ClassicalClassical andand IntegrativeIntegrative MedicalMedical ApproachesApproaches inin ChronicChronic LymeLyme Disease:Disease: NewNew ParadigmsParadigms inin DiagnosisDiagnosis && TreatmentTreatment

Dr Richard Horowitz Hudson Valley Healing Arts Center 4232 Albany Post Road Hyde Park, N.Y. 12538 845-229-8977 InvestigativeInvestigative TreatmentTreatment ProtocolsProtocols forfor LymeLyme DiseaseDisease andand MultipleMultiple CoCo--infectionsinfections Immune Cell Wall: dysregulation: Penicillin / ANA+, HLA DR4 + Cephalosporins Plaquenil ?Herbs / CAM tx Cyst: Flagyl/Plaquenil Ehrlichia/Anapl. Tetracyclines Macrolides / Ketolides Cleocin & Quinine Mepron&Zithromax Rifampin Lariam Septra/Bactrim Artemesia Malarone Bartonella Quinolones

?Neurotoxins Candida: Nystatin, Viruses ?Neurotoxins Diflucan, Acidophilus ?HBOT ?Heat Therapy ?Leaky Gut ? Mycoplasma ?Food Allergies ?IV Glutathione ?Food Allergies ? Chlamydia ?El syndrome, Heavy Anti-Virals metal toxicities ?Multiple chemical Therefore, drug regimens which are effective against multiple sensitivities organisms simultaneously and penetrate intracellularly and into Hormonal d/f the CNS may be necessary to achieve significant clinical improvement. ““VirtuallyVirtually allall humanhuman diseasesdiseases resultresult fromfrom thethe interactioninteraction ofof geneticgenetic susceptibilitysusceptibility factorsfactors andand modifiablemodifiable environmentalenvironmental factors,factors, broadlybroadly defineddefined toto includeinclude infections,infections, chemical,chemical, physical,physical, nutritional,nutritional, andand behavioralbehavioral factorsfactors””

OfficeOffice ofof GeneticsGenetics andand DiseaseDisease Prevention,Prevention, CDCCDC ChronicChronic LymeLyme Disease:Disease: DifferentialDifferential DiagnosisDiagnosis 1. InfectionsInfections:: a)a)BacterialBacterial:: LymeLyme disease,disease, EhrlichiosisEhrlichiosis,, BartonellaBartonella,, MycoplasmaMycoplasma,, Chlamydia,Chlamydia, RMSF,RMSF, Typhus,Typhus, Tularemia,Tularemia, QQ--Fever,Fever, TickTick paralysisparalysis…… b)b)ParasitesParasites:: BabesiosisBabesiosis andand otherother piroplasmspiroplasms,, filiariasisfiliariasis,, amebiasisamebiasis,, giardiasisgiardiasis…… c)c)VirusesViruses:: EBV,EBV, HHVHHV--6,6, HHVHHV--8,8, CMV,CMV, StSt LouisLouis Encephalitis,Encephalitis, WW Nile,Nile, PowassanPowassan encephalitisencephalitis andand otherother viralviral encephalopathiesencephalopathies d)d)CandidaCandida andand otherother fungifungi ChronicChronic LymeLyme Disease:Disease: DifferentialDifferential DiagnosisDiagnosis  2)2)ImmuneImmune dysfunctiondysfunction  3)3)InflammationInflammation  4)4)ToxicityToxicity:: MultipleMultiple ChemicalChemical Sensitivity,Sensitivity, EnvironmentalEnvironmental Illness,Illness, HeavyHeavy Metals,Metals, MoldMold andand NeurotoxinsNeurotoxins (external(external andand internalinternal biotoxinsbiotoxins))  5)5)AllergiesAllergies:: foods,foods, drugs,drugs, environmentalenvironmental……  6)6)NutritionalNutritional && EnzymeEnzyme DeficienciesDeficiencies// functionalfunctional medicinemedicine abnormalitiesabnormalities inin biochemicalbiochemical pathwayspathways  7)7)MitochondrialMitochondrial dysfunctiondysfunction ChronicChronic LymeLyme Disease:Disease: DifferentialDifferential DiagnosisDiagnosis

 8)8)PsychologicalPsychological:: stress,stress, PTSD,PTSD, abuse,abuse, depression,depression, anxiety,anxiety, OCDOCD……  9)9)EndocrineEndocrine abnormalitiesabnormalities:: thyroid,thyroid, GH,GH, adrenal,adrenal, sexsex hormones,hormones, pituitary,pituitary, VitVit DD defdef  10)10)SleepSleep disordersdisorders:: AcuteAcute andand ChronicChronic (OSA,(OSA, Medications,Medications, Pain,Pain, NocturiaNocturia,, Depression/Anxiety,Depression/Anxiety, RLSRLS……  11)11)AutonomicAutonomic NervousNervous SystemSystem (ANS)(ANS) Dys(fDys(f)) ChronicChronic LymeLyme Disease:Disease: DifferentialDifferential DiagnosisDiagnosis  12)12)GastrointestinalGastrointestinal:: LeakyLeaky Gut,Gut, Candida,Candida, DysbiosisDysbiosis,, CeliacCeliac Disease,Disease, Colitis,Colitis, CancerCancer……  13)13)ElevatedElevated LFTLFT’’ss:: ?AB?AB’’s,s, ETOH,ETOH, Hepatitis,Hepatitis, HemochromatosisHemochromatosis,, WilsonsWilsons disease,disease, αα--1AT1AT deficiency,deficiency, chemicalschemicals (carbon(carbon tet,drugstet,drugs))……  14)14)DrugDrug use/Addictionuse/Addiction  15)15)DeconditioningDeconditioning:: NeedNeed forfor PT/ExercisePT/Exercise program..program.. I:I: InfectionsInfections InIn ChronicChronic LymeLyme DiseaseDisease  1)Bacterial1)Bacterial :: a)a)BorreliaBorrelia burgdorferiburgdorferi:: CombineCombine drugsdrugs toto addressaddress allall 33 formsforms ofof BbBb simultaneouslysimultaneously 22ºº toto thethe abilityability ofof thethe organismorganism toto shiftshift betweenbetween differentdifferent forms,forms, gogo dormant,dormant, andand evadeevade immuneimmune surveillance.surveillance. ContinueContinue treatmenttreatment untiluntil thethe patientpatient isis 22 monthsmonths symptomsymptom freefree --Cell Wall forms →Amoxicillin, Augmentin, Ceftin ,Cedax, Omnicef, IM Bicillin, IV Rocephin, IV Claforan, IV Vancomycin, IV Primaxin… -Cystic forms ( L-forms, spheroplasts, CWD forms..) → Plaquenil (hydroxychloroquine), GSE, Flagyl (metronidazole), Tindamax (tinidazole) -Intracellular forms → tetracyclines (, minocycline, tetracycline HCL), macrolides (azithromycin, clarithromycin), quinolones (Cipro, Levaquin, Avelox), Rifampin… PersistencePersistence ofof LymeLyme BorreliosisBorreliosis:: AtypicalAtypical Forms/CysticForms/Cystic FormsForms  PreacPreac--MursicMursic,, VV etet al,al, FormationFormation andand CultivationCultivation ofof BorreliaBorrelia burgdorferiburgdorferi SpheroplastSpheroplast--LL--formform Variants,Variants, InfectionInfection 2424 (1996);No(1996);No 3:2183:218--2626  Brorson,OBrorson,O etet al,al, TransformationTransformation ofof cysticcystic formsforms ofof BorreliaBorrelia burgdorferiburgdorferi toto normal,normal, mobilemobile spirochetes,spirochetes, InfectionInfection 2525 (1997);(1997); NoNo 4:2404:240--45.45.  AlbanAlban PSPS etet al,al, SerumSerum--starvationstarvation inducedinduced changeschanges inin proteinprotein synthesissynthesis andand morphologymorphology ofof BorreliaBorrelia burgdorferi,burgdorferi, MicrobiologyMicrobiology (2000),(2000), 146:119146:119--2727  BrorsonBrorson,, OO etet al,al, AA rapidrapid methodmethod forfor generatinggenerating cysticcystic formsforms ofof BorreliaBorrelia burgdorferi,burgdorferi, andand theirtheir reversalreversal toto mobilemobile spirochetes,spirochetes, APMIS,APMIS, 106106 (1998):1131(1998):1131--4141

TreatmentTreatment RelapsesRelapses andand FailuresFailures withwith ShortShort--termterm TherapyTherapy  Logigian (1990) : After 6 mo’s of therapy, 10/27 patients treated with IV AB’s relapsed or had treatment failure.  Pfister (1991) : 33 patients with were treated with IV AB’s. After a mean of 8.1 months 10/27 were symptomatic and borrelia persisted in the CSF in 1 pt  Shadick (1994) : 10/38 pts relapsed (5 with IV) within 1 year of treatment, and had repeated AB treatment  Asch (1994) : 28% relapsed w/ major organ involvement 3.2 years after initial treatment  Valesova (1996) :10/26 relapsed or progressed at 36 mo  Trieb (1998) : >50% pts symptomatic after 4.2/+/- 1.2 yrs  Shadick (1999) : 69/184 (37%) report a previous relapse BenefitBenefit ofof LongerLonger treatmenttreatment RegimesRegimes forfor DisseminatedDisseminated LymeLyme DiseaseDisease

