Advanced Treatments for Autism and Strategies for Non-

Responders

Dan Rossignol, MD FAAFPInternational Child Development Resource Center

321-259-7111 www.icdrc.orgAutism One Conference 2009

May 21, 2009

ADHD AspergerSyndrome

PDD-NOS Autism

Autism Spectrum

Underlying pathophysiology

Psychologically / Behaviorally defined

Communication Stereotypicalbehaviors

Socialinteraction

???

Toxins

ImpairedGlutathione /Sulphation

OxidativeStress / MitoDysfunction

Inflammation:GI, Brain

Autism: Regression

Seizures (language regression) Inflammation [Connolly, 1999]

Maternal antibodies [Braunschweig, 2008]

Familial autoimmune problems Oxidative stress [Chauhan, 2004]

Fatty acid deficiencies [Bu, 2006]

GI problems [Valicenti-McDermott, 2008]

Mitochondrial dysfunction [Poling, 2006]

Non-responders

Existing / ongoing toxicity Brain inflammation / hypoperfusion Uncontrolled Oxidative stress Mitochondrial dysfunction Subclinical seizure activity

Detoxification “Detox”

Removal of toxic substances from the body Major function of the liver, kidneys, and

gastrointestinal system In people with kidney failure, dialysis is a

form of detoxification Impairments in detox can occur in some

individuals e.g., Acetaldehyde dehydrogenase: facial

flushing with ethanol

Alcohol Acetaldehyde Acetic acid

Genetic Finding

in AutismClinical Result

MTHFR, Adenosine Deaminase

Decreased production of glutathione

GST M1-nullIncreased susceptibility to mercury and xenobiotic toxicity; increased body burden of mercury

ALADIncreased susceptibility to lead toxicity; increased body burden of lead

PON-1Increased susceptibility to pesticide toxicity

HLA-DR4Increased allergy and intolerance to heavy metals

MTF1, SCL11A3 metal transporters

Might lead to impaired efflux of heavy metals

Windham et al., 2006 Environ Health Perspect 114:1438-44

The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs), 1.1–2.1], but not for aromatic solvents. The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride.

Roberts et al, 2007 Environ Health Perspect 115:1482-9

Multivariate a posteriori models comparing children of mothers living within 500 m of field sites with the highest nonzero quartile of organochlorine poundage to those with mothers not living near field sites suggested an odds ratio for ASD of 6.1 (95% confidence interval, 2.4-15.3).

Sources of toxins: Prenatal

Mom (good history needed):– Dietary (seafood consumption)

– Thimerosal containing vaccines; Rhogam

– Amalgams

– Smoking

– Alcohol use

– Lead stored in bone

– Mercury and other metals stored in tissues

– Occupational exposures (dentist, etc…)

– Psychological stress during pregnancy (hurricanes)

Sources of toxins: Postnatal

Child:– Thimerosal (flu) / aluminum from vaccines– Environmental / atmospheric– Dietary sources (arsenic, seafood)– Water ?– Household– Amalgams– Unusual: weighted vests, old bathtubs, lead

weights– Phenols, food dyes, propionic acid

Evaluation for Toxins

Unprovoked blood and urinary heavy metal samples reflect recent exposure

Hair tests reflect metals as long as hair has been there

Chelator challenge Urinary fractionated porphyrins Markers of autoimmunity Plasma sulphate / cysteine Urinary pesticide levels Propionic acid

Nataf et al., 2006 Toxicol Appl Pharmacol 214(2):99-108

The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (p < 0.001) but not significantly in Asperger's. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following DMSA there was a significant (p = 0.002) drop in urinary porphyrin excretion. These data implicate environmental toxicity in childhood autistic disorder.

Nataf et al., 2006 Toxicol Appl Pharmacol 214(2):99-108

Eppright et al., 1996 Mo Med 93(3):136-8

This case involves a 4 1/2-year-old boy diagnosed with autism, attention deficit hyperactivity disorder (ADHD), and an elevated blood-lead level of 42 mcg/dl. The child was treated for the elevated blood-lead with the chelating agent succimer. The parents reported a decrease in repetitive behaviors while on succimer with a regression to previous symptoms when medication was discontinued. Also seen was a decrease of hyperactive behavior while being treated with succimer.

