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  2. 2. MINDDD AND AUTISM: MEASURABLE ABNORMALITIES & NUTRITIONAL INTERVENTIONS Dr Robyn E Cosford MBBS(Hons)FACNEM Director Northern Beaches Care Centre Conjoint Lecturer, University of Newcastle
  4. 4. CHILDREN’S ILLNESS <ul><ul><ul><ul><li>In face of the great technological and medical advances of the ‘scientific age’, the patterns of childhood illnesses are changing : </li></ul></ul></ul></ul>
  5. 5. Autism <ul><li>Autism - previously est 4/10,000, (1985) </li></ul><ul><li>more recent est 48 mill worldwide </li></ul><ul><li>study UK (2001) 1/167 </li></ul><ul><li>rate of children with autism in US schools: from 5415 (1991-92) to 78,749 in 2000-01. </li></ul><ul><li>Increase of 1354% cf 28.4% increase all disabilities, or 26.75% for disabilities excluding autism </li></ul><ul><li>compared to from 1988-89 to 1997-98, rate of increase of 173% for autism and 16% for all disabilities </li></ul>
  6. 6. Autism (cont) <ul><li>California DDS (Dept Developmental Services) -since 1990, continually climbing rates </li></ul><ul><li>1969 - April 2001 (32 years) - 14,777 new children </li></ul><ul><li>2000- 13,054 people in system </li></ul><ul><li>2000-July 2005: new 14,992 </li></ul>
  7. 7. Mental Health <ul><li>study 4500 children age 4-17, 2001 </li></ul><ul><li>14 % Australian children with mental health problem </li></ul><ul><li>depression 3% </li></ul><ul><li>attention deficit hyperactivity 11% </li></ul><ul><li>( </li></ul>
  8. 8. Mental health <ul><li>US study 76,662 children age 3- 15 yrs, 1993-1996 </li></ul><ul><li>1/5th children psychiatric disorder </li></ul><ul><li>62% affected, boys </li></ul><ul><li>average age 8.5 yrs </li></ul><ul><li>5 commonest disorders - 94% all children with disorder </li></ul><ul><li>commonest: adjustment disorder (9.6%), ADHD (5.6%), ODD (4.4%), conduct disorder (3.1%), depression (2.1%) </li></ul>
  9. 9. Neurodevelopmental Disorders <ul><li>Developmental impairment speech, language now most common neurodevelopmental condition among children under five (UK), 5-8% of population affected on current figures </li></ul><ul><li>Toddlers with speech delay more likely to have social and emotional adjustments problems, dysfunction </li></ul>
  10. 10. Otitis media (OM) <ul><li>Prior to 1970s otitis media (middle ear infection) was uncommon </li></ul><ul><li>“ In recent years there has been an apparent increase in the incidence of serous otitis media” 1972 </li></ul><ul><li>(Sumio G et al, Allergic rhinitis and serous otitis media, in Pediatrics , Barnett H (ed), 15th Ed 1972, Appleton-Century-Crofts, NY) </li></ul>
  11. 11. OM <ul><li>disease patterns are shifting </li></ul><ul><li>previously incidence of respiratory tract infections and otitis media peaked at 4 to 6 years </li></ul><ul><li>1989 study 62% of children were affected by 12 months and 83% at age 3 years </li></ul>
  12. 12. OM <ul><li>(2000, USA) peak incidence 6 to 12 months old </li></ul><ul><li>48% of children by 6 months, 79% by 12 months, 91% by 24 months </li></ul><ul><li>in general, the earlier in life the first episode of AOM, the greater the frequency of recurrence, severity and persistence of middle ear effusion. </li></ul>
  13. 13. Glue Ear (OME) <ul><li>Otitis media with effusion (OME or ‘glue ear’) persists for weeks or months after acute otitis media (AOM) </li></ul><ul><li>usual first form of OM ) </li></ul><ul><li>(2000 study) affects infants for up to 30% of their days in their first year of life still found in up to 20 % of children at age 6 years in winter. </li></ul>
  14. 14. Gastrointestinal Dysfunction <ul><li>Gastro-oesophageal reflux increasing in incidence in infants in recent years </li></ul><ul><li>now major cause of illness and failure to thrive, particularly in neurologically impaired children. </li></ul><ul><li>S ymptoms from regurgitation, food refusal, failure to thrive, haematemesis, wheezing and aspiration pneumonia, to apnoea and SIDS </li></ul><ul><li>linked with asthma, respiratory infections, OM, childhood chronic sinusitis </li></ul><ul><li>gut dysfunction usual in autism: infantile reflux, later diarrhoea &/or constipation </li></ul>
  15. 15. Reflux and OME <ul><li>2002 study analysed effusions of 54 children with OME - pepsin (stomach digestive enzyme) present in 83% at levels greater than 1000 times that in the serum , </li></ul><ul><li>supports theory that stomach acid refluxing up into the ear, triggering inflammation followed by infection </li></ul>
  16. 16. Obesity, NIDDM <ul><li>incidence of obesity increasing </li></ul><ul><li>10% of children now weighing greater than the 97 th centile; 19% boys, 22% girls obese or overweight, 2002 ) , compared to 11% of boys, 12.2% of girls in 1985 </li></ul><ul><li>non-insulin dependent diabetes, previously very rare in the young, is being increasingly recognised in children and young adults </li></ul><ul><li>obesity increases the risk of asthma particularly in boys (50%) </li></ul>
  17. 17. Other Common Illnesses <ul><ul><ul><ul><li>Asthma doubled 20 years – was up to 35% children, Australia 3rd highest prevalence rate in the world </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Allergies increasing: 54% children UK atopic symptoms at some time Atopic eczema now affects about 18% children in first 2 years of life up from 2% a few decades ago </li></ul></ul></ul></ul>
  18. 18. Allergies <ul><li>Study Royal Children’s Hospital Melbourne, 2003: now nearly 30% children with food allergies </li></ul><ul><li>70% infants with colic improved after mothers placed on strict allergy-free diet </li></ul><ul><li>80% children will ‘grow out’ of reaction to egg, milk by 5 years old </li></ul>
  19. 19. Asthma and Behavioural disorders <ul><li>3 year study ,>600 children </li></ul><ul><li>Behavioural problems greater in preschoolers with asthma </li></ul><ul><li>particularly so if no family history of asthma </li></ul><ul><li>conjecture - that this is due to parental behavioural mismanagement </li></ul><ul><li>‘ parents need to know how to manage their child calmly and authoritatively’ </li></ul><ul><li>?interaction with immune system and neurological system ?common factor </li></ul>
  20. 20. Infections and Neurodevelopmental disorders <ul><li>Aust study : 12000 children 0-14 </li></ul><ul><li>1.7% speech disorder </li></ul><ul><li>boys 3x </li></ul><ul><li>>25% boys associated asthma, allergies, ear disorders, ‘mental health’ disorders </li></ul><ul><li>>1/3 girls associated UTI </li></ul><ul><li>( Association between infections in childhood and speech difficulties in boys </li></ul>
  21. 21. Infections and Neurodevelopmental Disorders <ul><li>Recurrent OM infancy also correlated with </li></ul><ul><li>greater incidence ADHD </li></ul><ul><li>increased distractability later in life later low IQ scores, poor performance on tests of reading, spelling, maths, increased retention in grade, increased attention deficits, and increased behaviour problems at school </li></ul>
  22. 22. Infections and Neurodevelopmental Disorders <ul><li>high correlation between prevalence OM and autism </li></ul><ul><li>earlier onset & increased incidence each correlated with more severe form autism </li></ul><ul><li>2005 study: 206 autistic children  3 yrs old: chronic, recurrent AOM, nearly 10/year, average 12 courses antibiotics (usually Augmentin). </li></ul>
  23. 23. Change in Patterns of Children’s Diseases <ul><li>Over last 30 years, increasingly last decade </li></ul><ul><li>increases in allergies, obesity, infections, antibiotic use, gastrointestinal dysfunction </li></ul><ul><li>increase in Th2-based disease </li></ul><ul><li>paralleling increases in mental illness and neurological diseases including autism </li></ul><ul><li>immune-gut-brain connection </li></ul>
  24. 24. Gut-Brain Axis <ul><li>“gut-brain interactions may be central to abnormal neural development and the subsequent expression of aberrant behaviors” </li></ul><ul><li>Andrew Wakefield </li></ul><ul><li>( </li></ul>
