restorative medicine approach multiple sclerosis › wp-content › uploads › 2017 › ...siegert...
TRANSCRIPT
Restorative Medicine Approach Multiple Sclerosis
Michaёl Friedman, NDFinancial Disclosure: Co- owner Restorative Formulations
1
PATHOPHYSIOLOGY OF MS
• Chronic Autoimmune,
inflammatory
neurological disease
of the CNS.
• Destroys myelin and
axons to varying
degree.
2
Calabresi PA . Diagnosis and management of multiple
sclerosis. Am Fam Physician. 2004 Nov 15; 70(10):1935-
44.
Demyelination
• Demyelination leading
to impaired saltatory
conduction of action
potentials.
3
Podbielska, Maria et al. “Myelin Recovery in Multiple Sclerosis:
The Challenge of Remyelination.” Brain Sciences 3.3 (2013):
1282–1324. PMC. Web. 4 Sept.2017.
SYMPTOMS OF MS
4
Goldenberg MM. Multiple Sclerosis Review. Pharmacy and Therapeutics. 2012;37(3):175-184.
MS LESIONS (MRI)
5
A
B
C
D
Poor prognosis predictors
• > 40 years of age at
onset
• Male sex
• Non-Caucasian origin
• Motor or polyregional
symptoms in first year of
attack.
• Brain stem lesion.
6
Hunter SF. Overview and diagnosis of multiple sclerosis. Am J Manag Care. 2016 Jun; 22(6 Suppl):s141-50.
7
8
9
Cervical Lesion
10
11
12
13
14
15
16
17
18
19
20
21
Neurologist
• what can account for
your success as drug
therapy alone can not
explain your results of
your MRI?
22
Gut Bacteria Changes the
Brain
• Hepatic Encephalophy
– Lactose & Lactulose
protective
Campollo O, Sprengers D, McIntyre N. The BCAA/AAA ratio of plasma amino acids in three different groups of cirrhotics. Rev Invest
Clin. 1992 Oct-Dec;44(4):513-8.
Gut Bacteria Produces
Neurotransmitters• Gut microbes like Bacillus
spp. Account for almost half
of the of body's DA
production.1
• Gut bacteria & Brain –
Bidirectional signaling
involving multiple
neuroendocrine mechanisms.
Eisenhofer, G., Aneman, A., Friberg, P., Hooper, D., Fandriks, L., Lonroth, H., Hunyady, B., and Mezey, E. Substantial production of
dopamine in the human gastrointestinal tract. J. Clin. Endocrinol. Metabolism. 1997; 82: 3864–3871
25
Microbiome and inflammatory
demyelinating disease
Ochoa-Repáraz J, Mielcarz DW, Haque-Begum S, Kasper LH. Induction of a regulatory B cell population in experimental allergic
encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes. 2010;1:103–8.
Autoimmune
Encephalomyelitis (EAE) is
the most commonly used
animal model for the human
inflammatory demyelinating
disease, multiple sclerosis
(MS).
LPS & Intestinal Inflammation
27LPS Inflamed intestines
Intestinal barrier and MS
•Changes in intestinal tight junction
permeability associated with industrial food
additives explain the rising incidence of
autoimmune disease.
•Glucose, salt, emulsifiers, organic solvents,
gluten, microbial transglutaminase, and
nanoparticles are the culprits involved in the
pathogenesis.
28
Autoimmunity ReviewsVolume 14, Issue 6, June 2015, Pages 479-489
Review
Fasano, Alessio. “Zonulin, Regulation of Tight Junctions, and Autoimmune Diseases.” Annals of the New York Academy of
Sciences 1258.1 (2012): 25–33. PMC. Web. 4 Sept. 2017.
Nuro-Endotoxins Up-Regulate
Inflammation
29
http://medical-dictionary.thefreedictionary.com/endotoxin
Lee, Jae Woong et al. “Neuro-Inflammation Induced by Lipopolysaccharide Causes Cognitive Impairment through Enhancement of
Beta-Amyloid Generation.” Journal of Neuroinflammation 5 (2008): 37. PMC. Web. 4 Sept. 2017.
All seven patients with MS
had elevated Candida tests
Good News
• Dysbiois can be
changed and alter
progression and
symptomology of MS
with Fecal Microbial
Transplant (FMT).