Toxic Metal Treatment(off-label use)

CaNa2 EDTA: FDA approved for lead toxicity, very poor absorption orally. Usually IV or suppository. Good for lead, ok for aluminum, poor for mercury.

DMSA: FDA approved for lead intoxication. Used orally or suppository. Good for mercury and lead, poor for aluminum.

DMPS: Not licensed in the US, but can be legally imported and compounded. Typically used IV or suppository. Good for mercury, fairly poor for lead.

D-penicillamine: FDA approved for Wilson’s disease and rheumatoid arthritis. Used orally. Good chelator of mercury. Crosses blood-brain barrier.

OTC products: Typically lack efficacy studies.

Typically Used Doses

CaEDTA: 10-50 mg/kg DMPS: 2-3 mg/kg (2 mg IV, 3 mg supp.) DMSA

– Oral: 10 mg/kg tid x 3 days / 11 days off– Suppository: 10-20 mg/kg, 2-3 x per week

D-penicillamine: 5-15 mg/kg/day oral

Other IV Therapies

Glutathione: 200-1200 mg N-Acetylcysteine: 200-600 mg Vitamin C: 2,000-4,000 mg Other vitamins/minerals

Brown et al., 2006 Pediatrics 118(2):e534-6

Possible Side-Effects of Chelators

Depressed white blood cell (WBC) count Elevated liver function tests (LFTs) Depletion of vitamins and minerals Dysbiosis Behavioral changes (stimming, hyperactive,

irritability) Allergic reaction / rash Anaphylaxis Use only under physician supervision

Laboratory monitoring

Initially, and generally every 2-3 months (unless problem identified):– Complete blood count (CBC)– CMP (liver enzymes, renal function)– Mineral stores (red blood cell elements)– Iron storage– Cysteine / sulphate– Thyroid function– Provoked urine toxic metals– GI testing as indicated (OAT, stool culture)

4 yo boy with autism

Had regression and lost words Now speaks 20-30 words Stimming: mild Social interaction: poor Hyperactivity: moderate GI: loose BM

Previous UTM after oral DMSA

Labs

CMP, TSH, ferritin, testosterone, lactic acid, ammonia normal

CBC shows mild anemia Cysteine 0.44 (ref 0.61-1.16) Sulfate 3.9 (ref 3.0-5.9)

UTM after DMSA suppository (20 mg/kg)

Immune Dysregulation

Deficiencies or dysfunctions: ineffective or defective immune response(s)

Hypersensitivity: over-reaction to innocuous foreign substances

Autoimmunity: inappropriate reaction to self, loss of self-recognition

Inflammation: damage to normal tissue (“bystander effect”) from over-reaction by immune system

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Immune System Evaluation

A child with autism who has recurrent infections deserves an immune evaluation for immunodeficiency.

A child with autism who has eczema, chronic nasal symptoms, asthma, significant GI symptoms, or recurrent respiratory infections deserves an allergy evaluation for IgE inhalant and food allergies.

Boris et al., 2004 J Nutr Environ Med 14(1):47-54

Autism and Neuroinflammation

Vargas et al., 2005 Ann Neurol 57(1):67-81

Over 4X Over 4X

Perivascular macrophages and microglia

Autism and Neuroinflammation

Vargas et al., 2005 Ann Neurol 57(1):67-81

Connolly et al., 1999 J Pediatr 134:607-13

Autism Control

Messahel et al., 1998 Neurosci Letters 241:17-20

Ming et al., 2005 Prostaglandins Leukot Essent Fatty Acids 73(5):379-84

in vivo vasoconstriction

Other tests

C-reactive protein / Sed rate Platelet count GI: fecal calprotectin / lactoferrin

Inflammatory comorbidities:– Eczema– Asthma– Allergies

Shultz et al., 2008 Neuropharmacology 54(6):901-11

Propionic acid (PPA) is a short chain fatty acid, a metabolic end-product of enteric bacteria in the gut, and a common food preservative. Recent evidence indicates that PPA can cause behavioral abnormalities and a neuroinflammatory response in rats. These findings suggest that PPA can change both brain and behavior in the laboratory rat in a manner that is consistent with symptoms of human ASD.