  26. 26. Inheritance - Autism <ul><li>Autoimmune disease common in relatives - hypothyroidism, Hashimotos’ thyroiditis, rheumatic fever </li></ul><ul><li>esp grandmothers,mothers, uncles, brothers, </li></ul><ul><li>Rate of auto-immune disorders even higher in relatives of autistic children than in relatives of children with autoimmune diseases </li></ul><ul><li>rate in PDD 1.87, 1.44 for autoimmune group, 0.93 non-autistic, nonautoimmune control group </li></ul><ul><li>suggests mother-son transmission of susceptibility </li></ul><ul><li>() </li></ul><ul><li>Not directly genetic inheritance – probably epigenetic </li></ul>
  27. 27. Autism- Inheritance <ul><li>Polygenic – no one gene, but genetic susceptabilities </li></ul><ul><li>‘ Large number (at least 20) of susceptibility genes, none of which has a large effect’ </li></ul><ul><li>More sharing of markers in autistic sibling pairs </li></ul><ul><li>This Stanford Uni study - slight increased linkage for chrom 1, less for chrom 17 </li></ul><ul><li>Other studies – genetic studies indicate linkage with chrom 2q,7q (strong association), 16p, 17 </li></ul>
  28. 28. Inheritance (cont) <ul><li>methylation common mechanism in the genome that silences specific genes </li></ul><ul><li>MTHFR allelic variations - result in reduced methylation capabilities </li></ul><ul><li>in each cell only about 15% of genome active </li></ul><ul><li>. . </li></ul><ul><li>remainder silenced by methylation and other mechanisms </li></ul><ul><li>explanation for epigenetic transmissable factors eg auto-immune </li></ul>
  29. 29. Maleness <ul><li>Incidence of neurodevelopmental disorders (speech delay, behavioural difficulties, ADHD, autism) 3-4x that in females </li></ul><ul><li>theories: increased need DHA, slower development male brain, </li></ul><ul><li>effects of testosterone on male brain- neonates, preference mechanical objects to human faces </li></ul>
  30. 30. Environmental Factors <ul><li>Numerous factors implicated in modern patterns of illness including autism: </li></ul><ul><li>pregnancy:smoking, caffeine, chemical exposure, sound, stress, intrauterine growth retardation </li></ul><ul><li>infancy: handling practices, breastfeeding, antibiotic use, vaccination </li></ul><ul><li>childhood: diet, television,chemicals, play </li></ul><ul><li>social:single parent families, SES, absent fathers etc </li></ul>
  31. 31. PREGNANCY-smoking <ul><li>21% Australian women smoke during pregnancy </li></ul><ul><li>damage foetal brainstem </li></ul><ul><li>heavy smokers (high cotinine levels) 33% chance poor pregnancy outcome - premature delivery <37/40 or IUGR, BW<5th centile </li></ul>
  32. 32. Smoking <ul><li>Well documented </li></ul><ul><li>pregnancy - IUGR, premature delivery, impaired lung devel boys, ADHD risk, later childhood and adult obesity, gastroesophageal reflux </li></ul><ul><li>passive - asthma, otitis media, SIDS, lung disorders </li></ul>
  33. 33. Pregnancy -alcohol <ul><li>over 55% adult population > 1/week; females average 33ml/day (ABS 1995) </li></ul><ul><li>foetal alcohol syndrome (>10 drinks/week)- physical abnormalities,  IQ, behavioural difficulties (ADHD, conduct disorder), psychiatric illness, gut neurotoxicity-> abnormal gut peristalsis </li></ul><ul><li>4 glasses/week dull foetal response to sound stimulus indicating brainstem damage </li></ul><ul><li>as little as one glass per week linked to 3-fold increased risk of clinically delinquent behaviour </li></ul>
  34. 34. Maternal Stress <ul><ul><ul><li>high psychological stress levels associated with significant impairment uterine blood flow in 25% </li></ul></ul></ul><ul><ul><ul><li>abnormal flow predictive of IUGR, pre-eclampsia </li></ul></ul></ul><ul><ul><ul><li>work-related stress - (waitressing, cooks, nursing assistants) associated with 3x risk pre-eclampsia, 2x risk gestational hypertension increased incidence of low birth weight </li></ul></ul></ul>
  35. 35. Maternal Stress <ul><li>Sustained maternal stress prenatally affects developing immune system,  susceptibility to asthma, atopy in predisposed individs </li></ul>
  36. 36. Low Birth Weight <ul><ul><ul><ul><li>prematurity, LBW and VLBW increasing incidence </li></ul></ul></ul></ul><ul><li>severe cognitive impairment (25%) </li></ul><ul><li>moderate to mild psychological problems (25%) </li></ul><ul><li>increased incidence ADHD </li></ul><ul><li>schooling difficulties requiring special education/ assistance (53-61%) </li></ul>
  37. 37. Maternal Chemicals <ul><li>Placental-foetal transfer chemicals, toxins </li></ul><ul><li>287 chemicals found in cord blood of neonates </li></ul><ul><li>180 of those known carcinogens, 217 known neurotoxins, 208 known teratogens </li></ul><ul><li>Pesticides, consumer product ingredients, industrial waste products, mercury, fire retardants, Teflon </li></ul>
  38. 38. Infancy- Child-handling Practices <ul><ul><ul><ul><li>‘ normal’ to cry for 3 hours per day at age 6 weeks in Western society </li></ul></ul></ul></ul><ul><ul><ul><ul><li>vs </li></ul></ul></ul></ul><ul><ul><ul><ul><li>tribal societies in Africa, Pacific Islands carry babies all day, and a village with 100 babies may not have a single baby who cries; </li></ul></ul></ul></ul><ul><ul><ul><ul><li>“ This system is not convenient to Western mothers” </li></ul></ul></ul></ul><ul><ul><ul><ul><li>‘ Controlled crying’ favoured form of management of infantile sleep difficulties Australian society </li></ul></ul></ul></ul><ul><ul><ul><ul><li>told to “resist comforting a crying baby so it can teach itself to go to sleep” . </li></ul></ul></ul></ul>
  39. 39. Infancy-Child-handling Practices <ul><li>“ research suggests that adverse experiences may make a difference to brain development” babies given greater physical stimulation by way of bathing, exercising, being taken out of capsule or cuddled show significant improvement in motor skills at about 4th month age – </li></ul><ul><li>4 th month recognised as critical time child development? such close physical contact required for appropriate neurological development </li></ul>
  40. 40. Maternal Nurture vs Nature <ul><li>Increased maternal nurture reduces stress in adult life - at least in rats: </li></ul><ul><li>infant rats receiving the most maternal licking and grooming, less stress-responsive in adulthood </li></ul><ul><li>Proposed mechanism: maternal care reduces methylation (locally), increased expression of receptor, more receptors in hippocampus, reduced reaction to stress </li></ul><ul><li>ie: effects localised to particular part of genome, single cell type, discrete developmental window </li></ul>
  41. 41. Retained primitive reflexes <ul><li>Prominent stress responses- activation flight/fright /fight responses (adrenergic pathways) </li></ul><ul><li>promotion primitive fear reflexes normally present in utero, up to 18 months old, gradually integrated </li></ul><ul><li>delay of integration of these reflexes into adult reflexes </li></ul><ul><li>common in ADHD, autism spectrum </li></ul>
  42. 42. Infancy Handling <ul><li>Stress known to alter GI permeability </li></ul><ul><li>Maternal deprivation (in rats) triggers significant increase in colonic permeability associated with bacterial translocation into the mesenteric lymph nodes, liver, spleen </li></ul><ul><li>Maternal deprivation promotes long term alterations in the colonic epithelial barrier associated with an exaggerated immune response to an external immune stimulus </li></ul><ul><li>Suggests a role for early psychological factors in the regulation of colonic mucosal barrier in later life. </li></ul>
  43. 43. Stress in Childhood and Illness <ul><li>Stress promotes Th2 immune shift </li></ul><ul><li>concomitant parental and personal conflicts  risk of asthma, allergic rhinitis and atopic dermatitis </li></ul>
  44. 44. Stress in Childhood and Illness <ul><li>postnatal stress may include </li></ul><ul><li>physical or sexual abuse </li></ul><ul><li>emotional neglect </li></ul><ul><li>harsh, inconsistent discipline </li></ul><ul><li>lack of parental bonding, handling or nurture </li></ul>
  45. 45. Breastfeeding <ul><li>86% breastfed at some time </li></ul><ul><li>prolonged nursing – 65% less than two months, decline to 50% at six months, </li></ul><ul><li>less than 10% over one year </li></ul><ul><ul><ul><ul><li>( </li></ul></ul></ul></ul>
