Multiple Sclerosis, An Autoimmune Inflammatory Disease: … · Multiple Sclerosis Alternative...

Alternative Medicine Review ◆ Volume 6, Number 6 ◆ 2001

Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

Parris Kidd, PhD (cell biology, University of California at Berkeley) – Contributing Editor, Alternative Medicine Review; healtheducator and biomedical consultant to the supplement industryCorrespondence address: 847 Elm St, El Cerrito, CA 94530

IntroductionMultiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating disease of the

central nervous system. It generally strikes at an early age, most often the early adult years. Itsmost frequent symptoms include numbness, impaired vision, loss of balance, weakness, blad-der dysfunction, and psychological changes. Fatigue is an early symptom in MS, often theearliest. The disease can wax and wane for up to 30 years, but in perhaps half of all cases itsteadily progresses to severe disability and premature death.1

Multiple Sclerosis, An AutoimmuneInflammatory Disease: Prospects for its

Integrative ManagementParris M. Kidd, PhD

AbstractMultiple sclerosis (MS) is aptly named for the many scars it produces in the brain andspinal cord. A sometimes fatal, often debilitating disease, MS features autoimmuneinflammatory attack against the myelin insulation of neurons. Thymus derived (T) cellssensitized against myelin self-antigens secrete tumor necrosis factor, cytokines,prostaglandins, and other inflammatory mediators that strip away the myelin andsometimes destroy the axons. Familial and twin inheritance studies indicate MS ismildly heritable. No single MS locus has been identified, but an HLA haplotype hasbeen implicated. Unique geographic distribution of the disease is best attributed tosome combination of vitamin D abnormality and dietary patterns. No pharmaceutical orother therapies exist that confer prolonged remission on MS, and obviousinterrelationships between toxic, infectious, and dietary factors make a persuasive casefor integrative management. The time-proven MS diet meticulously keeps saturatedfats low, includes three fish meals per week, and eliminates allergenic foods. Dietarysupplementation for MS minimally requires potent vitamin supplementation, along withthe thiol antioxidants, the anti-inflammatory omega-3 fatty acids, and adaptogenicphytonutrients. Gut malabsorption and dysbiosis can be corrected using digestiveenzymes and probiotics. Long-term hyperbaric oxygen therapy can slow or remit thedisease. Transdermal histamine offers promise, and adenosine monophosphate maysometimes benefit. Chronic viruses and other infectious load must be aggressivelytreated and exercise should maintain muscle tone and balance. Early intervention withintegrative modalities has the potential to make MS a truly manageable disease.(Altern Med Rev 2001;6(6):540-566)


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Alternative Medicine Review ◆ Volume 6, Number 6 ◆ 2001 Page 541

MS owes its name to the presence ofmultiple sclerotic (hardened) lesions in thebrain and spinal cord – multiple scars. Theoptic tract also is often involved. This diseasehas major autoimmune character, with T-cellsand other immune effector populationsentering the brain and attacking the nerve cells,stripping away their myelin insulation andsometimes destroying their axons and entireremaining structures. Principal patterns ofdemyelination and axonal degeneration areschematized in Figure 1.

MS is the mostcommon cause of neu-rologic disability inyoung adults. The le-sions of demyelinationare histopathologicallycharacteristic of thedisease. Brain exami-nation by MRI (mag-netic resonance imag-ing) can accurately de-tect these “white mat-ter plaques.” MRI cor-relates well with theclassic histopathologyof the lesions, and isprogressively a moresensitive tool for de-tecting the characteris-tic lesions of MS insitu, as compared toconventional functionalevaluation.

Currently ap-proved drug therapiesfor MS are highlytoxic; the immunosup-pressants cortisone,prednisone, methotrex-ate, and cytoxan arestill mainstays of con-ventional MS manage-ment. In 1993, inter-feron ß-1b was ap-

proved in the United States as attack preven-tion therapy,3 but this drug itself is burdenedwith frequent and severe adverse effects.4 Thelimitations of the conventional drug therapiesfor MS make imperative the development of aless toxic, integrative strategy for its manage-ment.

Figure 1. Demyelination and Axonal Degeneration in Multiple Sclerosis

ab

c

Normal MyelinationSecure Conduction

Acute DemyelinationConduction Block

Chronic DemyelinationMolecular Plasticity of AxonRestoration of Conduction

Axonal DegenerationPermanent Interruption of Conduction

A

B

C

D

Key: A, normal state; B-D, three degrees of damage severity. From Waxman.2



Diagnosis, Prevalence, andProgression of MS

Multiple sclerosis is a complex disease,perhaps encompassing more than a singleetiopathological entity and very likely subjectto multifactorial etiology.5 MS prevalenceworldwide is estimated at one million cases;in the United States this number is 250,000-350,000.6 Although not generally consideredlife threatening, this disease kills about 3,000people each year in the United States.7

MS overlaps extensively with numer-ous other syndromes, including acute dissemi-nated encephalomyelitis (ADEM), Marburg’svariant of MS, recurrent optic neuritis, neuro-myelitis optica (Devic’s syndrome), inter-nuclear ophthalmoplegia, acute transversemyelitis, and cerebellar, pyramidal, and dor-sal column dysfunctions. Weinshenker3 pro-posed grouping all these into a pathophysi-ological matrix of idiopathic inflammatorydemyelinating diseases of the CNS. Optic neu-ritis or other single demyelinating syndromescan develop over time into MS. Such “conver-sion” occurs especially in females with rela-tively early onset. MRI is currently the tech-nique of choice to identify those at risk forconversion to clinical MS.3 When a cliniciandetects exacerbation of symptoms, MRI willdetect new lesion activity in most cases. How-ever, patients without clinical activity can stillmanifest new lesion activity on MRI exami-nation. MRI lesion data may strongly predictprobability of subsequent attacks and progres-sion to disability.

Onset of MS is usually between theages of 10-59 years, but can occur as early asage two.7 Symptoms often begin as sudden buttransient motor and sensory disturbances,including blurred vision, dizziness, muscleweakness, and tingling sensations.8 In abouttwo-thirds of the cases onset is between ages20 and 40 (onset after age 50 is rare), andwomen are more frequently affected than men(60% and 40%, respectively). With the passage

of time, an almost bewildering array ofsymptoms can manifest.

MS is difficult to diagnose in its earlystages. Initial symptoms begin alone or in com-bination, and are highly variable in durationand expression. Typically they develop over afew days, remain for a few weeks, then recede.Motor symptoms tend to come first, and in-clude feelings of heaviness, weakness, legdragging, stiffness, tendency to drop things,and clumsiness.8 Sensory symptoms includevague numbness and tingling, and “pins andneedles” and electrical sensations. Often thesensory organs are also involved. Optic neuri-tis and other visual symptoms – blurring, fog-giness, haziness, eyeball pain, blindness,double vision – can appear early, and afflictmore than one-third of the cases. Problemswith the ear vestibular apparatus can causelightheadedness, dizziness, nausea, and vom-iting. Later in the disease process, genitouri-nary nerve tract involvement can create lossof bladder, sexual, and bowel function. Cumu-lative increase in the number, size, and distri-bution of lesions correlates well with the pat-terns of physical and mental disability.9

MS usually damages quality of life toa marked degree. Progressive motor degenera-tion leads to physical disability, while diffi-culties with mental functioning are measurablein some 43 percent of MS patients and canlead to job loss and social awkwardness. Lessthan five percent of cases develop severe de-mentia. Death by suicide occurs seven timesmore frequently in the MS population than inthe general population.3

The patterns of MS progression vary.Patients with relapsing-remitting (RR) MSconstitute 70-80 percent of all cases, and pri-mary-progressive (PP) MS make up the rest.But 80 percent of the RR MS patients developsecondarily progressive (SP) MS after someperiod, typically within 7-15 years.5 For mostpatients the transition from RR to SP meansthat extended periods of remission will no

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longer occur; and on MRI the lesions becomemore confluent and extensive.

Impairment scales are used to gradeclinical signs and symptoms based on objec-tive criteria; disability scales grade limitationson activities of daily living; and handicapscales grade limitations of social interactions.Currently the closest to a “gold standard” forclinical disability is Kurtzke’s EDSS (extendeddisability status scale).10 Scoring of disabilityextent is most useful to the patient, while forthe clinician lesion scoring is the more reli-able indicator of clinical status and progres-sion.