Wei, Yanling et al. “Successful Treatment with Fecal Microbiota Transplantation in Patients with Multiple Organ Dysfunction
Syndrome and Diarrhea Following Severe Sepsis.” Critical Care 20 (2016): 332. PMC. Web. 4 Sept. 2017.
Fecal Microbiota
transplantation
Fecal Microbiota
transplantation• What is it?• Administration of fecal material containing distal gut microbiota
from a healthy person to a patient with a disease or condition related to dysbiosis.
• Why do it?• Restore phylogenetic diversity and therefore microbiome
physiological functions.
• Replace and or inhibit pathogenic species.
• Does it work?• For recurrent C. difficile infections the efficacy of FMT is now
undisputed, with cure rates of 85-90% in case series.
1. Van Nood et al. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile NEJM 368;5
2. Kelly et al. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms and Outlook.
Gastroenterology 2015; 149: 223-237
FMT and MS
• Reported three wheelchair-bound patients with MS treated with FMT for constipation.
• Bowel symptoms resolved following FMT.
• Two of the patients with prior indwelling urinary catheters experienced restoration of urinary function.
Borody TJ, Leis S, Campbell J, et al. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS). Am J
Gastroenterol 2011; 106:S352ssion and ‘no evidence of active disease
• all three patients regaining the ability to
walk unassisted.
• In one patient of the three, follow-up MRI
15 years after FMT showed a halting of
disease progression
34Borody TJ, Leis S, Campbell J, et al. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS) [abstract].Am J
Gastroenterol 2011; 106:S352ssion and ‘no evidence of active disease.
Carlos walks after FMT
35
36
Microbial diversity
• How to Grow Your Microbiome
37
CNS Lymphatics
38
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J.
Corrigendum: Structural and functional features of central nervous system lymphatic vessels. Nature. 2016 May 12;533(7602):278.
Vitamin-D in MS
• High-dose vitamin D (∼10,000 IU/day) in
multiple sclerosis is safe, with evidence of
immunomodulatory effects.
• Patients had fewer relapses.
• Low Vit-D levels – Risk for MS development.
39
•J.M. Burton, MD, MSc, FRCPC, S. Kimball, MSc, MLT, R. Vieth, PhD, A. Bar-Or, MD, MSc, FRCPC, H.-M. Dosch, MD, PhD, R.
Cheung, MSc, D. Gagne, C. D'Souza, PhD, M. Ursell, MS, MSc, FRCPC, and P. O'Connor, MS, MSc, FRCPC. A phase I/II dose-
escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010 Jun 8; 74(23): 1852–1859.
•Alharbi, Fatimah M. “Update in Vitamin D and Multiple Sclerosis.” Neurosciences 20.4 (2015): 329–335.
Vit B12
❖Easily passes Blood Brain Barrier.
❖Neuroprotective & anti-oxidant agent
involved in the synthesis of
phospholipids and myelin.
40Moosavirad, Saeedeh Alsadat et al. “Protective Effect of Vitamin C, Vitamin B12 and Omega-3 on Lead-Induced Memory Impairment
in Rat.” Research in Pharmaceutical Sciences 11.5 (2016): 390–396. PMC. Web. 3 Feb. 2017.
Testosterone
41Pakpoor J, Wotton CJ, Schmierer K, Giovannoni G, Goldacre MJ. Gender identity disorders and multiple sclerosis risk: A
national record-linkage study. Mult Scler. 2016 Nov;22(13):1759-1762. Epub 2016 Feb 8.
➢ Low testosterone in males –
Increased risk of MS.
➢Testosterone – converted to
estrogen (estradiol) in brain.
➢Anti-inflammatory,
neuroprotective.
Modafinil and Neuroprotection
• Modafinil (50 and 100 mg/kg) - Prevented against
decrease of DA, 5-HT, and NA in the striatum and
GSH, GABA in the SN induced by MPTP in PD
models.
• This was due to antioxidant effects
42
Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, He BC. Neuroprotective mechanism of modafinil on Parkinson disease
induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Acta Pharmacol Sin. 2004 Mar;25(3):301-5.
Polyphenols
• Polyphenols - potential to block neural inflammation
and damage by modulation of inflammatory
cytokines.
