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The following article is published by the Brewer Science Library. Single copies of the article may be printed for the reader's personal research and study. Reproduction in any other manner, format or location is expressly prohibited.

Multiple Sclerosis & the Blood Brain Barrier:
A Novel Approach in Integrative Care
by Jeanne M. Wallace, Ph.D., C.N.C.
(reprinted from the Winter 2000/Spring 2001 New Horizons)

   One of the most widely accepted theories of multiple sclerosis (MS) etiology is that it is an autoimmune condition.  It is said to be a malfunction of the immune system in which the body’s own white blood cells attack the myelin sheath as if it were a foreign substance.  According to this theory, T-lymphocytes, through speculated causes, become sensitized to myelin basic protein (MBP).  Demyelination ensues.  Repeated inflammatory episodes eventually exhaust the reparative capacity of oligodendrocytes, resulting in permanent damage to axons.1
   Both conventional and complementary therapies for MS have focused almost exclusively on immune response, specifically the origin and behavior of autoreactive T-lymphocytes.  A comprehensive review of allopathic therapies currently used to alter the disease course in MS is available elsewhere.2 This article explores a novel concept in MS etiology:  the role of the blood-brain barrier.  New avenues are presented for nutritional and botanical support, which may complement the conventional care of MS patients.

Unanswered Questions
   The concept that MS is caused by immune system malfunction does not adequately explain several observations concerning the disease, including:

   *What accounts for the occurrence of localized areas of demyelination (as opposed to a universal attack throughout the central nervous system)?

   *How can we explain periods of remission?  If auto-antibodies are the cause, would not the course be continuous?

   *How do lymphocytes and auto-antibodies—which normally do not have access to the central nervous system (CNS)—gain entry?

   The development of myelin-sensitized lymphocytes should be irrelevant, because normally the blood-brain barrier (BBB) denies these cells access to the brain and spinal cord.  Perhaps a dysfunction of the BBB contributes to MS.
   According to this hypothesis, the blood-brain barrier is not working properly to screen out and prevent entry of unwanted immunological agents into the CNS.  Hence, a person with myelin-sensitized lymphocytes, who also experiences a weakening of the BBB, is likely to develop MS symptoms.  The severity of symptoms and location of attack will vary, depending on the extent and location of BBB disruption.  Individuals with a rapid, “galloping” progression of MS may actually be displaying a pronounced BBB dysfunction.  In contrast, those who have a slow, relapsing/remitting course may have periods of better BBB integrity.

Evidence Supporting BBB Disruption
   Compelling research (summarized in Table 1 below) demonstrates that, during an MS attack, the blood-brain barrier is compromised.4-9  Furthermore, the duration, intensity, and focal area of BBB disruption directly correlates with the duration and severity of MS attacks and with the locale of lesions, respectively.10,11  In animal models, drugs that restore BBB integrity slow the disease progression.12  Chronic BBB disruption may also alter nutrient supply to the brain, compromising the myelin repair process.13,14
   These findings suggest an important and as yet untapped avenue for therapeutic approaches to MS.  In our quest to discover more about disruptions in BBB integrity and MS, let’s first analyze the structure and functions of the BBB.

Table 1:  Evidence for alterations in BBB permeability in MS
     Fifteen MS patients were examined with CT and PET scans to measure the passage of a tracer-agent across the BBB (a marker of BBB breakdown).  An accumulation of the tracer was found in all four patients currently in an exacerbation period of the disease, but in none of those in remission.68
    Sixty-eight relapsing-remitting type MS patients were studied with monthly MRI’s over a three-month period.  Evidence of BBB breakdown was found in 78% of the patients studied.  The authors report a significant association between BBB breakdown and more severe disease course.69
     Three relapsing-remitting type MS patients were studied with weekly MRI scans.  A total of 38 new lesions appeared on MRI scans over the course of the study.  Every new lesion was associated with a breakdown in the blood-brain barrier at an early stage.70
    Breakdown of the BBB precedes symptoms and other MRI signs for new lesions in MR.71
    A linear relationship exists between BBB breakdown and the number of myelin lesions.  The greater the evidence of increased BBB permeability, the greater the number of MS lesions.  A direct relationship also exists between the duration of increased BBB permeability and the duration of clinical relapse.73