Some 20-40 percent of all MS casesbecome classified “benign” since they haveless than moderate disability after ten years(meaning the patient can walk more than a halfblock without a cane). This is a highly mis-leading term for these patients, since by theirfifteenth year with the disease many of themwill require some form of walking aid.3

Arresting the progression of MS meansarresting disability progression. The currentconventional drug therapies do not do so. Halfof all patients reach DSS 6 (moderate disabil-ity, basically unable to walk unaided) within12-15 years after onset; only about five per-cent are better than DSS 6 at 40 years. Theaverage life expectancy is decreased onlyslightly by MS, although for very disabled in-dividuals the probability of death is more thanfour-fold greater than the general population.Best estimates suggest more than three-quar-ters of MS patients live longer than 25 yearsafter diagnosis.3

Potential Etiological and TriggeringFactors

Numerous factors undoubtedlycontribute to the causation, exacerbation, orprogression of multiple sclerosis. There is afamilial component, although no single genehas been identified and the genetic contributionseems relatively minor.5 The gender

component of women having greatersusceptibility has been confirmed.11 Mostlikely the disease is a product of innatesusceptibility spread over several differentgenes that interact with multiple environmentalfactors. People who move from a low-risk to ahigh-risk area before age 15 have a higher riskof developing the disease.

The disease evolves over decades, go-ing through periods of relative stability andincreased activity in relation to exogenous trig-gers.3 Agents that can trigger exacerbationsinclude viral infections, emotional stress, preg-nancy, heat exposure, allergic reactions tofoods, and irritation or provocation by envi-ronmental agents. Among the short-term trig-gering factors, the best documented are minorrespiratory infections (which in one study pre-ceded 27 percent of relapses),12 sinusitis,3 andheat exposure. Although now obsolete, a hotbath test was formerly used in the diagnosisof MS.3

The major etiological factors best sup-ported by the available evidence are inheritedsusceptibility, microbial infection, and envi-ronmental toxin exposure. Diet has been lessstudied but undoubtedly makes important con-tributions.

The Genetics of MSAlmost one-quarter of multiple scle-

rosis patients have an affected relative, and agenetic influence on susceptibility is stronglysuggested from population, twin, and familystudies.5 One group of Class II MHC genes ofthe D class, located on chromosome 6p21, hasbeen consistently implicated.3 Studies of sev-eral ethnic groups confirmed that the humanleukocyte antigen (HLA) haplotypeDR2Dw2is a modest contributor to disease susceptibil-ity.5 In patients with this haplotype, certain T-cell polymorphisms are also MS risk factors.13

Several genome scans conducted onMS populations around the world have failedto indict any individual genes.5 This probablymeans that many genes contribute to MS, each

44 Alternative Medicine Review ◆ Volume 6, Number 6 ◆ 2001


with a small effect on disease susceptibility;but separate, “modifier” genes may control theclinical symptoms. A large Canadian study of15,504 patients did not find support for anytransmissible MS factor between spouses, butdid suggest that offspring of MS pairings havea substantially greater risk for developing thedisease.14

Studies with siblings and fraternaltwins indicate the genetic component of thedisease has relatively low penetrance. The con-cordance rate in identical twins is around 25-35 percent, suggesting that some 65-75 per-cent of MS must be attributable to non-geneticfactors.

One promising area for further geneticexploration is mitochondrial DNA. Whereveroxidative stress and/or inflammation are in-volved, cumulative failure of the mitochondria,the cells’ “energy power plants,” has to be ex-amined as a potential factor.15 Optic neuritis,which is common in RR MS, has similaritieswith Leber’s hereditary optic neuropathy(LHON), a known mitochondrial failure syn-drome which also can feature demyelination.MRI studies of the MS brain suggest energeticabnormalities, even in the normal appearingwhite matter.16 Findings from at least a dozenstudies seem to prove that MS can occur inindividuals lacking pathogenic mitochondrialmutations of any kind.16 However, a consis-tent association was found between the mito-chondrial ancestral K* and J* haplotypes andMS in caucasians.13

Candidates for InfectiousInvolvement

Epidemiological studies suggest mul-tiple sclerosis is initiated by a primary encoun-ter with an environmental (i.e., non-genetic)agent during childhood or early adulthood.Evidence that this might be an infectious agentis suggested by increased levels of IgG andthe presence of alkaline oligoclonal bands inthe CSF. These bands occur in greater than 95

percent of MS patients and in 10 percent ofother CNS diseases that are infectious. Thispattern of elevated IgG and oligoclonal bandsis thought to be characteristic of antibody pro-duction within the CNS in response to infec-tious agents.17

Viruses are obvious candidates for theinfectious villains in MS because several causedemyelination in humans and animals,8 con-ditions that can present clinically as relapsing-remitting symptoms.17 The demyelination ofMS may result from direct viral damage tobrain cells, or from viral infection leading toformation of antibodies, which then attack themyelin. Over the years many virus candidatesfor MS have been considered and discarded.Currently, human herpesvirus-6 (HHV-6) is thefront-runner candidate for MS causation ortriggering.

Human Herpesvirus Type 6(HHV-6)

HHV-6 is perhaps the mostneuroinvasive member of the herpesvirus fam-ily. It has been detected both in normal brainand in the brains of patients with MS.18 CNSinfection with HHV-6 is a major cause of sei-zures in children, as well as more severe pedi-atric neurological disorders, including dissemi-nated demyelination and infarction of the basalganglia.19 In both children and adults, the vi-rus can produce encephalitis that can be fatalunless successfully treated with antiviraltherapy.20 As with HIV, its genome becomesintegrated into the human genome (at chro-mosome 17); its intervention in AIDS mayresult in dementia. The recurrent infectionpattern of HHV-6 recalls the clinical relapsepatterns of MS.19

HHV-6 can be lethal even to immuno-logically intact adults. In this population, fo-cal encephalitis, chronic, demyelinating my-elopathy, and other CNS dysfunction cansometimes result in death.21 Particularly rel-evant to MS is that demyelination is the most

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consistent finding in HHV-6 attack on theCNS. The pattern and extent of HHV-6 asso-ciated demyelination range from diffuse andextensive loss of myelin to sharply circum-scribed foci of demyelination, combined withaxon destruction within those zones most se-verely involved.20,22 These parallel the distinc-tive histopathological features of MS.23,24

Challoner and colleagues showed inMS patients that the nucleic acid of strainHHV-6B was preferentially distributed in andaround the zones of demyelination.18 Sandersand colleagues found HHV-6 (and other herp-esviruses) generally more associated with ac-tive MS plaques than inactive ones,25 and Knoxand colleagues used immunohistochemicalstaining to identify cells in the CNS activelyinfected with HHV-6. They detected such cellsin 8 of 11 patients diagnosed with MS (73%),versus 2 of 28 controls (7%), comprising nor-mal persons and patients with non-MS inflam-matory demyelinative diseases. In the MS pa-tient group, 17 of 19 tissue slices showing ac-tive demyelination (90%) had HHV-infectedcells, compared with 3 of 23 tissue sectionsfree of active disease (13%; p<0.0001).

Knox et al found lymphoid tissuesamples from MS patients revealed activeHHV-6 infection (in six of nine patients ex-amined, or 67%; all controls negative).19 Bloodsamples from 22 of 41 MS patients (54%) hadactive HHV-6 infections, compared to 0 of 61control patients. Repeated blood analyses in-dicated the MS patients were more consistentlyburdened with active HHV-6 infection thanwere immunosuppressed patients, namelythose who had received liver transplants.

The Knox study made a pivotal con-tribution to the circumstantial case for HHV-6causal involvement in MS. Four argumentssupport this position: (1) HHV-6 can causedemyelinative CNS degeneration and activeHHV-6 infections are associated with otherdemyelinating diseases of the CNS; (2) astrong relationship was found between thepresence of cells actively infected with HHV-

6 and active demyelination; (3) the cumula-tive outcomes of previous studies pointed toan HHV-6 association with MS; and (4) thehigh degree of neuroinvasiveness of HHV-6combined with its capacity to establish latentinfections that periodically reactivate is con-sistent with the periodic exacerbations of clini-cal MS.

