immune globulin therapy and autism treatment a review of immune globulin therapy for autism...

Immune Globulin Therapy and Autism Treatment

A Review of Immune Globulin Therapy

for Autism TreatmentElizabeth Cohen

Amanda Davis

Jane Sondern(Caldwell College Graduate

Programs in Applied Behavior Analysis)


Overview• Understanding Immunoglobulins in the Immune System• IgG• Other Immunoglobulins• What is Immune Globulin Therapy?• History of Immune Globulin Therapy• Present day realities

– Indications– Routes of Administration– Contraindications– Off-label Utilization

• What does Immune Globulin Therapy have to do with autism?• Autism and IVIG: Claims


Overview• Research

– Gupta et al (1996)

– Gupta (1997)

– Singh (1997)

– Plioplys (1998)

– Singh (1999)

– DelGiudice-Asch et al (1999)

– Niederhofer et al (2003)

– Schneider et al (2006)

– Adams (2007)


Overview

• Criteria for Immune Globulin to Treat Autism

• Side Effects

• Other Considerations

• Conclusions

• References

• Questions/Discussion


Understanding Immuno-globulins in the Immune System

• Immune globulins are produced by B cells and are also known as antibodies.

• Immune globulins are naturally occurring in the blood plasma serum of healthy individuals.


Understanding Immuno-globulins in the Immune System

• The purpose of immune globulins is to neutralize and opsonize pathogens.

• There are 5 classes of immunoglobulins

– IgG

– IgM

– IgA

– IgE

– IgD


IgG

• IgG is the most prevalent immunoglobulin found in the bloodstream at about 80%. IgG is formed in large quantities, easily travels from the bloodstream to tissues, and lasts for approximately 1 month.

• IgG is produced upon second exposure to an antigen at which time it binds to the antigen.

• IgG is the only immunoglobulin that crosses the placenta and passes immunity from the mother to the newborn.

• IgG is broken into four subclasses:

- IgG1 - IgG3

- IgG2 - IgG4


Prevalence of IgG Subclasses in the total IgG serum in the

bloodstream

0

10

20

30

40

50

60

70

IgG1 IgG2 IgG3 IgG4

IgG Subclasses


IgG Subclasses• Functions of the IgG Subclasses

– IgG1 and IgG3 • rich in antibodies against proteins

– IgG2 • predominantly antibodies against the polysaccharide (complex

sugar/carbohydrate) coating or capsule of certain disease producing bacteria

– IgG4• function is largely unknown possibly due to it’s limited

prevalence in the total IgG serum• generally accepted that IgG4 works with IgG2 to bind to

carbohydrate antigens


Other Classes of Immunoglobulins

• IgA antibodies

– produced near mucous membranes and found in secretions

• IgE antibodies

– responsible for allergic reations and antibodies binding to antigens produce inflammatory sustances (histamine)

• IgM antibodies

– first antibodies to be formed in response to an infection to provide important protection during the early days of an infection

• IgD antibodies

– role not fully understood, found on the surface of B cells and may be involved in cell differentiation


What is Immune Globulin Therapy?

• Immune globulin therapy is a treatment to provide high doses of IgG.

• Immune globulin therapy is usually used as a replacement therapy.

• Immune globulin therapy products are derived from pooled human blood plasma.


History

• Immune globulin was first used to prevent infectious diseases in World War II.

• Processes for large-scale fractionization of human plasma were initially developed by Edwin Cohn and his colleagues at Harvard to provide albumin as a treatment for shock in World War II.

• Plasma cooled to 0°C, ethanol and buffer added, and four protein fractions were precipitated out of solution

• Cohn fraction II contained most antibodies


History

• 1952– Immune globulin therapy was first given to treat primary immune

deficiencies following Bruton’s description of agammaglobulinemia.

• 1960’s – Barundun and others from the Swiss Red Cross Laboratories

prepared IgG for intravenous use, however it was not FDA approved until the 1980’s.


History

• 1980’s– Early in the decade, new manufacturing processes were developed

to make immunoglobulin preparations that could be administered intravenously (IVIG). Prior to this, the only form of immune globulin therapy available was intramuscular injection (IM).

• 1992 to 2003– IVIG production tripled from 19.4 tons to 52.6 tons annually.

• 2006– The FDA approved preparations of immunoglobulin for

subcutaneous administration (SCIG).