1. Wahlberg,PWahlberg,P.. etet al,al, TreatmentTreatment ofof latelate LymeLyme borreliosisborreliosis.. JJ Infect,Infect, 1994.1994. 29(3):29(3): p255p255--6161 →→31%31% improvedimproved w/w/ 1414 dd RocephinRocephin,, 89%89% improvedimproved w/w/ RocephinRocephin ++ 100d100d ofof AmoxAmox andand ProbenecidProbenecid,, 83%83% improvedimproved w/w/ RocephinRocephin,, thenthen 100100 daysdays ofof cephadroxilcephadroxil 2. DontaDonta,, ST.,ST., TetracyclineTetracycline therapytherapy forfor chronicchronic LymeLyme disease.disease. ClinClin InfectInfect DisDis,, 1997.1997. 2525 SupplSuppl 1:1: p.S52p.S52--6.6. →→277277 ptspts withwith chrchr LDLD treatedtreated betweenbetween 11--1111 mo:mo: 20%20% cured,cured, 70%70% improved,improved, 10%10% treatmenttreatment failurefailure BenefitBenefit ofof LongerLonger treatmenttreatment RegimesRegimes forfor DisseminatedDisseminated LymeLyme DiseaseDisease 3. Oksi, J et al., Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis. Eur J Clin Microbiol Infect Dis, 1998. 17(10) :p 715-9 → 30 pts w/ chr Lyme treated for 100 d, 90% w/ good or excellent responses 4. Oksi, J., et al. Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Ann Med, 1999. 31(3):p.225-32 → 32/165 pts w/ disseminated Lyme treated for 1 or more months of AB’s showed that even > 3 mo of treatment may not eradicate the spirochete, longer term therapy may be necessary InfectionsInfections inin ChronicChronic LymeLyme DiseaseDisease  1)Bacterial:1)Bacterial: b)b)EhrlichiosisEhrlichiosis:: tetracyclines (doxy, minocycline) or rifampin for allergic/intolerant patients c)c)BartonellaBartonella,, MycoplasmaMycoplasma,, Chlamydia,Chlamydia, RMSF,RMSF, Typhus,Typhus, Tularemia,Tularemia, QQ--feverfever ((CoxiellaCoxiella))…… →these are all intracellular co-infections, and are difficult to completely eradicate from the intracellular compartment. Consider 2 intracellular drugs simultaneously to improve clinical outcomes (doxycyline w/ macrolide, macrolide + rifampin, tetracycline + quinolone…) and use Plaquenil to alkalize the intracellular compartment to achieve better intracellular killing (Maurin et al. Phagolyosomal Alkalinization and the Bactericidal Effect of . J. Infect Dis1992; 166:1097-1102) If one regimen of an intracellular combo fails, rotate the regimen to another double intracellular regimen, and consider treating other co-infections not addressed (Babesiosis, viruses..) InfectionsInfections InIn ChronicChronic LymeLyme DiseaseDisease  2)2) Parasites:Parasites: Babesiosis/PiroplasmosisBabesiosis/Piroplasmosis - Classical Treatment options: Mepron (atovaquone) and a macrolide (Zithromax, Biaxin) +/- Septra, Malarone, Larium (mefloquine), Cleocin and Quinine or Biaxin , ?Riamet.. -CAM: Artemisinin (wormwood): anti-malarial, antiparasitic, antiviral, anti-tumor. Modified form of Artemesinin, artesunate, has been found effective for Babesia in vitro. Complete inhibition of B. equi and caballi occurred at 0,2 and 1.0 mcg/ml respectively. -Dosage: 500mg/d x30-40 days for malaria, ? Best dosage for Bab -In malaria, effective dose is 500-1000mg 1st day, then 500 mg/day x4 days (but relapse rate = 39%) If the dosage is increased to 800 mg/day, relapse rate ↓ to 3% In China they use 800-1600mg/d x 3 days, repeated in 2 wks -Side effects: GI at high dose: ↓ apetite, N+, V+, diarrhea -Contraindications: Pregnancy ArtemesiaArtemesia:: ScientificScientific ReferencesReferences

 Eckstein-Ludwig, U. et al. Artemesinins target the SERCA of Plasmodium falciparum, Nature 2003;424(6951):957-61  Gordi et al. Artemesinin pharmacokinetics and efficacy in uncomplicated malarial patients treated with two different dosage regimens, Antimicrobial Agents Chemother 2002;46(4):1026-31  Wong, J. et al. Therapeutic equivalence of a low dose artemesinin formulation in falciparum malaria patients, Journal of Pharmacy and Pharmacology 2003;55(2):193  Jung, M. et al. Recent advances in artemesinin and its derivatives as antimalarial and antitumor agents, Curr Med Chem 2004;11(10):1265-84  Hatimi, S. et al. In vitro evaluation of antileishmania activity of Artemesia herba Asso, Bull Soc Pathol Exot 2001; 94(1):29-31  Kim, J. et al. In vitro antiprotozoal effects of artemesinin on Neospora caninum, Vet Parasitol 202;103(1-2):53-63 CHRONIC PERSISTENT BABESIOSIS AFTER ACUTE TREATMENT WITH CLEOCIN AND QUININE, AND ATOVAQUONE AND AZITHROMYCIN

12th International Scientific Conference on , April 1999, New York City Dr Richard Horowitz 4232 Albany Post Road Hyde Park, N.Y. 12538

Persistent parasitemia after acute babesiosis was described by Krause (NEJM 7/98, Vol 339, 160-165) when patients were given Cleocin and Quinine (C+Q), and an experimental regimen with Atovaquone and Azithromycin (M+Z) was noted to possibly cure human babesiosis. Horowitz described significant clinical improvement in a cohort of chronic Lyme patients co-infected with babesia when given Atovaquone + Azithromycin, but relapses were seen at the completion of therapy, and PCR studies were needed to elucidate the eradication rate of the organism (Horowitz, R.I.: Atovaquone and Azithromycin therapy: A new treatment protocol for Babesiosis in co-infected Lyme patients, in Abstracts of the 11th International Scientific Conference on Lyme disease, NYC, NY April 1998). This report describes PCR + RNA evidence of persistent parasitemia with both regimens. CHRONIC PERSISTENT BABESIOSIS AFTER ACUTE TREATMENT WITH CLEOCIN AND QUININE, AND ATOVAQUONE AND AZITHROMYCIN

