Understanding the Core of the Gut-Brain Connection in Autism and How to Fix it - James Bradstreet
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Understanding the Core of the Gut-Brain Connection and How to Fix It in ASD
James Jeffrey Bradstreet MD, MD(H) FAAFP Director, ICDRC Adjunct Professor, Pediatrics Southwest College of Naturopathic Medicine 321-259-7111 www.icdrc.org
Biomarkers
• We must define individual needs, issues and pathologies. • Assists the selection of proper treatment instead of trial and error and shotgun approaches. • Monitors efficacy of interventions
– When are we done treating – Did we give enough or too much treatment – Evaluation of possible side-effects
Reasoned Grounds for Intervention?
• Objective Biomarker indicating serious condition – diabetic model with glucose and insulin. • Apply this to oxidative stress, autoimmunity etc. • Serious, dangerous and life-changing medical conditions justify treatment based on reasoned approach even if proof of cure is not available. • Risk benefit estimates of any intervention become more critical where objective safety and efficacy are lacking. • Cost analysis of intervention should include time stress and money.
OXIDATIVE STESS = MtD
• Urine
– 8-OHG – Isoprostane
• Blood;
– Transferrin, Ceruloplasmin, – Ammonia and Lactate – Reduced Glutathione or GSSG - if available.
IMMUNOLOGICAL
• Urinary: Neopterin and Biopterin • Blood:
– – – – – – Anti-endothelial Antibodies at WUSTL, ASO and Anti-DNase B, IgG subclasses, IgM, IgA and IgE, CRP, Cytokines, TNF alpha, Complete Blood Count, Immune cell counts (CD and NK cell specifics)
• Special: intestinal permeability to lactulose and mannitol. • Fecal
– – – – – IgA Gluten, Casein, Egg, Soy etc. Pathogens: Yeast, Bacteria (both Probiotic and Pathogens) Calprotectin Eosinophil Protein X Blood and Leukocytes
• Antibody and PCR testing for HHV6, EBV, CMV, Chlamydia and Mycoplasma
Clostridia, Aerobes and Yeast
• Urine: Organic Acid test for markers of anerobic bacterial metabolism: Proprionic acid derivatives (HPHPA and others) and yeast metabolites. Arabinose by itself is not reliable. • Feces
– Culture is difficult and not reliable – PCR also challenging but will over time gain enough reliability to be gold standard – currently a research tool in my opinion.
METHYLATION AND TRANSSULFATION
• Urine
– Methylmalonic acid – B12 indicator
• Plasma
– Fasting Cysteine – Methionine – Taurine – Sulfate
• B12 and Folate levels
Cerebral Spinal Fluid (CSF)
• Special Investigations and Research • If Blood is positive for pathogens by PCR (DNA or RNA) then comparative CSF PCR data is important if treatment is going to be prescribed. Examples: HHV6, Mycoplasma and Chlamydia • Measles Virus testing will eventually become clinically relevant again. No commercially reliable testing available at this time. • Immune Markers: TNF alpha, cytokines, neopterin, autoantibodies. • CSF Methylfolate in some locked-in cases
HEAVY METALS
• Blood:
– Packed Erythrocyte Minerals and Toxic Metals – Lymphocyte Metallthionein pre/post induction
• Urinary:
– Fractionated Porphyrins – If porphyrins elevated or history strongly suggestive get post-chelation challenge = 6 or 24 hour urine toxic metal assay
WHY DID RECOVERY EFFORTS GET STUCK?
Chronic Unresolved Inflammation of the Brain & Gut with Brain Vasculitis and Pathogen Persistence (MV and others) combined with Permanent Injury (Purkinje Cell Loss), Mitochondria Dysfunction, and Oxidative Stress
Ann Neurol. 2005 Jan;57(1):67-81
Mar
k
A lial ed G
io ivat ct
n
Microvasculitis
Purkinje
Cell Los
s
Ann Neurol. 2005 Jan;57(1):67-81
Neuroinflammation is not an ICD-9 Diagnosis, but Encephalitis is. What they are afraid to say
Although the term "encephalitis" literally means "inflammation of the brain," it usually refers to brain inflammation resulting from a viral infection. The severe and potentially life-threatening form of this disease is rare. Experts suspect that the actual incidence of encephalitis is probably much higher — but because most people have such mild signs or symptoms, many cases go unrecognized. Encephalitis occurs in two forms — a primary form and a secondary form. Primary encephalitis involves direct viral infection of the brain and spinal cord. In secondary encephalitis, a viral infection first occurs elsewhere in the body and then travels to the brain.
