Transcript 1 mg/kg/day - Autism One

Advanced Treatments for
Autism and Strategies for NonResponders
Dan Rossignol, MD FAAFP
International Child Development Resource Center
321-259-7111 www.icdrc.org
Autism One Conference 2009
May 21, 2009
Autism Spectrum
ADHD
Asperger
Syndrome
PDD-NOS
Autism
Psychologically / Behaviorally defined
Communication
Stereotypical
behaviors
Social
interaction
Underlying pathophysiology ???
Toxins
Inflammation:
GI, Brain
Oxidative
Stress / Mito
Dysfunction
Impaired
Glutathione /
Sulphation
Autism: Regression
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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
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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 Autism
Clinical Result
MTHFR, Adenosine
Deaminase
Decreased production of glutathione
GST M1-null
Increased susceptibility to mercury and
xenobiotic toxicity; increased body
burden of mercury
ALAD
Increased susceptibility to lead toxicity;
increased body burden of lead
PON-1
Increased susceptibility to pesticide
toxicity
HLA-DR4
Increased allergy and intolerance to
heavy metals
MTF1, SCL11A3
metal transporters
Might lead to impaired efflux of heavy
metals
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.
Windham et al., 2006 Environ Health Perspect 114:1438-44
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).
Roberts et al, 2007 Environ Health Perspect 115:1482-9
Sources of toxins: Prenatal
 Mom (good history needed):
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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:
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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
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
Nataf et al., 2006 Toxicol Appl Pharmacol 214(2):99-108
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.
Eppright et al., 1996 Mo Med 93(3):136-8
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
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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
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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):
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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
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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
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Deficiencies or dysfunctions: ineffective
or defective immune response(s)
2 Hypersensitivity: over-reaction to
innocuous foreign substances
3 Autoimmunity: inappropriate reaction to
self, loss of self-recognition
4 Inflammation: damage to normal tissue
(“bystander effect”) from over-reaction
by immune system
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
Over 4X
Over 4X
Vargas et al., 2005 Ann Neurol 57(1):67-81
Autism and Neuroinflammation
Perivascular macrophages and microglia
Vargas et al., 2005 Ann Neurol 57(1):67-81
Autism
Control
Connolly et al., 1999 J Pediatr 134:607-13
Messahel et al., 1998 Neurosci Letters 241:17-20
in vivo vasoconstriction
Ming et al., 2005 Prostaglandins Leukot Essent Fatty Acids 73(5):379-84
Other tests
 C-reactive protein / Sed rate
 Platelet count
 GI: fecal calprotectin / lactoferrin
 Inflammatory comorbidities:
– Eczema
– Asthma
– Allergies
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.
Shultz et al., 2008 Neuropharmacology 54(6):901-11
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.
Stefanatos et al., 1995 J Am Acad Child Adolesc Psychiatry 34(8):1107-11
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.
Shenoy et al., 2000 J Pediatr 136(5):682-7
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.
Chez et al., 1998 Annals Neurology 44(3):539
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.
Boris et al., 2007 J Neuroinflammation 4:3
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).
Heuer et al., 2008 Autism Res 1(5):275-283
Gupta et al., 1996 J Autism Dev Disord 26(4):439-52
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.
Boris et al., 2006 J Nut Environ Med 15(4):1-8
 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
PANDAS
Pediatric 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)
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.
Penicillin VK 250 mg twice a day or
Zithromax 500 mg once a week
Snider et al., 2005 Biol Psychiatry 57(7):788-92
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.
Perlmutter et al., 1999 Lancet 354(9185):1153-8
6 yo girl with autism
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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
Oxidative Stress
Free Radical
Oxygen
8 electrons
1 electron
ejected
7 electrons
Antioxidant
Oxygen
8 electrons
SAMe
MTHFR
Folic
Acid
Methyl
Folate
Methionine
Methionine
Cycle
SAH
MS
Homocysteine
Oral B12
inactive
MB12
active Transsulfuration
Pathway
Folate Cycle
Detoxification
Toxic
Metals
Cysteine
Glutathione
Free
Radicals
Plasma methionine and the ratio of S-adenosylmethionine (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.
James et al., 2006 Am J Med Genetics Part B 141B:947-56
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
in vivo vasoconstriction
Ming et al., 2005 Prostaglandins Leukot Essent Fatty Acids 73(5):379-84
Testing: Oxidative Stress
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Urinary 8-OHDG
Urinary 8-OHG
Urinary Isoprostanes
Cysteine
Doses: Antioxidants
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Vitamin C: 100 mg/kg/day
CoEnzyme Q 10: 5-10 mg/kg/day
Acetyl-L-Carnitine: 50-100 mg/kg/day
L-Carnosine: 200-400 mg twice a day
Pycnogenol: 1 mg/kg/day (often higher)
MB12 injections: 75 mcg/kg every 1-3 days
Folinic acid 400 mcg twice a day
Omega-3’s: DHA and EPA ~800 mg/day each
Zinc 20-150 mg/day
Melatonin: 1-6 mg 30 mins before bedtime
Mitochondria
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ATP production in the mitochondria
through the electron transport chain (ETC)
from aerobic metabolism creates about 13fold more ATP from glucose than produced
from anaerobic metabolism
An electrochemical gradient is produced
across the inner membrane
Mitochondria are primary source of ROS
by electron leak from the electron transport
chain; 1-2% of oxygen normally produces
free radicals
Jain et al., 1990 Proc Natl Acad Sci USA 88:1913-17
Fernandez-Checa et al., 1998 BioFactors 8:7-11
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)
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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, 4565% chance of mitochondrial defect
upon muscle biopsy
Treatments: MtD
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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
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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
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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
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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
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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 selfstimulatory behavior
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).
Chez et al., 2006 Epilepsy Behav 8(1):267-71
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.
Giannotti et al., 2008 J Autism Dev Disord, in press
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 antiinflammatories
 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
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, placebocontrolled 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.
Chez et al., 2003 Journal of Pediatric Neurology 1(2):83-88
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