Results: 72 of 189 serum specimens were PCR positive, and 38 of 58 specimens were RNA positive. 33 charts were analyzed among patients who received one or more courses of M+Z or C+Q and remained PCR and/or RNA positive post treatment. PCR testing and RNA testing remained positive up to 9 months and 5 months respectively, with several patients who were both IFA and PCR negative turning PCR positive after treatment. The majority of patients clinically improved while on the regimens but relapsed shortly after the antibiotics were stopped, with flares occurring often during treatment. Only 4 out of 27 patients became PCR/RNA negative post treatment. Crossing over from one regimen to the other was generally ineffective as PCR/RNA values remained positive, except in 2 cases. M+Z was better tolerated than C+Q, and lab values generally remained within normal limits with both regimens, with an occasional mild elevation of liver functions. InfectionsInfections inin ChronicChronic LymeLyme DiseaseDisease  3)3)VirusesViruses:: EBV,EBV, CMV,CMV, HHV6HHV6 && 8,8, W.W. Nile,Nile, PowassanPowassan encephalitisencephalitis andand otherother viralviral encephalitisencephalitis --exex HHV6HHV6→→therethere isis aa linklink toto CFS/FM.CFS/FM. CausesCauses roseolaroseola inin childhoodchildhood && nearlynearly 100%100% ofof adultsadults areare exposed.exposed. CanCan reactivatereactivate laterlater inin lifelife 22ºº toto immunol/envirimmunol/envir factorsfactors→→ cancan leadlead toto hepatitis,hepatitis, meningoencephalitismeningoencephalitis.... ?cofactor?cofactor inin Autism,Autism, ADD,ADD, MS,MS, FM,FM, CFSCFS -ClassicalClassical treatmenttreatment: antivirals (Valtrex, Famvir, acyclovir, gancyclovir..) ? Valcyte (ongoing trial at Stamford University by Dr Montoya) -CAMCAM: Transfer factors (colostrum), mushroom derivatives that increase NK cells and T cells (1-3 and 3-6 B glucan..). Another scientifically proven compound is Olive leaf extract and its active component oleuropein. This was found by researchers at Upjohn labs to be virucidal against many viruses including herpes, influenza A, coxsackie and others. Juven B. et al. Sudies on the Mechanism of Antimicrobial Action of Oleuropein. Jnl of Applied Bacteriology 35 (1970), 559-567 I:I: InfectionsInfections inin ChronicChronic LymeLyme DiseaseDisease  4)Candida4)Candida andand otherother fungifungi:: ?? YeastYeast syndromesyndrome→→ yeastyeast overgrowthovergrowth inin thethe intestinalintestinal tracttract leadsleads toto fermentationfermentation ofof dietarydietary sugarssugars andand starches.starches. CanCan bebe 22ºº toto antibioticantibiotic useuse forfor LymeLyme diseasedisease SymptomsSymptoms include:include: fatigue,fatigue, HAHA’’ss,, dizziness,dizziness, brainbrain fog,fog, abdominalabdominal painpain withwith bloating,bloating, musclemuscle andand jointjoint pain..&pain..& maymay overlapoverlap withwith classicclassic LymeLyme symptomssymptoms TestingTesting:: StoolStool CDSA,CDSA, GenovaGenova DiagnosticsDiagnostics w/w/ sensitivitysensitivity toto fungalfungal agents.agents. MetametrixMetametrix OrganixOrganix testtest ClassicalClassical treatmenttreatment:: DiflucanDiflucan ((fluconazolefluconazole),), SporanoxSporanox,, OralOral NystatinNystatin CAMCAM:: HighHigh dosedose probioticsprobiotics (acidophilus),(acidophilus), SaccharomycesSaccharomyces boulardiiboulardii,, CandibactinCandibactin,, CaprylicCaprylic Acid,Acid, BerberainBerberain,, OreganoOregano oil,oil, Garlic,Garlic, PauPau DD’’ArcoArco II:II: ImmuneImmune DysregulationDysregulation andand LymeLyme  BlebsBlebs areare shedshed particlesparticles containingcontaining partialpartial DNA,DNA, frequentlyfrequently plasmids.plasmids. -Radolf JD et al. Analysis of Borrelia burgdorferi membrane architecture by freeze-fracture electron microscopy. Journal of Bacteriology. Jan 1994;176(1):21-31 -Garon CF; Dorward DW; Corwin MD. Structural features of Borrelia burgdorferi-the Lyme disease spirochete: silver staining for nucleic acids. Scanning Electron Microscopy. 1989 3:109-115  HighlyHighly stimulatorystimulatory toto thethe immuneimmune systemsystem -Whitmire WM; Garon CF. Specific and nonspecific responses of murine B cells to membrane blebs of Borrelia burgdorferi. Infection & Immunity, 1993 61:1460-1467  IntraIntra--cellularcellular blebsblebs convertconvert hosthost cellscells intointo targetstargets forfor thethe immuneimmune systemsystem -Beerman C; Wunderli-Allenspach H et al. Lipoproteins from Borrelia burgdorferi applied in liposomes and presented by dendritic cells induce CD8(+) T-lymphocytes in vitro. Cell Immunology May 2000;201 (2):124-131 II:II: ImmuneImmune DysregulationDysregulation andand LymeLyme  Positive ANA, RF and other autoimmune markers (Plaquenil)  Increased severity with genetic HLA markers (HLA DR2, 4)  Elevated pro-inflammatory cells: -IL-6, TNF-α, IFN gamma  Propensity to excessive proinflammatory response in Lyme borreliosis. Kisand et al, APMIS. 2007 Feb; 115(2):134-41  Interleukin-6 is expressed at high levels in the CNS in Lyme neuroborreliosis. Pachner et al. Neurology 1997 Jul;49(1)c147-52  INF-gamma alters the response of Bb activated endothelium to favor chronic inflammation. J. Immunol. 2007 Jan 15;178(2):1172-9  Decreased anti-inflammatory cells: IL-10  Abnormal helper/suppressor cell ratio (CD4/CD8).  Both Lyme and ASD have immune dysregulation, and it is known that systemic infections (Bb, viruses..) with associated inflammation can affect chronic neurodegeneration Perry et al. Nature Reviews Immunology 7, 161-167 (Feb 2007) MycoplasmaMycoplasma InfectionsInfections MayMay ContributeContribute toto ImmuneImmune DysregulationDysregulation inin ChronicChronic LymeLyme DiseaseDisease

 Discussion: (con’t) Mycoplasmas have been shown to interact non-specifically with B-lymphocytes resulting in the modulation of immunity promoting autoimmune reactions and rheumatoid diseases (Simecka et.al. Clin. Infect. Dis. 1993;17(Suppl 1):5176-5182). Mycoplasmal infections also increase proinflammatory cytokines including IL-1,2, and 6 (Mhlradt et.al. Infect. Immunol. 1991;58:1273-1280), and have been found in the joint tissues of patients with rheumatological diseases suggesting their pathogenic involvement (Furr et.al. Ann. Rheumatol. Dis. 1994;53;183- 184). Further studies therefore need to be done to elucidate the role of mycoplasmal infections in Lyme Disease patients with chronic persistent symptomatology. III:III: RoleRole ofof InflammatoryInflammatory MediatorsMediators inin NeurotoxicityNeurotoxicity  InflammInflamm processesprocesses areare involvedinvolved inin thethe neurotoxicityneurotoxicity ofof ADAD andand otherother CNSCNS diseases.diseases. MicrogliaMicroglia areare activatedactivated byby BB amyloidamyloid && proinflammproinflamm cytokines.cytokines. ActivatedActivated microgliamicroglia inin turnturn releaserelease proinflammproinflamm cytokinescytokines (IL(IL--11--ββ,, ILIL--6,6, TNFTNF--αα)) thatthat maymay leadlead toto neuronalneuronal deathdeath andand dys(fdys(f)) byby aa varietyvariety ofof mechanisms,mechanisms, including:including: 1) Enhancement of glutamate-induced excitotoxicity 2) Inhibition of long term potentiation, which limits (f) plasticity after neuronal injury 3) Inhibition of hippocampal neurogenesis Recent studies have reported ↑ TNF-α levels in the CSF of AD pts, and a single nucleotide polymorphism in the TNF-α gene is associated w/ earlier onset AD Lyme dx pts are known to have ↑ levels of IL-1, 6, & TNF-α. ?Role of these proinflamm cytokines w/ CNS LD & ? Role of Actos/LDN to modulate levels of TNF-α/cytokines RoleRole ofof InflammatoryInflammatory MediatorsMediators andand NO/ONOONO/ONOO CycleCycle inin IllnessIllness

 AA CommonCommon EtiologicEtiologic MechanismMechanism forfor CFS,CFS, MCS,MCS, FM,FM, PTSDPTSD andand ?CLD?CLD :: DrDr MartinMartin Pall,Pall, ProfessorProfessor ofof BiochemistryBiochemistry andand BasicBasic MedicalMedical Sciences,Sciences, WashWash StateState Univ.Univ.  AboveAbove illnessesillnesses shareshare manymany sxsx inin commoncommon  IllnessesIllnesses cancan bebe initiatedinitiated byby aa varietyvariety ofof factorsfactors (viral,(viral, bacterial,bacterial, physicalphysical oror emotemot trauma,trauma, exposureexposure toto VOSVOS’’ss ,, pesticidespesticides……))  TheseThese diversediverse stressorsstressors cancan allall ↑↑ NO,NO, andand severalseveral cancan ↑↑ NMDANMDA receptorreceptor activityactivity && ↑↑ NONO && itsits oxidantoxidant productproduct peroxynitriteperoxynitrite RoleRole ofof InflammatoryInflammatory MediatorsMediators andand NO/ONOONO/ONOO CycleCycle inin IllnessIllness

 NO →↑ peroxynitrite →↑ oxidative stress → stimulates NF- κB →↑ production of iNOS (nitric oxide synthetase) →↑ NO in a vicious cycle  NF-κB →↑ IL-1, IL-6, IL-8, TNF-α, IFNγ which may contribute to symptoms and signs of these varied illnesses  Testing for immune dys(f): Autoimmune panel (ANA, RF, ESR, ss +ds DNA, Sjogrens AB’s), Immunoglobulin levels and subclasses, HLA classes..  Classical therapy: immune modulators (Plaquenil, DMARD’s), drugs w/antiinflamm effect (macrolides, tetracyclines), IVIG for decreased immunoglob’s  CAM Therapy: focus on down-regulation of NO/ONOO cycle biochemistry with subsequent ↓ of inflammatory markers: Antioxidants, CoQ10, B vit’s, α-lipoic acid, Mag++, Zn++, omega 3 FA’s, glutathione precursors,… RoleRole ofof InflammatoryInflammatory MediatorsMediators andand CytokinesCytokines inin JHJH rxnsrxns

 JarishJarish--Herxheimer/FlareHerxheimer/Flare protocols:protocols: --Alkalize:Alkalize: lemons/limes,lemons/limes, AlkaAlka--SeltzerSeltzer goldgold 4x4x perper dayday (or(or NaNa bicarbbicarb)) xx 11--22 daysdays andand increaseincrease fluidsfluids --BurburBurbur oror ParsleyParsley 1010 dropsdrops qq 1010 minmin xx 11--22 hourshours --LDN:LDN: startstart 2mg2mg HS,HS, workwork upup toto 4.54.5 mgmg HSHS w/Pekanaw/Pekana drainagedrainage remediesremedies 1515 dropsdrops eacheach 3x/day3x/day --Glutathione:Glutathione: IVIV 2g,2g, oral,oral, PR,PR, dermaldermal IV:IV: ToxicityToxicity andand ChronicChronic LymeLyme DiseaseDisease  EnvironmentalEnvironmental toxins:toxins: MultipleMultiple ChemicalChemical SensitivitySensitivity (MCS),(MCS), EnvironmentalEnvironmental IllnessIllness (E.I.)(E.I.) duedue toto exposureexposure toto aa multitudemultitude ofof chemchem’’ss inin thethe environmentenvironment (PCB(PCB’’s,s, dioxins,dioxins, plastics,plastics, heavyheavy metals,metals, TCE,TCE, VOSVOS’’ss..)..) WeWe willwill focusfocus onon 33 majormajor categories:categories:  1)Heavy1)Heavy MetalsMetals  2)Mold2)Mold  3)Biotoxins3)Biotoxins 22ºº toto LymeLyme andand associatedassociated coco-- infections/infections/ ExternalExternal toxintoxin exposureexposure MagnitudeMagnitude ofof ExposureExposure toto ToxinsToxins

