Autism tests and treatments - recommened by Dr Singh

[Guest guest]

.... I find it very odd that his

findings and suggestions have not been explored by DAN! and others to

greater extent!

I have saved the text below a while ago, someone brought up discussion on one of the treatments..

here is a bit more on his work:

http://www.latitudes.org/articles/singh_neuro_ts.html

Autism, Autoimmunity and Immunotherapy: a Commentary by Vijendra K. Singh, Ph.D.

Department of Biology & Biotechnology Center, Utah State University, Logan

Scientific Board Member, Autism Autoimmunity Project

Autism is an early-onset biological disorder that causes severe

deficits of higher mental functions, as well as behavioral

manifestations. There is no single, clear-cut cause and no complete

cure for autism. Causally speaking, immune factors, neuro-chemical

factors, genetic susceptibility factors and environmental factors (such

as microbial infections and chemical toxicity) have been implicated. I

view autism as a very complex, multifactorial disorder. In this

article, I will attempt to describe succinctly the role of autoimmune

etiology and immune therapy for autism.

As a neuroimmunologist, I have been interested in the immunology of the

nervous system, i.e., the immune basis and immune therapy for brain

diseases and mental illnesses. I have studied autism as an autoimmune

disorder for over fifteen years. As a result, I firmly believe that up

to eighty percent (and possibly all) cases of autism are caused by an

abnormal immune reaction, commonly known as autoimmunity. The

autoimmune process in autism results from a complex interaction between

the immune system and the nervous system. I recently postulated a

"Neuroautoimmunity Model of Autism" which I discussed at two recent

conferences: first, the Biomedical Treatments for Autism and PDD

Conference held in Orlando, Florida (May, 1999); and second, the

Neuro-Immune Dysfunction Syndromes (NIDS) Conference held in Bethesda,

land (June, 1999). Briefly, I hypothesized that an autoimmune

reaction to brain structures, in particular the myelin sheath, plays a

critical role in causing the neurological impairments of patients with

autism. I suggested that an immune insult to developing myelin (after a

natural infection or vaccination) causes "nicks" or small changes in

the myelin sheath. These changes ultimately lead to life-long

disturbances of higher mental functions such as learning, memory,

communication, social interaction, etc.

I believe that autism can be treated successfully using some of the

therapies proven effective in treating other autoimmune diseases. I am

exploring specifically the role of autoimmune factors, (e.g., viruses,

autoantibodies, T cells, and cytokines) because they serve as the prime

targets of therapy with immune-modulating agents. I emphasize the need

to focus on immunotherapies, and I urge doctors toexamine autoimmunity

as a novel target on which to focus in treating autistic patients.

There is enormous potential for restoring brain function in autistic

children and adults through immunology.

Autoimmune Etiology in Autism

A disease is commonly referred to as "autoimmune" when the etiology and

pathogenesis is not well known or established. Autoimmunity is an

abnormal immune reaction in which the immune system becomes primed to

react against body organs, and the end result is autoimmune disease.

Several factors contribute to the pathogenic mechanism of autoimmune

diseases. These illnesses are commonly believed to be triggered by

infectious agents; further, they are generally linked to genes that

control immune responses. They cause immune abnormalities of T

lymphocytes (one type of white blood cell); they induce the production

of autoantibodies; they involve hormonal factors; and they generally

show a gender preference. This is also the case with autism: several

autoimmune factors have been identified in patients with autism,

suggesting the pathogenetic role of autoimmunity in autism. While some

of the key features are listed below, I will focus more on the current

research relating to three topics: viral studies; autoimmune testing;

and autoimmune therapy. Some generalities regarding the genetics and

immunology of autism are below:

Autism displays increased frequency of genetic factors for immune

responses, e.g., HLA, C4B null allele, extended haplotypes, etc.

Autism involves a gender factor, i.e., it affects males about four times more than females.