Additional History

• Procedures for further purification of gamma globulins and other proteins precipitating at lower concentrations of ethanol were then developed by Oncley et al. Gamma globulin rapidly replaced convalescent and animal sera for the prevention and treatment of infectious diseases such as measles, hepatitis, and polio, then came into widespread use as replacement therapy in the primary immune deficiencies, which emerged in the antibiotic era of the early 1950s. http://www.ncbi.nlm.nih.gov/pubmed/12165202


Present Day Realities

• Although it took 40 years to develop preparations of gamma globulin that could be safely given intravenously, the eventual accomplishment of that goal has led to better treatment of antibody deficiency syndromes and also the wide use of high-dose intravenous immunoglobulin in autoimmune and inflammatory diseases. Those uses continue to expand even as monoclonal antibodies are being introduced for specific infectious diseases in high-

risk populations. http://www.ncbi.nlm.nih.gov/pubmed/12165202


Present Day Realities:Indications

• FDA Approved Indications– Primary Immune Deficiency

– Idiopathic Thrombocytopenic Purpura

– Kawasaki Disease

– B-Cell Chronic Lymphocytic Leukemia

– HIV Infection (pediatric)

– Bone Marrow Transplantation


Present Day Realities:Administration

• Administration Routes of Immune Globulin Therapy– Intramuscular (IMIG)

– Intravenous (IVIG)

– Subcutaneous (SCIG)


Present Day Realities:Contraindications

Immune globulin therapy is contraindicated in anyone with a history of:

• kidney disease

• diabetes

• sepsis

• plasma cell disease

• volume depletion

• those taking medications that can cause kidney damage


Present Day Realities:Off Label Utilization

• Autism

• Chronic fatigue syndrome

• Chronic inflammatory demyelinating polyneuropathy (CIDP)

• Clostridium difficile colitis

• Dermatomyositis and polymyositis

• Graves' ophthalmopathy

• Guillain-Barré syndrome

• Kawasaki disease

• Muscular Dystrophy

• Inclusion body myositis

• Lambert-Eaton syndrome

• Lupus erythematosus

• Multifocal motor neuropathy

• Multiple sclerosis

• Myasthenia gravis

• Neonatal alloimmune thrombocytopenia


Present Day Realities:Off Label Utilization (cont’d)

• Parvovirus B19

• Pemphigus

• Post-transfusion purpura

• Renal transplant rejection

• Spontaneous Abortion/Miscarriage

• Stiff person syndrome

• Severe sepsis and septic shock in critically ill adults[7]

• Toxic epidermal necrolysis

• In chronic lymphocytic leukemia and multiple myeloma, as well as various rare deficiencies of immunoglobulin synthesis (e.g. X-linked agammaglobulinemia, hypogammaglobulinemia), IVIG is administered to maintain adequate immunoglobulin levels to prevent infections.


What does immune globulin therapy have to do with autism?

• Some people believe that people with autistic spectrum disorders are susceptible to immune deficiencies and that these deficiencies may produce some of the symptoms of autism.

• By injecting or swallowing immune globulin, an antibody used by the immune system to identify and neutralize foreign objects like bacteria and viruses, it is believed those abnormalities can be overcome and the symptoms of autism reduced.

http://www.researchautism.net/interventionitem.ikml?print&ra=19&infolevel=4



• Vijendra K. Singh, Ph.D. (neuroimmunologist)– Up to eighty percent (and possibly all) cases of autism are caused

by an abnormal immune reaction, commonly known as autoimmunity (http://www.crossroadsinstitute.org/newsletter/nlarticles/aug05/singhautism.html)

– 1992 study linked autism to heightened autoimmunity, finding autistic children have about an eight times greater incidence of antibodies to myelin basic protein (MBP) than control children

– 2002 study suggested that MMR-vaccinated children have abnormally high levels of measles virus antibodies, indicating autism may be a neuro-immune response to the vaccine



• Sudhir Gupta, M.D.

– Increased evidence in immunological abnormalities including T cells, B cells, NK cells, and complement system

– Data shows markedly dysregulated immune system in children with autism

• Marinos C. Dalakas, M.D.– High-dose intravenous immune globulin (IVIg) has emerged as an

important therapy for various neurologic diseases (

http://www.annals.org/cgi/content/full/126/9/721)


Autism and IVIGClaims

Researchers suggest they will demonstrate improvement in the following areas:

• Eye Contact

• Speech

• Behavior

• Echolalia

• GI signs and symptoms

• Hyperactivity

• Inappropriate stims

• Social Interactions

• Aberrant behaviors

• Other autistic behaviors


ResearchGupta, Aggarwal, Heads (1996)