1. PesticidesPesticides:: EPAEPA officeoffice ofof Prevention,Prevention, Pesticides,Pesticides, && ToxicToxic substancessubstances • 19991999 >> 44 billionbillion lbs.lbs. ofof pesticidespesticides producedproduced 2. EPAEPA:: 19821982 NationalNational AdiposeAdipose TissueTissue SurveySurvey • 100%100% ofof Americans:Americans: benzene,benzene, xylenexylene,, toluene,toluene, styrene,styrene, dioxin,dioxin, PCBsPCBs – These are some of the most potent cancer causing chemicals known to mankind 3. CDCCDC:: 2005,2005, 6.56.5 millionmillion dollardollar study.study. DiscoveredDiscovered 116116 differentdifferent toxinstoxins inin overover 50%50% patientspatients studiedstudied (13(13 heavyheavy metals,metals, 1414 combustioncombustion byproducts,byproducts, 1010 pesticidespesticides ToxicityToxicity AssociatedAssociated SymptomsSymptoms && ConditionsConditions

 Headaches  Panic attacks  Mineral imbalances (zn & ca)  Memory loss  Kidney dysfunction  Parkinson’s disease  Fertility problems  Broad mood swings  Abnormal pregnancy  Fatigue outcome   Immune system depression  Muscle weakness  Multiple chemical sensitivities  Unusual response to meds or  supplements  Recurrent yeast infections  Increasing sensitivity to  Tinnitus exogenous exposures: odors, medications, etc.  Contact dermatitis  Worsening of symptoms after  Learning disorders anesthesia or pregnancy  Cancer OVERLAPPINGOVERLAPPING SXSX OFOF HEAVYHEAVY METALSMETALS ANDAND TBDTBD’’SS SYMPTOMS HEAVY METAL LD/CO-INFX

Fatigue   FMS sx   Joint pain   Paresthesias   Cognitive d/f   Ataxia /   Incoordination Abd sx   Urinary sx   Visual sx   Auditory sx   Psych sx   Wt loss    Suscept to infection   MERCURY Sources Biochemistry Clinical Symptoms

- Mining and -SH binding -CFS, FMS, joint pain Chemical -Oxidative stress -metallic taste, changes Industries -Penetrates nerves and binds in vision & hearing - Fish/Shellfish to cysteines on Ach -tremors, ataxia receptors resulting in - Dental work and receptors resulting in -cognitive dysfunction, neurologic dysfunction. depression, irritability medical treatment depression, irritability -retrograde axonal transport -renal and GI (thimerasol) -renal and GI -Denervation of nerve fibers disturbances similar to the pathology of -weight loss MS, and Hg can leak into -increased the BBB and reduce nerve susceptibility to conduction velocity and infections VEP VEP - -autoimmunity LEAD Sources Biochemistry Clinical Symptoms -Drinking water -SH binding -Fatigue -Dinnerware with -Alters calcium-mediated -Encephalopathy with lead glazing cellular processes impaired concentration, short- -Paint products -Reduces nerve conduction concentration, short- velocity in peripheral nerves term memory deficits, -Soil around older insomnia, anxiety, -Interferes in the heme insomnia, anxiety, homes painted depression, irritability, biosynthetic pathway depression, irritability, with lead based decreased IQ with lead based leading to anemia decreased IQ paints are still -Elevated BP, chronic contaminated renal failure, anemia with lead - Abd colic, peripheral nerve dysfunction, reproductive dysfunction DMSADMSA  HeavyHeavy metalsmetals accumulateaccumulate xx yearsyears  leavesleaves thethe bloodblood  nono longerlonger measurablemeasurable therethere  startstart compartmentalizing.compartmentalizing.  DMSADMSA diffusesdiffuses intointo andand effectivelyeffectively competescompetes withwith tissuetissue bindingbinding sitessites  releasesreleases metalsmetals fromfrom sequesteredsequestered sitessites inin tissues.tissues.  RationaleRationale forfor provocationprovocation testtest w/w/ chelatingchelating agentagent  Toxic metals accumulate in non-exchange pools in specific tissues.  DMSA disturbs the body stores of toxic metals & binds to them, so a certain quantity will redistribute into the blood as a stable complex  eliminated in the urine  Do a 6 hour urine DMSA challenge (30 mg/kg 1x dose) LevelsLevels ofof heavyheavy metalsmetals postpost provocationprovocation w/w/ 66 hourhour urineurine DMSADMSA challenge:challenge:  Hg,Hg, PbPb,, As,As, CdCd ImportanceImportance ofof DetoxifyingDetoxifying HeavyHeavy MetalsMetals  1515--2020 %% ofof CLDCLD ptspts improveimprove sxsx ofof fatigue,fatigue, myalgiasmyalgias,, arthralgiasarthralgias,, andand neuroneuro--cognitivecognitive sxsx withwith detoxificationdetoxification ofof heavyheavy metalsmetals  ?? ResponsibleResponsible forfor AIAI overlapoverlap inin certaincertain CLDCLD ptspts (Hg)(Hg)  HeavyHeavy metalmetal burdenburden maymay leadlead toto mineralmineral deficienciesdeficiencies ((MagMag++,++, Zn)Zn) andand hashas anan effecteffect onon immuneimmune (f),(f), oxidativeoxidative stress,stress, andand inflammatoryinflammatory cytokinescytokines  TestingTesting: 66 hrhr urineurine DMSADMSA challengechallenge toto DoctorsDoctors Data.Data. UseUse 30mg/kg30mg/kg 1x1x asas aa loadingloading dosedose  TreatmentTreatment: ChelationChelation usingusing DMSADMSA 100100--200200 mgmg Q3rdQ3rd nightnight withwith AlgasAlgas (10(10 drops)drops) andand ChlorellaChlorella (split(split cell,cell, 77 tabtab’’s)s) w/w/ 600600 mgmg NAC,NAC, MedMed CapsCaps DPODPO (B(B vitamins,vitamins, NAC,NAC, αα--lipoiclipoic acid..),acid..), DMPS,DMPS, EDTAEDTA ReplaceReplace mineralsminerals thethe nextnext dayday (MTV(MTV w/w/ Ca,Ca, MagMag,, Zn)Zn) IV:IV: ToxicityToxicity andand LymeLyme DiseaseDisease  ApartApart fromfrom heavyheavy metalmetal toxicities,toxicities, thethe mostmost commoncommon toxictoxic exposuresexposures includeinclude externalexternal toxinstoxins (PCB(PCB’’s,s, Dioxins,Dioxins, PlasticsPlastics andand plasticizers,plasticizers, Pesticides,Pesticides, VOSVOS’’ss..)..) andand moldmold exposureexposure→ -CDC 2003: 6.5 million $ study w/ 2500 patients: found 116 different pollutants (13 heavy metals, 14 combustion byproducts, 10 pesticides) One of those toxins TCE, was responsible for a leukemia outbreak in Woburn, MA, and frequently causes learning disabilities, paresthesias...  TestingTesting:: AccuchemAccuchem labs,labs, Texas;Texas; StachybotrisStachybotris titerstiters  OtherOther toxinstoxins maymay resultresult fromfrom exposureexposure toto bacteriabacteria andand viruses,viruses, ieie biologicalbiological effectseffects ofof thesethese agentsagents inin ourour bodiesbodies (( BbBb toxtox 1,1, QuinolinicQuinolinic AcidAcid……)) RoleRole ofof EndogenousEndogenous ExotoxinsExotoxins  QuinolinicQuinolinic AcidAcid ((QuinQuin)) isis aa neurotoxicneurotoxic metabolitemetabolite ofof thethe LL--tryptophantryptophan--kynureninekynurenine pathwaypathway thatthat activatesactivates thethe NMDANMDA receptorreceptor classclass ofof excitatoryexcitatory AAAA receptorsreceptors toto produceproduce excitotoxicexcitotoxic lesions.lesions. LymeLyme dxdx ptspts havehave beenbeen shownshown toto havehave ↑↑ levelslevels ofof QuinolinicQuinolinic acid.acid. ?? RoleRole inin CNSCNS dxdx ?Role?Role forfor IVIV GSHGSH && antioxidantantioxidant therapiestherapies 1) -Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl W.M.H. Behan, et al. British Jnl Pharm (1999) 128, 1754-1760 2) -Enhanced neuronal damage by co-administration of quinolinic acid and free radicals, and protection by adenosine A2A receptor antagonists W.M.H Behan et al. British Jnl Pharm (2002) 35, 1435-1442 3) -Neuroprotective effects of the mGlu5R antagonist MPEP towards quinolinic acid-induced striatal toxicity: involvement of pre- and post-synaptic mechanisms and lack of direct NMDA blocking activity. Popoli et al. Jnl of Neurochemistry 2004, 89, 1479-1489 4) -Quinolinic Acid Is Extruded from the Brain by a Probenecid- Sensitive Carrier System: A Quantitative Analysis. Morrison et al, Jnl of Neurochemistry 1999, 72, 2135-2144 GlutathioneGlutathione