Autism often occurs in conjunction with a family history of

autoimmune diseases, e.g., multiple sclerosis, rheumatoid arthritis,

etc.

Autism also involves hormonal factors, e.g., secretin, beta-endorphin, etc.

Autism shows an association with infectious agents, in particular viruses.

Autistic patients have immune abnormalities, especially those that characterize an autoimmune reaction in a disease.

Autistic patients respond well to immune therapies.

Viral Studies in Autism

Viruses have been linked to autism, but this relationship is far from

fully explored. Certain viral infections can easily be acquired during

fetal life, infancy or early childhood. They can enter the brain

through the nasopharyngeal membranes or induce an autoimmune response

against the brain, thereby altering the development of brain function.

Since autism is an early-onset disorder, usually diagnosed before the

age of 30 months, it was suggested that viruses might serve as

teratogens (agents that cause developmental malfunctions) contributing

to autism.

Earlier studies implicated congenital rubella virus (RV), simply

because children with this infection also showed autistic behaviors.

Moreover, several autistic children did not produce antibodies to

rubella vaccine even after the repeated rubella immunization. Although

the reason for this problem has never been investigated, I think this

is due to a defect in T lymphocytes-these agents of immune response are

not functioning properly in these children. In an unpublished pilot

study, I found that the RV-induced lymphocyte proliferation response in

autistic children was only one-fourth of the response in normal

children, which clearly suggests a defect of T cell-mediated immunity

(a defense mechanism that helps fight virus infections).

A few cases of autism have also been described among children with

congenital cytomegalovirus (CMV). Interestingly, an autistic child with

CMV responded favorably to treatment with transfer factor, but there

was no follow-up to the study in which this was reported. A few years

ago I and coworkers conducted a study of IgG antibodies to CMV; we

found no statistical difference between autistic children and normal

children (V. Singh, D. Schubert and R. Warren, 1992; unpublished data).

Simply put, this means that CMV is probably not related to autism.

More recently, I conducted a study of measles virus (MV) and human

herpesvirus-6 (HHV-6) in autism. This was done by two types of

laboratory analysis: (a) virus antibody levels of MV and HHV-6; and (

brain autoantibody titers in the same samples as those assayed for

virus antibodies. This study showed two things in particular: first,

that the virus antibody levels in the blood of autistic children were

much higher when compared to normal children; and secondly, the

elevated virus antibody levels were associated with the brain

autoantibody titer. Interestingly, the viral antibody and brain

autoantibody association was particularly true of MV antibody and MBP

autoantibody (i.e., 90 percent of autistic children showed this

association). This observation led me to hypothesize that a measles

virus-induced autoimmune response is a causal factor in autism, whereas

HHV-6 via co-infection may contribute to pathophysiology of the

disorder. Although as yet unproven, I think it is an excellent working

hypothesis to explain autism, and it may also help us understand why

some children show autistic regression after the measles-mumps-rubella

(MMR) immunization.

Testing for Autoimmunity in Autism

Recent advances have clearly shown that autoimmunity plays a key role

in the pathogenesis of autism. Since the brain is the affected organ in

autism, the autoimmune response will be directed against this organ.

This response is commonly identified by certain autoimmune factors

which I have identified in autistic children. The

list includes brain-specific autoantibodies, viral antibodies, cytokine

profile or immune activation markers, as well as antinuclear antibodies.

Collectively, they are essential for identifying a brain-specific

autoimmune response, which can afterward be treated with immune

therapy. By performing blood tests we can determine if a patient shows

autoimmunity to brain tissues, if he or she is a candidate for experimental immune therapy, and if the response to therapy is effective. Therefore, this type of immune evaluation is very important in helping children with autism.

Brain autoantibodies: this test detects antibodies to two brain

proteins, namely the myelin basic protein (MBP) and neuron-axon

filament proteins (NAFP). The incidence of MBP antibody in the autistic

population (70% positive) is over twenty times higher than that of the

normal population (3% positive); hence, it serves as a primary marker

of the autoimmune reaction in autism. In contrast, the incidence of

NAFP antibody in autistic patients (55% positive) is only about twice

that of normal controls (27% positive), making it a secondary marker of

autoimmunity in autism. It is, however, recommended that the two

markers be tested simultaneously.