  46. 46. Breastfeeding (cont) <ul><li>Normal cognitive development should be defined on the basis of infants exclusively breastfed until about 6 months of age </li></ul><ul><li>( burden of proof on those who propose that bottle-feeding formula equal feeding milk from breast </li></ul>
  47. 47. Breastfeeding (cont) <ul><ul><ul><ul><li>breastfeeding for > 8months is associated with </li></ul></ul></ul></ul><ul><li>increased IQ </li></ul><ul><li>increased performance on standardised tests </li></ul><ul><li>higher teacher ratings and better high school achievement (after adjusting for other variables ) </li></ul>
  48. 48. Breastfeeding-ADHD <ul><li>Not breastfed correlated with </li></ul><ul><li>lowest scores on WISC </li></ul><ul><li>lowest teacher ratings of achievement in reading, maths </li></ul><ul><li>lowest level of high school attainment </li></ul><ul><li>highest level of leaving school without qualifications </li></ul><ul><li>bottlefeeding associated with 2x risk of ADHD </li></ul>
  49. 49. Breastfeeding -Autism <ul><li>Early weaning may contribute to autism </li></ul><ul><li> autism in areas  rates breastfeeding </li></ul><ul><li>weaning times 145 autistic cf 224 normal children : 24.8% autistic children weaned by 1 week vs normal 7.5% </li></ul>
  50. 50. Breastfeeding and allergies <ul><li>Breastfeeding promotes normal Th1 development </li></ul><ul><li>Allergy :breastfeeding>1 mo reduces </li></ul><ul><li>1. Food allergy at 1 and 3 yrs </li></ul><ul><li>2. hay fever and asthma to age 17yrs </li></ul><ul><li>risk of atopy and asthma closely linked to age at which non-breast milk first introduced Exclusive breastfeeding best protection against allergies, cow’s milk allergy </li></ul><ul><li>hydrolysed formula (rather than cow’s milk formula) best alternative to prevent allergy in high-risk children who cannot be exclusively breast fed </li></ul>
  51. 51. Breastfeeding and infections <ul><li>Breastfeeding also protects GALT, against </li></ul><ul><li>diarrhoea </li></ul><ul><li>respiratory illness- increased breastfeeding by 40% would reduce respiratory deaths by 50% and diarrhoeal deaths by 66% in children under 18 mo worldwide ( </li></ul><ul><li>Invasive HiB - protection significantly increases each week breastfeeding>13 weeks, lasts up to 10 yrs </li></ul>
  52. 52. Breastfeeding and coeliac disease <ul><li>52%  coeliac disease in babies breastfed at time of gluten introduction </li></ul><ul><li>prolonged breastfeeding also reduces risk </li></ul><ul><li>mechanisms -? prevention GI illness which predisposes to coeliac </li></ul><ul><li>? Human milk IgA reduces infant gut response to coeliac </li></ul><ul><li>( </li></ul>
  53. 53. Breastfeeding and Otitis Media <ul><li>formula feeding most significant predictor of OM </li></ul><ul><li>breastfeeding > 3-4 mo  protection up to 3 yrs against otits media </li></ul>
  54. 54. Breastfeeding - summary <ul><li>Protects cognition – DHA </li></ul><ul><li>Protects GALT – promotes normal TH1 </li></ul><ul><li>Protection against gut infections, infection, allergies </li></ul><ul><li>Reduction use antibiotics </li></ul>
  55. 55. Antibiotics <ul><li>In the year to December 1998 </li></ul><ul><li>$250,204,507 was spent on antibiotics, </li></ul><ul><li>up 1.66% on the previous year </li></ul><ul><li>Amoxicillin, commonly used in children, accounting for $22,732,397 and Augmentin, $17,654,519 . </li></ul><ul><li>Males under 15 years are the highest antibiotic usage group </li></ul><ul><li>6% having used antibiotics in a 2 week period </li></ul><ul><li>27% of which were for otitis media </li></ul>
  56. 56. Antibiotics and allergy <ul><li>Several studies linking prenatal and early infancy antibiotics to later allergy and asthma </li></ul><ul><li>study >450 children from birth to age 7 </li></ul><ul><li>49% had received antibiotics in first 6 months, most commonly penicillin </li></ul><ul><li>by age 7, children who received at least one antibiotics in first 6 months 1.5 x more likely to have allergies, 2.5 x more likely to have asthma </li></ul><ul><li>) </li></ul><ul><li>asthma, allergy generally regarded as markers of TH2 immune system shift </li></ul>
  57. 57. Antibiotics and allergy <ul><li>Children who have had fewer vaccines, fewer antibiotics and have diets containing live lactobacilli have  incidence atopy (13% cf 25%) </li></ul>
  58. 58. Antibiotics, Gut Bacteria and Leaky Gut <ul><li>change in gastrointestinal flora thought to be reason behind TH2 immune system shift documented post anti-biotics . loss protective gut flora, dysbiosis, Clostridia, (haemorrhagic enterocolitis), candidial overgrowth well documented </li></ul><ul><li> anaerobic bacteria- penicillin/metronidazole  1000x </li></ul><ul><li>resultant overgrowth of pathogenic bacteria which are translocated out of the intestinal tract into the surrounding lymphatic tissue (GALT) </li></ul><ul><li>Antibiotics can induce increased intestinal permeability (leaky gut) </li></ul>
  59. 59. Vaccination <ul><ul><li>introduced in Australia 45 years ago </li></ul></ul><ul><ul><li>number: over 30 vaccinations (some </li></ul></ul><ul><li>conjugates) before school age since HepB </li></ul><ul><li>intro </li></ul><ul><ul><li>noxious stimulus – associations pain, illness </li></ul></ul><ul><ul><li>injected – antigens, foreign proteins, viral particles, adjuvants ($9,445,057 adjuvants sold in 1997, NRA), preservatives </li></ul></ul>
  60. 60. Vaccination (cont) <ul><li>Vaccination induces immune system shift from TH1 (native immunity) to Th2 (allergy, antibody-dependant immunity) </li></ul><ul><li>Predominance Th2- biased pattern with impaired induction of cytotoxic T cells in response to vaccines in neonates and early life as compared to adults (mice). </li></ul><ul><li>Effect did not disappear with aging and was still reflected in adult responses to booster immunisation. </li></ul><ul><li>) . </li></ul>
  61. 61. Thimerosal <ul><li>Ethyl-mercury containing preservative </li></ul><ul><li>Voluntarily removed from most current paediatric vaccines, still in paediatric flu vaccine </li></ul><ul><li>Previous vaccine schedule (USA): children in first 2 years of life received approx 187 mcg Hg as thimerosal in vaccination </li></ul><ul><li>In vitro Hg known to induce  IgE,  CMI, apoptosis by induction of oxidative stress of immune cells </li></ul><ul><li>In vivo in genetically susceptible mice, Hg induces a shift from Th1 to Th2,  TNF, IL-6, autoantibodies to neural tissue </li></ul><ul><li>( Numerous other studies demonstrating adverse immunological and neurological effects </li></ul>
  62. 62. Thimerosal <ul><li>2.48x  incidence autism in children exposed to 62.5 mcg Hg before 3 months of age </li></ul><ul><li>) </li></ul><ul><li>“ As for the exposure evaluated at 3 months of age, we found increasing risks of ‘neurological developmental disorders’ with increasing cumulative exposure to thiomersol…within the group of ‘developmental disorders’… for the subgroup called ‘specific delays’, and within this subgroup for the specific disorder ‘developmental speech disorder’ and for ‘autism’, ‘stuttering’ and attention deficit disorder’ ”. </li></ul>
  63. 63. Thimerosal <ul><li>Thimerosal phased out in US from 1999, in Australia from 2004 </li></ul><ul><li>Declining rates of autism now being reported by Department of Developmental Services in California (CDDS) </li></ul><ul><li>2002 - peak - DSM IV autism (not PDD, NOS, Asperger’s) -3259 </li></ul><ul><li>2003 - 3125 </li></ul><ul><li>2004 - 3074 </li></ul><ul><li>1st half 2005 - 1470 (cf 1518 1st half 2004) </li></ul>
  64. 64. Thimerosal <ul><li>Analysis of VAERS & CDDS </li></ul><ul><li>“ the trends in newly diagnosed neurological disorders correspond directly with the expansion and subsequent contraction of the cumulative mercury dose to which children were exposed from the thimerosal-containing vaccines through the US immunisation schedule.” </li></ul><ul><li>“ very specific neurodevelopmental disorders are associated with thimerosal-containing vaccines” </li></ul>