Stefanatos et al., 1995 J Am Acad Child Adolesc Psychiatry 34(8):1107-11

The authors describe a child whose language and behavior regressed at 22 months and in whom pervasive developmental disorder was later diagnosed. At 6 years, he displayed a profound receptive-expressive aphasia accompanied by behavioral disturbances characterized by hyperactivity, impaired social interactions, tantrums, gestural stereotypies, and echolalia. Corticosteroid treatment resulted in amelioration of language abilities and behavior.

Shenoy et al., 2000 J Pediatr 136(5):682-7

Previously developmentally normal, he had symptoms of autism with rapid regression in developmental milestones coincident with the onset of lymphoproliferation and autoimmune hemolytic anemia. Low-dose steroid therapy induced early and complete remission in the ALPS phenotype. There was subjective improvement, followed by objective improvement in speech and developmental milestones. We propose that autism may be part of the autoimmune disease spectrum of ALPS in this child.

Chez et al., 1998 Annals Neurology 44(3):539

A prospective study was done with 44 children with language regression and abnormal Digitrace 24 EEG epileptiform activity in sleep. All the patients were treated with a form of Depakote or Depakene for 8 to 12 weeks and were reassessed with a 24-hour EEG before the addition of weekly bolus high-dose prednisone or methylprednisolone (10 mg/kg/wk). Results of poststeroid add-on treatment were available for 25 cases. Of these patients, EEG showed further improvement in 60% (n = 15), with no improvement seen in 40% (n = 10). Clinical speech data showed the combination of Depakote/Depakene and pulse dose steroid treatment yielding improvement in 82% (n=36). Side effects were unremarkable with no cushingoid complications even after 18 months of therapy.

Boris et al., 2007 J Neuroinflammation 4:3

A total of 25 children (average age 7.9 +/- 0.7 year old) were enrolled. Safety was assessed by measurements of metabolic profiles and blood pressure. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients.

Heuer et al., 2008 Autism Res 1(5):275-283

Children with autism have a significantly reduced level of plasma IgG (5.39+/-0.29 mg/mL) compared to the TD (7.72+/-0.28 mg/mL; P<0.001) and DD children (8.23+/-0.49 mg/mL; P<0.001). Children with autism also had a reduced level of plasma IgM (0.670.06mg/mL) compared to TD (0.79+/-0.05 mg/mL; P<0.05). Ig levels were negatively correlated with ABC scores for all children (IgG: r=-0.334, P<0.0001; IgM: r=-0.167, P=0.0285).

Gupta et al., 1996 J Autism Dev Disord 26(4):439-52

Boris et al., 2006 J Nut Environ Med 15(4):1-8

In documented autistic children, 400mg/kg IVIG was administered each month for 6 months. Baseline and monthly Aberrant Behavior Checklists were completed on each child in order to measure the child’s response to IVIG. The participants’ overall aberrant behaviors decreased substantially soon after receiving their first dose of IVIG. Further analysis of the total scores revealed decreases in hyperactivity, inappropriate speech, irritability, lethargy and stereotypy. However, 22 of the 26 children regressed to their pre-IVIG status within 2–4 months of discontinuing the IVIG.

Naltrexone increased T-helper cells and decreased T-suppressor cells in children with autism.

Scifo et al., 1996 Ann Ist Super Sanita 32(3):351-9

Bradstreet et al., 2007 Med Hypotheses 68(5):979-87

Anti-inflammatories:Typical doses

Prednisone: 1-2 mg/kg/day tapered unless using high-dose protocol

Spironolactone: 2-3 mg/kg/day target Actos: 15-60 mg/day Singulair: 4-10 mg/day Minocycline: 50-100 mg bid IVIG: 400-800 mg/kg once a month

Wilson et al., 2006 Brain Res 1098:126-8

5 yo girl with autism

On supplements including antioxidants, MB12, GFCF diet

Urinary neopterin is very elevated Mildly elevated platelet count Porphyrins mildly elevated History of eczema

Treatment

Singulair Spironolactone 2-3 mg/kg/day trial for

2-3 months HBOT

PANDASPediatric Autoimmune Neuropsychiatric Disorder

Associated with Streptococcus: Presence of obsessive-compulsive disorder and/or a tic

disorder Pediatric onset of symptoms Episodic course of symptom severity Association with group A Beta-hemolytic streptococcal

infection (a positive throat culture for Strep or history of Scarlet Fever)

Association with neurological abnormalities (motoric hyperactivity, or adventitious movements, such as choreiform movements)

Snider et al., 2005 Biol Psychiatry 57(7):788-92

Penicillin VK 250 mg twice a day orZithromax 500 mg once a week

Twenty-three subjects with PANDAS were enrolled in a double blind, randomized controlled trial. Antibiotic prophylaxis with penicillin or azithromycin was administered for 12 months. Penicillin and azithromycin prophylaxis were found to be effective in decreasing streptococcal infections and neuropsychiatric symptom exacerbations among children in the PANDAS subgroup.