Previous to the Knox study, efforts tounequivocally define HHV-6 involvement inMS produced mixed results. DNA of HHV-6had been detected in the brain tissues and oc-casionally in the cerebrospinal fluid (CSF) ofpatients with MS. Abnormally high titers ofantibodies to HHV-6 were found in the serum.The Polymerase Chain Reaction (PCR) is ameans to tremendously amplify DNA and fa-cilitate detailed matching of gene identities.A negative finding for HHV-6 DNA in the CSFwas probably due to interference with the PCRassay by CSF constituents, and perhaps alsoby the low absolute level of HHV-infected cellsambient in the CNS. When technologies wereused that could detect active HHV-6 infections,differences between MS patients and controlswere found. Techniques that did not distin-guish between active and latent HHV-6 infec-tions failed to show differences. Recent stud-ies demonstrated that at least 50-70 percent ofMS patients carry HHV-6 specific IgM anti-bodies, and at least 30 percent have HHV-6 intheir sera.19

The mechanisms by which HHV-6 af-fects demyelination and other degenerativeCNS changes in MS remain to be elucidated.Case reports establish beyond doubt that HHV-6 can trigger fulminant demyelinating diseaseand encephalitis in MS patients. Fulminantdemyelinating activity in the MS brain canfeature virtually total segregation of HHV-6from the areas free of demyelinative changes.19

This virus can infect and destroy oligodendro-cytes, the cells which produce myelin. How-ever, the relatively low number of HHV-6 in-fected cells in brains of MS patients, as com-pared with encephalitis patients, suggests



mechanisms other than direct cell destructionmay be involved.

The cytokine tumor necrosis factor-alpha (TNF-α) may be an indirect mediatorof HHV-6 damage to the CNS cell populationsof MS patients. Cells that produce this cytokinehave been identified in MS lesions,26 and theexpression of TNF-α in blood monocytes ofMS patients correlates with disease activity.As illustrated graphically in Figure 2,significant differences in cellular expressionof TNF-α were observed between clinically

active patients andpatients with activelesions from MRI,compared to stablepatients or healthycontrol subjects.27

HHV-6 is unique,even within its ownvirus family, for itsability to up-regulateTNF-α production inblood monocytes.28

A second in-direct mechanism ofdemyelinative dam-age to the CNS ofMS patients byHHV-6 may be theinduction of autoim-munity against CNStissues. A large bodyof evidence indicatesMS is an autoim-mune (as well as in-flammatory) disease.Antigen mimicry islikely involved,whereby one or moreantigenic determi-nants on an HHV-6protein may cross-react with a myelindeterminant, such asmyelin basic protein

or myelin oligodendrocyte glycoprotein.29 Ofthe majority of MS patients with RR MS, mostchange to a progressive disease course and atthe time of their death many have antibodiesspecific for myelin proteins bound within theirCNS tissues.30,31

The antiviral drug acyclovir, whichprovides effective prophylaxis against HHV-6 infections in bone marrow transplant pa-tients, has been shown to markedly reduce thefrequency of disease exacerbations in patientswith MS.32

Figure 2. Monocyte mRNA Indicating Tumor NecrosisFactor Synthesis Correlated with Relative Clinical Activityof MS

0

10

20

30

40

Patient groups

mR

NA

leve

ls (

rela

tive

units

)

Clinical active MS (n=14)Active MRI (n=6)Stable MS (n=9)Healthy donors (n=12)

From Rieckmann, et al.27

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ChlamydiaThe latest organism implicated as an

MS pathogen is Chlamydia pneumoniae, anintracellular bacterium known to infect hu-mans.17 A great deal of circumstantial evidencelinks Chlamydia to MS: (1) several chlamy-dial species produce a relapsing-remitting pat-tern of disease; (2) one species – C. trachomata– is more common in women than in men, andmay prefer the HLA-DR16 gene allele that isalso linked to MS; and (3) some chlamydialspecies are linked to immune-mediated, in-flammatory neurodegeneration. Still, directproof of C. pneumoniae involvement in MShas been lacking.

In 1999 Sriram, and collaborators33

reported isolating C. pneumoniae from theCSF of 64 percent of a group of 37 MS pa-tients, compared with 11 percent of non-MScontrols (n=27). Using sophisticated assaytechnology, they claimed the C. pneumoniaegene was present in the CSF of 97 percent oftheir MS patients, and that in 86 percent theCSF carried oligoclonal antibodies to the or-ganism.17

Unfortunately, other labs have so farbeen unable to replicate these remarkable find-ings.34 The organism has been identified fromCSF in only a minority of MS cases; sensitivetechniques of immunohistochemistry and insitu DNA hybridization failed to detect it inthe CNS tissue; and, in contrast to CSF, it didnot culture out of brain tissue.35 Little is knownabout how the MS host responds immunologi-cally to this infectious agent. It could be di-rectly causal for MS, or could nonspecificallypotentiate the disease. The degree of actual par-ticipation, if any, of C. pneumoniae in MS re-mains to be elucidated.

MycoplasmasOne under-appreciated microbe

present in MS is Mycoplasma pneumoniae.This virus-like, primitive bacterium has beenproven capable of invading the human CNS35

where it can cause acute meningoencephali-tis, perivascular demyelination, autoimmunesequelae, and a CNS vasculitis. In many casesthe organism cannot be detected by sensitiveDNA identification techniques, does not cul-ture out from CSF, and leaves no antibody trail.Nicolson and Nicolson reported 50 percent ofMS patients they examined had mycoplasmalinfections, often as coinfections with HHV-6(found in 60 percent of their patients), Chlamy-dia (20%), or other bacteria (25%).36,37 Theyalso reported finding mycoplasmas contami-nating commercial vaccines.36

Other VirusesUnder active investigation for MS are

Varicella zoster,38,39 retroviruses, andnidoviruses. The retroviruses can generatehuman CNS symptoms that closely resembleMS.40 Of the nidoviruses, Coronavirus pro-duces an MS-type demyelinating syndrome inexperimental animals.41 A virus called IM andclosely resembling the Japanese SMON (sub-acute-myelo-optic-neuropathy) virus report-edly was isolated from several MS patients.42

All MS patients are seropositive for Epstein-Barr Virus (EBV), although supposedly it doesnot reach the brain.43

Surveying the considerable bulk of in-formation about the wide variety of viruses orother microbes proven capable of entering thebrain, attacking cells therein, and creatingneurodegenerative damage, the thoughtfulreader might be tempted to suspect that anysingle one could be pathogenic in MS. Themicrobe that succeeds may be specified by thegenotypic and/or phenotypic characteristics ofthat individual; or conversely, the MS patient,while in a weakened state, may be subject tocolonization by any combination of these in-fectious agents. Some clinicians favor empiri-cal treatment against putative infectious agentsin MS; for example, doxycycline for Chlamy-dia pneumoniae and acyclovir or valacyclovirfor HHV-6 and/or other herpesviruses.7



A real-life approach to considerationof MS might suggest that virtually any acuteor chronic stressor that weakens the immunesystem – toxic attack, intensified oxidativestress, illness from a “garden variety” virus orbacterium, malnutrition, even sustained emo-tional stress – could conceivably create a timewindow for one of these organisms to enterthe brain and establish itself. After that, inter-action of the organism with responsive hostimmunity might set the stage for recovery orfor eventual progression to full-blown MS.

Toxins and Other EnvironmentalFactors Linked to MS

Environmental factors that are primecandidates for MS causation include toxins(solvents, pesticides), exposure to X-rays (di-agnostic or occupational), and exposure todomesticated animals (dogs, cats, cagedbirds).11

Multiple sclerosis can occur in highconcentrations within limited geographic ar-eas. These clusters are reminiscent of otherdisease clusters stemming from communityinfectious or toxic exposure. In 1973 Eastmanand colleagues reported on a cluster inMansfield, Massachusetts.44 There the fre-quency of MS in 1970 was 141 per 100,000 –two to three times the prevalence rate reportedin other portions of the northeastern UnitedStates. A historical analysis revealed that eightpatients had lived within several blocks of eachother in the center of the town in the 1930s.During that period the water supply washeavily contaminated with bacteria and per-haps also with toxins. The time window be-tween this exposure and subsequent develop-ment of MS – 23 years – was in line with theestimated incubation period for MS. The au-thors failed to mention the center of town alsohoused a large iron foundry.

The Mercury ConnectionIngalls reviewed and analyzed several

MS clusters45 and suggested Mansfield’s ironfoundry probably also produced compoundsof lead and/or mercury. He further demon-strated by mapping that the tiny town ofMossyrock, Washington (population 500) hada cluster of six very tightly localized cases.During the Great Depression one enterprisingyoung man sought to improve his lot by sal-vaging “quicksilver” (mercury) from cinnabar(HgS, mercuric sulfide) leftover from an oldmining venture in the area. He melted the cin-nabar on the family stove in the presence ofsix siblings and cousins aged 14 to 18, all ofwhom subsequently developed MS.