  65. 65. Measles <ul><li>Native measles attacks the reticuloendothelial system, immune system lining the gut </li></ul><ul><li>Selectively attacks Th1 lymphocytes, depresses Th1 immunity, requires effective Th1 immunity to combat infection </li></ul><ul><li>Native measles nootropic, enterotropic </li></ul>
  66. 66. Measles & Nervous system <ul><li>Measles encephalitis: 1/1000: most cases immune-mediated response to myelin protein, not direct viral infection of CNS </li></ul><ul><li>Model- EAE- experimental allergic encephalitis - disease-producing T cells react to myelin basic protein (MBP). Immune-mediated </li></ul><ul><li>SSPE - rare measles encephalitis, more common among children with measles before the age of twelve months, characterised by extremely high levels of antibodies to measles in the blood and CFS (ie not protective) </li></ul><ul><li>Measles virus found in SSPE brains </li></ul>
  67. 67. Measles & Autism <ul><li>Autism recognised in 1970s as a possible consequence of very early exposure to measles, mumps, rubella and other viruses in their native form </li></ul>
  68. 68. Measles & the gut <ul><li>gastrointestinal complications of measles include gastroenteritis, hepatitis, appendicitis, ileocolitis and mesenteric adenitis </li></ul><ul><li>measles associated with IBD </li></ul><ul><li>measles virus found in peripheral blood mononuclear cells in patients with IBD </li></ul>
  69. 69. MMR vaccine and the gut <ul><li>possible association measles vaccine and IBD </li></ul><ul><li>gastrointestinal disturbance usual in autism; lymphoid hyperplasia has been demonstrated in children with autism ‘autistic enterocolitis’ </li></ul><ul><li>confirmed by US independent US researchers: colonoscopy/biopsy of 43 children </li></ul>
  70. 70. MMR Vaccine and the Gut (cont) <ul><li>Measles virus found in 75 of 91 children with ileal lymphoid hyperplasia & enterocolitis cf 5 of 70 controls </li></ul><ul><li>evidence for a link is now becoming compelling </li></ul><ul><li>Study 275 children with regressive autism and GI symptoms (in progress): by June 2006, terminal ileal biopsy tissue from 82 children:85% histological evidence of measles virus, 14/70 currently verified by DNA PCR . </li></ul><ul><li>confirm earlier findings of measles virus in the terminal ileum and support an association between measles virus and ileocolitis/LNH </li></ul>
  71. 71. MMR vaccine and Gut (cont) <ul><li>Recent study confirms initial findings of unique of inflammatory bowel disease , ileocolonic lymphoid nodular hyperplasia (LNH) in autistic children </li></ul><ul><li>148 autistic children, ileocolonoscopy for gastrointestinal complaints; age 2-16 </li></ul><ul><li>compared to 30 nondisabled children </li></ul><ul><li>ASD children - 90% LNH ileum, 59% colon </li></ul><ul><li>cf controls - 30% LNH ileum, 23% colon </li></ul><ul><li>increased severity in ASD - 68% moderate to severe LNH cf 15% controls </li></ul>
  72. 72. MMR Vaccine, Gut and Autism <ul><li>Challenge-rechallenge study (2006) </li></ul><ul><li>Children with regressive autism </li></ul><ul><li>Comparing those received single dose with those received multiple doses </li></ul><ul><li>Data identified re-challenge effect on clinical symptoms and biological gradient effect on intestinal pathology </li></ul><ul><li>“ Links measles-containing vaccine exposure to autistic-like developmental regression and enterocolitis” </li></ul>
  73. 73. MMR, Immunity and Autism <ul><li>High levels of circulating antibodies to measles in blood of children with autism </li></ul><ul><li>Associated with raised anti-MBP in 93%, commonly found in association with neurodegenerative disorders </li></ul><ul><li>Like EAE model – form immune mediated encephalitis? </li></ul>
  74. 74. MMR vaccine <ul><li>Native measles known association with neurological and gastrointestinal sequelae, temporary suppression of Th1 </li></ul><ul><li>known vaccine association with Th2 shift and antibody production </li></ul><ul><li>serological evidence of abnormal measles antibodies and anti-myelin basic protein in children with autism </li></ul><ul><li>colonoscopy evidence of abnormal immune responses and virus presence in the gut in some </li></ul><ul><li>CAUTION MUST BE EXERCISED </li></ul>
  75. 75. Vaccination <ul><li>Adverse reaction reporting: </li></ul><ul><li>well documented (several trials) adverse reaction reporting rate for prescription medications including vaccination approx 5-10% true incidence rate </li></ul><ul><li>not compulsory for vaccinations </li></ul><ul><li>no long term trials for safety of current vaccination schedules </li></ul><ul><li>PRIMA NOCERE </li></ul>
  76. 76. Diet and Childhood Illnesses
  77. 77. Human Diet through History <ul><li>human diet has passed through at least 4 phases </li></ul><ul><li>original diet (Garden of Eden): high in plant foods, leafy vegetables, shoots, roots, seeds, berries, fruit & nuts </li></ul><ul><li>hunting, herding - increased meat </li></ul><ul><li>agricultural - increased carbohydrates, cereals, legumes </li></ul><ul><li>supermarket phase - consumption highly processed foods, high in sugar, salt , saturated and trans-saturated fatty acids </li></ul>
  78. 78. Primitive Diet <ul><li>change in diet since hunter-gatherer from </li></ul><ul><ul><li>predominantly protein-based diet (plant and animal) </li></ul></ul><ul><ul><li>little complex carbohydrate with no refined sugar </li></ul></ul><ul><ul><li>natural sugars from sources such as fruits, dates, figs and honey </li></ul></ul><ul><ul><li>higher omega-3 EFA (1:4 omega 6) </li></ul></ul><ul><ul><li>low saturated fats, almost no trans-fatty acids </li></ul></ul><ul><ul><li>high plant sterols </li></ul></ul><ul><ul><li>high fibre </li></ul></ul><ul><ul><li>high alkaline foods (vegetables, fruit) </li></ul></ul><ul><ul><li>high potassium intake, antioxidant intake </li></ul></ul><ul><ul><li>soured dairy products, goat’s, sheep’s milk </li></ul></ul><ul><ul><li>fermented foods </li></ul></ul><ul><ul><li>limited food intake </li></ul></ul>
  79. 79. Modern Diet <ul><li>High glycaemic load - high quantity, low quality refined cereal-based carbohydrates </li></ul><ul><li>higher omega-6 EFA </li></ul><ul><li>shift to predominantly carbohydrate-based diet </li></ul><ul><li>decrease in micronutrient intake </li></ul><ul><li>increase in acidity of diet </li></ul><ul><li>increase in sodium intake </li></ul><ul><li>decrease in fibre intake </li></ul>
  80. 80. Modern Diet <ul><li>Over consumption of food (more calories, not necessarily better nutrition) </li></ul><ul><li>children aged 10-15 yrs , 10 years from 1985 -1995: 15%  caloric intake boys, 12% girls </li></ul><ul><li>mainly  refined carbohydrates from cereals, cereal-based foods, confectionary, non-alcoholic beverages, sugar products </li></ul><ul><li>major factor in  childhood obesity </li></ul>
  81. 81. Modern Diet- Carbohydrates <ul><li>From time of industrial revolution onwards: around 1800 </li></ul><ul><li>introduction of refined sugar (sucrose), refined grains, high fructose corn syrup (HFCS) </li></ul><ul><li>carbohydrates, grains up to 1/4 total energy </li></ul><ul><li>85% refined - most of high GI foods are refined cereal grains </li></ul><ul><li>displaces minimally processed nutrient dense wild-plant, wild-animal foods </li></ul>
  82. 82. Modern Diet- Refined Sugar <ul><li>cane sugar in manufactured foods - 31.7kg per capita, refined sugar 11.1kg per capita, total 42.8kg per capita </li></ul><ul><li>high proportion total domestic sugar sales in non-alcoholic beverages (29% 1987) (ACIL Australia Pty Ltd.. </li></ul><ul><li>cf bread - 51 kg/yr </li></ul><ul><li>soft drinks, juice drinks major sources of sugars in modern Western diet </li></ul><ul><li>one 600ml soft drink exceeds WHO 2003 re c om m endation that sugars be less than 10% total caloric intake </li></ul>
  83. 83. Modern Diet: Fruit & Vegetable <ul><li>fruit, vegetable, fish and fresh food intake halved from 1961 to 1985. </li></ul><ul><li>1996 : estimated that inadequate fruit & veg intake responsible for 3% of total disease burden and 11% of cancers </li></ul><ul><li>low fruit intake esp adolescent males (only 37% ate fruit) </li></ul><ul><li>low vegetable intake other than potato (30-40%) </li></ul><ul><li>2001: adults - 30% people eating 4 or more serves vegetables, 53% 2 or more serves fruit </li></ul>