http://www.mayoclinic.com/health/encephalitis/DS00226
Chez et al. Pediatric Neurology: 2007;36:361-365
(Journal of Pediatrics. 1999;134:607-13)
CASE: Staining of Endothelium: Perinuclear
CONTROL: No Antibody Staining
Evaluating Cases Studies
Regressive Autism Variant
• Colton Snyder • Medical Records are in the Public Domain secondary to being a test case in the Omnibus Proceedings regarding Vaccine Related injuries and autism • Full discussion is available from my NAA talk in November of 2007
Colton Snyder’s Case Review
• Prenatal Maternal use of Prozac (ex 2: 0002), also positive ANA in 1996 (ex 2: 0056) • Pregnancy: Mild Hypertension final weeks (ex 2: 0009) • Born Jan 9, 1997 (ex 4: 0001) Term without apparent distress. • APGARS 9/9 with wt of 7Lb 3 oz (ex 3: 0003) • Several episodes of febrile illnesses in first 15 months of life with multiple courses of antibiotics. • MMR-II administered on 4/23/1998 • Pharyngitis and Regressive Symptoms begin 5/6/1998 • ER visit high fever 5/24/98 - Antibiotics fail to help • Hospitalized 5/26/98 • See my report Jan 29, 2001 (P Ex 1) • Strongly Favorable Response to IVIG • Intestinal Bx (+) MV RNA, CSF (+) MV RNA, Blood negative. • Detection of Measles Virus Genomic RNA in Cerebrospinal Fluid of Children with Regressive Autism: a Report of Three Cases. Bradstreet et al, Journal of American Physicians and Surgeons. Volume 9 Number 2 Summer 2004
My Clinical Concept of Colton’s Medical Problems Mercury Measles Vaccine
Immune Dysregulation – Autoimmune Brain and Gut Inflammation Oxidative Stress Glutathione Depletion MV Persistence
Bacteria - Dysbiosis
Laboratory
One Year Check-Up
Lost Weight After MMR
Diagnostic Evaluation
Language Deficit
Diagnostic Elements of ASD
CSF Measles RNA
Ex 21
Terminal Ileum RNA
PERSISTENT ILEAL MEASLES VIRUS in a La Cohort of Regressive rge Autistic Children WITH ILEOCOLITIS AND LYMPHONODULAR HYPERPLASIA: ReVisitation of a Ea n rlier Study June 1 -3 , 2 0 (IMFAR), Montre st rd 0 6 al,
Wa r, S.J., He r K., Sega J., & Krigsm n A., De rtme of lke pner a pa nt Hepne Se l, ga Krigsma Depa Physiology & Pharm cology, Wa Forest University School of rma ke Fore a st Medicine Winston-Salem NC 27101 USA dicine, le , m, , Me thods: Patients who ha bee diagnosed with a tie nts d be n gnose d utism a who were nd en we re re ferre d dia stroente nterologist for e lua va tion of chronic GI referred to a pe tric ga pedia rologist symptom we eligible to pa s re rticipa …Term l ile (TI) biopsy te Termina um ina tissue wa a yed by RT-PCR for the prese of me sle virus RNA s ssa nce presence m a s ea a PCR-positive sam s were sequence nd mple we nce ple re que d. Re sults: Me l a clinica da ha be collecte for >275 patie dica l ta ve en colle d tients Medica nd cted nts who fit the study inclusion crite . PCR a lysis on TI biopsy tissue ria na from a initia 82 pa nts showed tha 70 (8 %) w re positive for n l tie t 5 e the F ge a ne mplicon. Conclusions: Prelim ry re rge dia Pre ina results from this la cohort of pe tric limina sults pedia a utistic pa tients with chronic GI sym ptom confirm ea r findings of s e rlie a me sles virus RNA in the te ina ileum a support a a rm l ile n ssocia on ti m asle ea s um nd betwe m sle virus a ileocolitis / LNH. (pe en ea s nd ile rsona com unca l tion ocolitis (persona comm m with the le d a a uthor indica s a stra a va te ll ins re ccine related except one pt re te xce la d which is both WT a va nd ccine type.
Medical therapy = mostly IVIG Resulted in Remarkable Recovery
Medical therapy = IVIG, Dysbiosis Therapy and Special Diet
Medical Therapy = Remarkable Recovery
Special Cases
Immune/Gut Case male age 3
Immune/Gut Case male age 3
Absent Lactobacillus ~ Anerobic and Likely Clostridia
Metronidazole (Flagyl) Kills All Clostrida at Reasonable Doses
Immune/Gut Case male age 3
As noted earlier with immune activation comes oxidative stress: Isoprostane level was 3x greater than normal
DNA and RNA Oxidative Markers preliminary results in 110 Children w/Autism (age = 2-11 years old)
nmole/gCr 100
97±40
Autism
n=159 P > 0.001
43±27
Slides courtesy Robert Nataf MD Used with Permission
Control 50
n=32
p = NS
25±13 23±11
Autism
Control
8OHG ~ RNA
8OHdG ~ DNA
Ammonia and Lactate Problems
Immune/Gut Case male age 3
Increased excretion of a lipid peroxidation biomarker in autism.
Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Department of Neurosciences, UMDNJ-New Jersey Medical School, Newark, 07103, USA. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):379-84.
Hyperbaric oxygen therapy protects against mitochondrial dysfunction and delays onset of motor neuron disease in Wobbler mice.
Neuroscience. 2003;120(1):113-20.
Dave KR, et al. Department of Neurology, D4-5, University of Miami School of Medicine, The Wobbler mouse is a model of human motor neuron disease. Recently we reported the impairment of mitochondrial complex IV in Wobbler mouse CNS, including motor cortex and spinal cord. The present study was designed to test the effect of hyperbaric oxygen therapy (HBOT) on (1) mitochondrial functions in young Wobbler mice, and (2) the onset and progression of the disease with aging. HBOT was carried out at 2 atmospheres absolute (2 ATA) oxygen for 1 h/day for 30 days. Control groups consisted of both untreated Wobbler mice and nondiseased Wobbler mice. The rate of respiration for complex IV in mitochondria isolated from motor cortex was improved by 40% (P<0.05) after HBOT. The onset and progression of the disease in the Wobbler mice was studied using litters of pups from proven heterozygous breeding pairs, which were treated from birth with 2 ATA HBOT for 1 h/day 6 days a week for the animals' lifetime. Our data suggest that HBOT significantly ameliorates mitochondrial dysfunction in the motor cortex and spinal cord and greatly delays the onset of the disease in an animal model of motor neuron disease
Antioxidant ORAC/ 1 gram of whole food Freeze dried ACAI is > 420
NH3 - Lactate Interventions
• If confirmed to be this elevated must eval with muscle biopsy for Mitochondrial Disorder • Reduce protein intake if it is significant. • Antioxidants & Carnitine & Co Q10 (UBQH) • Alpha-ketoglutarate is one of the most important nitrogen transporter in metabolic pathways. The amino groups of amino acids are attached to it by transamination and carried to the liver where the urea cycle takes place. 3 ATPs per Urea • Alpha-ketoglutarate is transaminated, along with glutamine, to form the excitatory neurotransmitter glutamate. Glutamate can then be decarboxylated (requiring vitamin B6) into the inhibitory neurotransmitter GABA.
