Autism spectrum disorders
In recent years there has been a growing consensus both inside (see Harvard/Mass General Autism Project) and outside the medical community that gastrointestinal and nutritional problems contribute substantially to the symptoms of autism*. As we saw earlier, fungal overgrowth can contribute substantially to both gastrointestinal and nutritional problems.

Direct evidence for fungal contribution comes from clinical case studies where autistic children treated with antifungal drugs showed significant improvement in diagnostically relevant symptoms such as

• eye contact and speech
• sleep pattern
• imaginative play
• stereotypical behaviors

There is also evidence that autistic children have unusually high levels of fungal metabolites (tartaric acid) and partially digested dietary peptides (casomorphine and gliadinomorphine) in their urine. These peptides, casomorphine (derived from the milk protein casein) and gliadorphine (also known as gluteomorphine, derived from gluten found in wheat and other grass seeds) will be referred to as exorphines.

Children whose symptoms are more often linked to yeast (primarily candida) overgrowth are ones who

• developed normally until their second or third year and then developed autistic symptoms rapidly following an infectious disease treated by antibiotics or vaccination against measles/mumps/rubella.
• who received repeated/large doses of antibiotics for treatment of infection (most often for inner ear (otitis media) infection)
• who received immunosupressant drug therapy
• who were exposed to viruses that weaken the immune system such as herpes and chicken pox

So far three theories have been proposed to explain the development of late onset autism. The Leaky Gut Hypothesis, Metabolic Disorder Hypothesis and the Excess Opioid Hypothesis.

To us it appears that when taken together they form one coherent hypothesis and the difference is mainly in the emphasis given to different aspects of the same process.

The Leaky Gut Hypothesis puts forth the idea that in autistic patients the integrity of the intestinal lining is compromised. This allows partially digested particles to enter the bloodstream and evoke an immune response and to directly affect the nervous system as described in the Metabolic Disorder Hypothesis. Evidence in support of these theories is the following: many children with regressive autism develop a variety of gastrointestinal problems that appear coincidentally with the behavioral and cognitive symptoms. Physical examination of the lower gastrointestinal tract shows frequent abnormalities and inflammation of the intestinal mucosa and enlarged lymphoid nodules (part of the gut's own immune system). Some have described this condition as a subtle form of Inflammatory Bowel Disease.

Some autistic children have shown to have an immune reaction (allergy)to casein and gluten (most likely evoked by gliadorphine and casomorphine) and food intolerance and environmental sensitivity are very common among autistic children. These are non-diagnostic symptoms, nevertheless, they lend support to the Leaky Gut and Metabolic Disorder hypotheses.

According to the Excess Opioid Hypothesis autism can be explained by the effect of exorphines on neurotransmission (crosstalk of nerve cells) in the Central Nervous System. Casomorphin and gliadorphine interact with the brain's opioid system that is involved in modulating perception, cognition, emotions, mood and behavior and these peptides are likely to be the direct cause of many symptoms. The success of the gluten free casein free (GFCF) diet in decreasing or eliminating symptoms strongly supports this theory.

So how do these theories fit together?
For any exogenous molecule to have an effect on the brain, several events have to happen. First, a malfunctioning digestive (metabolic) system has to produce molecules (exorphines) that normally would not be present in the intestines. Second, these molecules have to enter the bloodstream.

As we have seen, a Leaky Gut is a condition that allows that to happen. Third, the molecule has to pass through the blood-brain barrier and enter the central nervous system. The blood-brain barrier is a complex system that is partly physical and partly biochemical. Its role is to protect the brain from chemical injury and under normal circumstances peptides such as casomorphin and gliadorphin cannot pass through. Infections (meningitis or encephalitis), autoimmune responses, the measles virus and mercury have all been shown to compromise this barrier.

It is important to stress that genetic predisposition underlies everything described here. It has been proposed that autistic children have biochemical deficiencies such as defective peptidase and/or Phenylsulphotransferase (PST). Peptidases are enzymes that break down peptides into amino acids and this deficiency can contribute to the formation of exorphines. Gliadophine (and potentially casomorphine as well) can damage the intestinal lining, as seen in Coeliac disease. These peptides cannot, however, enter the bloodstream without the breakdown of intestinal functions. PST is an enzyme that is necessary for maintaining the integrity of blood vessels, and connective tissue and disruption of these tissues contributes to the permeability of the intestinal mucosa.

Additional genetically determined factors can be an inherently weak immune system and/or blood-brain barrier or their susceptibility to be weakened by heavy metal exposure, infection, intestinal problems (candida overgrowth) or the combination of the above.

It is always the combination of genetic and environmental factors that will determine the severity of the symptoms and prognosis and this is why there is such a variability. Symptoms can be grouped, however, (classical autism, Asperger's syndrome, PDD-NOS) and it has been shown that characteristic differences in urine analysis profiles obtained from patients correlate well with their differing diagnoses. Therefore biochemical indicators can be good predictors of symptoms and vice versa, symptoms can be indicative of the underlying biochemical and physiological problems.

What role does candidiasis have in the etiology of autism?
Candidiasis can contribute to both the diagnostic (behavioral) and non-diagnostic symptoms.

To start with the latter, candida overgrowth will follow the breakdown of the intestinal ecology (dysbiosis), regardless if it is of genetic (peptidase deficiency followed by gliadorphine damage) or environmental origin. Candidiasis plays a major role in rendering and/or maintaining the intestines permeable. It then allows the entry into the blood of molecules that can evoke intolerances and/or allergies. The release of tartaric acid causes hypoglycemia (low blood sugar levels) that in turn causes low muscle tone and probably cognitive problems. The frequently described weak immune system in autistic individuals can also be related to candidiasis.