• limiting demyelination in MS
43Bhullar KS, Rupasinghe HPV. Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases. Oxidative
Medicine and Cellular Longevity. 2013;2013:891748.
Neurotrophins
44
Neurotrophins -
Neural survival,
development,
function, plasticity
BDNF
Considerably low in
Alzheimer’s &
cognitive impairment
Administration of S.
miltiorrhiza reduced
Aβ-induced
reductions in BDNF
in pre-clinical
models
Rosmarinic acid –
Increased BDNF
and restored
hippocampal BDNF
- Protective against
memory deficits
Lopresti, Adrian L. “Salvia (Sage): A Review of Its Potential Cognitive-Enhancing and Protective Effects.” Drugs in R&D 17.1 (2017):
53–64. PMC. Web. 7 Sept. 2017.
Fulgenzi A.et al A case of multiple sclerosis improvement following removal of heavy metal intoxication: lessons learnt from Matteo's
case. Biometals 2012 Jun;25(3):569-76.
• The Clinical data correlated with the
reduction of heavy metal levels in the urine to
normal range values.
• Case reports suggest that levels of toxic
metals can be tested in patients affected by
neurodegenerative diseases as MS.
Heavy Metals
MS
Dietary considerations
• The human brain is nearly 60 percent fat.
• Omega-3 fatty acids reduces the level of matrix
metalloproteinase (MMP) which plays an
important role in the migration of inflammatory
cells in the CNS fluid, which breaks down blood–
brain barriers.
46Jahromi SR, Toghae M, Jahromi MJR, Aloosh M. Dietary pattern and risk of multiple sclerosis. Iranian Journal of Neurology.
2012;11(2):47-53.
Dietary considerations
• Omega-3 fatty acids as immune system
regulators which act by reducing the levels
of inflammatory cytokines such as TNF-α,
IL-1, IL-2, and vascular cell adhesion
molecule (VCAM1).
• Shinto L, Marracci G, Baldauf-Wagner S, et al. Omega-3 fatty acid supplementation decreases matrix
metalloproteinase-9 production in relapsing-remitting multiple sclerosis. Prostaglandins, leukotrienes, and essential
fatty acids. 2009;80(2-3):131-136.47
❖n-3 PUFAs possibly have a role in promotion of
remyelination after toxic injury to CNS
oligodendrocytes via modulation of the immune
system or a direct effect on oligodendrocytes through
EPA-derived lipid metabolites as demonstrated in pre-
clinical studies.
n-3 PUFAs and Remyelination
Siegert E, Paul F, Rothe M, Weylandt KH. The effect of omega-3 fatty acids on central nervous system remyelination in fat-1 mice.
BMC Neuroscience. 2017;18:19. doi:10.1186/s12868-016-0312-5.
Brain needs oxygen
49
• Lipopolyscharide induced
demylination prevents and
decreases with oxygen and
thymoquinone found in Black
Cumin Seed Extracts.
•Noor NA, Fahmy HM, Mohammed FF, Elsayed AA, Radwan NM. Nigella sativa amliorates inflammation and demyelination in the
experimental autoimmune encephalomyelitis-induced Wistar rats. International Journal of Clinical and Experimental Pathology.
2015;8(6):6269-6286.
•Desai RA, Davies AL, Tachrount M, Kasti M, Laulund F, Golay X, Smith KJ.Cause and prevention of demyelination in a model
multiple sclerosis lesion. Ann Neurol. 2016 Apr;79(4):591-604.
Chronic Cerebrospinal Venous
Insufficiency (CCSVI) & MS
• Veins in the head and neck are narrowed resulting
in inefficient blood drain from the CNS.
• Reflux of blood back to the CNS due to pressure
caused by build-up of blood.
• Compensatory blood vessels developed lack the
same structural integrity and are leaky.
• Leaked blood with iron deposits in the CNS
triggering immune response and MS.
50Costello F et al. Validity of the diagnostic criteria for chronic cerebrospinal venous insufficiency and association with
multiple sclerosis. Canadian Medical Association Journal 2014 June 2
Exercise/ Physical activity
✓ Exercise - Shown to increase synaptic density and growth in
the hippocampus in the animal model of MS.
✓ Physical activity Increases levels of neurotrophic factors,
elevates expression of anti-inflammatory cytokines, and
reduces levels of pro-inflammatory cytokines and activates
microglia and is thus neuroprotective.