The largest-ever MS cluster observedwas the 1983-1985 “outbreak” of 30-40 casesthat occurred in Key West, Florida.45 Of 19cases confirmed as MS, three-fourths werewomen and seven were nurses who worked atthe same hospital. Across the street from thehospital was a landfill from which red matteroozed continuously, and which would regu-larly catch fire and fill the air with burningmatter. The red matter was strongly suspected,although never officially confirmed, to be anti-fouling ship paint containing mercury. Soonafter publishing his analysis of the Key Westcluster, Ingalls published a reasoned claim thathis own symptoms of MS were triggered byhis mercury dental fillings.46 Mercury is wellknown to combine with and alter the structureof numerous proteins. Huggins and Levy pub-lished a study47 which involved thephotolabeling of proteins in CSF drawn fromMS patients before and after removal of theirmercury amalgams. Previous to amalgam re-moval, the CSF had an abnormal content ofmultiple extraneous proteins. After amalgamremoval (24-48 hours) there was marked ab-sence of protein except for a single band ofalbumin. These researchers hypothesized thatmercury from amalgam in the body could gen-erate multiple abnormal proteins that mighthelp trigger MS.

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Siblerud and Kienholz48 examined twogroups each of 24 MS patients, one group whohad their mercury amalgams removed 2.75years previously and the other still with amal-gams. Subjects with amalgams had signifi-cantly lowered red blood cell counts, hemo-globin, and hematocrit, compared to thosewithout amalgams. The mercury-contaminatedgroup had significantly lowered thyroxine,serum IgG, total T-cells, and CD8 (suppres-sor) cells. This group also reported signifi-cantly more (33.7%) amalgams than during the

previous 12 months. Interestingly, the MS sub-jects combined had significantly higher hairmercury than did the non-MS control subjects.

In a previous study, Siblerud similarlycompared MS patients and determined theirmental and emotional status.49 Those still car-rying amalgams scored significantly higher fordepression, anger, hostility, psychosis, and ob-sessive-compulsive disorder.

Figure 3. Risk Estimates of Nine Studies on MS and Exposure toOrganic Solvents and the Results of Meta-analyses of Three Subsetsof the Studies

Amaducci, Italy 1982Flodin, Sweden 1988

Giuliani, Italy 1988Juntunen, Finland 1989

Koch-Henriksen, Denmark 1989Gronning, Norway 1993

Landtblom, Sweden 1993Nelson, USA 1994

Cassetta, Italy 1994

Pooled and meta-analysesRRMHpool

RRmeta

RRMHpool

RRmeta

RRMHpool

RRmeta

Selection 1

Selection 1

Selection 2

Selection 3

Selection 3

1 2 100.10.01

1001 2 100.10.01

From Landtblom, et al.50



Organic SolventsA number of epidemiological studies

have targeted occupational exposures, includ-ing exposures to organic solvents. Landtblomand colleagues did a sophisticated meta-analy-sis that covered all studies from the period1966-1994 and found 13 published studies.50

They then did three separate analyses, each ofwhich generated two slightly differing calcu-lations of relative risk (RR). Their results areillustrated in Figure 3. All six of their derivedRR estimates were in the range of 1.7-2.6,uniformly consistent with organic solvent ex-posures increasing the risk of MS. These find-ings, derived using solid methodology, pointto organic solvents as major toxic contendersfor MS causation.

While the field of immunity seeks mi-crobial antigens as possible explanations forMS causation, solvents and heavy metals orother toxins can also present novel antigens tothe immune system. By chemically reactingwith a biomolecule, they can change its topog-raphy or other antigenic aspects; this is knownas a haptenic reaction. As one example,Thrasher and colleagues demonstrated evi-dence of formaldehyde antibodies and alteredcellular immunity in persons exposed to form-aldehyde from contaminated homes.51

Dietary/Digestive Contributions toMS Etiology

Much of the epidemiological data inmultiple sclerosis is consistent with a role fordiet in its initiation, exacerbations, or progres-sion. This type of research is also unable toclearly differentiate between “risk factors” and“triggers.” Some of the dietary factors contrib-uting to the worsening of MS include a highanimal-fat diet; food allergies and intolerances;and digestive malfunctions, including malab-sorption and dysbiosis.

High Animal Fat DietSwank and his colleagues reported in

1952 on a comprehensive geographical assess-ment of diet and MS in Norway.52 The inlandfarming communities in Norway had a higherMS incidence than the coastal areas, and in-cluded much more animal and dairy productsthan did the coastal diets, which consistedlargely of cold-water fish. They reported astrong positive association between butterfatconsumption and MS incidence, and a strongnegative association with fish consumption.

Subsequent studies have supported astrong association between dietary animal anddairy intake and MS. Agranoff and Goldberg53

found an extremely high correlation betweenmilk consumption and MS in 1949-1967 mor-tality rates in the United States. Fish and veg-etable intake were negatively correlated. Theirprotective correlation data for fish and veg-etables held across 20 countries, while the di-etary categories total fat, animal protein, but-ter fat, and meat fat all were positively associ-ated with the disease. This pattern has basi-cally maintained through a number of subse-quent studies. As reviewed in Lauer,54 MS rateshave repeatedly correlated with consumptionof animal fat, animal protein, and meat fromnon-marine mammals. The negative correla-tion with vegetable and/or fish intake has alsoheld.

Controlled clinical trials support a ben-eficial role for certain long-chain fatty acidsin MS.54 A meta-analysis of three trials re-vealed that intakes of large amounts of linoleicacid, an omega-6 polyunsaturated fatty acid(17.2 or 23 grams per day) lowered severityof relapses and slowed progression in somecases.55 In another trial, when omega-3 fattyacids were added to this high omega-6 intakethe added benefits were few, if any.56 This wasa faulty trial design, as enzymes in the omega-6 fatty acid pathway are known to competewith those in the omega-3 pathway.57 None-theless, the cumulative epidemiological, ex-perimental, and clinical data dictate that MS

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patients reduce animal fat intake and increaseintakes of vegetables and cold-water marinefish.54

A modified-fat diet has been empiri-cally proven for MS. Beginning in 1948, Dr.Roy Swank began treating MS patients withhis modified diet consisting of 50-90 gramsof protein (with one egg per day and severalglasses of skim milk for animal protein); amaximum of 15 grams of animal fat, 10-15grams of fluid vegetable oils, and 5 grams ofcod liver oil; and carbohydrates as requiredfor calories. Margarine, shortening, and hy-drogenated oils were not allowed; three fishmeals per week were encouraged; and mostpatients increased their fruit and vegetable in-takes. This diet is not very different from whatwould currently be considered a healthy diet.

In 1988 Dr. Swank reported on 150patients followed long-term, from 1949 to1984.58,59 Those who complied, with daily fatconsumption of less than 20 grams of fat (<15grams of saturated fat), fared much better onmorbidity and length of life than did those whoconsumed larger amounts of fat. The death ratewas lower in the former group compared withthe latter (31 percent versus approximately 80percent). Swank also concluded that 95 per-cent of the patients placed on his diet beforethe development of disability suffered no sig-nificant increased disability from MS duringthe 35-year period.60,61

Food AllergiesDiets high in gluten and milk are gen-

erally much more common in areas with highMS prevalence,62,63 and a connection betweenMS and food allergies has been suspected sincethe 1930s. In addition, patients with general-ized allergy may be more readily susceptibleto symptom exacerbation. In one study of 15patients, the avoidance of allergenic foods,tobacco, or house dust led to almost completecontrol of symptoms.1

MS patients can manifest anatomicproof of food allergy. Small-intestinal biopsy

indicated 50 percent of a small group (6 of12) had inflammatory abnormalities of the lin-ing reminiscent of celiac disease and otherfood allergies.64 Celiac disease is closely linkedto gluten allergy, but negative findings fromcontrolled studies seemed to rule out any cen-tral role for gluten allergies in MS.8 But otherfoods, or the cumulative effects of food allergy,may be MS triggers. Thus, a 1952 study found31 percent of 49 MS patients improved whenthey avoided foods to which they were foundallergic.65 Reintroduction of such foods causedtheir symptoms to recur. According to Gaby,cow’s milk and sulfite food additives can trig-ger exacerbations, and in occasional MS casesthe degree of improvement from an allergyelimination diet can be highly impressive.1

Compelling rationale for an intestinal-immune system axis in MS has been articu-lated by Embry.66 Constituents of commonfoods are known to cause autoimmune dis-eases. Celiac disease is caused solely by glu-ten from grains. Clinical trials in rheumatoidarthritis and in Crohn’s disease have shownthat avoidance of milk, grains, and legumesresults in major symptom improvements. T-lymphocytes reactive with milk proteins arevery common in persons with MS; experimen-tally, such cells cross react with self-antigensin myelin. Peptides (small proteins) from milkhave been found to be molecular mimics ofself-antigens in myelin. Patterns of CNS de-generation closely resembling MS can be pre-cipitated in mice by injecting milk peptides orincluding them in the diet.