  84. 84. Modern Diet - Acid-Base Balance <ul><li>Foods differ in ability to produce acid or alkali when metabolised </li></ul><ul><li>human body slightly alkaline, need eat predominantly alkaline foods </li></ul><ul><li>cereal grains, refined CHO largest single nutritional source acid-producing foods </li></ul><ul><li>refined sugars, oils neutral, but displace alkaline producing fruits and vegetables </li></ul><ul><li>result - chronic metabolic acidosis </li></ul>
  85. 85. Modern Diet - EFA <ul><li>From industrial revolution  omega 6 EFA, (20:1 omega 3) ,trans- fatty acids because: </li></ul><ul><li>hydrogenation of oils </li></ul><ul><li>refined vegetable oils - especially soy oil- high omega 6 </li></ul><ul><li> reduced game meats eaten </li></ul><ul><li>domestic meats fed grain, feed -lots,  omega -3,  omega-6 </li></ul><ul><li>problem: xs omega-6 pro-inflammatory, TFA atherogenic (major risk factor for cardiovascular disease) </li></ul>
  86. 86. Diet -EFA <ul><li>reduction omega-3 EFA </li></ul><ul><li>omega-3 EFA essential for growth and functional devel brain in infants, maintenance normal brain function in adults </li></ul><ul><li>turnover of DHA in brain rapid </li></ul><ul><li>conversion of shorter chain precursor a-linolenic acid to EPA, DHA inefficient in man </li></ul><ul><li>DHA deficiencies common </li></ul>
  87. 87. Modern Diet - dairy (cow) <ul><li>high dairy intake (>90%),predominantly milk (70%) </li></ul><ul><li>mean intake of over 250gm milk per day </li></ul><ul><li>adolescent males highest mean intake dairy products </li></ul>
  88. 88. Dairy components <ul><li>Lactose : galactose-glucose </li></ul><ul><li>casein - beta-caseins (31%), alpha casein, (39%), kappa casein (11%) </li></ul><ul><li>whey proteins - soluble at pH4.6 -predominantly immunoglobulins, lactoglobulin, lactalbumin </li></ul>
  89. 89. Modern cow’s milk <ul><li>Modern herds predominantly Fresian - large output, different milk composition </li></ul><ul><li>Casein content 300 x that of human milk (beta-casein A1) </li></ul><ul><li>Fresians - chronic recurrent mastitis - streptococcus </li></ul><ul><li>Streptococcus&/or toxins isolated from milk in several studies </li></ul><ul><li>Processed milk </li></ul>
  90. 90. Traditional Milks <ul><li>Primitive diet - hunter-gatherer, nomadic </li></ul><ul><li>Herd of usually goats or sheep, later,small cattle (eg Jersey, Guernsey) </li></ul><ul><li>Different casein (beta casein A2), fat proportions </li></ul><ul><li>Milk drunk only fresh, raw </li></ul><ul><li>Soured, fermented milk products usual source dairy (no refrigeration) </li></ul><ul><li>No pasteurisation, homogenisation </li></ul>
  91. 91. Beta-casein A1 <ul><li>Predominant casein in Fresian dairy milk </li></ul><ul><li>Digested by gastrointestinal protease to a bioactive peptide beta-casomorphin -7 (BCM-7) </li></ul><ul><li>beta-casomorphin requires dipeptidase IV to be cleaved into peptide fragments </li></ul><ul><li>numerous in vitro studies and animal studies demonstrating biological activity beta-casomorphin, particularly via opioid pathway (schizophrenia, autism) (Reichelt) </li></ul><ul><li>dipeptidase IV often reduced in children with autism </li></ul><ul><li>basis for development of enzyme supplement ‘Serenase’ </li></ul>
  92. 92. Beta-casein A1 <ul><li>strongly immunogenic </li></ul><ul><li>human epidemiological studies demonstrating connections with type 1 diabetes in male children </li></ul><ul><li>increased prevalence of ASD in children with type 1 diabetes </li></ul><ul><li>Beta casein A1 also associated with  cardiovascular disease </li></ul>
  93. 93. Cow’s Milk Allergy <ul><li>Cow’s milk allergy affects approx 2-5% infants under 2 years </li></ul><ul><li>as measured by IgE mediated atopic reactions, T cell mediated reactions </li></ul><ul><li>clinical spectrum ranges from urticaria, angioedema, and atopic dermatitis to infantile colic, gastroesophageal reflux, oesophagitis, infantile proctocolitis, food-associated enterocolitis and constipation </li></ul>
  94. 94. Dairy Intolerance <ul><li>common association clinically with otitis media, nasal congestion, sinusitis, diarrhoea or constipation (common in autism) </li></ul><ul><ul><li>study 104 children with recurrent serous otitis media, food allergy in 78%, milk allergy commonest, in 38%. </li></ul></ul><ul><ul><li>elimination diets  resolution of serous otitis media in 86%, recurrence on provoked challenge in 94% children </li></ul></ul><ul><ul><li>dairy sensitivity may manifest as gastrointestinal symptoms such as diarrhoea gastrointestinal bleeding or chronic constipation </li></ul></ul>
  95. 95. Constipation <ul><li>Serious constipation with associated megarectum very common in autistic children </li></ul><ul><li>1 study - 36% autistic children moderate/severe constipation on AXR, 54% moderate to severe loading of rectum </li></ul><ul><li>consumption of milk strongest predictor of constipation </li></ul>
  96. 96. Dairy Effects <ul><li>Sleep abnormalities common ADHD children and in autism </li></ul><ul><li>cow’s milk allergy associated with sleep difficulties infants </li></ul><ul><li>high intake cow’s milk correlated with behavioural disorders and aggression in children </li></ul><ul><li> consumption dairy  significant  incidence antisocial behaviour in these children </li></ul>
  97. 97. Dairy- Osteoporosis <ul><li>Recent study USA over 2000 children </li></ul><ul><li>high rates osteoporosis, high dairy intake </li></ul><ul><li>good bone density not correlated with dairy intake </li></ul><ul><li>strong correlate bone density with weight -bearing exercise </li></ul>
  98. 98. Traditional Grains <ul><li>Hunter-gatherer, nomadic herders - little grain, except wild grains harvested </li></ul><ul><li>early agriculturalists - wide variety high protein grains, low gluten </li></ul><ul><li>Ancient wheat - spelt - low gluten content </li></ul><ul><li>low gluten grains - rye, oats, barley </li></ul><ul><li>non-gluten grains - amaranth, buckwheat, corn, millet, rice, quinhoa </li></ul><ul><li>Breads – unleavened (soaked grains) or sough dough (fermentation process which predigests the grains) </li></ul>
  99. 99. Wheat Intolerance <ul><li>Modern wheat - high in gluten </li></ul><ul><li>gluten difficult peptide to break down - limited enzyme capacity - DPPIV </li></ul><ul><li>modern breads - wheat, preservatives, stabilisers </li></ul><ul><li>Growing number of studies - wheat intolerance in IBS symptomatically </li></ul><ul><li>raised IgG antibodies recently demonstrated </li></ul>
  100. 100. Gluten Intolerance <ul><li>Severe wheat intolerance - coeliac disease- more common than previously thought </li></ul><ul><li>Est 1.5 mill USA (Arch Int Med 2003;163:286-292) </li></ul><ul><li>Often not diagnosed until adulthood </li></ul><ul><li>Raised gliaden AB, not full coeliac disease - partial coeliac, abnormal immunological reaction - ?precursor state </li></ul><ul><li>Precursor state common in ADHD, autism, Down Syndrome, gastrointestinal symptoms </li></ul>
  101. 101. Gluten & the Nervous System <ul><li>associations gluten reactivity and neurologic disease </li></ul><ul><li>schizophrenia </li></ul><ul><li>epilepsy with intracerebral calcifications </li></ul><ul><li>cryptogenic neurologic disease </li></ul>
  102. 102. Chemicals - food additives <ul><li>Progressive since WWII </li></ul><ul><li>Over 400 allowed additives (NRA) </li></ul><ul><li>no register of what is actually ingested </li></ul><ul><li>food additives known problem years - Feingold diet </li></ul><ul><li>numerous studies </li></ul>
  103. 103. Food Additives <ul><li>Recent UK study: 2000 preschool children (allergies & hyperactivity;neither; only hyperactivity; only allergies) </li></ul><ul><li>DBPCCO trial after 3 weeks period on diet with no artificial additives </li></ul><ul><li>daily drink either placebo or additives </li></ul><ul><li>‘ observed effect of food additives and colorings on hyperactivity in this community sample is substantial, at least for parent ratings’ </li></ul><ul><li>dose for additives ‘on the low side’ </li></ul><ul><li>effect also in children with neither allergies nor hyperactivity </li></ul>