• Claims– Autism is syndrome of neuro-development associated with

impairments in communication, social interaction, learning and thinking skills, repetitive and self-injurious behaviors

– Factors • Genetic• Infectious• Immunological

– Increased evidence in immunological abnormalities including T cells, B cells, NK cells, and complement system

– Data shows markedly dysregulated immune system in children with autism


ResearchGupta et al (1996)

• Participants– 25 children (ages 3-12, 17 male, 8 female)

– All diagnosis of autism according to the DSM III-R

– Immune system abnormalities were shown in participants

• 56% increased IgM & IgE

• 20% IgA Deficiency

• 20% IgG Subclass Deficiency



• Methods– 10 children given IVIG at 400mg/kg at 4 week intervals for 6

months

– Parents were instructed to pre-medicate with oral benadryl prior to arrival for infusion

– Information was obtained from speech and behavior therapists as well as psychiatrists for behavioral, cognitive, and developmental characteristics

– Psychiatrists were blind to type of treatment


Research Gupta et al (1996)



• Results– 6 months of IVIG infusion resulted in marked improvement in a

number of autistic characteristics including eye contact, calmer behavior, speech, echolalia, and so forth.

– Earliest observable effects were calmer behavior and improved eye contact

– Speech is slow to improve and spontaneous speech develops last



• Results (cont’d)– Discontinuation after the 6 months resulted in re-appearance of

autism characteristics for few patients• When re-started on IVIG, improvement was shown

– 2 patients were followed for 5 months prior and following the IVIG infusions

• Prior to IVIG: no significant changes were observed (positive or negative)

• Post-IVIG: significant changes with regard to spontaneous conversational speech, thinking and processing, oral reading and attention span



• Results (cont’d)– Unclear how long IVIG is indicated in autism

– Effect of age and gender on the response to IVIG cannot be determined based on small sample size and presence of only 1 female in the study

– Appears that younger children respond earlier (within 2-3 infusions) as compared to older children (within 4-5 infusions)



• Future research– Planning a controlled double-blind placebo multicenter study to

extend the observations and develop a profile of patient most likely to respond and examine the effect of IVIG on dysregulated immune functions in autism


ResearchGupta (1997)

• Grant funded by Cure Autism Now (CAN)

• Claims– Improved eye contact, speech, behavior, echolalia, and other

autistic behaviors

• Participants– 20 children enrolled

• 12 children randomly assigned placebo (Group 1)

• 12 obtained IVIG (Group 2)



• Methods– Double-blind placebo controlled study

– Study divided into 2 phases (6 treatments in each phase)

• Phase I: 4 week interval of IVIG for Group1 and a placebo for Group 2

• Phase II: 4 week interval of IVIG for Group 2 and a placebo for Group 1



• Results– As a group, there was no significant different between placebo and

IVIG

– Some children did show improvement but significance could not be determined based on study size


ResearchSingh (1997)

• Vijendra Singh has been studying autism as an autoimmune disorder for 15 years

• Unpublished data

– double-blind study shows that IVIG was found to decrease brain auto-antibody titers in 5 patients however, they were positive pre-therapy but negative post-therapy


ResearchPlioplys (1998)

• Participants– 10 children with immunological abnormalities

• 8 males• 2 females• Age range: 4 years 3 months to 15 years 7 months

• Methods– Intent of treatment program was to use 200mg/kg to 400mg/kg of

IVIG per treatment every 6 weeks for a total of 4 administrations– Actual dose administered ranged from 154 mg/kg to 375 mg/kg

(mean dosage 270 mg/kg) per administration.



• Methods (cont’d)– 6 children had the planned 4 infusions and one child each had 1, 3,

5, and 6 infusions– 7 children needed to be sedated prior to infusions (4 with rectal

pentobarbital and 3 with oral chloral hydrate)– In the child who received 6 infusions, two were administered by

the author and 4 by local physicians– In the child who received 5 infusions, the 5th infusion was given at

the request of the parents– The children who received 1 and 3 infusions were withdrawn from

the treatment program by the parents due to apparent lack of effectiveness



• Results (cont’d)– 4 made mild improvements with IVIG– 5 made no clinical changes– 1 progressed and “normalized” during the treatment– The 1 dramatic response that was demonstrated indicated that

there may but a subset of children with autism whose disorder is due to an autoimmune abnormality

– Following the study, none of the parents elected to continue intravenous immune globulin therapy. The parents felt that the costs and inconvenience involved with IVIG outweighed the slight improvements seen.