Immune/Gut Case male age 3
• Treatment options (in addition to GFCF) • Tappering dose of prednisolone (steroids) over 5 weeks • Probiotics = good bacteria • Antifungal = Fluconazole, and others in class or Nystatin or Amphotericin • Vancomycin = antibiotic (gut specific not absorbed orally) or Metronidazole or Nitazoxanide (Alinia™) • ACAI 1 scoop twice daily as antioxidant. • Remarkable turnaround within the first 2 weeks
Allergic Component to Inflammation in Gut
Gut Immune Issues with Significant Allergic Component: Age 21mo
What can reset the immune system? Helminthic therapy is the treatment of autoimmune diseases and immunological disorders by means of deliberate infection with a helminth or with the ova of a helminth. May represent our best option
Helminthic Therapy TSO
www.ovamed.org
http://www.ovamed.org/english/home/home.html
Treatment is dosed every 3 weeks
Gut Immune Issues with Significant Allergic Component: Age 21mo
Gut Immune Issues with Significant Allergic Component: Age 21mo
Gut Immune Issues with Significant Allergic Component: Age 21mo
• Treatment here requires more consideration for food allergy. • Gastrocrom blocks histamine release from allergy cells. • Enzymes break food down more quickly so it is less antigenic – maybe? • Rotation of foods (challenging in ASD) varies the allergens. • Antifungals and Antibiotics remove pathogens. • Probiotics rebuild immune response. • Anti-inflammatories may be required.
The Inflammation – Oxidative Stress Cycle: A vicious circle that must be broken for recovery to take place
Autonomic Nervous System
Acetyl Choline Nicotine effect
Adrenaline effect
Autonomic Nervous System Imbalances: the Gut Brain Connection?
Ch ol in er gi c
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The Very Important Vagus Nerve
• The vagus nerve supplies motor parasympathetic fibers to all the organs except the adrenal glands, from the neck down to the second segment of the transverse colon. Throat, pharyngeal constrictors • Muscles of the larynx (speech). • This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth,and keeping the larynx open for breathing.
Reduced cardiac parasympathetic activity in children with autism.
Brain Dev. 2005 Oct;27(7):509-16 Ming X, et al
Department of Neuroscience, New Jersey Medical School, UMDNJ, Newark, 90 Bergen Street, DOC 8100, NJ 07103, USA. mingxu@umdnj.edu
Many of the clinical symptoms of autism suggest autonomic dysfunction. results suggest that there is low baseline cardiac parasympathetic activity with evidence of elevated sympathetic tone in children with autism whether or not they have symptoms or signs of autonomic abnormalities.
Subclinical effects of prenatal methylmercury exposure on cardiac autonomic function in Japanese children.
Int Arch Occup Environ Health. 2006 May;79(5):379-86. Epub 2005 Dec 20. Murata K, Sakamoto M, Nakai K, Dakeishi M, Iwata T, Liu XJ, Satoh H
Department of Environmental Health Sciences, Akita University School of Medicine, 010-8543, Akita, Japan, winestem@med.akita-u.ac.jp.
Conclusions: Despite the potential limitations involved in the retrospective study, these findings suggest that prenatal methylmercury exposure (median of estimated maternal hair mercury at parturition, 2.24 mug/g) may be associated with reduced parasympathetic activity and/or sympathovagal shift.
Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action.
Eur J Neuroscience. 2007 Jul;26(1):79-89. Epub 2007 Jun 20.
Park HJ, et al Department of Neurology, Ajou University School of Medicine, Suwon, Korea. Epidemiological studies have reported that smoking is associated with a lower incidence of Parkinson's disease (PD), leading to theories that smoking in general and nicotine in particular might be neuroprotective. Recent studies suggested cholinergic anti-inflammatory pathway-regulating microglial activation through alpha7 nicotinic receptors. In the present study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether nicotine has a protective effect on the dopaminergic system through an antiinflammatory mechanism. Nicotine pretreatment considerably decreased microglial activation with significant reduction of tumour necrosis factor (TNF)alpha mRNA expression and TNF-alpha release induced by LPS stimulation. In co-cultures of microglia and mesencephalic neurons, nicotine pretreatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells, approximately twice more than the LPS-only treatment. alphaBungarotoxin, an alpha7 nicotinic acetylcholine receptor subunit-selective blocker, considerably blocked the inhibitory effects of nicotine on microglial activation and TH-ip neuronal loss. Chronic nicotine pretreatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the substantia nigra was dramatically decreased, which was clearly accompanied by a reduction in the formation of TNF-alpha. The present study demonstrated that nicotine has a neuroprotective effect on dopaminergic neurons via an anti-inflammatory mechanism mediated by the modulation of microglial activation. Along with various neuroprotective effects of nicotine, the anti-inflammatory mechanism of nicotine could have a major therapeutic implication in the preventive treatment of PD.
Microglia Alpha 7 receptors Down-regulate inflammation in response to nicotine
Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gp120.
Brain Res Bull. 2004 Aug 30;64(2):165-70.
Giunta B, et al Neuroimmunology Laboratory, College of Medicine, University of South Florida, 3515 E. Fletcher Avenue, Tampa, FL 33613, USA. Chronic brain inflammation is the common final pathway in the majority of neurodegenerative diseases and central to this phenomenon is the immunological activation of brain mononuclear phagocyte cells, called microglia. This inflammatory mechanism is a central component of HIVassociated dementia (HAD). Recent data from our laboratory indicates that cultured microglial cells also express this same receptor and that microglial antiinflammatory properties are mediated through it and the p44/42 mitogen-activated protein kinase (MAPK) system. Here we report for the first time the creation of an in vitro model of HAD composed of cultured microglial cells synergistically activated by the addition of IFN-gamma and the HIV-1 coat glycoprotein, gp120. Furthermore, this activation, as measured by TNF-alpha and nitric oxide (NO) release, is synergistically attenuated through the alpha7 nAChR and p44/42 MAPK system by pretreatment with nicotine, and the cholinesterase inhibitor, galantamine. Our findings suggest a novel therapeutic combination to treat or prevent the onset of HAD through this modulation of the microglia inflammatory mechanism.
Michael A. Matthay, Cardiovascular Research Institute, UCSF
Percentage of patients with clinically improved ulcerative colitis at week 4
Sandborn, W. J. et. al. Ann Intern Med 1997;126:364-371
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Therapeutic Effect of Ritalin SR 20
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Adverse Reactions to 7 mg/24hr Nicotine patch in young adults with ADHD
NS ???
