axons and reducing free radical damage and

glutamate toxicity can help reduce myelin damage. Garlic, magnesium, boron, DHA sulphate, lipoic acid, and

n-acetyl-cysteine can help modulate glutamate-NMDA activity.

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 (9). In most cases, folate and methylcobalamin injections improve MS symptomsand 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 (8).

Autoimmune Disease and Patterns of Relapsing-Remitting Episodes

The first two patterns of lesions observed in Lucchinetti's research were most common and resembled the

autoimmune destruction observed in T-cell mediated and antibody-augmented forms of experimentalautoimmune encephalomyelitis (13).

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 nervoussystem myelin, myelin-associated glycoprotein located on the inside of sheaths in both the PNS and CNS and

which functions in glia-axon interactions, and myelin-oligodendrocyte glycoprotein (MOG) located on the

outside of CNS myelin sheaths. MOG appears to be an important target antigen in multiple sclerosis (78).

Autoimmune T-cell responses to myelin components are being investigated for their role in initiating and/ormaintaining inflammatory responses resulting in myelin destruction. Myelin oligodendrocyte glycoprotein

(MOG) is a myelin protein that can elicit greater anti-MOG B-cell responses in MS patients (42). In another

study, MOG elicits similar T cell responses in MS patients and controls but with different cytokine activity. TheMS samples elicited increased levels of Tumor Necrosis Factor-alpha (TNF-alpha) compared to the control

samples (105). Tejada-Simon and associates found that MS patient MOG samples elicited anti-MOG antibodies


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reacting predominantly to the extracellular 1-60 region while control samples elicited anti-MOG antibody

reactions to the transmembrane/cytoplasmic domains (residues 154-218) (100).

Autoimmune reactions have also been shown against cardiolipin (important in heart mitochondrial function)

and DNA in MS patients (91).

Patterns resembling Virus and Toxin-induced Immune Responses

Pattern IV was found only in patients with primary progressive disease and patterns III and IV both resembled

viral or toxin-induced oligodendrocyte dystrophy.

Mercury Toxicity

Mercuric chloride is toxic at low concentrations to oligodendroglial cells, resulting in cell death throughapoptosis. (37). 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, compromisedimmune function and cardiovascular disease (79). Mercury levels are often elevated in MS patients, and may

result from a variety of sources.

1. 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 beused to monitor MS include CSF, S100B and Glial-Fibrillary Acidic Protein (GFAP) (35). 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 (75).

2. Mercury contamination in fish and soil . Mercury is a major environmental concern, traditionally infreshwater 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 (66). Shark and Swordfish are

reported to have the highest methyl mercury levels, and shrimp, scallops and salmon the lowest concentrationsin ocean fish (33). Fish farms may not be safer than ocean fish. Fish farms may be producing fish with higher

pesticide and mercury concentrations due to the use of contaminated feed sources (22).

3.Elevated insulin levels allow the cellular entry of heavy metals. Insulin is elevated by large meals, high sugarand refined carbohydrate diets, and oxidative stress. Antioxidants can help protect the cells from heavy metal

toxicity.

4.Leaky Gut Syndrome can be caused by Candida endotoxins, alcohol, nutritional deficiencies,etc.which allowsheavy metals and macromolecules to enter the bloodstream, causing immune and autoimmune responses, freeradicals, and cell injury and death. An animal study by Keshavarzian and associates demonstrated that

supplementation with oats prevented gut leakiness and endotoxin-induced liver damage (44).

Chelating factors in various foods can prevent mercury absorption, including citric acid, tartaric acid, and

cysteine, (24), selenium (31), garlic (52), chlorella (also an anti-inflammatory) (117), and cilantro (72). Methyl

mercury can bind with L-cysteine and be transported across the blood brain barrier. L-leucine inhibits this


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transport. A balanced leucine/cysteine ratio is found in whey protein (79). Calcium and magnesium are alsoprotective against mercury and methyl mercury toxicity (92). EDTA oral and i.v. 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 is a proven

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 (46).

Medicinal Plants

Ecinacea purpurea and Panax ginseng significantly enhanced Natural Killer activity and antibody-dependent

cellular immunity against human herpesvirus 6 infected cells (87).