• Rossi S., Furlan R., De Chiara V., Musella A., Lo Guidice T., Mataluni G. (2009) Exercise attenuates the clinical, synaptic
and dendritic abnormalities of EAE. Neurobiol Dis 36: 51–59.
• Svensson M, Lexell J, Deierborg T.Neurorehabil Neural Repair. Effects of Physical Exercise on Neuroinflammation,
Neuroplasticity, Neurodegeneration, and Behavior: What We Can Learn From Animal Models in Clinical Settings. 2015
Jul;29(6):577-89. 51
Seasonality of MS – Role of
Melatonin
52
Seasonal
changes (length
of day and night)
Melatonin levels
Negatively
correlate
with MS
Melatonin
treatment
ameliorates MS
Induces expression
of transcription factor
Nfil3, promotes
generation of
protective Tr1 cells
Influence
differentiation
of T cells
Farez, Mauricio F. et al. “Melatonin Contributes To The Seasonality Of Multiple Sclerosis Relapses.” Cell 162.6 (2015):
1338–1352. PMC. Web. 7 Sept. 2017.
Variation in
Serum Glutamate and MS
• Neurotransmitter Glutamate –
Implicated in autoimmune
demyelination in MS.
MS Control
Serum
Glutnmol/ml
1.318 ±
0.543
0.873 ±
0.341
53
The mean
serum glutamate levels
determmined by ELISA
Al Gawwam G, Sharquie IK. Serum Glutamate Is a
Predictor for the Diagnosis of Multiple Sclerosis.
ScientificWorldJournal. 2017;2017:9320802.
Cholinergic signaling in
remyelination
54Fields RD, Dutta DJ, Belgrad J, Robnett M. Cholinergic signaling in myelination. Glia. 2017 May;65(5):687-698.
• Cholinesterase inhibitors - Shown to
improve remyelination in animal models
of MS.
• Cholinergic signalling in oligodendroglial
development and myelination seems
possible
Progesterone and
Remyelination• Progesterone and synthetic progestins
• modulate inflammatory responses and partially
reverse the age-dependent decline
in remyelination.
• Progesterone and Nestorone promoted repair of
severe chronic demyelinating lesions induced by
feeding cuprizone to female mice for up to 12
weeks,
55
El-Etr M, Rame M, Boucher C, Ghoumari AM, Kumar N, Liere P, Pianos A, Schumacher M, Sitruk-Ware R. Progesterone and
nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex. Glia. 2015
Jan;63(1):104-17.
T3 and Remyelination
• Thyroid hormone (T3) promotes remyelination.
• T3 promotes Kruppel-like factor 9 (KLF9)
transcription factor a novel integral component of
signaling cascade that promotes the regeneration
of lost myelin.
56Dugas, Jason C., Adiljan Ibrahim, and Ben A. Barres. “The T3-Induced Gene KLF9 Regulates Oligodendrocyte Differentiation and
Myelin Regeneration.” Molecular and cellular neurosciences 50.1 (2012): 45–57. PMC. Web. 7 Sept. 2017.
57
Treating the Terrain
Healthy
Microbiome
Acetylcholine
Epinephrine
GABA
Serotonin
Dopamine
58
Treating the Terrain
Sick
MicrobiomeBlood Brain
PermeabilityNeuroinflammation
Gut Permeability
59
Treating the Apparent Mechanism
Neuroinflamation
Polyphenols
Exercise
Omega 3
Microbiome
Diterpenes
Cortisol
60
Treating the Apparent Mechanism
Oxidation
Microbiome
Melatonin
Glutathione
Detoxification
Monoclonal Antibodies
Modafinil
Dimethyl fumarate
Antioxidants
61
Treating the Apparent Mechanism
GlutamateKava
Neurosteroids
GABA
Green Tea
(Theanine)
62
Treating the Apparent Mechanism
Demylination
Oxygen Omega 3
Neuroprotecants
63
Treating the Apparent Mechanism
Monoclonal
Antibodies
Phytollaca
(Poke)
Dimethyl
Fumarate
Interferon
Glatiramer
Acetate
Immunomodulation
64
Treating the Apparent Mechanism
Remylination
T3
Microbiome
Turmerones
Lion’s Mane
Mushroom
Exercise
Deiodinase