Cytokine profile:

two immune activation markers or cytokines, namely interleukin-12

(IL-12) and interferon gamma (IFN-g), play key roles in the induction

of autoimmune diseases, i.e., they initiate an autoimmune reaction.

They are selectively elevated in autistic patients and should be

measured as a sign of altered cellular autoimmunity-a function of Th-1

type white blood cells.

Virus serology: this

test measures levels of antibodies to measles (rubeola) virus (MV) and

human herpes virus-6 (HHV-6). The antibody levels are elevated, which

is a sign of a present infection, past infection, or reaction to

measles-mumps-rubella (MMR) vaccine. The HHV-6 and measles viruses are

etiologically-linked to autism because they are related to brain

autoantibodies and demyelinating diseases.

Antinuclear antibodies:

this test assays for antinuclear antibodies (ANA). They are

non-specific antibodies but are often present in patients with

autoimmune diseases. Approximately one-third of autistic children

tested have positive titers of ANA (V. Singh, 1992; unpublished data).

Immunotherapy in Autism

The aforementioned laboratory findings clearly point to an autoimmune

pathogenic mechanism in autism. The idea that autism is an autoimmune

disorder is further strengthened by the fact that autistic patients

respond well to treatment with immune modulating drugs. Immune

interventions can produce immune modulation-a state of suppression or

stimulation. Depending on the nature of the immune abnormality, the

goal of therapy should be to normalize or reconstitute the immune

response instead of inducing immune suppression or stimulation. This

will maintain a balance within the normal immune response, avoiding

major fluctuations of overt immune activity which could be detrimental

to the patient. Immune therapy should always be done in consultation

with physicians. The following immune interventions can be used:

Steroid therapy:

steroids such as Prednisone and/or ACTH (adrenocorticotropin hormone)

are commonly used as anti-inflammatory and/or immunosuppressive drugs

for treating patients with autoimmune diseases, inflammatory diseases,

etc. In autism, however, there is only one study that showed

improvement of autistic-like symptoms in children when they were

treated with an ACTH analogue. This result indicated that steroids are

potentially useful in alleviating clinical symptoms of autism. Steroids

are the first course of treatment for patients with autoimmune diseases

and infantile spasm; however, their efficacy has not been evaluated in

autism.

Intraveneous immunoglobulin (IVIG):

this type of treatment has been used to treat children with autism.

Open-label trials of both low-dose and high-dose IVIG have shown that

most but not all autistic children respond favorably to this treatment.

My collaborators and I recently found that the high-dose IVIG was

better than the low-dose IVIG (J. Bradstreet, V. Singh and J. El-Dahr,

paper presented at the International Symposium on Autism, Netherlands,

December 28-30, 1999). Clinically, children so treated have shown

improvements in language, communication, social interaction and

attention span. In a double-blind study, (V. Singh, 1997; unpublished

data) the IVIG treatment was found to decrease brain autoantibody

titers in five patients (they were positive pre-therapy but became

virtually negative post-therapy) who also showed clinical improvement

of autistic characteristics. In spite of the success of IVIG, this

treatment is not for everyone. Before this treatment is administered, a

proper immune evaluation is highly recommended to assess the nature of

the immune problem.

Oral tolerance with autoantigens: this treatment is a means of inducing

immune suppression by feeding patients autoantigen. I have shown that

the candidate autoantigen in autism appeared to be a myelin basic

protein (MBP); this suggested that the MBP-containing myelin products

can be used to treat autistic patients. Indeed, one such product known

as Sphingolin

has been used with success. Recently, the parents, school

psychologists, and other professionals have anecdotally reported

tremendous improvements of autistic symptoms in their children. These

reports are undoubtedly quite encouraging and promising, but a

well-designed clinical trial is warranted.