Perlmutter et al., 1999 Lancet 354(9185):1153-8

In children, exacerbations of tics and obsessive symptoms may occur after infection with group A beta-haemolytic streptococci. Children with severe, infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, were randomly assigned treatment with plasma exchange (five single-volume exchanges over 2 weeks), IVIG (1 g/kg daily on 2 consecutive days), or placebo (saline solution given in the same manner as IVIG). Plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders.

6 yo girl with autism

Obsessive and compulsive Extensive self-stimulatory behavior Episodic course to some degree Unusual movements Never had strep throat as far as parent

recall

PANDAS

Antibiotic prophylaxis:– Zithromax 500 mg once a week– PCN 250 mg bid

IVIG 1 gm/kg/day x 2 days May need serotonin modulator

Free Radical

Oxygen

8 electrons 7 electrons1 electronejected

Oxidative Stress

Antioxidant

Oxygen

8 electrons

SAMeSAMe

CysteineCysteine

GlutathioneGlutathione

MB12active

SAHSAH

HomocysteineHomocysteine

MethionineMethionine

Oral B12inactive

FolicAcid

MethylFolate

MTHFR

FreeRadicals

ToxicMetals

MS

Folate Cycle

MethionineCycle

Trans-sulfurationPathway

Detoxification

James et al., 2006 Am J Med Genetics Part B 141B:947-56

Plasma methionine and the ratio of S-adenosyl-methionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. Plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.

Based on reports of abnormal methionine and glutathione metabolism in autistic children, it was of interest to examine the same metabolic profile in the parents. The results indicated that parents share similar metabolic deficits in methylation capacity and glutathione-dependent antioxidant/detoxification capacity observed in many autistic children.

James et al., 2008 J Autism Dev Disord 38(10):1966-75

Ming et al., 2005 Prostaglandins Leukot Essent Fatty Acids 73(5):379-84

in vivo vasoconstriction

Testing: Oxidative Stress

Urinary 8-OHDG Urinary 8-OHG Urinary Isoprostanes Cysteine

Doses: AntioxidantsDoses: Antioxidants Vitamin C: 100 mg/kg/dayVitamin C: 100 mg/kg/day CoEnzyme Q 10: 5-10 mg/kg/dayCoEnzyme Q 10: 5-10 mg/kg/day Acetyl-L-Carnitine: 50-100 mg/kg/dayAcetyl-L-Carnitine: 50-100 mg/kg/day L-Carnosine: 200-400 mg twice a dayL-Carnosine: 200-400 mg twice a day Pycnogenol: 1 mg/kg/day (often higher)Pycnogenol: 1 mg/kg/day (often higher) MB12 injections: 75 mcg/kg every 1-3 daysMB12 injections: 75 mcg/kg every 1-3 days Folinic acid 400 mcg twice a dayFolinic acid 400 mcg twice a day Omega-3’s: DHA and EPA ~800 mg/day eachOmega-3’s: DHA and EPA ~800 mg/day each Zinc 20-150 mg/dayZinc 20-150 mg/day Melatonin: 1-6 mg 30 mins before bedtimeMelatonin: 1-6 mg 30 mins before bedtime

MitochondriaMitochondria ATP production in the mitochondria through the ATP production in the mitochondria through the

electron transport chain (electron transport chain (ETCETC) from aerobic ) from aerobic metabolism creates about 13-fold more ATP from metabolism creates about 13-fold more ATP from glucose than produced from anaerobic glucose than produced from anaerobic metabolismmetabolism

An electrochemical gradient is produced across An electrochemical gradient is produced across the inner membranethe inner membrane

Mitochondria are primary source of ROS by Mitochondria are primary source of ROS by electron leak from the electron transport chain; electron leak from the electron transport chain; 1-2% of oxygen normally produces free radicals1-2% of oxygen normally produces free radicals