 IVIV GSHGSH hashas beenbeen shownshown toto bebe effectiveeffective inin aa subsetsubset ofof resistantresistant LymeLyme patients,patients, implyingimplying aa needneed toto includeinclude aa detoxificationdetoxification regimeregime inin thethe treatmenttreatment plan.plan.  DetoxDetox protocolsprotocols wouldwould includeinclude MagMag++,++, NAC,NAC, GLY,GLY, αα lipoiclipoic acid,acid, DIM,DIM, sulforaphanesulforaphane glucosinalateglucosinalate,, dietdiet ww ↑↑ protprot,, crucifcrucif vegveg’’ss  IVIV GSHGSH alsoalso addressesaddresses heavyheavy metalmetal burden,burden, butbut itit isis unclearunclear whichwhich chemchem’’ss/toxins/toxins areare beingbeing removedremoved w/w/ treatment.treatment. SinceSince GSHGSH maymay havehave anan effecteffect withinwithin minmin’’ss inin selectselect ptspts toto improveimprove CNSCNS (f),(f), isis therethere anan effecteffect onon removingremoving inflamminflamm cytokinescytokines && QuinolinicQuinolinic acid?acid? Intravenous Glutathione: A Novel Approach for Treating Resistant Symptoms in Chronic Lyme Disease Background: Chronic Lyme Disease must be seen in the light of multiple tick borne diseases, including HME, HGE, Babesiosis, Mycoplasma infections, and Bartonella henselae. The mechanisms responsible for ongoing symptoms have been hypothesized to be secondary to persistent Borrelial infection, occult and/or resistant co-infections, autoimmune mechanisms, and/or other neurotoxins.

Among known toxins, heavy metals such as mercury and lead have been found in Lyme disease patients with a small percentage of patients (10-15%) reporting improvement in resistant symptoms (fatigue, joint aches, cognitive dysfunction) with removal of the corresponding heavy metals (Horowitz, Abstract 16th International Lyme Conference, June 2003).

A novel approach to remove toxins from the body involves Glutathione (GSH) (Perlmutter, 2000). GSH is an endogenous peptide made in the liver, which plays an important role in various metabolic functions including its role as an antioxidant and in Phase II liver detoxification of various chemicals. A trial of GSH was therefore undertaken to determine its role in patients with Lyme Disease with chronic resistant symptoms. Method: 118 patients with Lyme Disease were given IV GSH over a 5-10 minute period. 80 patients were given 1000mg of GSH and 38 patients were given 2000mg of GSH. The GSH was stored in a refrigerator and protected from direct light until patient administration. Patients’ symptoms scores before and after treatment with GSH (0- 100% self reported scale) were recorded after a 30-minute interval.

Results: Among 80 patients given 1000mg GSH, 36% (29/80) had no clinical improvement (0% improvement on self-reported scale), 40% (32/80) had a mild clinical improvement (1 to 10% improvement), 6% (5/80) had moderate clinical improvement (11 to 20% improvement), and 18% (14/80) had marked clinical improvement (21 to 60% improvement in clinical symptom scores). Mean improvement in symptoms after 30 minutes of 1000mg of GSH administration was 9%. Among 37 patients given 2000mg of GSH, 27% (10/37) had no clinical improvement, 46% (17/37) had mild clinical improvement, 16% (6/37) had moderate clinical improvement, and 11% (4/37) had marked clinical improvement. Mean improvement in symptoms after 30 minutes of 2000mg of IV GSH was 9.5%. Improvements from a single dose of IV GSH lasted from several hours to 2-3 days before patients experienced a relapse in symptoms. There were no significant adverse effects from GSH except for transient nausea & rare pressure like feelings and paresthesias. One patient had a vagal event with needle insertion (before GSH administration) and 2 patients experienced a flare up of Lyme symptoms after injection, which subsequently resolved. Intravenous Glutathione: A Novel Approach for Treating Resistant Symptoms in Chronic Lyme Disease Results: (cont’d) There were also 8 chronic Lyme Disease patients who underwent a 1-2 month GSH trial, with doses ranging from 400mg IV 3x/wk to 2000mg per day. These patients generally comprised a group of difficult to treat “non-responders”. There were no adverse side effects from longer-term use of GSH. Among that group, 1 patient out of 8 had no clinical response, and the other 7 patients had sustained positive clinical improvements ranging from 10% to 35%, with a mean improvement of 20%. These patients reported consistent improvements in cognitive functioning, , headaches, muscle strength, muscle pain, and joint pain. Discussion: Patients who experienced the most significant benefit from Glutathione were often patients who had failed multiple antibiotic regimens in the past and were considered treatment resistant. Several patients who had significant neurologic dysfunction with dysarthria, incoordination, and muscle weakness experienced a rapid and dramatic improvement in symptoms with a single dose of IV GSH. Metabolic functions of GSH include DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, enzyme activation, prevention of oxidative cell damage, enhancement of immune system function, and metabolism of toxins and carcinogens (Annals of Pharmacotherapy: Glutathione in Health & Disease: pharmacotherapeutic issues:1995 Dec., Vol. 29, 1263-1273). Since patients reported improvement in fatigue, joint pain, muscle pain, mood swings, headaches, balance, dizziness, speech problems, and cognitive difficulties within 30 minutes of administration, GSH may be acting to metabolize toxins in the short term, and may have an effect on prostaglandins, interleukins, oxidative stress & immune modulation in the long term. Alternatively, the rapid initial improvement in symptoms may be a placebo response due to the novelty of trying a new treatment approach; however, the sustained response among patients given longer term treatments suggests that something other or in addition to a placebo response is in effect. Modulators of Phase I Metabolic Pathways of the Liver Cytochrome P450

Ellagic Acid Watercress glucosinolates Green Tea Catechins Silymarin

Upregulation of Phase II Metabolic Pathways of the Liver

Glutathione Sulfation Amino Acid Glucuronidation Acetylation Methylation Conjugation •Sodium Sulfate Conjugation •Preventium •Pantothenic Acid •Folate •Glutathione •MSM •Glycine •Artichoke Leaf •Magnesium •Vitamin B12 •NAC •Cysteine •Vitamin B6 •Vitamin B6 •Ellagic Acid •Alpha Lipoic Acid •Watercress •Silymarin

Estrogen Testosterone Estrogen Estrogen Prostaglandins Thyroxine Fat Soluble Vitamins Mercury Bile Acids PABA Histamine Leukotrienes Cortisol Steroid Hormones Lead Petroleum Distilates Adrenaline Pesticides (DDT) Cadmium Melatonin Dopamine DHEA Epinephrine Optimize bowel health Insure hydration (Probiotics, fiber, colon cleanses)

Minimize toxic ↑Antioxidant Exposure Detoxification Reserve (air & H2O purifiers, clean diet) Principles (alpha lipoic acid, diet)

Optimize Assist & mitochondrial function Balance biotransformation (NT factor, CoQ 10, NADH) (NAC, Gly, B vit’s) Detoxification/Detoxification/ChelationChelation/Nutritional/Nutritional SupplementationSupplementation  DetoxificationDetoxification:: SkinSkin (saunas),(saunas), ColonColon ((probioticsprobiotics,, fiber,fiber, ??QuestranQuestran,, cleanses),cleanses), KidneysKidneys ((↑↑fluids),fluids), liverliver (( vitvit’’ss,, minmin’’s,s, herbsherbs toto ↑↑ phasephase II && IIII detoxdetox pathways)pathways)  ChelationChelation :: 66 hrhr urineurine DMSADMSA challenge,challenge, thenthen usingusing oraloral (DMSA,(DMSA, DEPEN..),DEPEN..), rectalrectal (EDTA),(EDTA), transdermaltransdermal (DMPS,(DMPS, GSH),GSH), oror IVIV (DMPS,(DMPS, EDTA)EDTA) toto removeremove heavyheavy metals,metals, replacingreplacing minerals.minerals. AA recentrecent studystudy atat thethe HVHACHVHAC foundfound thatthat 100mg100mg DMSADMSA QQ 33rd nightnight xx momo’’ss toto bebe safesafe && effective,effective, w/w/ ALA,ALA, chlorella,chlorella, NAC,NAC, replacingreplacing vitvit/min/min’’ss  NutritionalNutritional SupplementationSupplementation :: FocusFocus onon usingusing NAC,NAC, GlycineGlycine,, DIM,DIM, SulforaphaneSulforaphane glucosinalateglucosinalate,, MedMed CapsCaps DPO,DPO, αα lipoiclipoic acid,acid, MTVMTV w/w/ minmin’’ss ((MagMag++,++, Zn+..)Zn+..)  EffectEffect ofof ToxinsToxins onon anan Individual:Individual: NotionNotion ofof ToxicToxic loadload// individualindividual susceptibility/geneticssusceptibility/genetics V:V: AllergiesAllergies andand CLDCLD  Food allergies are frequently seen in the general population, especially to common allergens such as wheat, dairy, corn, nuts, shellfish, food dyes and additives, etc. It may present as an immediate hypersensitivity reaction (IgE), or delayed hypersensitivity reaction (IgG)  Allergies are a common complaint of indiv’s with CFS & FM, and are frequently seen in E.I. Syndrome  They may be related to Candidiasis and a leaky gut, and should prompt investigation into these 2 diagnoses  Common manifestations: fatigue, headaches, allergic rhinitis, eczema, asthma, irritability, concentration prob’s  Testing: local IGE (Quest, expanded food allergy profile), or IgG (Metametrix 90 food allergy panel)  Treatment: Classical: Avoidance, rotation diets, Immuniz’s  Treatment: CAM: plus treat underlying Candida or leaky gut if present, use enzyme therapy, ?NAET, NMT…. VI:VI: NutritionalNutritional && EnzymeEnzyme deficienciesdeficiencies