Case Response: 6 yo male w/ASD
• • • • Positive antibodies to brain endothelium Elevated Neopterin Intestinal Dysbiosis Stereotypia, verbal stimming, cognitive deficits, socially withdrawn, auditory processing delays and both expressive and receptive language deficits. • Hypotonia and sensory processing issues • Huge bowel movements • NONRESPONDER
Email from Mom after first dose
Dear Dr. Bradstreet, The Nicoderm patch (1/4 of 7 mg patch) really made a difference for our son. We just got reports back from his teachers that have us jumping up and down. They report improved eye contact, improved attention and focus, class participation, reduced anxiety, significant decrease in hyperactivity and more. His school has no idea what we have done -- or what to look for. Hence, the report is unbiased and quite reliable. We have seen the same at home:0) This is REALLY exciting. But, I have been online reading quite a bit about the downside of the patch. Of course I am concerned about Nicotine addiction, long term use, carcinogenic effects, etc.... So the next question is what do we do now? Should I continue w/ the patch for now? How long can we safely do this? I have never been more excited in my life. This is without a doubt the most significant change we have seen in all our efforts thus far. Thanks for your time. Warmest Regards
Data from ABC scoring 9 yo female after 2 months
• • • • • • • Teacher Pre total ABC score = 42 Teacher Post total ABC score = 9 Change = 33 Mother Pre total ABC score = 57 Mother Post total ABC score = 18 Change = 39 All domains dramatically reduced
Teacher Comments
Keep dose low to prevent stimulation of sympathetic system
• At synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds and activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons principally release noradrenaline (norepinephrine). Prolonged activation can elicit the release of adrenaline from the adrenal medulla.
TDN
• • • • • Step 1 = 21 mg/per 24 hrs Step 2 = 14 mg/24 hrs Step 3 = 7 mg/24 hrs Usual dose we are using is ¼ to ½ of 7mg patch which is under 0.15 mg per hour Manufacturer warns NOT to cut the patch, but in practice thus far it has worked extremely well. Skin reactions #1 issue: less with generic Nausea and dizziness next Cigarettes deliver 2-3 mg per cigarette or 40 to 120 mg per 24 hours for typical smokers
• • •
Acetylcholine is made from Choline and Acetyl-CoA
Su
n leme pp
ta
holin lC
e
Androgen (Male Hormone Issues) Not that common in our practice. Case of Immune, Gut and Androgen Problems all Combined
Immune, Gut and Androgen Dysregulation: Age 3
Immune and Androgen Dysregulation: Age 3
Immune and Androgen Dysregulation: Age 3
Immune and Androgen Dysregulation: Age 3
“The observed increase in urinary native neopterin in autism agrees with our previous observations and indicates activation of cellular immunity in these children thus supporting the possible involvement of autoimmunity in the pathogenesis of autism.”
Messahel et al, Neuroscience Letters 241 (1998) 17–20
Intervention in this case
• If Bone Age reveals no bone growth acceleration the main concern is immune activation. • Spironolactone is a unique choice in this situation. • Combined with Gastrocrom, enzymes and dysbiosis therapy (Vancocin and probiotics) significant improvement occurred in all areas of ASD symptoms. • Lupron is an additional option for the elevated male hormones but it is not anti-inflammatory. • HBOT for vasculitis issues 1.5 to 1.75 ATA
Lupron = Leuprolide Acetate Depo
Monthly Dosing will reduce the Androgen burden if Spironolactone fails, may consider starting with Lupron and changing to Spritonolactone after levels are under control for 3 months. Cost ~ $800/month for 7.5 and $1500 for 15 mg
7 yo boy with persistent severe OCD and ASD issues
Heavy Metal and the use of Biomarkers Remember the Vagus Nerve is Poisoned by Hg as easily as the Brain is
Heavy Metal Detoxification Stop Exposure
Requires Expert Medical Supervision, Informed Consent, a Logical Toxicological Exposure History, Appropriate Lab Data, Good Renal Function, Compatible Physical Findings, and Proper Micronutrient Support
Common Chelators in Use: All are off-label uses unless specific toxic criteria met
• DMSA: (Succimer) FDA approved for children with lead intoxication. Only 20% absorbed orally. No IV form. Suppositories well tolerated • DMPS: (Dimaval) Not licensed in the US, but available legally via compounding pharmacies. More reactive than DMSA. IV form available. 50% absorbed orally. Suppositories well tolerated and effective. Considered better Hg chelator. • CaNa2 EDTA: (Calcium Disodium Edetate) Licensed for Lead. Poorly absorbed orally (2%). IV or Suppository. • D-Penicillamine: 5-15 mg/kg per day – issues with safety. Check CBC and LFTs frequently – rashes – allergy. INTERESTING: also used in autoimmune disease.
Pre and Post 9 months of oral D-Penicillamine
THE ATYPICAL KETO-ISOCOCPROPHYRIN = PRECO IN NATAF STUDY
Porphyrinuria in Childhood Autistic Disorder: Implications for Environmental Toxicity
Robert Nataf a, Corinne Skorupkab, Lorene Ametb, Alain Lama, Anthea Springbettc, Richard Lathed
Laboratoire Philippe Auguste, Paris, France Toxicol Appl Pharmacol. 2006 Jun 15; [Epub ahead of print]
The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder, N=106 (p<0.001) but not significantly in Asperger’s N=11. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) N= 11, with a view to heavy metal removal. There was a significant (p=0.002) drop in urinary porphyrin excretion following DMSA. These data implicate environmental heavy metal toxicity in childhood autistic disorder.