  104. 104. Food Additives <ul><li>‘We showed there was an effect on perfectly normal children. If that is confirmed by further research, then there is a public health issue’ </li></ul>
  105. 105. Modern Diet - Agricultural Chemicals <ul><li>chemicals used in agricultural/dairy industry for food production totalled $1,236,248,833 (NRA 1997) </li></ul><ul><ul><ul><ul><li>$713,601,454 herbicide </li></ul></ul></ul></ul><ul><ul><ul><ul><li>$268,380,569 insecticide. </li></ul></ul></ul></ul><ul><li>human exposure to pesticides far greater than previously estimated </li></ul><ul><li>children at particularly high risk for neurotoxic effects from regular inadvertant exposure to pesticides from common foods </li></ul>
  106. 106. Agricultural Chemicals <ul><li>As many as 3% of developmental and neurological deficits in children are caused by exposure to known toxic substances </li></ul><ul><li>additional 25% of all developmental and neurological defects stem from environmental factors working in conjunction with genetic predisposition </li></ul>
  107. 107. Chemicals (cont) <ul><li>US companies annually report releasing into the environment 1.2 billion pounds of chemicals, “more than half … are known or suspected developmental or neurological toxins” </li></ul>
  108. 108. <ul><li>Historically, all foods non-GMO, grown organically </li></ul>
  109. 109. GM Foods <ul><li>introduced last 10 years </li></ul><ul><li>Controversial </li></ul><ul><li>3 main issues: </li></ul><ul><li>spread to non-GM crops well documented- even certified organic products have been found to contain traces </li></ul><ul><li>increased use of pesticide in food chain eg Round-up resistant GM soy - legislated for 200x  use </li></ul><ul><li>evidence that GM DNA can survive into the human small intestine, transfer to gut flora </li></ul>
  110. 110. Organic Foods- Chemical Residues <ul><li>nowhere on planet now 100% chemical free </li></ul><ul><li>less than 2% of pesticide reaches target pest: 98% onto beneficial insects, bees, food crops, grass, soil, water </li></ul><ul><li>organically-grown crops have on average 1/4 pesticide residues of conventionally-grown </li></ul><ul><li>surveys of data from USDA, California Dept Pesticide Regulation, US Consumer Union show organic fruit, vegetables have significantly less pesticide residue </li></ul><ul><li>eg grapes 25% vs 28%, capsicum 9% vs 69%, peaches 50% vs 93% </li></ul>
  111. 111. Organic Food- Chemical Residues <ul><li>Recent study:Children who consume organic foods have substantially lower levels of pesticide residue </li></ul><ul><li>feeding organic foods resulted in substantial declines in body levels of malathion and chlorpyrifos </li></ul>
  112. 112. Organic Foods- Phytochemicals <ul><li>levels of vitamins/minerals generally higher - depend on farming practices and soil quality </li></ul><ul><li>vitamin C, carotene, calcium, iron higher in organic foods </li></ul><ul><li>levels of plant phytochemicals consistently higher </li></ul><ul><li>natural plant defenses against insects, fungi, infections </li></ul><ul><li>powerful antioxidants, immune stimulants </li></ul><ul><li>new area of focus in nutritional medicine </li></ul><ul><li>level inversely proportional to level of nitrates in soil- XS nitrates occur with high pesticide use </li></ul><ul><li>one study - 58.5% higher levels in corn, 50% berries, 19% strawberries </li></ul>
  113. 113. TV and Attention Disorders <ul><li>Direct connection between TV exposure at ages one and three and the risk of attention problems at age seven </li></ul><ul><li>longitudinal study of 2600 children USA </li></ul><ul><li>1/4 children aged 2 or younger had TV own room </li></ul><ul><li>new recommendations: </li></ul><ul><li>no TV under age of 2 </li></ul><ul><li>older children no more than 1-2 hours/d quality TV or video </li></ul><ul><li>no electronic media in young children’s bedrooms </li></ul>
  114. 114. Play Behaviour <ul><li>Play behaviour present in all animal species </li></ul><ul><li>animal studies suggest that play as important as sleeping and dreaming </li></ul><ul><li>necessary for normal development, social relationships and status </li></ul>
  115. 115. <ul><li>Numerous factors in modern Western society which impact upon health of our children </li></ul><ul><li>difficult to quantify these influences </li></ul><ul><li>no single causative factor </li></ul><ul><li>Diet, antibiotics, vaccinations, chemicals, heavy metals strong influences </li></ul><ul><li>need to be open-minded and cautious </li></ul>
  116. 116. Abnormalities in Autism
  117. 117. Psychiatric or metabolic? <ul><li>Rumination syndrome (1960s-1970s) - </li></ul><ul><li>‘ psychiatric disease of infancy’, ‘the syndrome of maternal deprivation’: </li></ul><ul><li>persistent vomiting associated with autistic symptoms, usual onset ages 3-6mo, in underprivileged homes/orphanages. </li></ul><ul><li>?Formula feeding cow’s milk/ loss protective breast milk, gastrointestinal flora/nurture. </li></ul>
  118. 118. Gastrointestinal Abnormalities in Autism
  119. 119. Gastrointestinal Abnormalities in Autism <ul><li>Already documented: </li></ul><ul><li>gastric hypochlorhydria with resultant raised pH (Horvath) </li></ul><ul><li>duodenitis (Horvath) </li></ul><ul><li>reduced intestinal disaccharidase enzyme function (Horvath) & dipeptidase function </li></ul><ul><li>Colitis, lymphonodular hyperplasia (Wakefield,Krigsman) </li></ul><ul><li>increased intestinal permeability (Eufemia) </li></ul>
  120. 120. The Gut in Autism <ul><li>Clinically, GI symptoms usual in ASD </li></ul><ul><li>2006 study 150 children: 50 ASD, 50 developmental normal, 50 other developmental disorders </li></ul><ul><li>History of GI symptoms in 70% ASD cf 28% normal development, 42% other disabilities </li></ul>
  121. 121. Intestinal permeability <ul><li>Increased intestinal permeability marker for food allergies found in various auto-immune disorders (eg RA,), inflammatory bowel disease, </li></ul><ul><li>found previously in ADHD and autism </li></ul>
  122. 122. Intestinal permeability <ul><li>Viral, bacterial, dietary antigens </li></ul><ul><li> inflammation </li></ul><ul><li> transport of macromolecules across intestinal wall, GALT (gut associated lymphoid tissue) and portal circulation  alteration of routes of transport  allergenic stimulus favouring allergenic reactions </li></ul>
  123. 123. Intestinal Permeability and Food Allergy <ul><li>Food allergy/sensitivity significant in subgroup of ADHD </li></ul><ul><li>EEG changes have been demonstrated to occur immediately following the ingestion of previously identified sensitising food </li></ul>
  124. 124. Food Reactions and Autism <ul><li>GI symptoms usual in autistic children </li></ul><ul><li>‘ digestive and food allergies’ common, (study 55,000 households Nat Health Interview Survey), cf non-autistic children - more frequent asthma </li></ul>
  125. 125. Intestinal Flora <ul><li>Intestinal flora affects gut permeability </li></ul><ul><li>in the absence of beneficial intestinal microflora, disturbance in intestinal absorption of macromolecules is more severe than in its presence </li></ul><ul><li>(Salminen S et al. Probiotics and the stabilisation of the gut mucosal barrier. Asia Pac J Clin Nutr 1996;5) </li></ul>
  126. 126. Faecal Microbiology of patients with CFS and Autism <ul><li>Patients </li></ul><ul><li>normal microbiology </li></ul><ul><li>bacterial dysbiosis (colonosis) </li></ul><ul><ul><li>abnormal aerobes/anaerobes ratio </li></ul></ul><ul><li>CFS Autism </li></ul><ul><li>(n=19) (n=36) </li></ul><ul><li>2 (10.5%) 6 (16.6%) </li></ul><ul><li>17 (89.4%) 30(83.3%) </li></ul><ul><li> </li></ul><ul><li>5 (26.3%) 17(47.2%) </li></ul>Bioscreen data 2001 © © Bioscreen 2001