Digestive Malfunctions andDysbiosis

Aside from food allergy per se, poorGI function seems endemic in MS. Accordingto Wright, a majority of the patients he seeswith MS have poor digestion and assimilationof nutrients.68 Most have poor stomachfunction, with inadequate acid and pepsinproduction. Some have inadequate intestinal



digestive enzyme secretion. This problem iscommonly seen in otherwise healthyindividuals as they age. Gupta and colleaguesexamined 52 MS patients and found 42 percenthad fat malabsorption, 41 percentdemonstrated undigested meat fibers, 27percent had abnormal absorption, and 12percent experienced malabsorption of vitaminB12.67 Pancreatic enzyme preparations mayhelp correct malabsorption as well as to helpdisperse circulating immune complexes.

Gut dysbiosis has been implicated inMS.1 Perlmutter reported finding anti-Candidaantibodies or Candida immune complexes inseven of ten MS patients evaluated.7 Eight ofthese patients also demonstrated depressedlevels of colonic symbiotic bacteria

(Lactobacillus species). Aggressive anti-Candida treatment together with therequisite re-colonization of probioticorganisms has been claimed tooccasionally resolve MS symptoms.68

Gut dysbiosis is also commonlyrecognized in patients with inflammatorybowel disease (IBD). One study usedMRI to look at MS-type lesions (“whitematter plaques”) in IBD patients com-pared to normal individuals (Figure 4).69

Hyper-intense, focal lesions 2-8mm in diameter were found in 42 per-cent of patients with Crohn’s disease andin 46 percent of those with ulcerativecolitis. Only 16 percent of the healthyvolunteers showed lesions. The authorsstated, “The frequency of focal white-matter lesions in the patients with inflam-matory bowel disease was almost as highas that in patients with multiple sclero-sis.…”69

Current Medical Managementof MS

Conventional drug developmenthas yielded several new drugs to treatmultiple sclerosis, all classed as “par-tially effective.” Interferon ß-1b

(Betaseron®), interferon ß-1a (Avonex®), andglatiramer acetate (Copaxone®) have all beenapproved by the U.S. Food and Drug Admin-istration for use in relapsing forms of MS.70

Each of these reduces clinical evidence ofacute, relapse-associated worsening of the dis-ease. In addition, evidence from European tri-als indicates a role for intravenous immuno-globulin in reducing relapses.

The use of these drugs is not withoutside effects, however. Investigators from Eu-rope and Canada report that doses of interferonß-1a, exceeding those previously evaluated inthe United States, reduced clinical and MRIevidence of disease progression.70 But this drug(Avonex) produced flu-like symptoms in up

Figure 4. Magnetic Resonance Image ofFocal White-matter Lesion in Parietal Lobe of18-year- old Woman with Crohn’s Disease

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to 61 percent of patients who took it at thecurrently recommended lower dose, as wellas nausea in 33 percent and anemia in eightpercent.71 In another study, interferon ß-1b wasshown to delay clinical and MRI worseningin patients with secondary progressive MS.This drug (Betaseron) produced flu-like symp-toms in 76 percent of the patients receiving itand significant injection site reactions in 85percent. It caused asthenia in 49 percent, my-algia in 44 percent, menstrual disorders in 28percent of the female patients, sweating in 23percent, was liver toxic in 19 percent, andcaused depressed white cell counts in 16 per-cent of patients.4

These drugs are regarded by some par-ties as significant therapeutic advances againstMS, although they are expensive (at approxi-mately $11,000 per year in U.S. currency),inconvenient since they are not effective bymouth, and have marked adverse effects. Al-though they reduce relapse rate by 35 percent,to date no effort has been made to collect datathat might help assess long-term benefits forquality and length of life.

Copaxone is a synthetic peptide drugdesigned to interfere with receptors on myelin-sensitized T-cells. It does appear to have a de-gree of effectiveness against the autoimmuneaspect of the disease. Although it may beslightly less toxic than the interferons,Copaxone has a fierce adverse effects profile.Some of the more frequent toxic effects re-ported from clinical trials include bacterialinfection, lymphadenopathy, vaginal monilia-sis, edema, weight gain, eye disorders, palpi-tations, vasodilatation, dyspnea, nausea, andpruritus.72

A number of other possible drugtherapies are in the pipeline for MS, but thedevelopment scenario has become morechallenging. To demonstrate benefits thatwould exceed the existing “partially effective”therapies would require longer and larger trials.The most promising among these are:Valacyclovir, an anti-herpesvirus medication;

TNF inhibitors and other inhibitors of pro-inflammatory cytokines; pentoxifylline;transforming growth factor-ß, and other agentsto enhance the TH2 arm of immunity; d-penicillamine and other matrixmetalloproteinase inhibitors; antibodies ofmany kinds to manipulate MHC and other T-cell antigenic sites; inhibitors of cathepsin B,a proteinase linked to the inflammatorydemyelination of MS; oxygen radicalscavengers; autologous bone marrowtransplantation; gene therapy; implantation ofoligodendroglial precursor cells; and the useof mathematical modelling to conduct virtualclinical trials that screen new agents.70

Rational Bases for IntegrativeManagement of MS

Multiple sclerosis is a frustratingdisease to have, to treat, and to study,particularly since its etiology and triggers areso poorly understood. The seemingly arbitrarywaxing and waning of MS symptoms and theomnipresent likelihood of disease exacerbationnecessarily dictate strict adherence to a basicplan, with willingness to augment or otherwisemodify the plan as circumstances change. Aswith many other diseases, diet and lifestylechanges, dietary supplementation, andmoderate physical exercise all contribute tobetter quality of life in MS, but additionalmedical modalities also show promise.

Anti-Inflammatory DietSteadily accumulating data indicate the

“mainstream” Western diet is pro-inflamma-tory, imposing oxidative challenge on the bodywhile failing to adequately support antioxidantdefenses. One class of pro-inflammatory di-etary constituents is the animal-source fats.These have a significant content of saturatedfats; a low content of the anti-inflammatoryomega-3 fatty acids docosahexanoic acid(DHA) and eicosapentanoic acid (EPA); anda high proportion of their omega-6 fatty acids



in the form of long-chain omega-6 arachidonicacid (AA). Unlike the omega-6 linoleic acid,AA is a precursor to pro-inflammatory pros-taglandins; and as reviewed by Lauer, coastalpopulations that consume more fish, thereforeless AA and more DHA and EPA, have lowerMS rates.54

The delicate endothelial linings of theblood vessels are vulnerable to pro-inflamma-tory attack,57 and inflammation of blood ves-sels in the brain is characteristic of MS.73

Plaques frequently arise around a vein orvenule, and active inflammation in these ves-sels is often accompanied by thrombosis andincreased platelet stickiness.74 Omega-3 fattyacids help maintain anti-inflammatory balancein the circulation, while supporting myelina-tion and nerve cell membrane renewal. Wrightmonitors systemic fatty acid (FA) balance bytesting red cell membrane FA profiles, thenprescribes omega-3 FAs as necessary.68

Swank’s healthy-fat MS diet probablybenefits MS in several ways. From its overallcomposition it would be expected to lowercholesterol and reduce platelet stickiness.Polyunsaturated oils appear to help prevent MSdeterioration;55 cod liver oil inhibits autoim-munity in experimental animals;1 and keep-ing the “bad” fatty acids low (saturates, trans-fats) reduces their competition with the “good”fatty acids, including the omega-6 gamma-li-nolenic acid and the omega-3 alpha-linolenicacid, EPA, and DHA.57

Another implication from its anti-in-flammatory orientation is that the Swank Dietshould down regulate autoimmunity in the MSpatient. The potent immune-suppressing ste-roids have short term symptomatic efficacy,but dietary rebalancing of the omega-6 toomega-3 ratio could favorably reset the body’sautoimmune-inflammatory set point.

Rational Dietary SupplementationAs with the other neurodegenerative

diseases, supplementation of the diet with vi-tamins and other nutrients is indicated, both

to support well being and to ameliorate defi-ciencies engendered by the ongoing demyeli-nating, autoimmune-inflammatory process.