Structure and Function
   The concept of the BBB has shifted recently from that of a passive, immutable structure to that of a dynamic interface between the blood and CNS, enabling the brain to maintain an optimal internal environment.
   Anatomically, the BBB is a specialized component of the circulatory system.  It is composed of endothelial cells that line the cerebral capillaries.  Surrounding the endothelial cells is a dense extracellular matrix made up of collagen, fibrin, and other proteins.  Together, the cerebrovascular endothelium and the surrounding extracellular matrix comprise the functional unit of the BBB.15
   The “barrier” function is created by the endothelia being bound together much more tightly than they are in the rest of the body.  In peripheral capillaries, endothelia are loosely connected, with large gaps existing between cell walls.  These gaps allow fairly large molecules—including white blood cells—to pass in and out of the capillaries.  At the brain and spinal cord, however, endothelia are very tightly cemented to each other.  Free passage of nutrients, hormones, drugs, toxins, and immune components to the CNS is restricted.  Enzymes present in the endothelial cells metabolize neurotransmitters, drugs, and toxins before they can enter the brain and disrupt function.16

Loss of Barrier Integrity
    While the exact mechanisms implicated in MS-related BBB disruption have not yet been determined, a number of causes of BBB breakdown are known.  These factors are listed below (references are cited here for those factors not further discussed in this article).

   *Trauma, such as head injury;17,18

   *Alcohol consumption;

   *Viral infection;

   *Deficiency of nutrients essential to capillary strength;

   *Heavy metal toxicity;

   *Oxidative damage;

   *Elevated homocysteine;

   *Mediators of inflammation:  prostaglandins, leukotriends, levuglandins, platelet-activating factor, tumor necrosis factor alpha, bradykinin, kallikreins, and histamine,21,22 and

   *The action of metalloproteinase enzymes.

   In the sections that follow, several of these factors are highlighted, and therapeutic intervention possibilities are discussed.

Thiamin Deficiency
   Thiamin is known to strengthen the blood-brain barrier, and thiamin deficiencies have been demonstrated to result in leaky BBB.23,24  BBB compromise due to hypothiaminosis is manifested by extravasation of IgG across the BBB, as is found in MS, and damage to brain tissues.25,26  Case reports suggest MS patients benefit from daily injections of thiamin (60 mg in 10cc solution).27,28  A safe, therapeutic dose of oral thiamin during a relapse is 100 mg daily; thereafter, a daily dose of 10 mg can be taken for maintenance.

Free-Radical Damage
   Peroxidative mechanisms have consistently been implicated in demyelinating diseases,29-31  and the application of antioxidants has been shown to offer clinical improvements.32,33  And yet, the majority of investigations into the role of redox imbalances have focused on direct damage to the myelin rather than at the level of the BBB.  However, oxidative damage to the vascular structure of the BBB has been demonstrated in MS.34-36  Increased BBB permeability does result from increased free radicals, and the subsequent administration of antioxidants can restore BBB integrity.37-40
   Sources of oxidative stress need to be identified and addressed.  An often overlooked source of oxidative stress is imbalanced hepatic detoxification (i.e., “pathological detoxifier” status, wherein Phase I detoxification exceeds the capacity of Phase II detoxification.  As a result, copious free radicals are generated).  Oxidative stress analysis and functional hepatic detoxification status are useful assessments in MS.  Administration of a broad-sprectrum, high-potency antioxidant formula is recommended.  Alpha-lipoic acid (ALA) is known to increase endogenous glutathione levels.  Preliminary human studies suggest ALA may be effective in neurodegenerative disorders.41  The recommended dose is 10-50 mg/day.

Homocysteine Connection
   Hyperhomocysteinemia, known for its association with cardiovascular disease, has been implicated in cerebrovascular diseases.42,43  Raised plasma homocysteine levels have been noted in MS.44  Interestingly, clear historical associations have been demonstrated between deficiencies of two key homocysteine-reducing nutrients and MS; vitamin B12 and folic acid.
   A significant relationship exists between vitamin B12 deficiency and MS.45-47  More than 30% of MS patients have serum vitamin B12 levels below 147pmol/L (normal range = 232 to 1,18pmol/L).48  Vitamin B12 deficiency results in severe neurological disturbances and demyelination, similar to that which occurs in MS.49

Prostaglandins
   Manipulation of dietary fat intake, especially the restriction of saturated fats, has been a clinical approach for MS since the 1950s.  Inflammatory eicosanoids, such as prostaglandin E2 (PGE2) derived from arachidonic acid, may be responsible for dirupting the BBB in MS.53-55
   Journal Editor’s Note:  Not all eicosanoids derive from AA; only PGE2.
    Research shows a significantly higher production of PGE2 in patients with chronic progressive MS, than in healthy controls or MS patients in remission.56  And lipid profiles of MS patients reveal staggering deficiencies of omega-3 fatty acids, precursors of the less inflammatory PGE3.57  Dietary changes in fatty acid intake to modulate prostaglandin production remain essential to integrative treatment protocols for MS.  Agents that block the actions of cyclooxygenase (COX) and 5-lipoxygenase can also prevent BBB disruptions.58  Natural agents that block these enzymes include bromelain, pancreatic enzyme preparations, curcumin, ginger, quercetin, and other bioflavonoids.