  127. 127. Alterations of the faecal aerobic microbial flora in patients with autism (n=36) Butt HL, Cosford RE, Roberts TK, Dunstan HR,McGregor NR, Ellis L University of Newcastle Bioscreen <ul><li>The mean % distribution of Escherichia coli for the autistic patients was 56.3% of the total aerobic flora, compare to 80% in healthy control subjects (p=0.03). </li></ul><ul><li>Enterococcus/Streptococcus spp., was significantly higher in counts (40.1%) in the autistic patients than in healthy subjects (5%). (p<0.0007) </li></ul>P<0.0007 P=0.03
  128. 128. Correlates with Enterococcal/Streptococcal colonosis <ul><li>Colonic activity - Malabsorption </li></ul><ul><ul><li>Enterococcus/Streptococcus negatively (p=0.046) correlate with anaerobic activities (coprostanol) </li></ul></ul><ul><li>Fat Malabsorption </li></ul><ul><ul><li>Enterococcus/Streptococcus positively (p<0.013) correlate with C18 FA (cis-9 octadecenoic, trans-9-octadecanoic, octadecanoic) </li></ul></ul><ul><li>Neurocognitive symptoms </li></ul><ul><ul><li>high faecal streptococci significantly and positively correlate with cognitive dysfunction (nervousness, memory loss, forgetfulness, confusion, mind going blank) in adults with fatigue (Bioscreen data 2001) </li></ul></ul>
  129. 129. Gastrointestinal Dysfunction in Autism <ul><li>Increased gastrointestinal permeability </li></ul><ul><li>Gastrointestinal inflammation </li></ul><ul><li>Gastrointestinal dysbiosis with colonosis </li></ul><ul><li>Predominant overgrowth of streptococcal/enterococcal species </li></ul><ul><li>Markers for malabsorption </li></ul><ul><li>Disruption of normal gastrointestinal flora function and metabolites </li></ul><ul><li>Metabolic sequelae </li></ul>
  130. 130. The Brain and Immunology in Autism
  131. 131. The Brain in Autism <ul><li>A number of abnormalities have been demonstrated: </li></ul><ul><li> cerebral blood flow (SPECT) </li></ul><ul><li>loss Purkinje fibres (Biopsy) </li></ul><ul><li> neurotransmitters & neuropeptides </li></ul><ul><li>encephalitis, demyelination (rarely) </li></ul>
  132. 132. Brain development in autism <ul><li>Head circumference at birth below/near normal, increases from 3 months of age, dramatic increase from 6 months so that are greater than 97th centile through childhood, slow growth then until adolescence </li></ul><ul><li>MRI - brain volumes significantly larger </li></ul><ul><li>MRI - cerebellum, amygdala, hippocampus increased size cf normal, developmental delay </li></ul>
  133. 133. Immunology in Autism <ul><li>No single immunological abnormality in all </li></ul><ul><li>Th2 shift -  CD4+ T cells,  IL-4, TNF,  IFN-gamma </li></ul><ul><li> IgA </li></ul><ul><li> IgE </li></ul>
  134. 134. Immunology in Autism : Th2 shift <ul><li> deficiency in cell mediated immunity (CMI) </li></ul><ul><li>may  infection with and/or persistence of microbes (eg measles) </li></ul><ul><li>may  lymphoid hyperplasia in the gut, and in the brain, encephalitis and neuronal loss </li></ul><ul><li>Th2 shift results in allergies and autoimmunity in a susceptible host. </li></ul>
  135. 135. Immunology in Autism: autoantibodies <ul><li>High levels of autoantibodies against myelin basic protein (MBP) and neuron axonal filamentary protein in children with autism (60 to 70%) </li></ul><ul><li>various other antibodies to neuronal tissue also documented </li></ul>
  136. 136. Immunology in Autism: autoantibodies (cont) <ul><li>Antibodies to 3 cross reactive peptides also raised in children with autism cf controls (IgG, IgA, IgM) </li></ul><ul><li>chlamydia pneumoniae (CPP) </li></ul><ul><li>streptococcal M protein (STM6P) </li></ul><ul><li>milk butyrophilin (BTN) </li></ul>
  137. 137. Immunology <ul><li>Abnormal immunology: </li></ul><ul><li>Th2 shift </li></ul><ul><li>Reduced CMI </li></ul><ul><li>Abnormal autoantibodies to neuronal tissue and other antigens </li></ul>
  138. 138. Abnormal Patterns on Metabolic Studies
  139. 139. Metabolic abnormalities <ul><li>Numerous metabolic abnormalities have been documented in autism by various researchers, including: </li></ul><ul><li>Abnormal sulphur metabolism (Waring) </li></ul><ul><li>Abnormal fatty acid profiles with accumulation of very long chain fatty acids indicating a peroxisomal disorder (Kane) </li></ul><ul><li>Abnormal metallothionine levels and/or function (Pfeiffer Institute) </li></ul>
  140. 140. Metabolic abnormalities <ul><li>Raised oxidative stress: </li></ul><ul><li>Reduced glutathione – intramitochondrial antioxidant, hepatic conjugation; altered metabolism of methionine (NB glutathione needed to metabolise paracetomol) </li></ul><ul><li>Carboxyethylpyrrole, product of lipid peroxidation, in cortex of children with ASD </li></ul><ul><li>Elevated levels lipofuscin, product of lipid peroxidation, in 3 language related areas of brain in children with ASD </li></ul>
  141. 141. Heavy Metal Toxicity <ul><li>Lower hair mercury in children with autism cf controls (first hair-cut) </li></ul><ul><li>higher levels of mercury excreted in urine post DMSA challenge (221 ASD cf 18 controls) </li></ul><ul><li>consistent with concept that autistic children have reduced capacity to excrete mercury </li></ul><ul><li>reduced metallothionine levels - zinc- inducible </li></ul><ul><li>( </li></ul>
  142. 142. Heavy Metal Toxicity <ul><li>Porphyruria: high serum prophyrins can cause neurological disturbances </li></ul><ul><li>Mercury, arsenic known to cause raised urinary porphyrins by blockade of enzymes in synthesis of heme from protoporphyrin </li></ul><ul><li>Study 269 children with neurodevelopmental disorders, urinary porphyrin levels </li></ul><ul><li>Several porphyrins, known markers of heavy metal toxicity (pentacarboxyprophyrin, precoporporphyrin, coproporphyrin), raised in ASD, epilepsy and mental retardation with epilepsy </li></ul><ul><li>Reduction in prophyrinuria post chelation therapy (11) </li></ul>
  143. 143. B6 Metabolism <ul><li>Raised serum B6 in children with ASD, up to 75% greater </li></ul><ul><li>Reduced levels pyridoxal-5-phosphate (P-5-P), active form </li></ul><ul><li>Depressed enzyme activity for pyridoxal kinase, converts B6 to P-5-P </li></ul><ul><li>P-5-P enzymatic cofactor for 113 enzymes, plays key role in neurotransmitter formation </li></ul>
  144. 144. Metabolic Abnormalities <ul><li>Pilot study (University of Newcastle) </li></ul><ul><li>Urinary metabolites </li></ul><ul><li>Red Blood cell fatty acids </li></ul>
  145. 149. Summary : Autism <ul><li>Multisystem disorder: </li></ul><ul><li>neurological </li></ul><ul><li>immunological </li></ul><ul><li>gastrointestinal </li></ul><ul><li>biochemical </li></ul><ul><li>Neuro-Immune-Gastrointestinal Dysfunction Syndrome (NIGDS) (Cosford RE , Mind of a Child Proceedings 1999) </li></ul><ul><li>M etabolic Immunological Neurological Digestive Disorder (MINDD), </li></ul><ul><li>Or MINDDD (Developmental Disorder) </li></ul>
  146. 150. WHAT CAN BE DONE? Some Therapeutic Interventions
  147. 151. Prevention is better than cure: <ul><li>Public Health Measures: </li></ul><ul><li>Pregnancy - nutrition, smoking, alcohol, stress </li></ul><ul><li>Infancy- handling practices, breastfeeding, vaccination, antibiotic use </li></ul><ul><li>Childhood - passive smoking, diet, exercise, TV, chemicals, EMR </li></ul>
  148. 152. Otitis media <ul><li>Prevention/ management: </li></ul><ul><li>encourage breastfeeding </li></ul><ul><li>avoid early cow’s milk exposure </li></ul><ul><li>avoid exposure to passive smoking </li></ul><ul><li>avoidance antibiotics -  drug resistance Strep pneum in acute and unresponsive otitis media, persistent effusions and chronic suppurative otitis media </li></ul><ul><li>trial probiotics, dairy exclusion </li></ul>
  149. 153. Biomedical Therapeutic Interventions <ul><li>Dietary (intestinal permeability, food reactions) </li></ul><ul><li>Nutritional biochemistry (catabolism , enzyme blocks, heavy metal toxicity, oxidative damage ) </li></ul><ul><li>Restoration of gastrointestinal flora (abnormal gastrointestinal bacteria, intestinal permeability, metabolic sequelae) </li></ul><ul><li>Antimicrobials ( abnormal bacteria, occult infection ) </li></ul><ul><li>Immune modulation (Th2 shift) </li></ul><ul><li>Chelation (heavy metal toxicity) </li></ul>
  150. 154. Dietary Change- Does it work?