Linoleic AcidLinoleic acid is an essential omega-6

fatty acid, meaning a deficiency state is knownand it must be obtained from the diet. Homaand collaborators found abnormally low lev-els in the red cells of 14 percent of their MSpatients.75 Plant oil sources of linoleic acidwere administered to MS patients in threedouble-blind, placebo-controlled trials. Theresults were mixed: two of the trials foundbenefit while one did not. A meta-analysis ofthe 181 patients concluded that linoleic acidat 20 grams per day reduced disability and theseverity and duration of relapses, especiallyin patients with early disease and minimal dis-ability.55

Gamma-Linolenic Acid (GLA)Gamma-linolenic acid contributes to

anti-inflammatory balance by competing withthe pro-inflammatory arachidonic acid. Theuse of GLA bypasses the enzymatic conver-sion of LA to GLA, which is subject to inacti-vation by a number of factors including viralactivity. Initial studies used encapsulatedevening primrose oil as a source of GLA andfailed to find effectiveness in MS. Horrobintheorized that the capsule dyes (tartrazine,Ponceau R) interfere with GLA utilization.76

Working with two collaborators, he conducteda preliminary non-controlled trial on 14 pa-tients using primrose oil in dye-free capsules,either by itself or in conjunction with colchi-cine. They reported that five of eight patientsbenefited from primrose oil supplementation(2.4 mL/day) and four out of the remainingsix benefited from primrose oil plus colchi-cine (2.4 mL/day plus 1.0 mg/day, respectively.New Zealand researchers noted that MS pa-tients often have cold hands and feet, usuallyan indication of impaired peripheral blood

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flow. Their non-controlled study on 16 pa-tients77 concluded that GLA from primrose oilimproved peripheral blood flow characteris-tics and consequently, hand-grip strength.

Omega-3 Fatty AcidsOmega-3 fatty acids include alpha-li-

nolenic acid from flax, and the longer-chainEPA and DHA from cold-water fish and al-gae. Immunological experiments showedomega-3 fatty acids suppressed inflammatoryreactivity in the mouse EAE model of MS, andincreased omega-3 FA intake in humans hasbeen shown beneficial for the autoimmunediseases rheumatoid arthritis and Crohn’s dis-ease. From red cell analysis, it was suggestedMS patients might have low systemic DHAand EPA content.78 A small clinical trial (12patients) with no control patient group sug-gested that omega-3 fatty acid supplementsfrom fish oil might reduce MS exacerbations.79

AntioxidantsDue to their high propensity for oxi-

dation, long-chain fatty acid preparationsshould always be administered in conjunctionwith high intakes of antioxidants. These nu-trients offer benefit in virtually any clinicalscenario that involves inflammation and oxi-dative stress. There is little doubt that oxida-tive stress is increased in MS.80 Vitamin E wasreported low in MS patients’ serum, and lipidperoxidation markers were increased in theCSF, especially during periods of disease ex-acerbation. The enzyme glutathione peroxi-dase (GP), which detoxifies peroxides, ismarkedly decreased in the red cells,81,82 thewhite cells,82 and the CSF80 of MS patients. Agroup in Denmark82 gave a high-dose mixedantioxidant supplement (sodium selenite 6 mgper day, providing 2,740 micrograms of el-emental selenium; vitamin C 2000 mg; vita-min E 480 mg) to 18 MS patients daily forfive weeks. GP activity, which was abnormallylow at baseline, increased five-fold to the nor-mal range without significant side effects.

The GP enzyme has an absolute re-quirement for selenium, a dietarily essentialtrace mineral, at its active sites. It also has anabsolute requirement for the thiol (–SH) tri-peptide glutathione (reduced glutathione;GSH) as its substrate cofactor. Perlmutter hasreported cases of successful oral applicationof GSH precursors in Parkinson’s,Alzheimer’s, stroke, and multiple sclerosis.7

GSH replacement, whether by mouthor combined with intravenous supplementa-tion, is safe and well tolerated. But when takenorally, GSH may have poor systemicbioavailability. One orally effective GSH pre-cursor is N-acetylcysteine (NAC), a potentantioxidant. Following its intestinal absorp-tion, NAC is first metabolized to cysteine, thencysteine is incorporated into GSH in depletedpatients.

The antioxidant alpha-lipoic acid(ALA) is another orally effective GSH repleter.ALA is a broad-spectrum, fat- and water-phaseantioxidant with potent electron-donating ca-pacity (more so even than GSH), and has addedbiochemical versatility as a Krebs cycle co-factor. ALA has shown consistently impres-sive efficacy for the treatment of neuropathiesin a number of controlled trials.83

FlavonoidsDerived from plant sources, these po-

tent free-radical scavengers support overallantioxidant defense and particularly protectcapillary integrity. In an effort to decrease in-testinal epithelial and blood-brain barrier per-meability, both of which are reported abnor-mal in MS, standardized preparations of fla-vonoids may offer benefit.

The popular Ginkgo biloba leafcontains, in addition to flavonoids, terpenesubstances which are also anti-inflammatories.One such terpene, ginkgolide B, is a potentinhibitor of platelet-activating factor, a well-characterized inflammatory mediator. In adouble-blind, placebo-controlled trial,ginkgolide B failed to acutely reduce MS



exacerbations. The extremely short period ofstudy – only seven days – limits the meaningof this trial.84

Vitamin D, Possible Key to MSGeographical Distribution

One factor that correlates with MS islatitude. The higher latitudes, in both the north-ern and southern hemispheres, have up to 10times higher rates of MS (50 to 100 cases per100,000 population, versus 5 to 10 cases per100,000 in the tropics).8 One hypothesis mostlikely to explain this phenomenon is the influ-ence of latitude over production of vitamin Din the skin.

Availability of vitamin D, the “sun-shine vitamin,” decreases with increasing lati-tude in patterns closely correlated with increas-ing MS rates.85 Individuals with a high expo-sure to sunlight have a significantly lower riskof MS, independent of country of origin, age,sex, race, and socioeconomic status. Con-versely, most MS patients have vitamin D de-ficiency, which leads to low bone mass andhigh risk of fracture, compounded by theosteopenic effects of the glucocorticoidswidely used in MS therapy.86

Fish oil is an excellent vitamin Dsource. Within specific nations, fishing com-munities located on the coast consistently havelower MS incidence compared with farmingcommunities living inland.52,54 In addition tolower rates of MS in coastal communities, ratesare generally lower in countries in which a lotof fish is eaten. Perhaps the vitamin D com-ponent of fish oil complements the benefitsafforded by the omega-3 fatty acids. The casefor this vitamin being the determinant of MSgeography is circumstantial, but in any case itis an important dietary supplement for MSpatients.

MineralsCalcium and magnesium complement

and balance each other, and are essential min-erals involved in human metabolism. Goldberg

and collaborators87 administered dietarysupplements with calcium (about 1,100 mgdaily), magnesium (about 680 mg), and 20grams of cod liver oil to 16 young MS patientsfor periods of one to two years. They foundthe number of exacerbations observed duringthe program was less than one-half the pre-dicted number.

Injectable NutrientsVitamin B12

Vitamin B12 is a key nutrient factorsupporting myelin formation. Acquired B12deficiency and inborn errors in its metabolismare recognized causes of CNS demyelination,so its deficiency in MS would be expected tocontribute to progression. Early studies of B12status in MS produced conflicting results, butimproved testing techniques confirmed B12levels were lower in the CSF of MS patients,if not always lower in the serum.88 For morethan 30 years, clinicians have been reportingconsistent clinical improvement of MS fromB12 injections. Many integrative physiciansroutinely prescribe intramuscular injections ofB complex with B12 and folic acid to theirMS patients, reportedly with improvement.

Reynolds and colleagues at Kings Col-lege, London, reported on a significant asso-ciation between MS and disturbed B12 me-tabolism. They discovered some of their MSpatients were significantly macrocytic, a con-dition reminiscent of classic B12 deficiency.Their patient group also had significantly lowerserum B12.88 Kira and collaborators confirmedthis observation in Japan, administeringmethylcobalamin by mouth at a large dose of60 mg per day to patients for six months.89

They observed improvement in sensory nervepotentials, but no motor nerve improvement.Immune-suppressive steroids or cyclophos-phamide can produce comparable results, butwith severely adverse side effects.8

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Adenosine Monophosphate (AMP)Fatigue can be a significant factor in

MS. Wright reported success from patientsself-administering intramuscular injections ofAMP, which is a precursor of the “energy cur-rency” substance ATP (adenosine triphos-phate). AMP has been used to treat viral in-fections and other conditions. In one uncon-trolled study, 16 patients with severe disabil-ity from established MS received a series ofAMP injections over 6-10 months. Markedimprovements were noted in endurance andin bladder function.90 Intravenous AMP admin-istration is not advised.68

PhytotherapiesSome of the herbs used in traditional

folk medicine may make a difference in MS.In a double-blind study, 100 MS patients re-ceived a traditional Tibetan herbal formulaknown as Adaptrin (formerly Padma 28).91

Half of the patients who received this formulaexperienced overall improvement in additionto increased muscle strength and improvedbladder function.