Fernandez-Checa et al., 1998 BioFactors 8:7-11

Jain et al., 1990 Proc Natl Acad Sci USA 88:1913-17

Atkuri et al., 2009 Proc Natl Acad Sci U S A., in press

Mitochondrial Disease (MD)

• Primary mitochondrial disease typically refers to genetic defects leading to mitochondria dysfunction (MtD)

• Secondary mitochondrial disease (dysfunction) refers to impaired functioning of mitochondria

• Organs with highest aerobic demand are most affected (CNS, heart, and skeletal muscle), but any organ can be affected including GI and endocrine

Symptoms / Signs of MtD

• “Any symptom in any organ at any age” [Munnich, 1996]

• Developmental delay• Hypotonia (low muscle tone)• Constipation / GI dysmotility• Slow cognitive processing speed• Fatigue [Weissman, 2008]

• Seizures• Oxidative stress

Labs: MtD (blood)

• Basic chemistry (CO2, anion gap)

• Liver enzymes (AST, ALT)• Ammonia• Creatine kinase• Lactic acid and pyruvate• Plasma amino acids: alanine (compared to

lysine), glycine, proline, sacrosine, tyrosine• Fasting plasma acylcarnitine analysis

Chances of Mito Dysfunction in ASD?

• Epidemiological studies: 4-7% mito disease, 20% mito dysfunction

• If you suspect mito dysfunction, and especially if lactic acid is elevated, 45-65% chance of mitochondrial defect upon muscle biopsy

Treatments: MtD

• CoEnzyme Q10: 5-10 mg/kg/day• Idebenone: 45-360 mg/day• Acetyl-L-Carnitine: 50-100 mg/kg/day• L-Carnitine (Carnitor)• Thiamine (B1): 15 mg/kg/day• Pyridoxine: 5-15 mg/kg/day• Riboflavin (B2): 15 mg/kg/day• Pantothenic acid: 15 mg/kg/day• Vitamin E: 15 IU/kg/day

Treatments: MtD, con’t

• Vitamin C: 25 mg/kg/day• Alpha-lipoic acid: 15 mg/kg/day• Vitamin K3: 5-80 mg/day• Folate: 1-10 mg/day• Creatine monohydrate: 5-10 g/day• B12, selenium, succinate, Ginkgo biloba• D-ribose• Antioxidants• Chelation / HBOT

Case # 2: 4 yo boy with autism

• Multiple regressions with illnesses

• Chronic constipation

• Seizures

• Speech: has 10 words

• Stimming: moderate

• Social interaction: poor

• No family history of mitochondrial disease

Case #2 con’t

• Pregnancy/birth history unremarkable

• Parents saw regression with vaccines

• Gets 10 hours of ABA/week

• No meds, takes MVI and fatty acids

• Diet: large protein intake

• No recent labs

• PE significantly for moderate hypotonia

Initial labs: Case #2

• CBC, CMP, TSH, lead, ferritin normal

• Ammonia 62 (ref 11-32)

• Lactic acid 2.6 (ref 0.4-2.0)

• Cysteine 0.43 (ref 0.61-1.16)

• Plasma amino acids (alanine to lysine ratio = 4.3, ref < 2.5)

Mitochondrial biogenesis• When energy needs of a cell are high,

mitochondria divide• Increased ROS triggers mtDNA proliferation;

nDNA can also trigger increased mitochondrial division

• If mitochondrion cannot maintain ATP production, then undergoes apoptosis

• Cells normally remove old mitochondria (autophagy) and synthesize new mitochondria (biogenesis)

Gutsaeva et al., 2006 Neuroscience 137:493-504

CONCLUSION: Children with autism who received hyperbaric treatment at 1.3 atm and 24% oxygen for 40 hourly sessions had significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children who received slightly pressurized room air.