 DigestiveDigestive disordersdisorders whichwhich areare commoncommon inin CFSCFS maymay stemstem fromfrom anan enzymeenzyme deficiencydeficiency  EnzymeEnzyme deficienciesdeficiencies →→ poorpoor digestiondigestion ofof proteins,proteins, carbohydrates,carbohydrates, andand fatsfats →→ deficiencydeficiency ofof vitalvital nutrientsnutrients necessarynecessary forfor properproper cellularcellular functionfunction  DetoxificationDetoxification reactionsreactions ofof environmentalenvironmental chemicalschemicals requirerequire anan ongoingongoing supplysupply ofof essentialessential vitamins,vitamins, minerals,minerals, AAAA’’s,s, fattyfatty acidsacids andand phytonutrientsphytonutrients toto bebe effective.effective. TheThe higherhigher thethe toxictoxic load,load, thethe moremore likelylikely nutritionalnutritional deficienciesdeficiencies willwill bebe presentpresent inin anan individualindividual EffectEffect ofof MineralMineral DeficienciesDeficiencies onon BiochemicalBiochemical (f)(f)  Mag++ → Nec in appx 300 detox enzymes in the body. Deficiency results in muscle spasm, tremors, anxiety, Raynauds phen, arrhythmias,  Cu+→ SOD (free radicals), polyphenol oxidase (detox chem’s), tyrosinase & dopa oxidase (neurotransmitters), Cytochrome C oxidase (energy)  Zn++ → Nec in > 90 enzymes (alcohol dehydrogenase, Phase I rxn, converts alcohols→ aldehydes. If low, biochem bottleneck, with shift to chloral hydrate and toxic brain symptoms) -Older pts gen have signif lower level of plasma Zn, ↑ levels of inflammatory cytokines and IL 10, and ↑ plasma oxidative stress. Compared to the placebo gp, Zn supplemented gp had ↓ incidence of infections, ↓ TNF-α, & ↓ plasma oxidative stress markers (NIH funded study) Am J Clin Nutr 2007; 85: 837-844 VI:VI: NutritionalNutritional && EnzymeEnzyme deficienciesdeficiencies  TestingTesting:: serumserum mineralsminerals ((MagMag++,++, Zn..),Zn..), RBCRBC mineralsminerals ((MagMag++),++), AAAA && FAFA analysis,analysis, IONION test/test/ OrganixOrganix testtest ((MetametrixMetametrix labs)labs) toto testtest functionalfunctional biochemicalbiochemical pathwayspathways  LipidLipid peroxides,peroxides, sulfates,sulfates, nitratesnitrates ((MetametrixMetametrix)) toto checkcheck freefree radicalradical exposureexposure (important(important inin CNSCNS disease,disease, ALSALS……),), detoxdetox pathways,pathways, NONO pathwaypathway (indirect)(indirect)  TreatmentTreatment:: ReplaceReplace vitvit’’ss,, minerals,minerals, AAAA’’s,s, EFAEFA’’ss,, enzymesenzymes (plant(plant oror pancreaticpancreatic w/amylase,w/amylase, lipase,lipase, proteases)proteases)  CAMCAM:: ?? RoleRole ofof enzymesenzymes betweenbetween mealsmeals forfor viralviral infinf’’ss// inflammationinflammation -Morley, J.E. et al. Nutritional Modulation of Neural Function. UCLA Forum in Medical Sciences 28 (San Diego, CA: Academica Press, 1988) -Jaeger, C.B, et al. “Polymer Encapsulated Dopaminergic Cell Lines as ‘Alternative Neural Grafts’ Progress in Brain Res 82 (1990), 41-6 VII:VII: MitochondrialMitochondrial DysfunctionDysfunction  MitochondrialMitochondrial membranemembrane componentscomponents areare especiallyespecially susceptiblesusceptible toto freefree radicalradical damage,damage, asas theythey areare exposedexposed toto molecularmolecular 0202 whichwhich isis constantlyconstantly utilizedutilized forfor ATPATP production,production, andand havehave highhigh concentrationsconcentrations ofof moleculesmolecules thatthat areare easilyeasily oxidizedoxidized (unsaturated(unsaturated fattyfatty acids).acids).  CertainCertain nutrientsnutrients areare essentialessential forfor properproper mitochmitoch (f)(f) andand energyenergy production,production, ieie CoQ10,CoQ10, NADH,NADH, LL--carnitinecarnitine,, essentialessential phospholipids,phospholipids, αα--ketoketo glutarateglutarate  TestingTesting:: lipidlipid peroxides,peroxides, OrganixOrganix testtest ((MetametrixMetametrix)) maymay provideprovide indirectindirect evidenceevidence throughthrough nutritionalnutritional deficiencies,deficiencies, freefree radicalradical exposureexposure  TreatmentTreatment:: NTNT factorsfactors ((gycosylatedgycosylated phospholipids),phospholipids), CoQ10,CoQ10, NADH,NADH, LL--carnitinecarnitine -Laboratory Evaluations in Molecular Medicine: Nutrients, Toxicants, and Cell Regulators. J. Alexander Bralley, PHD. IAMM, Norcross, GA -Seidman, M. Polyunsaturated PC in NT factor improves mitochondrial function. Anti Aging Med Nov 2001

VIII:VIII: PsychologicalPsychological FactorsFactors InIn CLDCLD

 ManyMany patientspatients withwith CLDCLD havehave overlappingoverlapping psychologicalpsychological dys(fdys(f),), ieie historyhistory ofof depression,depression, anxiety,anxiety, OCD,OCD, PTSDPTSD withwith abuseabuse (physical,(physical, emotional,emotional, sexual)sexual)  LymeLyme andand associatedassociated coco--infectionsinfections willwill causecause previousprevious psychologicalpsychological patternspatterns toto intensify,intensify, oror causecause newnew patternspatterns toto emergeemerge ((ieie psychosis,psychosis, manicmanic--depressivedepressive disorder..)disorder..)  HealthHealth carecare providersproviders shouldshould askask aboutabout previousprevious psychpsych hxhx,, andand referrefer forfor counseling/psychiatriccounseling/psychiatric help.help.  TreatmentTreatment:: MedicationsMedications ((SSRISSRI’’ss,, buproprionbuproprion,, RemeronRemeron,, anxiolyticsanxiolytics,),,), StressStress reductionreduction (yoga,(yoga, meditation,meditation, TaiChiTaiChi)) CAMCAM:: HerbsHerbs (SJW,(SJW, Valerian,Valerian, KavaKava KavaKava LL--theaninetheanine),), CognitiveCognitive processingprocessing therapytherapy (PTSD),(PTSD), JourneyJourney workwork (Brandon(Brandon Bays),Bays), ?EFT?EFT…… IX:IX: EndocrineEndocrine AbnormalitiesAbnormalities