Markedly Elevated Porphyrins Pre
Response to DMPS IV
Response to CaEDTA
After a 6 Month Course Improvement
Summary
• Follow the history, physical & make a medical diagnosis: eg encephalitis, heavy metal intoxication, inflammatory bowel disease, vagal or cholinergic imbalance etc • Obtain objective biomarkers whenever possible • Check to make sure your treatment is effective at correcting underlying pathophysiology • Continue to monitor at regular intervals
Understanding the Core of the Gut-Brain Connection and How to Fix It in ASD
James Jeffrey Bradstreet MD, MD(H) FAAFP Director, ICDRC Adjunct Professor, Pediatrics Southwest College of Naturopathic Medicine 321-259-7111 www.icdrc.org
Biomarkers
• We must define individual needs, issues and pathologies. • Assists the selection of proper treatment instead of trial and error and shotgun approaches. • Monitors efficacy of interventions
– When are we done treating – Did we give enough or too much treatment – Evaluation of possible side-effects
Reasoned Grounds for Intervention?
• Objective Biomarker indicating serious condition – diabetic model with glucose and insulin. • Apply this to oxidative stress, autoimmunity etc. • Serious, dangerous and life-changing medical conditions justify treatment based on reasoned approach even if proof of cure is not available. • Risk benefit estimates of any intervention become more critical where objective safety and efficacy are lacking. • Cost analysis of intervention should include time stress and money.
OXIDATIVE STESS = MtD
• Urine
– 8-OHG – Isoprostane
• Blood;
– Transferrin, Ceruloplasmin, – Ammonia and Lactate – Reduced Glutathione or GSSG - if available.
IMMUNOLOGICAL
• Urinary: Neopterin and Biopterin • Blood:
– – – – – – Anti-endothelial Antibodies at WUSTL, ASO and Anti-DNase B, IgG subclasses, IgM, IgA and IgE, CRP, Cytokines, TNF alpha, Complete Blood Count, Immune cell counts (CD and NK cell specifics)
• Special: intestinal permeability to lactulose and mannitol. • Fecal
– – – – – IgA Gluten, Casein, Egg, Soy etc. Pathogens: Yeast, Bacteria (both Probiotic and Pathogens) Calprotectin Eosinophil Protein X Blood and Leukocytes
• Antibody and PCR testing for HHV6, EBV, CMV, Chlamydia and Mycoplasma
Clostridia, Aerobes and Yeast
• Urine: Organic Acid test for markers of anerobic bacterial metabolism: Proprionic acid derivatives (HPHPA and others) and yeast metabolites. Arabinose by itself is not reliable. • Feces
– Culture is difficult and not reliable – PCR also challenging but will over time gain enough reliability to be gold standard – currently a research tool in my opinion.
METHYLATION AND TRANSSULFATION
• Urine
– Methylmalonic acid – B12 indicator
• Plasma
– Fasting Cysteine – Methionine – Taurine – Sulfate
• B12 and Folate levels
Cerebral Spinal Fluid (CSF)
• Special Investigations and Research • If Blood is positive for pathogens by PCR (DNA or RNA) then comparative CSF PCR data is important if treatment is going to be prescribed. Examples: HHV6, Mycoplasma and Chlamydia • Measles Virus testing will eventually become clinically relevant again. No commercially reliable testing available at this time. • Immune Markers: TNF alpha, cytokines, neopterin, autoantibodies. • CSF Methylfolate in some locked-in cases
HEAVY METALS
• Blood:
– Packed Erythrocyte Minerals and Toxic Metals – Lymphocyte Metallthionein pre/post induction
• Urinary:
– Fractionated Porphyrins – If porphyrins elevated or history strongly suggestive get post-chelation challenge = 6 or 24 hour urine toxic metal assay
WHY DID RECOVERY EFFORTS GET STUCK?
Chronic Unresolved Inflammation of the Brain & Gut with Brain Vasculitis and Pathogen Persistence (MV and others) combined with Permanent Injury (Purkinje Cell Loss), Mitochondria Dysfunction, and Oxidative Stress
Ann Neurol. 2005 Jan;57(1):67-81
Mar
k
A lial ed G
io ivat ct
n
Microvasculitis
Purkinje
Cell Los
s
Ann Neurol. 2005 Jan;57(1):67-81
Neuroinflammation is not an ICD-9 Diagnosis, but Encephalitis is. What they are afraid to say
Although the term "encephalitis" literally means "inflammation of the brain," it usually refers to brain inflammation resulting from a viral infection. The severe and potentially life-threatening form of this disease is rare. Experts suspect that the actual incidence of encephalitis is probably much higher — but because most people have such mild signs or symptoms, many cases go unrecognized. Encephalitis occurs in two forms — a primary form and a secondary form. Primary encephalitis involves direct viral infection of the brain and spinal cord. In secondary encephalitis, a viral infection first occurs elsewhere in the body and then travels to the brain.