Natural Interferon TreatmentWhereas the beta-interferons currently

approved for MS drug therapy are synthetic, anatural alpha-interferon derived from leuko-cytes could prove just as advantageous andperhaps with a better benefit-risk profile. Inthree preliminary studies conducted between1987 and 1991, 45 patients were treated with5-30 million units per week for 3-12 months,and were observed for two years.92 Side ef-fects included flu-like symptoms, myalgias,and fatigue which caused some patient drop-out. In the first year of treatment, 58 percentof the patients improved and 22 percent stabi-lized, and after the second year 53 percent re-mained improved and 22 percent stable. Ad-ditional controlled studies are needed.

Histamine ReplacementRediscovered

Histamine is a small orthomoleculewhich exists naturally in the body. In humans,histamine is synthesized from histidine, a con-ditionally-essential amino acid. Histamine isa proven mediator of allergy, and one of themost persistent dogmas in medicine is thatantihistamines are the best way to block al-lergy. Yet in MS patients, raising histaminemay help block autoimmunity.

According to Drs. Gillson and Wrightand their collaborators,93 in the 1940s whileantihistamines were being discovered, Hortonand others at the Mayo Clinic were achievingremarkable results for allergies and other ill-nesses by raising the body’s histamine(through injection). Later, Horton’s discipleDr. Hinton Jonez set up a clinic in Tacoma,Washington, exclusively for MS management.Treatments included elimination of food- andother allergies, injections of histamine, B12and AMP, and physical therapy. The clinic wasclosed after Dr. Jonez died in 1952.

Physicians at the Tahoma Clinic, inKent, Washington, recently collaborated in arevival of histamine application for MS. A pro-prietary transdermal cream (Procarin) wasdeveloped by Elaine Delack, RN, herself af-flicted with MS, and was administered throughthe clinic to 55 MS patients. It was judged ef-fective in 67 percent of the cases.93 Patientsimproved in one or more areas, including ex-tremity strength, balance, bladder control, fa-tigue, activities of daily living, and cognitivefunctioning, sustained for periods of up to threemonths. This promising work continues.

Oral Antigen TherapyOral tolerance is the phenomenon

whereby oral dosing of an antigen can neu-tralize the body’s immune sensitization againstthe molecule. Oral tolerance was first observedwhen guinea pigs given hen’s egg proteinorally were found to become resistant to the



anaphylactic reactions normally induced by theingested protein. In 1986 the oral administra-tion of human collagen was employed to sup-press collagen-induced arthritis. Subsequently,attention turned to MS.

In experimental allergic encephalomy-elitis (EAE), rats develop an MS-like diseasethat features autoimmune reactivity againstmyelin basic protein (MBP). When such ratswere orally fed MBP, their EAE was sup-pressed, demyelination was reduced, clinicalneurological signs improved, and antibodiesagainst MBP decreased.94 A preliminary studywith human subjects indicated they did pro-duce the class of T-cells required (in theory, atleast) to suppress autoimmunity in the brain,but with appreciable subject-to-subject varia-tion.95 However, a later controlled human trialfailed to find significant clinical improve-ment.96 Recent reports from animal researchhave sparked debate about possible adverseeffects.97

Hyperbaric Oxygen Therapy(HBOT)

Hyperbaric oxygen therapy involvesexposure to oxygen at pressures higher thannormal air, in multiple sessions repeated al-most on a daily basis. Most HBOT protocolsinvolve 20 sessions of 90 minutes each for fourweeks, in a chamber with oxygen supplied at1.75-2.0 times normal atmospheric pressure.Side effects are generally minor. Earlier, un-controlled trials and anecdotal reports indi-cated benefit from HBOT for MS. The firstdouble-blind trial reported initial marked im-provement in 12 of 17 patients, with more fa-vorable and lasting response in those with lesssevere disease.98 Seven controlled trialsshowed virtually no improvement. A 1995meta-analysis of these eight available studiesconcluded HBOT therapy had little to offer forMS;99 however, all these trials were short term,lasting less than two months.

The Federation of Multiple SclerosisTherapy Centres in the United Kingdom hasvery different data on HBOT outcomes in MS.Their HBOT protocol involves indefinite long-term treatment, preferably on a weekly basis,following the initial intense treatment periodof four weeks. Their network of 56 treatmentcenters has treated more than 10,000 patientsover a period of 14 years. In 1996, theFederation’s Perrins and James reported on theprogress of 703 patients followed for up to 13years;100 the results suggested HBOT signifi-cantly benefits MS.

The degree of benefit obtained fromHBOT was clearly related to the number andfrequency of treatments the patients obtainedover the years. Patients with all the MS sub-types were interviewed immediately follow-ing the initial course and assigned a KurtzkeDisability Scale (KDS) score. They were laterassessed at three years (2-4), seven years (6-8), and 10-13 years after beginning treatment.After the initial course there was little aver-age change in the KDS, although 25 percentof the RR patients had improved scores. Ofall the patients, 59-77 percent reported symp-tomatic improvement. Visual defects were re-ported by 51 percent of the patients, but manyresolved during the initial course. Other ini-tial adverse effects occurred in a minority ofthe patients, and featured mostly fatigue, legweakness, and limb numbness, none of whichpersisted. Minor problems with eardrum pres-sure did not necessitate stopping treatment.

Following the initial treatment course,66 percent of the patient cohort continued forthree years, 34 percent for seven years, and 24percent for a minimum of 10 years. At threeyears there was overall average deteriorationon the KDS, but those patients with more treat-ments had deteriorated less. At seven years,none of the 10 RR patients who had receivedat least eight treatments in every quarter ofeach year had deteriorated and four of themhad actually improved.

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At 10-13 years, 447 patients of theFederation’s initial cohort of 703 remainedeligible for assessment. Of these, 23 percentwere no worse after regular treatments for 10-13 years; seven percent had actually improved;and the eight percent who had received lessthan one follow-up treatment per year hadseriously deteriorated. Further analysisrevealed that a minimum of one treatmentevery two weeks was correlated withappreciable arrest of progression, and that oneper week was probably most effective.Consistent with the known natural history ofMS, the relapsing-remitting patients and thosewho began HBOT at earlier stages experiencedgreater benefit. The Federation’s studyconcluded that the degree of KDS maintenance

or improvementattainable after 10years could make thedifference betweenremaining mobilewithout assistanceand needing canes ora wheelchair.

HBOT in theUK has proven ben-eficial, practical, andcost-effective withminimal adverse ef-fects. The Federationalso advises its pa-tients to take advan-tage of physiotherapyand to adopt healthydietary habits consis-tent with the Swankdiet and other naturalp r i n c i p l e s .1 0 1

Perlmutter7 and otherpractitioners makeHBOT available toMS patients in an in-tegrative medical set-ting.

Emerging Options for ModulatingMS Autoimmunity

The immune system is normally ableto distinguish between foreign invaders and“self” body tissues in healthy individuals.102

Autoimmunity results when the immunesystem inappropriately attacks self tissues. InMS the targets of autoimmunity are mainly themyelin-producing cells in the CNS.103 T-cellsreactive to the major constituents of myelinsuch as myelin basic protein and proteolipidprotein (PLP), migrate from the peripheralcirculation, across the blood-brain barrier, andinto the brain. There they proceed to attackmyelin-ensheathed axons and myelin-producing cells, initiating an inflammatory

Figure 5. Proposed Mechanism for Activation ofMyelin-Reactive T-cells by Molecular Mimicry

MBP Specific T Cell

Viral Peptide

Antigen presenting cell

Periphery

Central nervous system

CNS antigenpresenting cell

Myelin basicprotein peptide

Blood brain barrier

Activated T Cells

From Wucherpfenning and Strominger.100



cascade that eventuates in the white matterlesion or plaque of multiple sclerosis.

Myelin-reactive T-cells in the periph-eral circulation may become activated by mi-crobes. Structural similarities between the for-eign antigens on the microbe, and the self-an-tigens of myelin may lead to inadvertent auto-sensitization of the T-cell against self. This isthe concept of molecular mimicry (Figure 5).104

MBP, for example, shares extensive homolo-gies in amino acid sequences with measles,influenza virus, adenovirus, herpesviruses,papilloma virus, and bacteria, includingpseudomonas.

