Alterna(ve Treatments for Mul(ple Sclerosis Karl F. Gross, MD Feb. 6, 2018 Key Biscayne, Florida
Short Biography •
Vienna – Austria: – Medical School (M.D. 1981) – Family Prac(ce Residency (‘81-’84)
•
Denver, Colorado: – Neurology Residency (’84-’87) – Private prac(ce (‘87-’99) – Assistant Clinical Professor of Neurology, UCHSC in Denver (‘91-’06)
•
1999: MS-diagnosis
n Since that (me, lecturer and consultant for
MS-organiza(ons and pharmaceu(cal companies in U.S. and Europe
Disclosures • Since the year 2000, I have received lecture- and consultant- honoraria, as well as reimbursement for travel expenses, from the following pharmaceu(cal companies: - Berlex, Schering, Bayer, Sanofi-Aven(s, Genzyme, Novar(s, Cephalon Today’s lecture is not sponsored by any pharmaceu(cal or other company. It was organized by the Key Biscayne Community Founda(on.
Physician- and/or Patient- Perspective
Physician-Perspective: “rational/scientific”
Janus face downloaded from http://bgweiz.at/unterricht/ latein/stichworte/?sw=janus
Patient-Perspective: “emotional/subjective”
Symptoms of Mul(ple Sclerosis •
MS can cause a wide variety of symptoms, depending on which loca(ons in the brain and/or spinal cord are affected by the MS-lesions. Cerebellum
Cortex
Slurred speech, coordination problems
fatigue, depression, cognitive problems Optic nerve
Swallowing problems, slurred speech
Visual disturbances, blindness
Spinal cord
Face Trigeminal neuralgia, etc. Bladder/bowel Urinary frequency/ urgency, urinary and fecal incontinence Extremities Sensory disturbances, „pins & needles,“ numbness, pain Diener HC, Weller M. Schattauer Verlag, Stuttgart, 2007.
Brainstem
Weakness, paralysis, numness, incontinence Sexual organs Sexual dysfunction, Muscles Weakness, paralysis, tremors, coordination problems
Mul(ple Sclerosis – typical course 10,0
CIS
Clinically definite MS (CDMS)
Disability scale Secondary-progressive MS (SPMS)
Relapsing remitting MS (RRMS)
clinical threshold
E D
Total lesion load
atrophy Disease activity
S S
Active inflammatory lesions Time
0,0
KIS, klinisch-isoliertes Syndrom; RRMS, relapsing-remitting multiple sclerosis, schubförmige Multiple Sklerose; SPMS, sekundär progrediente Multiple Sklerose; EDSS, Extended Disability Status Scale, erweiterte Behinderungsskala.
“Benign” MS 9 1986-1987 1996
8
Kurtzke EDSS Score
7 6 5 4 3 2 1 0 0
5
10
15
20
25
30
35
40
45
Duration of illness in years Hawkins SA, McDonnell GV. J Neurol Neurosurg Psychiatry. 1999;67:148-152.
50
55
Mul(ple Sclerosis – Epidemiology •
Prevalence of MS per 100 000
World Health Organization, 2008.
Mul(ple Sclerosis – Defini(on Mul(ple Sclerosis = immune-mediated chronic inflammatory disease of the CNS
demyelination
axonal damage
Gold R et al. Georg Thieme Verlag, Stuttgart, 2008; Diener HC, Weller M. Schattauer Verlag, Stuttgart, 2007.
Possible causes/triggers of MS
genetic factors infections
Abnormal immune response
environment
MS
MS = multiple sclerosis Gilden DH Lancet Neurol 2005;4:195-202, Noseworthy et al. N Engl J Med 2000;343:938
A Model of Immune Mechanisms in MS: Overview
Disease-Modifying Therapeutic Strategies: Immunosuppression
Disease-Modifying Therapeutic Strategies: Immunomodulation
“Conven(onal” medica(ons for MS
“Alterna(ve” treatments for MS
What does “alterna(ve” mean? • La(n: alternare – “to do one thing ager another, to change back and forth” • In medical parlance: treatments that have not (yet) been proven and thus have not been approved and accepted by FDA, etc. • Low (or no) risk of untoward effects is usually assumed (“natural can’t hurt”) – not always true! • Important: “In addi(on to” versus “instead of” regular medical treatment(s)
Categories of alterna(ve MS-treatments • Treatments that are virtually already mainstream (but have not [yet] been formally approved) – such as vitamin-D and bio(n • Treatments that may well be somewhat useful and are probably harmless (GLA, “fish-oil”/ omega-3s, alpha-lipoic acid, taurine, co-enzyme Q10, probio(cs, curcumin) • Beneficial non-pharmacological measures (QiGong, Lian Gong, Tai-Chi, acupuncture, Yoga, mindfulness-medita(on, physical exercise, diet, avoiding smoking, etc.)