http://www.mayoclinic.com/health/encephalitis/DS00226
Chez et al. Pediatric Neurology: 2007;36:361-365
(Journal of Pediatrics. 1999;134:607-13)
CASE: Staining of Endothelium: Perinuclear
CONTROL: No Antibody Staining
Evaluating Cases Studies
Regressive Autism Variant
• Colton Snyder • Medical Records are in the Public Domain secondary to being a test case in the Omnibus Proceedings regarding Vaccine Related injuries and autism • Full discussion is available from my NAA talk in November of 2007
Colton Snyder’s Case Review
• Prenatal Maternal use of Prozac (ex 2: 0002), also positive ANA in 1996 (ex 2: 0056) • Pregnancy: Mild Hypertension final weeks (ex 2: 0009) • Born Jan 9, 1997 (ex 4: 0001) Term without apparent distress. • APGARS 9/9 with wt of 7Lb 3 oz (ex 3: 0003) • Several episodes of febrile illnesses in first 15 months of life with multiple courses of antibiotics. • MMR-II administered on 4/23/1998 • Pharyngitis and Regressive Symptoms begin 5/6/1998 • ER visit high fever 5/24/98 - Antibiotics fail to help • Hospitalized 5/26/98 • See my report Jan 29, 2001 (P Ex 1) • Strongly Favorable Response to IVIG • Intestinal Bx (+) MV RNA, CSF (+) MV RNA, Blood negative. • Detection of Measles Virus Genomic RNA in Cerebrospinal Fluid of Children with Regressive Autism: a Report of Three Cases. Bradstreet et al, Journal of American Physicians and Surgeons. Volume 9 Number 2 Summer 2004
My Clinical Concept of Colton’s Medical Problems Mercury Measles Vaccine
Immune Dysregulation – Autoimmune Brain and Gut Inflammation Oxidative Stress Glutathione Depletion MV Persistence
Bacteria - Dysbiosis
Laboratory
One Year Check-Up
Lost Weight After MMR
Diagnostic Evaluation
Language Deficit
Diagnostic Elements of ASD
CSF Measles RNA
Ex 21
Terminal Ileum RNA
PERSISTENT ILEAL MEASLES VIRUS in a La Cohort of Regressive rge Autistic Children WITH ILEOCOLITIS AND LYMPHONODULAR HYPERPLASIA: ReVisitation of a Ea n rlier Study June 1 -3 , 2 0 (IMFAR), Montre st rd 0 6 al,
Wa r, S.J., He r K., Sega J., & Krigsm n A., De rtme of lke pner a pa nt Hepne Se l, ga Krigsma Depa Physiology & Pharm cology, Wa Forest University School of rma ke Fore a st Medicine Winston-Salem NC 27101 USA dicine, le , m, , Me thods: Patients who ha bee diagnosed with a tie nts d be n gnose d utism a who were nd en we re re ferre d dia stroente nterologist for e lua va tion of chronic GI referred to a pe tric ga pedia rologist symptom we eligible to pa s re rticipa …Term l ile (TI) biopsy te Termina um ina tissue wa a yed by RT-PCR for the prese of me sle virus RNA s ssa nce presence m a s ea a PCR-positive sam s were sequence nd mple we nce ple re que d. Re sults: Me l a clinica da ha be collecte for >275 patie dica l ta ve en colle d tients Medica nd cted nts who fit the study inclusion crite . PCR a lysis on TI biopsy tissue ria na from a initia 82 pa nts showed tha 70 (8 %) w re positive for n l tie t 5 e the F ge a ne mplicon. Conclusions: Prelim ry re rge dia Pre ina results from this la cohort of pe tric limina sults pedia a utistic pa tients with chronic GI sym ptom confirm ea r findings of s e rlie a me sles virus RNA in the te ina ileum a support a a rm l ile n ssocia on ti m asle ea s um nd betwe m sle virus a ileocolitis / LNH. (pe en ea s nd ile rsona com unca l tion ocolitis (persona comm m with the le d a a uthor indica s a stra a va te ll ins re ccine related except one pt re te xce la d which is both WT a va nd ccine type.
Medical therapy = mostly IVIG Resulted in Remarkable Recovery
Medical therapy = IVIG, Dysbiosis Therapy and Special Diet
Medical Therapy = Remarkable Recovery
Special Cases
Immune/Gut Case male age 3
Immune/Gut Case male age 3
Absent Lactobacillus ~ Anerobic and Likely Clostridia
Metronidazole (Flagyl) Kills All Clostrida at Reasonable Doses
Immune/Gut Case male age 3
As noted earlier with immune activation comes oxidative stress: Isoprostane level was 3x greater than normal
DNA and RNA Oxidative Markers preliminary results in 110 Children w/Autism (age = 2-11 years old)
nmole/gCr 100
97±40
Autism
n=159 P > 0.001
43±27
Slides courtesy Robert Nataf MD Used with Permission
Control 50
n=32
p = NS
25±13 23±11
Autism
Control
8OHG ~ RNA
8OHdG ~ DNA
Ammonia and Lactate Problems
Immune/Gut Case male age 3
Increased excretion of a lipid peroxidation biomarker in autism.
Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Department of Neurosciences, UMDNJ-New Jersey Medical School, Newark, 07103, USA. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):379-84.
Hyperbaric oxygen therapy protects against mitochondrial dysfunction and delays onset of motor neuron disease in Wobbler mice.
Neuroscience. 2003;120(1):113-20.
Dave KR, et al. Department of Neurology, D4-5, University of Miami School of Medicine, The Wobbler mouse is a model of human motor neuron disease. Recently we reported the impairment of mitochondrial complex IV in Wobbler mouse CNS, including motor cortex and spinal cord. The present study was designed to test the effect of hyperbaric oxygen therapy (HBOT) on (1) mitochondrial functions in young Wobbler mice, and (2) the onset and progression of the disease with aging. HBOT was carried out at 2 atmospheres absolute (2 ATA) oxygen for 1 h/day for 30 days. Control groups consisted of both untreated Wobbler mice and nondiseased Wobbler mice. The rate of respiration for complex IV in mitochondria isolated from motor cortex was improved by 40% (P<0.05) after HBOT. The onset and progression of the disease in the Wobbler mice was studied using litters of pups from proven heterozygous breeding pairs, which were treated from birth with 2 ATA HBOT for 1 h/day 6 days a week for the animals' lifetime. Our data suggest that HBOT significantly ameliorates mitochondrial dysfunction in the motor cortex and spinal cord and greatly delays the onset of the disease in an animal model of motor neuron disease
Antioxidant ORAC/ 1 gram of whole food Freeze dried ACAI is > 420
NH3 - Lactate Interventions
• If confirmed to be this elevated must eval with muscle biopsy for Mitochondrial Disorder • Reduce protein intake if it is significant. • Antioxidants & Carnitine & Co Q10 (UBQH) • Alpha-ketoglutarate is one of the most important nitrogen transporter in metabolic pathways. The amino groups of amino acids are attached to it by transamination and carried to the liver where the urea cycle takes place. 3 ATPs per Urea • Alpha-ketoglutarate is transaminated, along with glutamine, to form the excitatory neurotransmitter glutamate. Glutamate can then be decarboxylated (requiring vitamin B6) into the inhibitory neurotransmitter GABA.