Reticulosa

Reticulosa is a peptide-nucleic acid immunomodulator that boosts immune system activity in virally-infectedpatients (51). It has broad-spectrum antiviral activity that includes the stimulation of gamma interferon

interleukin-1, interleukin-6 and Tissue Necrosis Factor-alpha (34). 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 (46).

Sea Cucumber

Sea cucumber (Cucumaria japonica) (102) and coumarins from lemon peels (67) 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 (29) 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 (97).


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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 (11).

Thymus:

Ikehara reports that the success rate of bone marrow transplants in patients over 45 years of age is low, due tothe 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. (36). NatCell Thymus, a thymus extract providing a broad spectrum of thymic peptides(www.atrium-bio.com) is being used successfully to restore immune balance in patients with autoimmune

disease who are not on immune suppressants.

Adrenal Support:

Krenn presents a case of Adrenoleukodystrophy that mimicks the symptoms of multiple sclerosis. Bothconditions include lesions of the white matter which may be alleviated with adrenal support.(49). Adrenal

insufficiency is present in 85% of the childhood cerebral forms and in about 70% of the adult forms of

adrenoleukodystrophy (28) and may contribute to white matter lesions in multiple sclerosis as well. Sinceadrenal 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 (63).

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. (68).

Interleukin-17

Interleukin-17 (Il-17) increases interferon-gamma that promotes nitric oxide synthesis that is toxic to neurons

especially in the presence of free radicals. Il-17 also stimulates the production of interleukin 1B and interleukin-6 and may play a role in inflammatory neurological diseases such as multiple sclerosis.

Interleukin-19

Interleukin-19 (Il-19) assists in the modulation of cytokines to preserve a balance in the system and preventautoimmune disorders. Il-19 was shown to suppress inflammation in the development of experimenta

autoimmune encephalomyelitis in mice.


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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 (96). Unfortunately, it has a high cost, needs to be given every three weeks and does not result in

remissions.

Growth Factors

The more we learn about brain regeneration, the more complex it becomes. Certain growth factors can help

stimulate oligodendrocyte cells and the production of myelin. However, oligodendrocytes and myelin also

inhibit the growth of axons. It would seem that the system has a time for myelin production and a time for

axonal growth. Therefore the alternate use of certain growth factors is suggested.

Glial Growth Factor:

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival ofoligodendrocytes. Mice with experimental autoimmune encephalomyelitis were treated with recombinanthuman GGF2 during both acute and relapsing phases leading to increased remyelination, decreased symptom

severity and statistically significant reductions in relapse rate (59).

Platelet-Derived Growth Factor

Platelet-Derived Growth Factor (PDGF) promotes oligodendrocyte progenitor cell proliferation and maturity

(113).

Neurotrophin-3

Neurotrophin-3 (NT-3) promotes oligodendrocyte progenitor cell proliferation and maturity (113)

Incorporating the gene of NT-3 in umbilical cord derived stem cells may help promote oligodendrocyte

maturation in multiple sclerosis patients.

Leukemia Inhibitory Factor

Leukemia Inhibitory Factor (LIF) can be produced by myelin-reactive T cells in MS patients and is able to

protect oligodendrocytes from tumor necrosis factor alpha-induced programmed cell death.

Insulin-like Growth Factor

Insulin-like Growth Factor promotes maturation in oligodendrocyte precursor cells (113).

Fibroblast Growth Factor 2

Fibroblast Growth Factor 2 (FGF2) inhibits oligodendrocytes and myelin production but stimulates axonal

growth.


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Brain Derived Neurotrophic Factor

Brain Derived Neurotrophic Factor (BDNF) stimulates neural stem cell growth and provides neuroprotection in

the growth and differentiation of neural precursors.

Growth Hormone

Growth Hormone (GH) has been found to be deficient in the cerebrospinal fluid of multiple sclerosis patients

Growth hormone is neuroprotective, supports myelination, and regulates insulin growth factor-1, which helps

the development of oligodendrocyte precursors.

Granulocyte Colony-Stimulating Factor

Granulocyte Colony-Stimulating Factor (G-CSF) has the ability to mobilize bone marrow stem cells. However,with multiple sclerosis, G-CSF can either promote inflammation and exacerbate the symptoms of MS, or it can

act as an anti-inflammatory.