 HypothalamicHypothalamic--pituitarypituitary axisaxis maymay bebe affectedaffected →→checkcheck FSH,FSH, LH,LH, GHGH andand IGF1,IGF1, TSHTSH && ACTHACTH levels,levels, DHEA/DHEA/CortisolCortisol,, sexsex hormoneshormones  ImptImpt toto testtest fullfull TFTTFT’’ss (new(new rangerange TSHTSH 0.50.5--2.5;2.5; 11 oror lessless maymay bebe necessarynecessary forfor significantsignificant clinicalclinical improvement)improvement) withwith thyroidthyroid ABAB’’s,T3,s,T3, T4,T4, rT3,rT3, T3/rT3T3/rT3 ratio.ratio. ConsiderConsider TRHTRH stimulationstimulation test=test= GoldGold standard.standard. AA poorlypoorly functioningfunctioning thyroidthyroid convertsconverts T4T4 toto rT3rT3 (can(can bebe w/w/ stress,stress, fasting,fasting, illness,illness, increasedincreased cortisolcortisol)) && leadsleads toto lowlow T3T3 syndromesyndrome  ““NormalNormal”” rangesranges maymay notnot bebe applicableapplicable  ?? XenoestrogensXenoestrogens/toxins/toxins blockingblocking receptorreceptor sitessites→→ certaincertain ptspts needneed toto havehave hormonehormone levelslevels atat thethe higherhigher rangerange ofof ““normalnormal”” toto havehave clinicalclinical improvementimprovement EndocrineEndocrine ProblemsProblems AmongAmong LymeLyme PatientsPatients :: AdrenalAdrenal FatigueFatigue  AdrenalAdrenal fatiguefatigue:: AA spectrumspectrum disorderdisorder inin betweenbetween AddisonAddison’’ss andand CushingCushing’’ss diseasedisease  EtiologyEtiology:: AnyAny formform ofof chronicchronic stressstress (physical,(physical, emotional,emotional, psychological,psychological, environmental,environmental, infectious,infectious, inin combination)combination)  SymptomsSymptoms:: fatigue,fatigue, nonnon--regenerativeregenerative sleep,sleep, saltsalt craving,craving, hypoglycemia,hypoglycemia, ↓↓ libido,libido, lowlow BP/BP/ posturalpostural hypotension,hypotension, depression/irritability,depression/irritability, ↓↓ memory/focus,memory/focus, ↑↑ timetime toto recoverrecover fromfrom illness,illness, injury,injury, oror traumatrauma  AssociatedAssociated DiseasesDiseases:: CFS,CFS, Fibromyalgia,Fibromyalgia, alcoholism,alcoholism, RA,RA, ChronicChronic allergies/asthmaallergies/asthma LaboratoryLaboratory TestingTesting forfor AdrenalAdrenal FatigueFatigue  ProblemsProblems w/w/ bloodblood testingtesting:: populationpopulation usedused toto standardizestandardize thethe teststests maymay havehave includedincluded manymany peoplepeople w/w/ somesome levellevel ofof adrenaladrenal fatigue,fatigue, && lablab teststests areare defineddefined && standardizedstandardized basedbased onon statisticalstatistical norms,norms, notnot physiologicallyphysiologically optimaloptimal normsnorms  2424 hrhr urinaryurinary cortisolcortisol testtest→→ ifif levelslevels areare inin thethe bottombottom 1/31/3 ofof ““NormalNormal”” range,range, suspectsuspect ↓↓ adrenaladrenal (f)(f)  BloodBlood teststests:: dodo notnot measuremeasure tissuetissue levelslevels  ACTHACTH ChallengeChallenge:: ++ ifif cortisolcortisol levelslevels << 2x2x ↑↑  DHEA/DHEA/CortisolCortisol salivarysalivary testingtesting:: measuresmeasures tissuetissue levels,levels, reliablereliable marker.marker. Labs:Labs: Aeron,Aeron, MetametrixMetametrix,, GenovaGenova,, DiagnostekDiagnostek..  ConsiderConsider adrenaladrenal supplsuppl’’ss (B(B vitvit’’ss,, VitVit C,C, rhodiolarhodiola,, licorice..)licorice..) andand lowlow dosedose CortefCortef forfor replacementreplacement ifif ↓↓ levelslevels X:X: SleepSleep DisordersDisorders

 ImpairedImpaired sleepsleep correlatescorrelates directlydirectly withwith impairedimpaired immuneimmune functioningfunctioning -Sleep and the immune system. Int J Immunopharmacol 1995;17:649-54 -Sleep, neuroimmune and neuroendocrine functions in fibromyalgia and chronic fatigue syndrome. Adv Neuroimmunol 1995;5:39-56 -Adv Management of sleep disorders in fibromyalgia. Rheum Dis Clin North Am. 2002;28:53-65

 Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age/stress disorders, such as RA, FM, and CFS. -Lorton D et al. Neuroimmunomodulation. 2006;13(5-6):357-74. Epub 2007 Aug 6 -M. Haack, et al. J Pain; April 2004, Supplement 1, Vol 5, no 3

 Chronic sleep restriction leads to elevations in IL-6 and pain symptoms in healthy volunteers. -M. Haack, et al. J Pain; April 2004, Supplement 1, Vol 5, no 3 X:X: SleepSleep DisordersDisorders

 Causes:Causes: ObstructiveObstructive SleepSleep apnea,apnea, Medications,Medications, Caffeine,Caffeine, NocturiaNocturia,, Depression/Anxiety,Depression/Anxiety, RLS..RLS..  Evaluation:Evaluation: SleepSleep StudyStudy ifif unresponsiveunresponsive toto standardstandard treatmenttreatment regimensregimens  TreatmentTreatment :: ActivatingActivating AgentsAgents inin thethe AM,AM, SleepSleep promotingpromoting agentsagents inin thethe PM,PM, especiallyespecially thosethose thatthat encourageencourage stagestage 3/stage3/stage 44 REMREM sleepsleep ((LyricaLyrica,, TrazadoneTrazadone,, GabitrilGabitril,, SeroquelSeroquel,, XyremXyrem))  CAM:CAM: checkcheck neurotransmitterneurotransmitter levels.levels. BalanceBalance neurotransmittersneurotransmitters withwith 55--HTP,HTP, toto increaseincrease GABA.GABA. ValerianValerian root,root, LL--theoninetheonine alsoalso usefuluseful X:X: SleepSleep Disorders,Disorders, NormalizingNormalizing thethe AmplitudeAmplitude ofof CircadianCircadian RhythmRhythm  ActivatingActivating AgentsAgents (AM)(AM)  SleepSleep PromotingPromoting (PM)(PM)  Modanifil (Provigil)  Pregabilin (Lyrica)  Stimulants  Trazadone  Bupropion (Wellbutrin)  Gabitril  Noradrenergic Agents  Seroquel  SSRI’s  Xyrem  Activating Atypicals  Non-Benzos: Ambien,  Thyroid Lunesta, Sonata  Benzodiazepines  Mirtazipine (Remeron)  Doxepin, Elavil  Melatonin, Ramelton XI:XI: AutonomicAutonomic NervousNervous SystemSystem DysfunctionDysfunction  TheThe ANSANS involvesinvolves elementselements ofof thethe CNSCNS (brain(brain && spinalspinal cord),cord), andand PNS,PNS, sensorysensory motormotor branches,branches, whichwhich isis controlledcontrolled byby thethe hypothalamus.hypothalamus. ItIt regulatesregulates automaticautomatic bodybody functionsfunctions suchsuch asas breathing,breathing, heartheart rate,rate, andand digestion.digestion.  TheThe ParasympatheticParasympathetic nervousnervous systemsystem:: ↓↓ heartheart rate,rate, andand BP,BP, butbut increasesincreases gastricgastric secretionsecretion andand intestinalintestinal activityactivity  TheThe OrthosympatheticOrthosympathetic nervousnervous systemsystem isis associatedassociated withwith arousalarousal andand stress,stress, increasesincreases heartheart rate,rate, BPBP andand musclemuscle tensiontension andand regulatesregulates thethe contractioncontraction andand expansionexpansion ofof bloodblood vessels.vessels. XI:XI: AutonomicAutonomic NervousNervous SystemSystem DysfunctionDysfunction  CertainCertain ChronicChronic LymeLyme diseasedisease patientspatients willwill complaincomplain ofof fatigue,fatigue, dizziness,dizziness, && concentrationconcentration problemsproblems despitedespite classicalclassical therapies.therapies. BPBP willwill bebe lowlow onon examexam (<(< 90/60),90/60), withwith associatedassociated tachycardiatachycardia (>(> 100100 BPM)BPM) atat rest.rest.  TestingTesting:: TiltTilt tabletable test,test, bloodblood pressurepressure loglog withwith homehome readingsreadings  TreatmentTreatment:: saltsalt (minimum(minimum 33--44 grams/day),grams/day), increaseincrease fluidsfluids (3(3 litersliters +),+), considerconsider FlorinefFlorinef,, CortefCortef,, and/orand/or BB blockersblockers ifif inadequateinadequate responseresponse XII:XII: GastointestinalGastointestinal DisordersDisorders

 CeliacCeliac diseasedisease:: oneone ofof severalseveral malabsorptionmalabsorption syndromes,syndromes, duedue toto glutengluten sensitivity.sensitivity. ClinicalClinical featuresfeatures includeinclude musclemuscle wasting,wasting, smallsmall stature,stature, weightweight loss,loss, paresthesiasparesthesias,, musclemuscle cramps,cramps, diarrhea.diarrhea. LookLook forfor laboratorylaboratory evidenceevidence ofof malabsorptionmalabsorption:: ↓↓ albumin,albumin, cholchol,, Ca++,Ca++, MagMag++,++, B12,B12, w/w/ macrocyticmacrocytic anemia,anemia, ↓↓ Fe,Fe, K+K+  TestingTesting:: AntigliadinAntigliadin AB,AB, TTG,TTG, avoidavoid glutengluten asas therapeutictherapeutic trialtrial  OtherOther GIGI:: CrohnsCrohns,, UC,UC, parasites,parasites, Candida/LeakyCandida/Leaky gut/gut/dysbiosisdysbiosis,, otherother malabsorptionmalabsorption syndromessyndromes XIII:XIII: ElevatedElevated LFTLFT’’ss