ResearchSingh (1999)

• Open-label trials of low and high dose IVIG have shown most (but not all) children have responded favorably with a better response seen in children receiving a high dose

• Clinical results demonstrate improvement in language, communication, social interaction, and attention span


ResearchDelGiudice-Asch, Simon, Schmeidler, Cunningham-Rundles, Hollander (1999)

• Participants– Seven children, ages 3½-6 years (6 male, 1 female)– The diagnosis of autism was established using the Autism

Diagnostic Interview (ADI; Le Couteur, Rutter, Lord, & Rios, 1989) and DSM IV criteria (APA, 1994)

– All children were enrolled in full day educational program in addition to receiving IVIG

– Immunologic testing was not performed and past histories of the children were not notable for an increased frequency of infections or seizure disorder.


ResearchDelGuidice et al (1999)

• Methods– Five children ages 3M-6 years (4 male, 1 female) completed 6

months of IVIG clinical treatment in a highly monitored outpatient setting

– One child withdrew from the study after receiving 2 months of IVIG (considered diagnosis of Laudau-Kleffner syndrome)

– Another child opted to receive the final 2 IVIG infusions through a private home care company



• Methods (cont’d)– Bimonthly behavioral assessments were performed by an

experienced educator who was not blind to the treatment using the following scales:

• The Ritvo-Freeman Real Life Rating Scale

• The Children Yale-Brown Obsessive-Compulsive Scale

• The Clinical Global Impression Scale for Autistic Disorder

• The Autism Modification of the NIMH Global Obsessive-Compulsive Scale



• Results– Study suggests that IVIG does not appear to be beneficial

• Future Research– Further systematic research on therapeutic interventions is needed


ResearchNiederhofer, Staffin, and Mair

(2003)

• Participants– 12 patients (4.2-14.9 yrs.)– No immunological abnormalities– Patients received no medication 1 month before procedure

• Methods– Double-blind crossover design– Participants continued to receive educational and behavioral

interventions– Checked at 6 & 12 weeks


Research Niederhofer et al (2003)

• Results– The study demonstrated mixed results:

• Showed improvement on Abberant Behavior (ABC) and symptom checklist

• No significant difference between placebo and IVIG treatment group

• Doubtful statistical difference of outcome


ResearchNiederhofer et al (2003)


ResearchSchneider, Melmed, Enriquez,

Barstow, Ranger-Moore, Ostrem (2006)

• Hypothesis– Gastrointestinal disturbances associated with autistic disorder (AD)

may be due to an underlying deficiency in mucosal immunity, and that orally administered immunoglobulin would be effective in alleviating chronic GI dysfunction in these individuals.

• Claims– Improved GI signs and symptoms, significant behavioral

improvements


ResearchSchneider et al (2006)

• Participants– 12 male subjects diagnosed with AD– evaluated using a GI severity index (GSI) while receiving daily

dosing with encapsulated human immunoglobulin

• Methods– 8-week, open label, fixed dose evaluation of the safety and

efficacy of oral immunoglobulin (Panglobulin) taken at a dose of 420 mg (IgG) prior to bedtime



• Methods (cont’d)– A follow-up visit was conducted at week 12, 4 weeks after

discontinuation of study medication

• Results– Thirty four adverse events were recorded during the study

• 28 categorized as mild

• 6 categorized as moderate

• No serious adverse events were recorded during the study



• Results (cont’d)– Oral human immunoglobulin administered for eight weeks at daily

doses of 420 mg were shown to be well tolerated and effective in improving the clinical course of the GI signs and symptoms experienced by subjects

• Future research– Larger, controlled trials will be necessary to answer the most

important questions regarding the relationship, if any, between GI symptoms and core behavioral aspects of AD


ResearchAdams (2007)

• Claims– Improved aberrant behaviors, speech, hyperactivity, inappropriate

stims, and social interactions

• Participants– 26 autistic children

• Methods– received IVIG every 4 weeks for 6 months (dosage 400mg/kg)

• Results– 22 of the 26 children regressed within 4 months after IVIG was

discontinued


Criteria for IVIG for the Treatment of Autism

• In order to be considered for IVIG, the patient must meet:– All 5 absolute criteria

– 2 contributing major criteria

– 1 contributing minor factor

(http://www.webpediatrics.com/ivig.html)


Criteria for IVIG for the Treatment of Autism

Absolute Criteria Contributing Major Criteria Contributing Minor Criteria

met criteria for DSM IV diagnosis of Autism

Illness within 6 weeks before onset of symptoms

Positive immunodeficiency battery (lymphocyte phenotyping; D8/17+ cells >12%)

diagnosed as “classical” autism, PDD, or PPD-NOS

Received a viral vaccine within 6 weeks of onset

Abnormal complement studies (C3, C4, CH50)