Platelet Activating Factor
    Platelet activating factor (PAF), and inflammatory cytokine, can be produced by endothelial cells (also by platelets, monocytes, and macrophages).  PAF increases BBB permeability.59  Some natural agents that inhibit PAF include decosahexanoic acid (DHA) from fish oil60 and Ginkgo biloba ginkgolides,70 which are potent PAF antagonists.  Separate research has independently demonstrated the clinical efficacy of both of these agents in MS. 71,72  Their benefit may be derived from altering PAF’s effects on BBB permeability.  In an experimental study of 10 patients with MS in acute relapse, treatment with gingkolide B led to improved neurological scores in 80% of patients.73  The recommended dose is 80 mg, tid, standardized Ginkgo biloba extract.

Tumor  Necrosis  Factor
   Tumor necrosis factor (TNF)-alpha is a principal mediator in the inflammatory response, and may be important in the pathogenesis and progression of MS.  High levels of TNF-alpha are found in the cerebrospinal fluid of MS patients with progressive disease (but in none of those with stable disease).61   TNF-alpha has been shown to alter BBB permeability and to promote perivascular infilitration of immune cells and demyelination.63

Metalloproteinases
   Matrix metalloproteinases (MMPs) are enzymes, secreted by immune cells, which can dissolve components of the extracellular matrix.  For most parts of the body, these actions are useful in allowing white blood cells access to areas of injury or infection.  However, release of these enzymes in CNS capillaries can result in BBB breakdown.  Inhibition of these enzymes reverses the progression of disease in MS animal models, apparently by restoring BBB integrity.64
   Flavonoids, well-known for their capillary-strengthening effects, can inhibit the activity of MMPs.  Flavonoids, particularly proanthocyanidins and anthocyanins, are taken up into the cellular matrix.  Receptor sites on the flavonoids bind metalloproteinase enzymes, thereby preventing their liquefying effect on the matrix.65  Bilberry anthocyanosides can restore damaged BBB permeability.66,67  Flavonoids are also highly anti-inflammatory and potent antioxidants, and may protect the BBB via these mechanisms.  Supplementation should include bilbery (with 25% anthocyanin content, 80-160 mg. tid).  Grape seed or pine bark extracts (150-300 mg/day) can be added for their proanthocyandin content.

Conclusion
   Our understanding of the anatomy and physiology of the BBB is still in its infancy.  There is much to learn about the role of the BBB in the pathogenesis of MS.  Certainly, it still makes sense to focus on the modulation of the immune aspects of the disease.  However, addressing the dynamics of BBB integrity may improve the efficacy of treatments for MS.  Complementary therapies that protect BBB integrity may provide an excellent adjunct to conventional therapies.

Table 2:  Natural Agents to Address BBB Permeability in MS

AGENT-----DAILY DOSE-----RATIONALE

Thiamin                                  10-20 mg maintenance         Essential nutrient for BBB integrity

Vitamin B12                           1,000 + mcg                          Lowers homocysteine, assists re-myelination

Folate                                      800 + mcg                             Lowers homocysteine, assists re-myelination

Vitamin B6                             10-20 mg                               Lowers homocysteine

Betaine TMG                          100-200 mg                           Lowers homocysteine

Phosphatidylserine (PS)          300 mg                                  Reduces TNF-alpha

Ginkgo biloba                          240 mg                                  Antioxidant, inhibits PAF

Antioxidants                                                                         Reduce oxidative damage to BBB + myelin

Lipoic Acid                              10-50 mg
Vitamin C                                1 gram
Vitamin E                                 400 IU
Selenium                                  100 mcg

Bioflavonoids                                                                       Strengthen extracellular matrix against MMP

Bilberry                                    240-480 mg                          actions, antioxidant, anti-inflammatory, reduce

Grape seed extract                    150-300 mg                          capillary fragility
Pycnogenol                               150-300 mg

Botanicals                                                                             Block PGE2 and COX, anti-inflammatory

Bromelain (1,800+mcu)           1,5000-2,250 mg
Curcumin                                  1,200 mg
Ginger                                       1,000-3,000 mg
Quercetin                                   900 mg

This information was reprinted from the International Journal of Integrative Medicineâ, Vol. 1, No. 5, pgs 11-16   For subscription information, contact IMPAKT Communications, 1-800-477-2995, or e-mail info@impakt.com

Dr. Jeanne Wallace is now only developing nutritional protocols  with cancer patients.  Her website:  www.Nutritional-Solutions.net

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