Immune/Gut Case male age 3
• Treatment options (in addition to GFCF) • Tappering dose of prednisolone (steroids) over 5 weeks • Probiotics = good bacteria • Antifungal = Fluconazole, and others in class or Nystatin or Amphotericin • Vancomycin = antibiotic (gut specific not absorbed orally) or Metronidazole or Nitazoxanide (Alinia™) • ACAI 1 scoop twice daily as antioxidant. • Remarkable turnaround within the first 2 weeks
Allergic Component to Inflammation in Gut
Gut Immune Issues with Significant Allergic Component: Age 21mo
What can reset the immune system? Helminthic therapy is the treatment of autoimmune diseases and immunological disorders by means of deliberate infection with a helminth or with the ova of a helminth. May represent our best option
Helminthic Therapy TSO
www.ovamed.org
http://www.ovamed.org/english/home/home.html
Treatment is dosed every 3 weeks
Gut Immune Issues with Significant Allergic Component: Age 21mo
Gut Immune Issues with Significant Allergic Component: Age 21mo
Gut Immune Issues with Significant Allergic Component: Age 21mo
• Treatment here requires more consideration for food allergy. • Gastrocrom blocks histamine release from allergy cells. • Enzymes break food down more quickly so it is less antigenic – maybe? • Rotation of foods (challenging in ASD) varies the allergens. • Antifungals and Antibiotics remove pathogens. • Probiotics rebuild immune response. • Anti-inflammatories may be required.
The Inflammation – Oxidative Stress Cycle: A vicious circle that must be broken for recovery to take place
Autonomic Nervous System
Acetyl Choline Nicotine effect
Adrenaline effect
Autonomic Nervous System Imbalances: the Gut Brain Connection?
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The Very Important Vagus Nerve
• The vagus nerve supplies motor parasympathetic fibers to all the organs except the adrenal glands, from the neck down to the second segment of the transverse colon. Throat, pharyngeal constrictors • Muscles of the larynx (speech). • This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth,and keeping the larynx open for breathing.
Reduced cardiac parasympathetic activity in children with autism.
Brain Dev. 2005 Oct;27(7):509-16 Ming X, et al
Department of Neuroscience, New Jersey Medical School, UMDNJ, Newark, 90 Bergen Street, DOC 8100, NJ 07103, USA. mingxu@umdnj.edu
Many of the clinical symptoms of autism suggest autonomic dysfunction. results suggest that there is low baseline cardiac parasympathetic activity with evidence of elevated sympathetic tone in children with autism whether or not they have symptoms or signs of autonomic abnormalities.
Subclinical effects of prenatal methylmercury exposure on cardiac autonomic function in Japanese children.
Int Arch Occup Environ Health. 2006 May;79(5):379-86. Epub 2005 Dec 20. Murata K, Sakamoto M, Nakai K, Dakeishi M, Iwata T, Liu XJ, Satoh H
Department of Environmental Health Sciences, Akita University School of Medicine, 010-8543, Akita, Japan, winestem@med.akita-u.ac.jp.
Conclusions: Despite the potential limitations involved in the retrospective study, these findings suggest that prenatal methylmercury exposure (median of estimated maternal hair mercury at parturition, 2.24 mug/g) may be associated with reduced parasympathetic activity and/or sympathovagal shift.
Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action.
Eur J Neuroscience. 2007 Jul;26(1):79-89. Epub 2007 Jun 20.
Park HJ, et al Department of Neurology, Ajou University School of Medicine, Suwon, Korea. Epidemiological studies have reported that smoking is associated with a lower incidence of Parkinson's disease (PD), leading to theories that smoking in general and nicotine in particular might be neuroprotective. Recent studies suggested cholinergic anti-inflammatory pathway-regulating microglial activation through alpha7 nicotinic receptors. In the present study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether nicotine has a protective effect on the dopaminergic system through an antiinflammatory mechanism. Nicotine pretreatment considerably decreased microglial activation with significant reduction of tumour necrosis factor (TNF)alpha mRNA expression and TNF-alpha release induced by LPS stimulation. In co-cultures of microglia and mesencephalic neurons, nicotine pretreatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells, approximately twice more than the LPS-only treatment. alphaBungarotoxin, an alpha7 nicotinic acetylcholine receptor subunit-selective blocker, considerably blocked the inhibitory effects of nicotine on microglial activation and TH-ip neuronal loss. Chronic nicotine pretreatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the substantia nigra was dramatically decreased, which was clearly accompanied by a reduction in the formation of TNF-alpha. The present study demonstrated that nicotine has a neuroprotective effect on dopaminergic neurons via an anti-inflammatory mechanism mediated by the modulation of microglial activation. Along with various neuroprotective effects of nicotine, the anti-inflammatory mechanism of nicotine could have a major therapeutic implication in the preventive treatment of PD.
Microglia Alpha 7 receptors Down-regulate inflammation in response to nicotine
Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gp120.
Brain Res Bull. 2004 Aug 30;64(2):165-70.
Giunta B, et al Neuroimmunology Laboratory, College of Medicine, University of South Florida, 3515 E. Fletcher Avenue, Tampa, FL 33613, USA. Chronic brain inflammation is the common final pathway in the majority of neurodegenerative diseases and central to this phenomenon is the immunological activation of brain mononuclear phagocyte cells, called microglia. This inflammatory mechanism is a central component of HIVassociated dementia (HAD). Recent data from our laboratory indicates that cultured microglial cells also express this same receptor and that microglial antiinflammatory properties are mediated through it and the p44/42 mitogen-activated protein kinase (MAPK) system. Here we report for the first time the creation of an in vitro model of HAD composed of cultured microglial cells synergistically activated by the addition of IFN-gamma and the HIV-1 coat glycoprotein, gp120. Furthermore, this activation, as measured by TNF-alpha and nitric oxide (NO) release, is synergistically attenuated through the alpha7 nAChR and p44/42 MAPK system by pretreatment with nicotine, and the cholinesterase inhibitor, galantamine. Our findings suggest a novel therapeutic combination to treat or prevent the onset of HAD through this modulation of the microglia inflammatory mechanism.