Rossignol et al., 2009 BMC Pediatr 9:21

Seizures

Need high index of suspicion Look for absence seizures Think of subclinical seizures in children who

are slow to respond to standard treatments Consider 24-hour hour EEG or SPECT scan Lamotrigine (Lamictal): also blocks

glutamate, is a mood stabilizer Gabapentin (Neurontin): may help with self-

stimulatory behavior

Chez et al., 2006 Epilepsy Behav 8(1):267-71

This retrospective review of 24-hour ambulatory digital EEG data collected from 889 ASD patients presenting between 1996 and 2005 shows that 540 of 889 (60.7%) subjects had abnormal EEG epileptiform activity in sleep with no difference based on clinical regression. The most frequent sites of epileptiform abnormalities were localized over the right temporal region. Of 176 patients treated with valproic acid, 80 normalized on EEG and 30 more showed EEG improvement compared with the first EEG (average of 10.1 months to repeat EEG).

Giannotti et al., 2008 J Autism Dev Disord, in press

Results suggested that the regressed group had higher incidence of circadian rhythm disorders than non-regressed children. The regressed group showed higher Children's Sleep Habits Questionnaire Bedtime Resistance, Sleep Onset Delay, Sleep Duration and Night-Wakings scores. Epilepsy and frequent epileptiform EEG abnormalities were more frequent in regressed children. This study is an initial step in better understanding sleep problems in regressed children with autism, further studies are necessary to better investigate these aspects.

12 yo girl with autism

Almost complete lack of speech, which did not progress while other symptoms were improving over time

Staring spells Improved speech was observed with

the addition of lamotrigine after SPECT scan performed

6 yo boy with autism

Slow to progress with standard biomed However, did respond to anti-

inflammatories Severe refractory self-stimulatory

behavior SPECT performed due to slow progress Improvement in speech and almost

complete cessation of stimming with Gabapentin

Proceedings of the 11th International Congress on Hyperbaric Medicine

Acute nicotine treatment has been found to reduce symptoms of attention deficit/hyperactivity disorder in adults. Acute and chronic nicotine treatment significantly attenuated the rise in hit reaction time standard error over session blocks on the Conners Continuous Performance Test. Acute nicotine significantly reduced severity of clinical symptoms on the Clinical Global Impressions scale. Nicotine caused a significant decrease in self-report of depressive mood as measured by the Profile of Mood States test.

Levin et al., 2001 Exp Clin Psychopharmacol 9(1):83-90

Chez et al., 2003 Journal of Pediatric Neurology 1(2):83-88

Forty-three patients (35 males, 8 females, average age 6.8 yrs., range 2.1-10.3 yrs), with diagnoses of Autistic Spectrum Disorders enrolled in a randomized six-week, double blind, placebo-controlled trial of donepezil hydrochloride, with an additional six weeks of open-label treatment. Expressive and receptive speech gains, as well as decreases in severity of overall autistic behavior, were documented after 6-weeks for the treatment group. These improvements were statistically significant when compared to placebo, and were clinically meaningful as assessed over time.

When parent and teacher scores were combined, mean scores were slightly lower during treatment with galantamine than during treatment with placebo for irritability classified by ratings of the aberrant behaviour checklist (galantamine 11.5 (7.6) v placebo 15.1 (5.4), P=0.039), hyperactivity (17.2 (12.8) v 21.7 (15.4), P=0.038), inadequate eye contact (placebo 7.6 (3.2) v 8.4 (5.2), P=0.049), and inappropriate speech 4.7 (3.1) v 6.2 (2.4), P=0.045).

Niederhofer et al., 2002 BMJ 325:1422

Open-label add-on therapy was offered to 151 patients with prior diagnoses of autism or Pervasive Developmental Disorder Not Otherwise Specified over a 21-month period. Results showed significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although self-stimulatory behaviors comparatively improved to a lesser degree.

Chez et al., 2007 J Child Neurol 22(5):574-9

METHODS: Oxytocin and placebo challenges were administered to 15 adult subjects diagnosed with autism or Asperger's disorder, and comprehension of affective speech (happy, indifferent, angry, and sad) in neutral content sentences was tested. RESULTS: All subjects showed improvements in affective speech comprehension from pre- to post-infusion.

Hollander et al., 2007 Biol Psychiatry 61(4):498-503

Clinical Pearls

Loss of speech (regression): oxidative stress / brain inflammation (autoantibodies)

Low muscle tone / constipation: mitochondrial dysfunction

Improvement with motrin / rarely sick: immune activation / inflammation

Immediate response to chelation: oxidative stress OCD / self-stimulatory behavior: low serotonin,

PANDAS, Clostridia Toe-walking: think tryptophan depletion Don’t forget iron deficiency and hypothyroidism