Useless “treatments” • Bee s(ngs • Venous angioplasty for presumed “CCSVI” (but recently claim of improved fa(gue and headaches) • Hyperbaric oxygen • Fake “stem-cell transplants” • Removing old dental fillings containing mercury (“amalgam”) • Various “chela(on” protocols
S(ll unclear: • Cannabinoids – some usefulness for MS-related spas(city and chronic pain, but proven nega(ve effects on cogni(on, unclear effects on immune system • Complex and specific diet-instruc(ons (Wahl, Gundry, Swank, etc.) … however, low-salt/lowcarb diet probably a good idea • Me(culous aoen(on to dental hygiene: obviously makes sense for general health, may be beneficial in MS • Various an:bio:c regimens (e.g., tetracyclines)
Supplements & medica(ons that may s(mulate the immune system (and thus may be harmful in MS!) • Echinacea – no clear proof of harmfulness in MS that I am aware of, but the general recommenda(on is to avoid it in MS… • Most other supplements that claim to “boost” the immune system probably don’t have a big effect (elderberries, ginger, zinc, “astragalus,” etc., etc.) • Most of these claims of “boos(ng the immune system” are exaggerated anyway, but one really never knows… • Especially with obscure “Chinese herbs,” cau(on is advisable! • Avoid also Cime(dine (Tagamet™) and other (newer) H2-blockers (Zantac™, Pepcid™, Axid™)
Important general principles to keep in mind when evalua(ng ANY treatment • Correla:on does NOT equal causa:on • Avoid the error of “post hoc ergo propter hoc”-reasoning • Absence of evidence does NOT equal evidence of absence • Sta:s:cal significance does NOT equal clinical significance • Avoid inappropriate generaliza:ons from single “case reports”
Vitamin D • • • • • • • • •
Cholecalciferol – Vit. D3 1 IU = 0,025 microgram RDA in US: 600 IU (15 mcg) ages 1 to 70 RDA of 800 IU (20 mcg) if age >70 Ins(tute of Medicine (2010): Safe up to a maximum of 4000 IU/d (100 mcg) Many MS pa(ents use 5000 IU/d (125 mcg) Deficiency in childhood: rickets Helps to prevent osteoporosis ? May help to prevent colon cancer
Vitamin D in MS • Low vitamin D levels in childhood (and even in the mother during pregnancy) correlate with later MS-risk • Low vitamin D levels in MS-pa(ents correlate with higher disability ra(ngs and MRI-ac(vity • Vitamin D shows an effect in an animal model of MS (“EAE”) • 10,400 IUs/d reduce (IL)17-CD4+ T-cells • No defini(ve proof yet that vitamin D supplementa(on improves the clinical course of MS • However: hop://www.mdedge.com/ neurologyreviews/ar(cle/116917/mul(ple-sclerosis/ vitamin-d-add-therapy-may-improve-mri-outcomes-ms
Vitamin-D-levels: what’s normal? …and what’s ideal? • In “healthy people” 20-50 ng/ml are considered normal, and <12 ng/ml as definitely “deficient” • Problems with standardiza(on of assays • Unclear what an “ideal” blood level in MS would be – probably a minimum of 50-60 ng/ml • Some(mes the level will be reported in units of “mmol/l” – tables available to convert to ng/ml
Vitamin D toxicity • Generally only with very high doses (for example: 50,000 IU/d long-term) • Hypercalcemia, nausea, kidney stones, polyuria, muscle weakness, confusion, arrhythmias, weight loss • In a 6-month study of 10,400 IU/d, 3/19 pa(ents needed to stop because of side effects, and 1/19 needed to reduce the dose • During long-term therapy: check levels!