Phospholipids

Lipids, along with myelin protein assist in maintaining a normal myelin structure. Lipids include

sphingomyelin, phosphatidylcholine and phosphatidylserine promote myelin stability. With demyelinationthere is an increase in lipid polyunsaturation and negatively charged phosphatidylserine and a decrease in

sphigomyelin, phosphatidylcholine and sulfaides. This composition allows greater myelin fluidity, reductions in

myelin adhesion, increases in membrane curvature and greater risk of demyelination.

Additional Factors

Uric Acid:

Uric acid suppresses the MS animal model experimental autoimmune encephalomyelitis. In a study involving

humans, the MS patients were found to have lower average serum uric acid levels than the controls. (18). Scott

and associates showed that uric acid selectively inhibits a highly neurotoxic combination of nitric oxide andhydrogen peroxide called peroxynitrite in multiple sclerosis and improves experimental autoimmune

encephalomyelitis in mice (86).

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 (94). Inosine should not be

used in patients prone to gout and arthritis.

Chen and associates found that the administration of inosine to rat models for experimental stroke resulted in

significant axonal rewiring and improved motor function (16) and may therefore also improve axonal growth inMS patients. Further work concluded that the mode of inosine in experimental allergic encephalomyelitis was

via its metabolism to uric acid (87).


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High copper levels induce low levels of uric acid while also having a pro-inflammatory effect. Thus a lowcopper diet may be indicated. Vitamin B2 is a cofactor for xanthine oxidase, and xanthine oxidase deficiency

can also contribute to low uric acid levels (40).

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 (89).

Vitamin B12 Injections (Methylcobalamin rather than cyanocobalamin):

Cyanocobalamin activates glutamate receptors and promotes inflammation. Methylation is important inremyelination. Methyl donors include folate, betaine, methionne and S-adenosylmethionine. Vitamin B12

deficiencies are associated with demyelination and axonal degeneration (15). Methylcobalamin improves

evoked potentials and nerve regeneration (48,50).

Ginseng:

Ginseng increases Nerve Growth Factor which stimulate the growth of new oligodendrocytes (38).

Gingko biloba:

Gingko biloba contains factors that stimulate Glial Cell Line-derived Neurotropic Factor in astrocytesHowever, 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 withnoninflammatory neurological disease (82). All-trans-retinoic acid (in cod liver oil) increases Ciliary

Neurotrophic Factor, important in oligodendrocyte maturation and myelin production (111, 57). Retinoic acid

also promotes myelin immune defense (57).

Taurine:

Taurine is an amino acid that plays a role in cell membrane stability, bile salt formation, calcium homeostasis,

growth modulation, cell osmosis, and modulating inflammation and immune response.

Moderate sunshine/vitamin D:


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Vitamin D is associated with alleviating autoimmune disorders. Vitamin D stimulates Brain DerivedNeurotropic Factor which protects thymocyte precursors and regulatory feedback mechanisms involved in

thymocyte differentation and immune function (60).

Spasticity

Threonine:

Hauser and associates used the amino acid L-threonine with 26 ambulatory MS patients with spasticity.Threonine at a daily dose of 7.5 g reduced signs of spasticity without the side effects of sedation and increased

motor weakness found in anti-spasticity drugs used for MS. Threonine is a precursor for glycine biosynthesis

and may enhance glycinergic postsynaptic inhibition of the motor reflex (32). Also see the section on

magnesium below.

Antioxidants

Free radicals, including peroxynitrite are induced in Multiple Sclerosis. Antioxidants can help protect the neuraltissue from damage, induced by inflammatory cascades that result in free radical pathology and oxidative stress

Nordik investigated the clinical effects of providing dietary advice, vitamin supplementation and fish oil

supplementation to newly diagnosed multiple sclerosis patients. At the end of a two year period, there was asignificant reduction in the mean annual exacerbation rate and the mean Expanded Disability Status Scale

(EDSS) as compared to pre-study values. Plasma total phospholipid n-3 fatty acids increased and n-6 fatty acids

decreased significantly (70). The cod liver oil and fish oils used should be free of heavy metals.

Antioxidants and Tissue Necrosis Factor alpha:

TNFalpha, a pro-inflammatory cytokine, has been associated with demyelinating disorders, including MultipleSclerosis. It reduces the gene expression (PPARdelta), responsible for oligodendrocyte survival and

differentiation in oligodendrocyte progenitor cells. The reduction in PPARdelta gene expression results in

reductions in myelin synthesis, maturation and turnover (17). TNFalpha is inhibited by green tea, curcumin

(85), quercetin (39) and resveratrol (109).