Michael A. Matthay, Cardiovascular Research Institute, UCSF
Percentage of patients with clinically improved ulcerative colitis at week 4
Sandborn, W. J. et. al. Ann Intern Med 1997;126:364-371
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Adverse Reactions to 7 mg/24hr Nicotine patch in young adults with ADHD
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Case Response: 6 yo male w/ASD
• • • • Positive antibodies to brain endothelium Elevated Neopterin Intestinal Dysbiosis Stereotypia, verbal stimming, cognitive deficits, socially withdrawn, auditory processing delays and both expressive and receptive language deficits. • Hypotonia and sensory processing issues • Huge bowel movements • NONRESPONDER
Email from Mom after first dose
Dear Dr. Bradstreet, The Nicoderm patch (1/4 of 7 mg patch) really made a difference for our son. We just got reports back from his teachers that have us jumping up and down. They report improved eye contact, improved attention and focus, class participation, reduced anxiety, significant decrease in hyperactivity and more. His school has no idea what we have done -- or what to look for. Hence, the report is unbiased and quite reliable. We have seen the same at home:0) This is REALLY exciting. But, I have been online reading quite a bit about the downside of the patch. Of course I am concerned about Nicotine addiction, long term use, carcinogenic effects, etc.... So the next question is what do we do now? Should I continue w/ the patch for now? How long can we safely do this? I have never been more excited in my life. This is without a doubt the most significant change we have seen in all our efforts thus far. Thanks for your time. Warmest Regards
Data from ABC scoring 9 yo female after 2 months
• • • • • • • Teacher Pre total ABC score = 42 Teacher Post total ABC score = 9 Change = 33 Mother Pre total ABC score = 57 Mother Post total ABC score = 18 Change = 39 All domains dramatically reduced
Teacher Comments
Keep dose low to prevent stimulation of sympathetic system
• At synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds and activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons principally release noradrenaline (norepinephrine). Prolonged activation can elicit the release of adrenaline from the adrenal medulla.
TDN
• • • • • Step 1 = 21 mg/per 24 hrs Step 2 = 14 mg/24 hrs Step 3 = 7 mg/24 hrs Usual dose we are using is ¼ to ½ of 7mg patch which is under 0.15 mg per hour Manufacturer warns NOT to cut the patch, but in practice thus far it has worked extremely well. Skin reactions #1 issue: less with generic Nausea and dizziness next Cigarettes deliver 2-3 mg per cigarette or 40 to 120 mg per 24 hours for typical smokers
• • •
Acetylcholine is made from Choline and Acetyl-CoA
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Androgen (Male Hormone Issues) Not that common in our practice. Case of Immune, Gut and Androgen Problems all Combined
Immune, Gut and Androgen Dysregulation: Age 3
Immune and Androgen Dysregulation: Age 3
Immune and Androgen Dysregulation: Age 3
Immune and Androgen Dysregulation: Age 3
“The observed increase in urinary native neopterin in autism agrees with our previous observations and indicates activation of cellular immunity in these children thus supporting the possible involvement of autoimmunity in the pathogenesis of autism.”
Messahel et al, Neuroscience Letters 241 (1998) 17–20
Intervention in this case
• If Bone Age reveals no bone growth acceleration the main concern is immune activation. • Spironolactone is a unique choice in this situation. • Combined with Gastrocrom, enzymes and dysbiosis therapy (Vancocin and probiotics) significant improvement occurred in all areas of ASD symptoms. • Lupron is an additional option for the elevated male hormones but it is not anti-inflammatory. • HBOT for vasculitis issues 1.5 to 1.75 ATA
Lupron = Leuprolide Acetate Depo
Monthly Dosing will reduce the Androgen burden if Spironolactone fails, may consider starting with Lupron and changing to Spritonolactone after levels are under control for 3 months. Cost ~ $800/month for 7.5 and $1500 for 15 mg
7 yo boy with persistent severe OCD and ASD issues
Heavy Metal and the use of Biomarkers Remember the Vagus Nerve is Poisoned by Hg as easily as the Brain is
Heavy Metal Detoxification Stop Exposure
Requires Expert Medical Supervision, Informed Consent, a Logical Toxicological Exposure History, Appropriate Lab Data, Good Renal Function, Compatible Physical Findings, and Proper Micronutrient Support
Common Chelators in Use: All are off-label uses unless specific toxic criteria met
• DMSA: (Succimer) FDA approved for children with lead intoxication. Only 20% absorbed orally. No IV form. Suppositories well tolerated • DMPS: (Dimaval) Not licensed in the US, but available legally via compounding pharmacies. More reactive than DMSA. IV form available. 50% absorbed orally. Suppositories well tolerated and effective. Considered better Hg chelator. • CaNa2 EDTA: (Calcium Disodium Edetate) Licensed for Lead. Poorly absorbed orally (2%). IV or Suppository. • D-Penicillamine: 5-15 mg/kg per day – issues with safety. Check CBC and LFTs frequently – rashes – allergy. INTERESTING: also used in autoimmune disease.
Pre and Post 9 months of oral D-Penicillamine
THE ATYPICAL KETO-ISOCOCPROPHYRIN = PRECO IN NATAF STUDY
Porphyrinuria in Childhood Autistic Disorder: Implications for Environmental Toxicity
Robert Nataf a, Corinne Skorupkab, Lorene Ametb, Alain Lama, Anthea Springbettc, Richard Lathed
Laboratoire Philippe Auguste, Paris, France Toxicol Appl Pharmacol. 2006 Jun 15; [Epub ahead of print]
The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder, N=106 (p<0.001) but not significantly in Asperger’s N=11. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) N= 11, with a view to heavy metal removal. There was a significant (p=0.002) drop in urinary porphyrin excretion following DMSA. These data implicate environmental heavy metal toxicity in childhood autistic disorder.
Markedly Elevated Porphyrins Pre
Response to DMPS IV
Response to CaEDTA
After a 6 Month Course Improvement
Summary
• Follow the history, physical & make a medical diagnosis: eg encephalitis, heavy metal intoxication, inflammatory bowel disease, vagal or cholinergic imbalance etc • Obtain objective biomarkers whenever possible • Check to make sure your treatment is effective at correcting underlying pathophysiology • Continue to monitor at regular intervals