Plasmapheresis:

although it is not commonly recommended, this procedure is used for

treating patients with infections, autoimmune diseases, immune complex

diseases, etc. Because this method removes harmful substances (e.g.,

autoantibodies) from the blood, it is considered a viable immune

therapy. The method has been used to treat certain brain disorders, for

example Rasmussen's encephalitis (RE) and obsessive-compulsive disorder

(OCD), in which autoimmunity has been implicated as a basis of the

disorder. Plasmapheresis produced positive responses in patients with

these disorders, and the responses were much better with plasmapheresis

when compared to the IVIG treatment. In each case, the benefit to the

patient was associated with the lowering of the anti-neuronal antibody

titers. Since autistic patients also have positive titers of brain

autoantibodies, they should also respond to plasmapheresis. Although

this treatment has long been suggested for use in autism (V. Singh,

1997), plasmapheresis has thus far not been tried in patients with this

disorder.

Conclusion

The evidence is rapidly accumulating to suggest that autism is an

autoimmune disorder. The autoimmune response is most likely directed

against the brain myelin, perhaps secondary to a viral infection.

Measles virus is a candidate but other possibilities remain to be

explored. More importantly, the patients respond to treatment with

immune therapies. Therefore, I conclude that autoimmunity offersstrong

prospects for drug discovery and therapy for autism. Naturally, it

deserves prompt attention from all those who want to help people with

autism.

Selected Reading

Singh, V. K., "Plasma Increase of Interleukin-12 and Interferon-gamma:

Pathological Significance in Autism" (Journal of Neuroimmunology, vol.

66, pp. 143-145 [1996]).

Singh, V. K., "Immunotherapy for Brain Diseases and Mental Illnesses," (Progress in Drug Research, vol. 43, pp. 129-146 [1997]).

Singh, V. K., "Serological Association of Measles Virus and Human

Herpesvirus-6 With Brain Autoantibodies in Autism" (Clinical Immunology

and Immunopathology, vol. 89, pp. 105-108 [1998]).

Singh, V. K., "Autoimmunity and Neurologic Disorders" (Latitudes, vol. 4, pp. 5-11 [1999]).

Dr. Singh received his doctorate from the University of British

Columbia, Vancouver, Canada. His post-doctoral fellowship was completed

in neurochemistry and neuroimmunology. Spanning over twenty years'

experience in neurobiology and immunology research, Dr. Singh studied

brain diseases, particularly infantile autism and Alzheimer's disease.

Having authored over a hundred scientific publications, he is both a

pioneer and an international authority on autoimmunity in autism. Dr.

Singh is a member of the American Association for the Advancement of

Sciences, the American Association of Immunologists, and the New York

Academy of Sciences. He is listed in American Men and Women in Science

(United States, R. R. Bowker, publisher) and The International Who's

Who of Intellectuals (Cambridge, England, International Biographical

Centre).

For further information, please contact Dr. Vijendra Singh, Ph.D., at

the Biotechnology Center, Department of Biology, Utah State University,

4700 Old Main Hill, Logan, UT 84322-4700 [E-mail:

singhvk@...].

Reprinted from AAPN, The Autism Autoimmunity Project Newsletter, vol. 1, number 2, December 1999.

Links

"Autoimmunity and Neurological Disorders," interview with V. K. Singh in Latitudes, newsletter of the Association for

Comprehensive NeuroTherapy, http://www.latitudes.org/index.html, vol. 4, no. 2, Spring 1999, by Sheila

: http://lib.tcu.edu/www/staff/lruede/latitudes

"V. K. Singh: Selected Research on Autism," http://www.gti.net/truegrit/ : Findings in Immunology

"Vijendra K. Singh, Ph.D.: Selected Work on Alzheimer's Disease," (http://lib.tcu.edu/www/staff/lruede/alzheimers)

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