Normal development until onset of symptoms

Followed a period of apparently normal psychological development

Abnormal cytokine levels (IL-1-alpha, IL-2, IL-6, IFN-gamma and TNF-alpha)

Normal levels of IgA in quantitative immunoglobulin assay

Onset of symptoms was SUDDEN (and period of days/weeks) or INTERMEDIATE weeks (up to 3 months)

Presence of serum myelin basic protein antibody and /or neuro-axon filament protein antibody

Ages between 2 and 10 years Elevated viral titers (Rubella, Measles, Human Herpes Virus, etc.)


Side Effects

• pain at the injection site

• allergic/anaphylactic reactions

• acute renal failure

• venous thrombosis

• aseptic meningitis

• hives or rash

• dermatitis - usually peeling of the skin of the palms and soles

• redness of the face

• chills

• fever

• sweating

• unusual tiredness or weakness


Side Effects (cont’d)

• dizziness

• headache

• backache

• leg cramps

• joint or muscle pain

• general feeling of discomfort

• chest tightness

• pulmonary edema from fluid overload, due to the high colloid oncotic pressure of IVIG

• upset stomach

• vomiting


Other Considerations• Hazards

– IVIg treatment is usually well tolerated. Most adverse effects are mild and are usually related to the rate of infusion. However, according to MedlinePlus, IVIG can cause a number of significant, life-threatening hazards.

– It can cause kidney failure, especially in those with a history of kidney disease, diabetes, sepsis, plasma cell disease, or volume depletion, or in those taking medications that can cause kidney

damage


Other Considerations

• Hazards (cont’d)– Immune globulin therapy carries the risk of potentially fatal

transmission of blood-borne pathogens (i.e. HIV, hepatitis, etc). Pharmaceutical grade immune globulin is prepared commercially by separating immunoglobulin fractions from pooled human blood specimens. Several steps in the process are added to ensure that any live viruses or bacteria in the specimens are inactive – but there is still a risk.

– There is potentially an unknown risk of contracting variant Creutzfeldt-Jakob disease (vCJD).



• Insurance– Many patients receiving immune globlin therapy for FDA

approved indications have difficulty with insurance approval

– Most private health insurance carriers as well as public health assistance (i.e. MediCare and MediCaid) will not cover the expense of any medication or treatment for off label uses.



• Expense– Approximate wholesale price paid by hospitals or retail

pharmacies is approximately $18.00 to $25.00 per gram of IVIG.

– Health Health insurers are charged $46.00 to $80.00 per gram by hospitals, home infusion companies, and physicians who

administer the drug.



• Expense (cont’d)– Combined total retail cost amounts to $6,400 to $11,200 per month

for the drug alone to treat a patient of average weight (154lbs)– The cost of treatment also depends on whether the drug is

administered in a hospital, an outpatient clinic, or a home-infusion program and on whether it is given in 2 days or 5 days

– Total monthly charges for immune globulin therapy can range from $8,500 to $20,000.



• Availability– Availability is directly connected to the number of blood plasma donors

donating at plasma donation centers– Though a national shortage has not been declared, in the last few years,

many patients receiving immune globulin therapy for FDA approved indications have had their treatment impacted due to limited availability including:

• Change in brand• Decrease in dosage• Missed infusions• Change in infusion location• Decreased frequency of infusions



• Availability (cont’d)– There may be ethical considerations with using IVIG for

off-label/experimental uses when availability is limited and there is a potential for shortage. Life saving dosages could be withheld from patients receiving IVIG for FDA Approved Indications and given to patients when the effectiveness is minimal or unknown.

– IVIG effectiveness is heavily contingent upon maintaining consistent levels of IgG in the blood. Determining effectiveness for off-label uses may be difficult if dosages or infusions are missed due to limited availability.


Conclusions

• There is strong evidence that immune globulin is ineffective in the treatment of the majority of people with autistic spectrum disorders.

• It is also expensive, inconvenient to use, and potentially harmful.• It is strongly recommended that immune globulin therapy is not used

as a treatment for autism in children because of the substantial risks and the lack of proven benefit associated with this intervention.– The FDA has not approved immune globulin therapy as an intervention

for autism

• If it is used, it should only be undertaken with great caution and only as part of formal research studies. http://www.researchautism.net/interventionitem.ikml?print&ra=19&infolevel=4


Conclusions

• Pseudoscience– Definition: A procedure, method or therapy that is adopted rapidly

in the presence of little validating research

• Immune Globulin and Pseudoscience– The research on immune globulin as a treatment for autism has not

shown any significant clinical improvements in any of the claims stated. The studies have also shown that few of the changes were long-lasting.