  151. 155. Effects of Dietary Change in Autism <ul><li>GFCF - 64% (724) </li></ul><ul><li>‘ anti-Candida diet’ - sugar, additive, refined carbohydrate free 52% (605) </li></ul><ul><li>Feingold- additive-free, low salicylate and amines - 51% (645) </li></ul><ul><li>removal chocolate 49% (1491) </li></ul><ul><li>removal dairy, milk products 48% (4950) </li></ul><ul><li>removal sugar 47% (3392) </li></ul><ul><li>rotation diet 47% (678) </li></ul><ul><li>removal wheat 46% (2701) </li></ul><ul><li>(ARRI Parent Rating Scale, 2002) </li></ul>
  152. 156. GFCF Diet in Autism <ul><li>autism studies confirming benefit from removal of casein </li></ul><ul><li>Clinical response to GFCF evident in 60% </li></ul><ul><li>(Shattock, Reichelt, Knivsberg, Whitely, personal data) </li></ul><ul><li>dairy - rapid response - hours/days/weeks </li></ul><ul><li>gluten - may be immediate (vomiting) </li></ul><ul><li>- often delayed - months </li></ul>
  153. 157. Problems with standard GFCF <ul><li>Major problem </li></ul><ul><li>typically, GFCF simply involves replacement of cow’s dairy with rice milk or soy milk and wheat with rice-based products </li></ul><ul><li>diet still very high in refined carbohydrates, added sugar, preservatives, low in fresh fruit, vegetables, nuts, seeds </li></ul>
  154. 158. Specific Carbohydrate Diet <ul><li>Based on premise of gut damage and dysfunction in autism </li></ul><ul><li>intestinal hyperpermeability, loss of disaccharidase enzymes, reduced capacity to digest carbohydrates </li></ul><ul><li>in essence, very similar to primitive diet </li></ul><ul><li>anecdotal evidence of effectiveness in some people with gastro-intestinal inflammation and dysfunction </li></ul>
  155. 159. Primitive Diet <ul><li>Also called paleolithic, hunter-gatherer diet </li></ul><ul><li>foods caught or collected </li></ul><ul><li>fresh game meats, birds, fish </li></ul><ul><li>nuts, seeds, fruits, vegetables especially root vegetables </li></ul><ul><li>herders- usually goats, sheep, sometimes cattle - drank small amounts of fresh milk, but most dairy curdled/soured </li></ul>
  156. 160. Primitive Diet <ul><li>Little grain - wild grains </li></ul><ul><li>sweet - dates, figs, occasional honey </li></ul><ul><li>some cooking - BBQ, stews </li></ul><ul><li>no processing </li></ul><ul><li>no additives </li></ul><ul><li>organic, picked fresh </li></ul>
  157. 161. The Primitive/Paleolithic Diet in a Modern World <ul><li>5 P’s </li></ul><ul><li>Primitive - simple, raw (at least 50%), </li></ul><ul><li>Processing - avoid </li></ul><ul><li>Preservatives, additives, colourings, no numbers </li></ul><ul><li>Packaged - avoid </li></ul><ul><li>Pre-prepared - fast foods - avoid </li></ul>
  158. 162. Practically <ul><li>Change for whole family </li></ul><ul><li>Read all labels - no numbers, no sugar/sucrose/glucose/fructose, no names that don’t sound like food </li></ul><ul><li>aim for 9 serves of fruit & veg daily </li></ul><ul><li>more protein, less grain-based carbohydrates </li></ul><ul><li>nuts, seeds- in recipes, as flours, on things, to nibble </li></ul>
  159. 163. Practically <ul><li>Oils - natural butter, coconut oil, olive oil, flaxseed oil (not for cooking) </li></ul><ul><li>dairy - goat, sheep, organic A2 milk if available (and child not reactive) </li></ul><ul><li>if grains - GF, wholegrain </li></ul><ul><li>no GM foods </li></ul><ul><li>Fermented foods – dairy, breads, vegetables </li></ul>
  160. 164. Supplementation <ul><li>Key supplements: </li></ul><ul><li>EFA </li></ul><ul><li>Magnesium, B6 </li></ul><ul><li>Zinc </li></ul><ul><li>Vitamin C </li></ul><ul><li>Probiotics </li></ul><ul><li>Numerous other supplements used with various levels of evidence </li></ul>
  161. 165. Diet- omega 3 EFA <ul><li>omega-3 EFA deficiency in hyperactive boys cf boys without hyperactivity </li></ul><ul><li>abnormalities in metabolism of EFA preventing precursor alpha-linolenic acid (ALA) (nuts, seeds) being converted to active DHA (fish oil, breast milk) required in brain, eyes </li></ul>
  162. 166. ADHD and omega 3 EFA <ul><li>DHA def assoc with foetal alcohol syndrome, ADHD, melacholia and aggressive hostility </li></ul><ul><li>supplemental DHA in normal formula fed infants improves visual acuity </li></ul><ul><li>dietary DHA improves learning ability </li></ul><ul><li>higher DHA levels in boys assoc fewer learning problems, less hyperactivity, overall improved academic achievement and ability in mathematics (supplement) </li></ul>
  163. 167. Developmental Disorders and omega 3 EFA <ul><li>Study 117 children DCD- developmental co-ordination disorder (dyspraxia): overlaps with ADHD, autism, dyslexia </li></ul><ul><li>supplementation with omega 3 80%/omega 6 20% </li></ul><ul><li>academic and cognitive gains (reading, spelling, reduction ADHD symptoms) </li></ul>
  164. 168. B6, Magnesium <ul><li>21/22 studies B6/magnesium positive in c. 50% cases </li></ul><ul><li>C. Dose B6 4mg/kg/d, magnesium 600mg/70kg/d </li></ul><ul><li>Results pyridoxal HCL (usual supplemental form B6) equivalent to P5P </li></ul><ul><li>10% children P5P deterioration behaviour, best to use pyridoxal HCL </li></ul><ul><li>NB – B6 toxicity only documented in 7 patients, doses 2000-6000mg/d, with no added magnesium or other B vitamins </li></ul>
  165. 169. Antioxidants <ul><li>DBPC trials - Vitamin C – 8gm/70kg/d or carnosine 400 mg bd, improved autistic behaviour </li></ul><ul><li>DB study: multivitamin/mineral (with vitamin C, B6, magnesium in base supplements): significant improvements in sleep, GI symptoms </li></ul>
  166. 170. Chelation <ul><li>Effective clinically : 470: 75% ‘good’ </li></ul><ul><li>Most used – Ca-EDTA iv </li></ul><ul><li>Increasingly, transdermal chelating agents/ oral nutritional supplements used </li></ul>
  167. 171. Allied Therapies-MINDDD <ul><li>cranial osteopathy </li></ul><ul><li>neuro-biofeedback </li></ul><ul><li>sound therapies </li></ul><ul><li>chiropractic - primitive reflexes </li></ul><ul><li>kinesiology </li></ul><ul><li>behavioural therapies </li></ul><ul><li>movement therapies </li></ul>
  168. 172. Play behaviour <ul><li>Abnormal play characteristic in autism </li></ul><ul><li>recent therapy PLAY project - intensive method of guided play </li></ul><ul><li>1 year pilot 41 young autistic children- half good/excellent progress, 1/3 fair </li></ul>
  169. 173. <ul><li>Autism: metabolic disorder: </li></ul><ul><li>Immunological, gastrointestinal, metabolic abnormalities with effect on neurodevelopment: MINDD </li></ul><ul><li>Environmental factors causation </li></ul><ul><li>Interventions: multimodal, no single therapeutic modality </li></ul><ul><li>Dietary change, basic supplementation, heavy metal detoxification cornerstone biomedical intervention </li></ul>
  170. 174. Dr Robyn Cosford Northern Beaches Care Centre For a copy of references, and other related materials,contact 1789 Pittwater Rd Mona Vale, NSW 2103 02 99799444 Fx 02 99799016