Vitamin D & MS • Further informa(on: hop://www.medscape.com/viewar(cle/856871 hops://www.ncbi.nlm.nih.gov/pmc/ar(cles/ PMC4727614/ hops://www.ncbi.nlm.nih.gov/pmc/ar(cles/ PMC5318363/ hops://www.ncbi.nlm.nih.gov/pmc/ar(cles/ PMC5318363/
Bio(n • Old names: Vit. B7, Vit H
Bio(n • Co-enzyme of carboxylase – involved in synthesis of faoy acids, isoleukine, and valine • Significant role also in gluconeogenesis • Bio(n-deficiency can (theore(cally) occur due to insufficient intake (?) or because of an enzyme deficiency (bio(nidase) & other extremely rare enzyme-deficiencies • Normally, certain gut bacteria synthe(ze bio(n • Probable importance of healthy “microbiom” • Avidin in raw egg-white blocks bio(n
Bio(n
• Currently, no official “RDA” established for bio(n • USA: intake of 30 microgramm/d is considered “adequate” • Dose used in the MS studies (since 2015) - 100 milligram 3x/d (10,000-fold amount!) • Unclear if there is a good scien(fic ra(onale for this dose – or if this is just a “patentstrategy”…
Large phase-3 study underway • A large trial is underway now in North America & Europe: • hops://mul(plesclerosisnewstoday.com/ 2017/05/09/medday-new-phase-3-trial-andbelief-in-bio(n-poten(al-to-treat-progressivems-interview-with-frederic-sedel/ • hops://clinicaltrials.gov/ct2/show/ NCT02936037? term=bio(n&cond=MS&rank=2
Pragma(c summary of bio(n in MS • Probably harmless & possibly effec(ve for progressive MS – however, also some reports of clinical worsening and increased atrophy on MRI • Most appropriate dose not yet clear • Bio(n interferes with a number of lab tests (especially hormones, pregnancy tests, troponin, and maybe others) • Must avoid raw/undercooked egg-whites • Do not take at the same (me as alpha-lipoic acid and pantothenic acid
Some more bio(n-links • hops://clinicaltrials.gov/ct2/show/NCT02220933 • hops://mul(plesclerosisnewstoday.com/ 2016/04/27/meddays-md1003-reversed-diseaseprogression-in-not-ac(ve-progressive-ms/ • hops://clinicaltrials.gov/ct2/show/NCT02220244 • hop://journals.sagepub.com/doi/abs/ 10.1177/1352458516667568
Qi Gong, Lian Gong, Tai Chi
Resources • Marius Robinson – right here on Key Biscayne!
Review ar(cles on medical benefits • hops://www.ncbi.nlm.nih.gov/pmc/ar(cles/ PMC3085832/ • hops://www.ncbi.nlm.nih.gov/pmc/ar(cles/ PMC3085832/pdf/nihms281835.pdf • hops://www.ncbi.nlm.nih.gov/pmc/ar(cles/ PMC5690748/ • hops://www.ncbi.nlm.nih.gov/pmc/ar(cles/ PMC5690748/pdf/medi-96-e8517.pdf
A few personal observa(ons • Remarkable effects on general physical wellbeing while inducing a relaxed mental clarity and overall gentleness – calm strength & flexibility. • Importance of learning directly from an experienced teacher. DVDs, books, and youtubeclips can be helpful in addi(on, but they don’t replace a teacher. • It’s best to have an open mind towards the tradi(onal explana(ons of “how and why” these disciplines work – but don’t become dogma(c. • Relax, and give it (me to work on you…
Some other poten(ally useful â&#x20AC;&#x153;alterna(ve treatmentsâ&#x20AC;?
Co-Enzyme Q10 for MS • A rela(vely small (n=48) study with decent design (double-blind, etc.) • 500mg/d had a posi(ve effect on fa(gue & depression • hops://www.ncbi.nlm.nih.gov/pubmed/ 25603363 • Some inflammatory parameters (IL-6, MMP-9, and TNF-α) were reduced • hop://www.tandfonline.com/doi/full/ 10.1179/1476830513Y.0000000106?src=recsys
“Omega-3,” “Fish-Oil,” “Omega-6,” “Gamma-Linoleic Acid,” etc. • Many confusing & to some extent contradictory “studies” - all sorts of doses, sources, generally poor design, etc. … • No shortage of “claims” by proponents – but no hard proof • If you take more or less reasonable doses of good quality fish oil and gamma-linoleic acid, there is probably very liole risk • There is very liole hope for defini(ve answers
Linoleic-Acid in MS • 1970’s: 3 studies of linoleic acid for MS in England…weak effect on progression of disability, but not on relapses • Rather dubious methodologies • Dworkin RH, et al. Linoleic acid and mul:ple sclerosis: a reanalysis of three double-blind trials. Neurology 1984;34:1441-1445.