Cytokines are small peptide substancesthat act as cell-to-cell messengers to regulateimmune cell activity. Patterns of cytokine pro-duction can set the immune system into oneof two dominant modes: T-helper types 1 (Th1)or 2 (Th2).102 Th1 activation features predomi-nantly cell-mediated cytotoxicity, and inflam-matory and hypersensitivity reactions. Th2activation features predominantly antibody-mediated, allergic responses. Various chronicdiseases show differing cytokine patterns; inMS the Th1 pattern clearly dominates. Of theknown Th1 cytokines, interferon-gammaworsens disease when given systemically toMS patients, and IL-12 has been implicatedin a number of experimental autoimmune dis-eases; both these cytokines were found to beup-regulated in MS patients.105 IL-12 was evenfound abnormally elevated in the serum of sec-ondary progressive MS patients. Therapeuticsare being pursued that down-regulate Th1cytokines, with the goal of systemically turn-ing off the autoimmunity of MS.

Vitamin D3 is a potent immune-modu-lating substance;106 it acts via specific recep-tors carried on antigen-presenting cells andactivated T-cells. Exogenous 1,alpha,25-dihydroxyvitamin D3 (DHD3), the biologi-cally active metabolite of vitamin D3, can in-hibit different experimental models of autoim-mune disease and can significantly ameliorateEAE, the “mouse multiple sclerosis.”105,106

Experiments conducted in vitro and in vivowith both DHD3 and its synthetic analogueRo 63-2023 showed specific inhibition of theTh1 cytokines IL-12 and IFN-gamma. As aconsequence of this down-regulation of Th1,inflammation, demyelination, and axonal losswere markedly lowered in the EAE mice.105

Interestingly, this effect did not up-regulateTh2 pathways; but appeared to calm anoveractivated Th1 immune mode. Th1 may notbe typically pro-inflammatory, but in the caseof EAE/MS, this pathway has seemingly be-come locked into an exaggerated sensitivityto myelin-related antigens.

An Integrative ManagementStrategy for MS

A few physicians have been practic-ing for decades what is effectively integrativemedical management of MS. They concur thatthe implementation of a personalized regimenearly in the course of MS can facilitate symp-tom-free, long-term stabilization of the diseasewith good quality of life, all without the useof pharmaceuticals.17,68,91 Dietary supplemen-tation combined with dietary reform can haltthe deterioration and bring about improvement,as achieved by 94 percent of the patients withnewly diagnosed RR-MS over a period of twoyears.107 Conscious adherence to an anti-in-flammatory diet that incorporates the Swankprinciples, and aggressive dietary and inject-able supplementation with nutrients, are thefoundation of the patients’ responsibility formanaging their disease.

In addition to the obvious aspects ofdietary and lifestyle modification required ofthe integrative, personalized approach to healthmaintenance, other measures of personal at-tention to good health are important, includ-ing moderate exercise that reinforces balanceand muscle tone,108 and the conscious avoid-ance of toxic situations, excessive fatigue,emotional stress, or marked hot and cold tem-perature oscillations.

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An integrative protocol for MS man-agement is submitted (Table 1). For the mosteffective management of MS, it is suggestedthe practitioner work closely with the patientto eliminate toxic metals (e.g., lead, mercury)and chemicals from the daily environment andto deplete the total body load. All solvents, in-secticides and other pesticides, and for somepatients every synthetic in their environment,

must be consid-ered suspect.Mere exposureto cigarettesmoke can be anexacerbating fac-tor.109 Allergies,food or inhalant,should be testedfor and elimi-nated. Patients atan early stage ofsymptoms arelikely to benefitfrom intestinaldetoxif icationand normaliza-tion, includingfood allergy test-ing. Correctionof nutrient defi-ciencies, GI mal-absorption, andprobiotic bal-ance often re-sults in multisys-tem improve-ment. The viral-microbial loadshould be identi-fied and treated.

For thosefew unfortunatepatients who sin-cerely imple-ment an integra-tive program but

still progress to significant disability, a desiremay arise to try a pharmaceutical intervention.At this point it becomes crucial to retain theintegrated program, as a means to protectagainst the toxicity attendant with any of theapproved MS pharmaceuticals. Hyperbaricoxygen might first be tried, if it is available.Although a fully controlled study on HBOT isstill lacking, the use of this modality seems to

Table 1. Ten-Phase Integrative Management Program forMultiple Sclerosis

1. Establish firm diagnosis using MRI and neural function-disability testing.

2. Identify toxic load through testing: mercury-dental amalgams, other heavy metals, environmental toxins. Detoxify as necessary. Support liver functions using glutathione, antioxidants, other nutrients as indicated. Consider nontoxic immune-enhancing nutrients.37

3. Sample and culture for HHV-6 and other chronic viruses, mycoplasmas, Chlamydia sp. Treat aggressively with antibiotics and/or antiherpes antivirals, with probiotic and nutritional support, until eliminated (sometimes >1 year).37

4. Assess gastrointestinal acid production, digestive enzyme secretion. Prescribe pancreatic enzymes as necessary. Test for parasites and Candida albicans; treat aggressively. Recolonize GI tract with probiotics as necessary.

5. Implement anti-inflammatory diet. Avoid sugar, additives, “junk” foods. Fresh, quality flaxseed oil (1-2 Tbsp) can serve as salad dressing.

6. Dietary supplements: high-potency multivitamin-mineral; selenium, vitamin B12; potent B complex; vitamin C, vitamin E, CoQ10; DHA-EPA from fish oils; high-bioavailability flavonoid extract.

7. Implement disciplined moderate exercise.8 For spastic or severely weakened limbs, massage and other physical therapy are helpful. Tai chi chuan helps maintain balance.105

8. Allow minimum 3-6 months for these measures to take effect. Re-assess using MRI for lesion stabilization or progression, and disability measures.

9. If stabilization is evident, recommit to existing protocol. If disease progression is evident, consider hyperbaric oxygen therapy (HBOT) with aggressive nutritional support.

10. If prolonged HBOT (>2 years) fails to halt progression, consider pharmaceutical options but continue with integrative protocol.



offer an additional dimension for healing withlittle risk. And the histamine strategy may pro-vide breakthrough benefit for some patients.

Making a commitment to explore“natural” treatment modalities does not haveto mean abandoning opportunities for benefitfrom pharmaceutical medications, and viceversa. Nutrients and other modalities supporthomeostasis and help protect the system fromthe shock of synthetic monotherapies such asAvonex, Betaseron, and Copaxone.

Prospects for Eventual EffectiveManagement of MS

Its unpredictable behavior and appar-ent complex etiopathogenesis render multiplesclerosis a particularly challenging disease.Whatever the perspectives brought to bear onfurther studies of MS, it is clear these will re-quire large sample sizes and longer periods ofstudy in order to adequately define benefit.Experts in the MS field have much to disagreeabout, but there is consensus that MS has sig-nificant genetic and environmental compo-nents. The genetic contributions are progres-sively being defined, but discrete environmen-tal factors (viruses, chemical toxins) are stillpoorly defined.

Most workers in the field agree thatinfectious agents play a key role in MS, butno one of the several current candidate agentshas been conclusively proven. Exogenous tox-ins are linked with MS clusters but do not ac-count for the north-south gradient of diseaseprevalence. A role exists for diet, but (withnotable exceptions) hardly any organized ef-fort has been made to investigate dietary fac-tors. The overlapping areas of nutrition,lifestyle, and the overall potential for an au-thentic integrative strategy to stabilize or re-verse the disease have generally been neglectedin favor of the pharmacological interventionmodel. Authentic research into the integrativemanagement of MS is sorely needed.

Multiple sclerosis, once established, islikely to lead to serious disability, and in thisscenario the best prognosis is partial improve-ment. But if management is begun early, anauthentic integrative strategy will in manycases achieve near-complete relief of symp-toms. Strict adherence to diet and lifestylechanges; elimination of toxic and microbialbody load; aggressive use of nutrients; andexceptional commitment to minimizing stress,are all mandatory requisites for a quality co-existence with this disease.

A number of ambitious new strategies,mainly high-tech, are being brought to bearon MS. These include the predictable trio ofgene therapy, stem cell transplantation, andpharmacological neuroprotection. But the un-raveling of its autoimmune component maywell be the final frontier for conquering MS.Once this challenging task can be achieved,multiple sclerosis should yield to integrativemedical management.

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