 PatientsPatients frequentlyfrequently presentpresent withwith ↑ LFT’s at some pointpoint duringduring treatment.treatment.  Etiologies:Etiologies: TickTick--borneborne disordersdisorders -- ((Ehrlichiosis/AnaplasmosisEhrlichiosis/Anaplasmosis,, QQ--Fever,Fever, BabesiaBabesia..),..), antibiotics,antibiotics, ETOHETOH use,use, Hepatitis,Hepatitis, HemochromatosisHemochromatosis,, WilsonWilson’’ss disease,disease, Autoimmune,Autoimmune, hyperlipidemiahyperlipidemia,, chemicalchemical oror drugdrug exposureexposure  Testing:Testing: ANA,ANA, HepHep B,B, CC screen,screen, FeFe--TIBC/TIBC/FerritinFerritin,, CeruloplasminCeruloplasmin levels,levels, αα--antitrypsinantitrypsin levels,levels, ticktick--borneborne panel,panel, lipidlipid levels..levels..  Treatment:Treatment: TreatTreat symptomaticallysymptomatically ifif aboveabove etiologiesetiologies ruledruled out.out. CAM:CAM: MilkMilk thistlethistle ((silymarinsilymarin),), HepaHepa #2#2 (TCM),(TCM), NAC,NAC, alphaalpha lipoiclipoic acid..acid.. XIV:XIV: DrugDrug Use/Use/ AddictionAddiction XV:XV: DeconditioningDeconditioning  SomeSome CLDCLD patientspatients presentpresent withwith severesevere pain,pain, andand maymay bebe onon chronicchronic NSAIDNSAID’’ss && highhigh dosedose narcoticsnarcotics toto controlcontrol pain.pain.  NarcoticsNarcotics maymay interfereinterfere withwith deep,deep, regenerativeregenerative sleep,sleep, andand reboundrebound painpain andand headachesheadaches maymay resultresult whichwhich becomesbecomes partpart ofof aa chronicchronic symptomsymptom complexcomplex whichwhich isis difficultdifficult toto treat.treat. ConsiderConsider aa painpain managementmanagement specialistspecialist forfor resistantresistant painpain andand detoxdetox programprogram ifif appropriate.appropriate.  PatientsPatients needneed toto bebe placedplaced onon aa regularregular exerciseexercise programprogram onceonce theirtheir physicalphysical conditioncondition permits.permits. StartStart slowslow andand referrefer toto PT/OTPT/OT ifif overlappingoverlapping musclemuscle weaknessweakness andand finefine motormotor coordinationcoordination areare affected.affected. RoleRole ofof IntegrativeIntegrative TherapiesTherapies inin CLDCLD

 HVHACHVHAC hashas seenseen overover 11,00011,000 CLDCLD ptspts overover thethe lastlast 2020 years.years. AntibioticsAntibiotics areare usefuluseful inin treatingtreating thethe underlyingunderlying infections,infections, butbut dodo notnot clinicallyclinically appearappear toto completelycompletely eradicateeradicate thethe infectionsinfections asas thethe vastvast majoritymajority ofof patientspatients relapserelapse uponupon discontinuationdiscontinuation ofof antibiotics.antibiotics. ThereforeTherefore CAMCAM therapiestherapies havehave beenbeen investigatedinvestigated asas anan alternativealternative toto antibiotics.antibiotics.  SuccessSuccess inin treatingtreating patientspatients requiresrequires addressingaddressing thethe 33 II’’ss:: Infection,Infection, Immunity,Immunity, andand InflammationInflammation whilewhile investigatinginvestigating otherother overlappingoverlapping etiologiesetiologies responsibleresponsible forfor ongoingongoing sxsx (hormones,(hormones, heavyheavy metals,metals, neurotoxins,neurotoxins, viruses,viruses, parasiticparasitic infections,infections, leakyleaky gut,gut, foodfood allergies,allergies, autoimmunityautoimmunity…….).) Herbal/CAMHerbal/CAM therapiestherapies usedused forfor ChronicChronic LymeLyme DiseaseDisease  BuhnerBuhner protocolprotocol ((SamentoSamento,, AndrographisAndrographis,, JapaneseJapanese knotwoodknotwood..)..)  SchartSchart protocolprotocol ((DiflucanDiflucan// Pen)Pen)  ZhangZhang protocolprotocol ((TCMTCM→→CoptisCoptis,, HH,HH, CircCirc P)P)  HomeopathicHomeopathic protocolsprotocols ((LedumLedum,, syphiliticsyphilitic andand malarialmalarial nosodesnosodes))  SaltSalt && VitVit CC protocolprotocol  RifeRife machinesmachines --NoneNone ofof thesethese havehave beenbeen scientificallyscientifically validatedvalidated byby largelarge controlledcontrolled studiesstudies CowdenCowden ProtocolProtocol ResultsResults  Full Cowden protocol, no AB’s : N=50 → 70% had improvement in sx (scale -3 to +3), median at 2 (moderate improvement) w/ 6/50 (12%) w/ mild improvement, 14/50 (28%) w/ moderate improvement, and 15/50 (30%) w/ significant improvement. There was also a 35% overall improvement (scale 0-100%)  Limited Cowden protocol, no AB’s : N= 32 → 72% had improvement in sx (scale -3 to +3), median at 2 (moderate improvement) w 6/32 (19%) w/ mild improvement, 11/32 (34%) w/ moderate improvement, and 7/32 (22%) w/ significant improvement. There was also a 13.7% overall improvement (scale 0-100%)  Full Cowden protocol, w/ AB’s : N=13 → 77% had improvement in sx (scale -3 to +3), median at 1 (mild improvement) w/ 8/13 (62%) w/ mild improvement,1/13 (8%) w/ moderate improvement, and 2/13 (15%) w/ signif improvement. There was also a 12.7% overall improvement in sx (scale 0-100%)  Limited Cowden protocol, w/ AB’s : N=37 →66% had improvement in sx (38% mild improvement, 28% moderate to signif improvement), median at 1 (mild improvement) w/ 1.5% overall improvement (scale 0-100%)

PuttingPutting ItIt Together:Together: IntegratingIntegrating ClassicalClassical andand CAMCAM therapiestherapies

 HerbsHerbs cancan bebe addedadded atat anyany timetime duringduring anan antibioticantibiotic protocolprotocol toto addressaddress inflammationinflammation andand elevatedelevated cytokinescytokines ((andrographisandrographis,, polygonum/resveratrolpolygonum/resveratrol,, smilax,smilax, stephaniastephania,, samentosamento……)) andand toto ↓↓ thethe numbernumber ofof antibioticsantibiotics used,used, especiallyespecially ifif therethere isis GIGI intoleranceintolerance  OnceOnce aa patientpatient hashas achievedachieved aa significantsignificant levellevel ofof improvement,improvement, considerconsider rotationrotation ontoonto anan herbalherbal protocol,protocol, andand maintainmaintain forfor atat leastleast 11 yearyear (relapses(relapses werewere seenseen withwith thethe CowdenCowden protocolprotocol << 66 months).months).  ControlledControlled clinicalclinical trialstrials needneed toto bebe donedone toto evaluateevaluate thethe rolerole ofof differentdifferent herbalherbal medicinesmedicines inin ChronicChronic LymeLyme Disease.Disease. ItIt isis notnot knownknown atat thisthis timetime whichwhich combinationcombination ofof herbsherbs inin differentdifferent clinicalclinical circumstancescircumstances maymay yieldyield thethe safestsafest andand mostmost efficaciousefficacious results.results. PuttingPutting ItIt Together:Together: IntegratingIntegrating thethe 1515 DifferentialDifferential DiagnosesDiagnoses intointo aa ComprehensiveComprehensive TreatmentTreatment PlanPlan  ChronicChronic LymeLyme DiseaseDisease isis aa symptomsymptom complexcomplex ofof borreliosisborreliosis andand multiplemultiple coco--infectionsinfections withwith associatedassociated inflammationinflammation andand immuneimmune dysfunction.dysfunction. TreatTreat thethe 33 ““II’’ss”” simultaneouslysimultaneously  TreatingTreating allall 33 formsforms ofof Bb,Bb, coco--infections,infections, hormonalhormonal abNabN’’ss,, heavyheavy metalsmetals andand neurotoxins,neurotoxins, sleepsleep d/od/o,, psychiatricpsychiatric issues,issues, andand nutritionalnutritional deficienciesdeficiencies areare thethe mostmost commonlycommonly foundfound abNabN’’ss atat thethe HVHACHVHAC thatthat havehave thethe greatestgreatest impactimpact onon regainingregaining healthhealth  EvaluateEvaluate allall 1515 differentialdifferential diagnosticdiagnostic categoriescategories andand prioritizeprioritize thosethose thatthat mostmost needneed toto bebe addressedaddressed earlyearly onon inin thethe illnessillness PuttingPutting ItIt Together:Together: ChronicChronic InfectionsInfections andand NeurobiologicalNeurobiological EffectsEffects  TheseThese agentsagents createcreate inflammationinflammation throughthrough variousvarious pathwayspathways (IL(IL--1,1, ILIL--6,6, TNFTNF--αα,, NONO andand itsits metabolites)metabolites) whichwhich createscreates freefree radicalsradicals andand oxidativeoxidative stressstress whichwhich damagesdamages cellcell membranes,membranes, mitochondria,mitochondria, andand nervenerve cellscells  SomeSome infectiousinfectious agentsagents produceproduce neurotoxinsneurotoxins ((QuinolinicQuinolinic Acid..)Acid..) whichwhich affectaffect nervenerve cellscells  AutoimmunityAutoimmunity maymay alsoalso resultresult fromfrom antibodiesantibodies crosscross reactingreacting withwith ourour ownown tissuetissue antigensantigens  MitigatingMitigating thesethese effectseffects requiresrequires treatingtreating thethe 33 II’’ss (infection,(infection, immuneimmune issues,issues, inflammation)inflammation) whilewhile supportingsupporting detoxdetox pathwayspathways andand eliminatingeliminating environmentalenvironmental triggerstriggers (heavy(heavy metals)metals) whichwhich ↑↑ inflammationinflammation asas wellwell asas addressingaddressing ALLALL issuesissues foundfound duringduring thethe evaluationevaluation ofof 1515 differentialdifferential diagnosesdiagnoses “Wisdom is the marriage of knowledge and experience bound by compassion.”