Most diagnostic symptoms can be linked to the action of exorphines. As mentioned above, these molecules interact with the opioid system that is important in modulating perception, cognition, emotions, mood and behavior. In addition the release of ethanol and canditoxin is also likely to have a profound effect.

Opioids are also involved in directing the development of the nervous system. Initially the nervous system contains many more neurons (nerve cells) than necessary for proper functioning. Removal of the excess neurons starts before birth and continues in infancy. It is a crucial process for proper development of the nervous system and it has been shown to be defective in autistic children.

* we use the term autism for all disorders in the Autism Spectrum Disorder group

References:

Assessment of Antifungal Drug Therapy in Autism by Measurement of Suspected Microbial Metabolites in Urine with Gas Chromatography-Mass Spectrometry William Shaw, PhD, Ellen Kassen, MT(ASCP), Enrique Chaves,MD. Alternative Medicine Magazine 1(1), 15-26
Intestinal pathophysiology in Autism. White JF. Exp Biol Med (Maywood). 2003 Jun;228(6):639-49
Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Reichelt KL, Knivsberg AM. Nutr Neurosci. 2003 Feb; 6(1): 19-28.
Neurodevelopmental disorders after Thimerosal-containing vaccines: A brief communication. Geier MR, Geier, DA. Exp Biol Med (Maywood). 2003 Jun;228(6):660-4
Brain barrier systems: a new frontier in metal neurotoxicological research. Zheng W, Aschner M, Ghersi-Egea JF. Toxicol Appl Pharmacol. 2003 Oct 1; 192(1): 1-11.
The blood-brain barrier in systemic lupus erythematosus. Abbott NJ, Mendonca LL, Dolman DE. Lupus. 2003; 12(12): 908-15.
Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'Leary JJ, Murch SH. Aliment Pharmacol Ther. 2002 Apr; 16(4): 663-74.
Intra-monocyte pathogens delineate autism subgroups. Binstock T. Med Hypotheses. 2001 Apr; 56(4): 523-31.
Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'Leary JJ, Murch SH. Aliment Pharmacol Ther. 2002 Apr; 16(4): 663-74.
Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Whiteley P, Shattock P. Expert Opin Ther Targets. 2002 Apr; 6(2): 175-83.
Autism, an extreme challenge to integrative medicine. Part 1: The knowledge base. Kidd PM. Altern Med Rev, 2002 Aug: 7(4):292-316
Traversal of Candida albicans across human blood-brain barrier in vitro. Jong AY, Stins MF, Huang SH, Chen SH, Kim KS. Infect Immun. 2001 Jul; 69(7): 4536-44
Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance. Mahmoud A. Ghannoum and Louis B. Rice. Clinical Microbiology Reviews, October 1999, p. 501-517, Vol. 12, No. 4

A large number of links with detailed information and additional references can be found on our Links page.

AD/HD
Attention Deficit Disorder (ADD) and Attention Deficit Hyperactive Disorder (ADHD) are generally defined as a persistent pattern of inattentiveness and/or hyperactivity with impulsiveness. They are a very heterogeneous group of disorders and in this discussion we will use their combined abbreviation as AD/HD.

The major diagnostic criteria briefly are:

• Short attention span
• Decreased concentration
• Difficulty sitting still
• Impulsivity and aggressive behavior
• Irritability and nervousness
• Mood swings
• Periods of high energy followed by fatigue

AD/HD is very common in children with a history of frequent middle ear infections (otitis media) that were treated with antibiotics. It is becoming increasingly accepted that in most cases adverse reactions (allergies, intolerances) to food, environmental sensitivities and exposure to heavy metals (most often lead in drinking water) are major etiological factors, along with genetic predisposition.

It is also being recognized that many individuals (adults and children) with AD/HD suffer from candidiasis. By looking at the development of candidiasis the connection between antibiotic use and various allergies and sensitivities becomes clear. Therefore it is safe to say that in many cases candidiasis is at the center of the complex syptomatology of this disorder.

The most commonly cited triggers of AD/HD symptoms are

• dairy products
• refined white sugar
• artificial sweeteners (aspartame, saccharin)
• artificial food coloring
• preservatives
• caffeine

In addition, nutrient (essential fatty acids, primarily the omega-3 group), vitamin (B6) and mineral deficiencies and mineral deficiencies (zinc, calcium and magnesium) have been linked to AD/HD, but it is quite possible that these are a consequence of candidiasis rather than a cause. They, however, contribute considerably to the behavioral symptoms.

Also the contribution of canditoxin, ethanol and casomorphine should be considered (see details under autism spectrum disorders).

In addition to the overwhelming anecdotal evidence in support of the above, a clinical study compared the outcome of treatment with Ritalin versus supplements (containing probiotics, vitamins, minerals, phytonutrients, amino acids, essential fatty acid and phospholipids) in children with AD/HD. The results showed virtually identical outcomes, therefore, probiotics and dietary supplementation can be an effective alternative treatment to stimulants.

References:

Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD. Harding KL Judah RD Gant C. Altern Med Rev 2003 Aug. 8(3):319-30.
Attention deficit/hyperactivity disorder (ADHD) in children: rationale for its integrative management. Kidd PM. Altern Med Rev 2000 Oct. 5(5):402-28.

A large number of links with detailed information and references can be found on our Links page.