Gamma-Linoleic-Acid • In animal trials GLA (although it is an omega-6 faoy acid!) demonstrates an an:-inflammatory effect • No real “evidence” for effect in MS • Popular with MS pa(ents in Great Britain & USA • Major sources: oils of “evening primrose” and “borage” • ?Dosis – ca. 240 - 300 mg/d of GLA
Alpha-Lipoic-Acid • 600mg 2x/d for 2 years vs. placebo in progr. MS: Reduc(on of brain atrophy on MRI, plus improvement of walking speed • hop://www.neurologyadvisor.com/aan-2016coverage/poten(al-treatment-benefit-oflipoic-acid-in-ms/ar(cle/490542/ • hops://mul(plesclerosisnewstoday.com/ 2016/09/19/ectrims2016-an(oxidant-lipoicacid-may-slow-spms-neurodegenera(on
Alpha-Lipoic-Acid • Remember: Mutual antagonism in regards to absorp(on between bio(n & alpha-lipoic-acid! • Some researchers stress the importance of the R-enan(omere instead of the racemic form • Reported side effects: headaches, paresthesias, rashes, muscle cramps, “insulin-auto-immunesyndrome” (hops://www.ncbi.nlm.nih.gov/pmc/ ar(cles/PMC3161272/)
“Probio(cs” • Many different prepara(ons with different bacteria strains, potencies, etc. • For several years now, intense interest to find connec(ons between gut bacteria and autoimmune-diseases • No truly defini(ve findings, but many very interes(ng connec(ons • Unknown poten(al risk
Recent probio(cs links hop://www.pnas.org/content/early/ 2017/09/05/1711235114 (abstract) hop://www.pasadenanow.com/main/gut-bacteriamay-play-role-in-onset-of-mul(ple-sclerosis/ #.Wbvv3Yprz_Q (review of ar(cle) hops://www.ncbi.nlm.nih.gov/pubmed/27669638 (abstract) hop://journals.sagepub.com/doi/full/ 10.1177/1352458517737390 (gla(ramer & probio(cs [VSL#3] in MS - full ar(cle)
Taurine • An “acid with an amino group” – but technically not an “amino acid” in the usual sense • Occurs naturally in meat, bile, but also an ingredient of some “energy drinks” • ταῦρος – “bull, ox” • May help to s(mulate “re-myelina(on” • hops://www.nature.com/ar(cles/nchembio. 2517 • ? Dosis (600mg 2x/d used in diabetes)
Curcumin • 18-month UCLA-study of “Theracurmin” 90 mg 2x/d in non-demented adults showed benefit in memory and aoen(on tasks, as well as effects on PET-scans • hops://www.sciencedirect.com/science/ar(cle/ pii/S1064748117305110?via%3Dihub • Curcumin in MS pa(ents (?effect on Th17-cells) - • hops://www.ncbi.nlm.nih.gov/pubmed/ 29079885
Good and reliable resources
? absorp(on from the gut, ? interac(ons with each other
Summary - 1 Avoid cigareoe smoking, etc. Take care of your general health! If “overweight,” reduce body fat percentage Consistent, tailored, & vigorous exercise program with proper precau(ons against “overhea(ng” & injuries • Aoen(on to diet: low-carb/high fat & (?) low-salt, watch for new developments… • Manage MS-symptoms “aggressively” (fa(gue, cogni(ve problems, pain, sleep disturbances, tremors, depression, spas(city, paroxysmal symptoms, bladder & bowel problems, etc.) • • • •
Summary - 2 • Vitamin D, bio(n, and alpha-lipoic-acid have good chances to become part of the standard treatments of MS • Omega-3-faoy acids, γ-linoleic-acid, Co-enzymeQ, taurine, curcumin, etc. have some poten(al & are probably safe • “Probio(cs” – theore(cal poten(al, but s(ll insufficient data • Marijuana is inadvisable except when carefully and competently managed for MS-related pain syndromes and spas(city
Summary - 3 • Qi Gong, Lian Gong, Tai Chi • “Mindfulness – medita(on” • Gentle “Yoga” - but avoid inverted yoga posi(ons (headstand, etc.), as well as any other extremes – such as “high-heat-yoga,” etc. • Pay aoen(on to “emo(onal” & “psycho-social” aspects … • Don’t let “hope & fear” tyrannize you – keep an open mind…and a sense of humor!
Thank you for your aoen(on! Ques%ons?