Antioxidants and Lipopolysaccharide

The "leaky gut" syndrome allows bacterial lipopolysaccarides to enter the blood stream. Lipopolysaccharides(LPS) are associated with extensive oligodendrocyte death (53). Several natural products have the ability to

protect the microglia from lipopolysaccharide-induced neurotoxicity. LPS is a component of the bacterial wall

of gram-negative bacteria and is one of the most potent activators of host inflammatory response and tissueinjury. LPS treatment of microglial cells activates both p38 mitogen-activated protein kinase and nuclear factor-kappaB (NFkappaB), with consequent increases in interluekin-1 alpha, tumor necrosis factor-alpha (TNF-

alpha), and nitric oxide (NO) production (55). LPS also increases stress indicators, including plasma

corticosterone and glucose concentrations; alterations in brain oxidative status, including elevatedmalondialdehyde levels (a lipid peroxidation index) and decreases in reduced glutathione; and brain metabolism

disturbances including reductions in ATP/ADP ratios and increases in mitochondrial/cytosolic hexokinase ratios

(45).


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1) Silymarin from milk thistle can reduce LPS-induced superoxide generation and nuclear factor kappaB

activation (110).

2) In in vitro studies, Vitamin E (alpha-tocopherol) activates microglial activity and silences an LPS-activated

NF kappa B signaling cascade. The results suggest that alpha-tocopherol can induce quiescence to pathways

associated with acute or chronic inflammatory conditions in the central nervous system (23).

3) Melatonin functions as an antioxidant and has the ability to protect neurons from lipopolysaccharide-inducedoxidative stress (80). Blue light (420-480 nm) has been found to increase serotonin, a precursor for melatonin

(see Dr. Payne's MS article at http://14ushop.com/wizard/)

4) N-acetylcysteine, a thiol antioxidant significantly reduces LPS-induced ROS production (superoxide anion)TNF alpha levels and NF-kappa B activity in macrophages from mice with lethal endotoxic shock. The levels

approached those of macrophages from the control animals (105).

5) Estrogen and progesterone, at concentrations consistent with late pregnancy, inhibit LPS-induced nitric

oxide and TNF-alpha production by activated microglia, and may contribute to the decreased severity of MSsymptoms associated with pregnancy (21). Dr. Bansil and associates found a relationship between relapsing-

remitting MS in 30 women and hormone fluctuations in the menstrual cycle. Those patients with a high

estrogen to progesterone ratio had a significantly greater number of active MRI lesions than those with a low

ratio (4). Progesterone is a known immune quieting agent.

Foods as Medicine

6) Green Tea, containing catechin and (-)-epigallocatechin-3-gallate (EGCG), has the ability to inhibit

lipoplysaccharide and gamma-interferon-induced oxidative stress (3). Black tea has similar effects from

inhibiting LPS-induced IkappaB kinase and NFkappaB activity (74).

7) Artichoke (118) has protective properties against inflammatory mediators, TNF alpha and LPS, in vitro.

8) Carnosol is a naturally occurring phytopolyphenol found in rosemary. Carnosol functions as an antioxidant

and anticarcinogen. Carnosol significantly reduced LPS-induced nitric oxide and NF-kappa B production in a

dose-dependent manner (56).

9) Quercetin (in onions and garlic) significantly inhibited LPS-induced nitric oxide production and suppressedthe release of NF-kappaB (69).

10) The combination of Ginkgo biloba and quercetin were effective in inhibiting LPS-induced NF-kappa B as

well as TNF-alpha activation (107).

11) Avocado contains antioxidants (persenone A and B) that can inhibit superoxide and nitric oxide generation

induced by lipopolysaccharide and interferon-gamma in mouse macrophage cells (47).

12) Resveratrol in grape juice (red wine's alcoholic content can increase homocysteine levels-(7) hasantioxidant and anti-inflammatory effects. Resversatrol strongly inhibits LPS-induced superoxide radical and

hydrogen peroxide, arachidonic acid release, and cyclooxygenase-2 induction (62).


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13) Curcumin is the active ingredient in Indian curry. It has antitumor, antioxidant, and anti-inflammatoryproperties. Curcumin inhibits two enzymes involved in inflammation, cyclooxygenase-2 (COX-2) and

lipoxygenase (LOX).