Conclusions

• Gupta– 2 studies 1996 and 2000.

– His research showed children with autism treated with IVIG improve in several areas.

– However…….


Conclusions

• Gupta’s research is flawed– No control group

– Group was too small

– Research cannot be replicated

– Anecdotal observations

– Research published in Journal of Autism and Dev. Disability


Conclusions

• No Control Group– In 1996 study, Gupta had treated Group1 with IVIG, and gave

Group 2 placebo. After 4 weeks, he administered Group 1 with placebo and gave Group 2 IVIG.

• Group Size was too small– The sample size was too small and one female. The effect of age

and gender on the responsiveness of IVIG cannot be ascertained.


Conclusions

• Research cannot be replicated.– Plioplys, Adams, Schneider, Neideholfer,Staffen and Mair,

andDelgiudice- Asch

– All tried to replicate the research

– All have mixed results.


Conclusions• DelGuidice et al (1999)

– Not a double-blind, placebo-controlled study resulting in a unclear answers as to whether a subgroup of patients may be responders or if a longer treatment is needed.

– Small sample, large number of measures, and high variance of the measures limits the generalization it of the findings.

– No effects

• Plioplys (1998) – Limited results


Conclusions• Niederhofer et al (2003)

– Limited results– Non Scientific - continue to receive other interventions – ABC ratings by teacher and parents – subjective and anecdotal. – Clinician - insignificant differences between placebo and immune

globulin• “For that reason, our results should be understood as a strong

cautionary word against the growing indiscriminate use of intravenous immunoglobulin in treating autistic children.”

• Schneider et al (2006)– Limited results


Conclusions

• Research published in Journal of Developmental Disabilities– In instructions for authors, under checklist states, “A brief report

may not meet the demands of scientific rigor required of an article can be preliminary findings.”


Conclusions

• Singh– In a study in 1997, Singh found IVIG decrease symptoms of

autism. The data on this study is not published. In a paper presented in 1999, high dose of IVIG was found to produce better results than low dose in reducing autism symptoms.


Conclusions

• Singh’s research is flawed– Data not published

– Speaking out of his profession

– Observations anecdotal

– Group too small


Conclusions

• NY State Dept of Health and Clinical Practice

– “It is strongly recommended that intravenous immune globulin therapy not be used as a treatment for autism for children in autism in children because of substantial risk and lack of proven benefit associated with this intervention.”

• The evidence that has been presented has not proven to be reliable so far. It is in our opinion that IVIG not be used as a treatment for children with autism.


References

• Adams, J. A. (2007). Summary of biomedical treatments for autism. Autism Research Institute Publication 40, 1-28.

• Blaese, R. M. & Winkelstein, J. A. (Eds.). (2007). Patient & Family Handbook for Primary Immunodeficiency Diseases. Towson, Maryland: Immune Deficiency Foundation.

• DelGiudice-Asch, G., Simon, L., Schmeidler, J., Cunningham-Rundles, C., Hollander, E. (1999). Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. Journal of Autism and Developmental Disorders, 29(2), 157-160.

• Gupta, S., Aggerwal, S., & Heads, C. (1996). Brief report: Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. Journal of Autism and Developmental Disorders, 26(4), 439-452.


References• Gupta, S. (1997). A double-blind placebo-controlled crossover study

of the effects of intravenous immunoglobulin (IVIG) in autism. Retrieved June 6, 2008, from http://www.autismspeaks.org/science/ research/grants/funded_1997_can.php

• Niederhofer, H., Staffen, W., & Mair, A. (2003). Immunoglobulins as an alternative strategy of psychopharmacological treatment of children with autistic disorder. Neuropsychopharmacology, 28(5), 1014-1015.

• Plioplys, A., V. (1998). Intravenous immuneglobulin treatment of children with autism. Journal of Child Neurology, 13(2), 79-82.

• Schneider, C. K., Melmed, R. D., Enriquez, F. J., Barstow, L. E., Ranger-Moore, J., & Ostrem, J. A. (2006). Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study. Journal of Autism and Developmental Disorders, 36(8), 1053-1064.

immune globulin therapy and autism treatment a review of immune globulin therapy for autism...

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