Alpha-Lipoic Acid

Alpha lipoic acid was administered to mice with experimental autoimmune encephalomyelitis resulting inminimal inflammation and reductions in demyelination and axonal loss in the spinal cord. Alpha lipoic acid

inhibited the activity of metalloproteinase-9 in a dose-dependent manner. The authors conclude that alpha lipoic

acid is highly effective at suppressing and treating experimental autoimmune encephalomyelitis and does so by

inhibiting T cell trafficking into the spinal cord, perhaps by acting as a metalloproteinase inhibitor (59).

Vitamin E Succinate and all-trans-retinoic acid:

Vitamin E Succinate suppressed Epstein-Barr growth by 87% in vitro and all-trans-retinoic acid blocked

Epstein-Barr activity by 58% in vitro, via transforming growth factor beta (103). Transforming Growth Factor

Beta plays a role in neuronal survival and regeneration in Schwann Cell lesions (64). Vitamin E has directneuroprotective antioxidant effects as well as anti-inflammatory indirect effects. Vitamin E inhibits microglia

activation by suppressing the LPS-induced p38 MAPK and Nfkappa B signaling effects necessary for

microglial activation (55).

Multiple Antioxidant Therapy

Odinak treated 14 patients with relapsing-remitting MS with a combination of antioxidants and neuroprotectors

with various mechanisms of action (lipoic acid, nicotinamide, Acetyl cysteine, Beta-carotine, alpha-tocopheryl

acetate, ascorbic acid, selenium, pentoxifylline, cerebrolysin, and Amantadine hydrochloride for a duration of

one month, twice a year. The treatment resulted in a significant reduction (2-3 times) of relapse frequencies inmultiple sclerosis patients and a decrease of required corticosteroid medication. After antioxidant therapy the

content of lipid peroxide products was significantly reduced and the author recommends antioxidant and

neuroprotective program in relapsing-remitting multiple sclerosis (71).

Autoimmune Suppression

Moderate Sunlight/Vitamin D

Dihydroxyvitamin D3 can either prevent or markedly suppress experimental autoimmune encephalomyelitis

rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. Theanimals also needed to be on moderate to high calcium diets. Vitamin D hormone stimulates transforming

growth factor and interleukin-4 production, which may suppress inflammatory T cell activity (20). In an animal

study using the multiple sclerosis model of autoimmune encephalomyelitis, the administration of 1,25-

dihydroxyvitamin D3 demonstrated rapid clinical improvement in the rats, accompanied by an inhibition ofCD4, MHC class II and type II nitric oxide synthase expression (27). 1,25-dihydroxyvitamin D3 has also been

reported to increase intracellular levels of glutathione, important in protecting neurons from oxidative stress-

induced injury (90).


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In addition, photoimmunology studies have shown that ultraviolet B can specifically attenuate autoimmune

disease processes, perhaps by increasing vitamin D levels (76).

Cyclosporin A is widely used as an immunosuppressant by suppressing cytokine gene expression and inhibiting

T lymphocytes. It may also protect against white matter lesions in stroke during hypoperfusion (108). However,

the use of cyclophosphamide, either alone or in combination with Cyclosporin showed a significant reduction inoligodendrocyte-mediated remyelination in rat spinal cord demyelinated lesions (93).

Anti-inflammatory Diet

Vegan Diets

Quasi-vegan diets are beneficial in the management of rheumatoid arthritis, MS, and SLE (65) In his IntegrativeManagement approach to Multiple Sclerosis, Dr. Kidd suggests a diet low in saturated fats, three fish meals per

week, and the elimination of allergenic foods and products. Small frequent meals are preferable to large three

meals a day. Also avoid animal fats, fried foods, sugars and sweets, and processed and refined foods.

Fresh, whole fruits, vegetables, grains, legumes, nuts and seeds include a synergy of bioavailable nutrientsenzymes, antioxidants and fiber that can retard and reverse age-related declines in cognitive and motor

performance in rats (26) and can be an important component in a total lifestyle program for maximizing

neuronal and cognitive function and reversing disease in humans.

Nicotinamide is a potent inhibitor of inflammation. Nicotinamide is the amid form of niacin, (vitamin B3) andplays an important role in ATP synthesis (adenosine 5'-triphosphate) in the energy producing mitochondria of

the cell. ATP is called molecular currency - a form of energy that can maintain the integrity of DNA and cell

membranes against insults and inflammation. Foods containing niacin include brewer's yeast, chicken, fish,

eggs, legumes, leafy vegetables, broccoli, tomatoes, carrots, carrots, dates, asparagus, and avocados.

Reduce Allergenic Foods

The avoidance of milk may benefit patients with MS. Peptides in milk can mimic antigens in myelin. CNS

degeneration that resembles MS can be induced in mice with milk peptide injections (46).

Fatty Acids

Dietary omega-3 fatty acids can be of great benefit to MS patients. Omega-3 fatty acids have been shown toalleviate pain in autoimmune disorders by inhibiting inflammatory mediators (eicosanoids and cytokines) in

peripheral tissues as well as in glial cells Omega-3 fatty acids modulate voltage-gated calcium channels in heart

and brain cells, preventing electrical hyperexcitability and a cascade of events leading to cell depolarizationoxidative stress, inflammation, cell injury and pain. Omega-3 fatty acids are safe as long as they supply less

than 10% of the total energy intake and are given with sufficient amounts of vitamin E (88). Cod liver oil with

its vitamin A and D content (1 tablespoon 2-3 times a day) is often of great benefit to MS patients.

Lecithin


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Abnormal lipid metabolism in the brain is often seen in subjects with multiple sclerosis. Lecithin cholesterolacyltransferase from the cerebrospinal fluid was investigated in 16 subjects, half control subjects and half with

active demyelinating disease. The levels of lecithin cholesterol acyltransferase in patients with active

demyelinating disease or multiple sclerosis was only about half of that found in the control subjects (1).

Magnesium

Magnesium, zinc and calcium have been found to be deficient in central nervous system tissue in MS patientsespecially in white matter tissue (116). Magnesium is important for the metabolism of thiamine, calcium,

potassium, phosphorus, iron, sodium, hydrogen chloride, acetylcholine, nitric oxide, and for many enzymes, and

for the elimination of lead and cadmium. Calcium and magnesium are also important in the developmentstructure and stability of myelin (30). A magnesium deficiency is associated with increased inflammation. The

pathologies associated with magnesium deficiency range from cardiovascular disease to cancer and includeperoxynitrite damage in multiple sclerosis (41). The effects of magnesium glycerophosphate oral therapy were

studied in a woman with severe spastic paraplegia resulting from MS. There was significant improvement in the

spasticity after only one week of treatment. No side effects were reported(81). Natural sources of magnesium

include fresh green vegetables (chlorophyll), raw wheat germ, soybeans, low fat milk, whole grains, fish, figscorn, apples, and almonds.

Octacosanol contained in wheat germ and wheat germ oil increased endurance, total body reaction times, ECG

brachial pulse waves, pulse rate test, basal metabolism and oxygen intake tests in a physical training program

with 894 subjects (19). Octacosanol is a constituent of Policosanol, now being used for cardiovascular health.

Dr. Payne has created a diet with supplements suggested before and after meals at

http://www.14ushop.com/wizard/DrPaynesMSsupportregimen32506.html .

Digestion, Assimilation and Gut Flora

Patients with Inflammatory Bowel Disease have shown MS type lesions on the MRI, suggesting a link between

gut dysbiosis and brain disorders (46).

Pancreatic enzymes

Pancreatic enzymes have been used to help reduce malabsorption and help disperse circulating immune

complexes.

Anti-Candida Programs

Candida antibodies are often present in MS patients, suggesting an on-going chronic gastrointestinal yeasinfection. This irritates the gut causing increased gut permeability and the subsequent absorption of glial toxic

lipopolysaccharides. Transfer Factor, in conjunction with an aggressive anti-Candida program and probiotic

recolonization should improve this condition.

In conclusion, there are a number of factors that can help restore myelin, axonal regrowth, cellular energy

production, reduce viral infections and inflammation, promote antioxidant defenses against oxidative stress and
http://www.14ushop.com/wizard/DrPaynesMSsupportregimen32506.htmlhttp://www.14ushop.com/wizard/DrPaynesMSsupportregimen32506.html


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balance the gut flora, if needed. Test results of specific nutritional deficiencies should be used to devise rotating

diets for each MS patient.

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