Part 2 of 3 (Part 1 Part 3)
James R. Laidler, M.D.
The DAN! mercury detoxification consensus group met in Dallas, Texas on February 9 - 11, 2001 to gather some of the top scientists and practitioners in the field to develop a protocol for mercury detoxification in the autistic child.
Rationale
Many of the features of autism bear striking similarity to certain features of mercury poisoning, especially the immune dysfunctions1,2, visual disturbances3,4, and motor/coordination defects5 seen in a growing number of autistic children. Treating autistic children with agents to remove mercury and/or other heavy metals has brought about significant improvement in many of them, sometimes dramatic improvement.
This improvement is coincident with increased excretion of mercury and/or other metals in most but not all patients. Some have theorized that those who improve without increased mercury excretion are suffering from some other metal toxicity. Another possibility, which also explains those patients who improve without significant heavy metal excretion, is that the chelating agents are working in some other fashion and that the heavy metal excretion is coincidental to this other effect.
For example, there are clinical studies showing that autistic children with significant allergy problems have elevated cysteine/sulfate ratios in their blood, and there are other indications of disordered sulfur amino-acid chemistry. Sulfhydrylbearing agents, such as DMSA and others, remove cysteine6 and thereby improve some sulfur amino acid imbalances.
Yet another possibility under investigation is the anti-oxidant effect of the drugs and supplements used and their ability to compensate for deficiencies in the native anti-oxidant systems. Quite a few autistic children have laboratory evidence of anti-oxidant deficiency; low intracellular glutathione is commonly found in these children.
What may be happening in these children is that the DMSA7 and other agents "put out the fire" of intracellular oxidation and help restore the 7 normal anti-oxidant functions. Whatever the action may be, DMSA therapy has been shown to help a large number of autistic children. It is important to remember that autism is a syndrome, not a disease.
The "diagnosis" of autism covers a wide spectrum of children, many as different from each other as they are different from "typical" children. No one causative factor has been identified for autism and the possibility exists that autism is not a single disease but several individual diseases that share a similar presentation.
With that in mind, it is not surprising that no single treatment has been found that works for all children with autism. Preparatory treatment Many, if not most, autistic children suffer from some degree of intestinal dysbiosis, abnormal intestinal permeability and nutritional derangements which must all be corrected as much as possible prior to any attempt at detoxification.
Without this preparatory treatment, the adverse side effects of therapy may be magnified. Without the correction of their intestinal dysfunctions, any improvement from the treatment may be hard to detect. Many of the drugs and supplements used for mercury detoxification are rich sources of nutrition for bacteria and fungi.
If treatment is started while the child is suffering from overgrowth of abnormal or pathogenic organisms, they will experience explosive growth of these organisms with subsequent worsening of their symptoms. This monograph is but a part of the DAN! treatment protocol for autistic children, so this is not the place for a detailed discussion of how to correct their intestinal problems. However, a brief outline of the process is included (Appendix B) to help practitioners who are not familiar with the process.
Inclusion testing
Urine, blood and hair mercury are typically normal or negative unless the mercury exposure has been fairly recent. On occasion, urinary mercury will be elevated if the child is in a catabolic state due to growth or malnutrition. In these situations, the mercury stored in tissues may be released as those cells are broken down.
Provoked excretion of mercury and heavy metals is the only accurate way to estimate the total body burden of heavy metals. This is performed by administering a chelating agent prior to collection of urine for heavy metal analysis. The usual provoking agents are 2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-propane-sulfonate (DMPS). Of these two, DMSA is safer, but DMPS is somewhat more effective8,9.
The usual way to gather a provoked urine specimen is to administer the chelating agent and then to collect the next six to twelve hours of urine produced. The usual DMSA dose for a single-dose provocation is 10 mg/kg. No reference ranges exist for provoked urinary heavy metal excretion, so the interpretation of the results is problematic.
Given that the problem in autistic children may be excessive sensitivity to mercury or other heavy metals, any level over the reference range for unprovoked urine heavy metals may be sufficient indication for a trial of therapy. In addition to mercury, lead, cadmium, arsenic, antimony and many other metals are extracted by DMSA10, so the urine metal analysis may show a number of toxic metals. 8
Other than looking for the heavy metals directly, one can look for evidence of their effects. Mercury and other heavy metals suppress the effect of a number of enzymes, some of which can be easily tested. The most commonly available of these is glucose-6 phosphodiesterase (G-6PD); a quantitative G-6PD activity may reveal levels intermediate between normal and deficient in heavy metal poisoning11.
Of note, there has been one report of hemolysis in a patient with absolute G-6PD-deficiency12, but DMSA has been used extensively in populations with a high incidence of G-6PD deficiency and sickle cell disease without problems. Less commonly available is glutathione reductase, which is also reduced in heavy metal poisoning13.
Low glutathione levels in the red cells are not specific for heavy metal toxicity, but may be supporting evidence. Another commonly available test is blood or urine pyruvic acid. Pyruvic acid can be elevated for a number of reasons, but mercury is notorious for interfering with the mitochondrial pyruvate dehydrogenase complex, where it binds to and deactivates the lipoic acid coenzyme, resulting in elevated pyruvic acid.
Mercury and other heavy metals interfere with heme synthesis, leading to urinary excretion of uroporphyrin and coproporphyrin. Mercury also causes production of pre-coproporphyrin, which may be considered a specific marker for mercury poisoning14,15. Analysis of uroporphyrin and coproporphyrin can be done at most clinical laboratories; pre-coproporphyrin analysis can also be done, but most laboratories do not routinely have that test available.
Mercury and other heavy metals (such as lead) can cause progressive myelin degeneration with the development of antibodies to myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP)16,17. While these changes are not diagnostic of mercury intoxication, they point to ongoing degeneration in the central nervous system.
Depletion or deficiency of the cellular antioxidant systems is seen in a number of autistic children. A common finding in autistic children is an abnormally low erythrocyte glutathione level. The potential causes for this deficiency in cellular antioxidant substances are myriad, ranging from congenital deficiency to toxins; heavy metals are well-documented causes of intracellular antioxidant depletion.
Whether the cause is too little production, rapid consumption or a combination of the two, many of these children can benefit from exogenous antioxidant support. Since DMSA and many of the other supplements used to treat mercury and heavy metal intoxication are powerful antioxidants, this may be mechanism of action in some children who improve, especially those who show little excretion of toxic metals.
Since it is possible that neither removal of metals nor supplementing cellular antioxidants are the mechanism of action, an empiric trial of DMSA therapy may be warranted. This trial should be done for a limited time and without changing any other therapy, including physical therapy, occupational therapy, speech therapy, etc. If no definitive results are seen in four to six weeks, discontinue therapy and look again for any changes.
Pre-treatment testing
DMSA can cause bone marrow suppression and is potentially hepatotoxic18. There have been no reports yet of permanent bone marrow suppression or liver damage, but the literature has many case reports of significant neutropenia and thrombocytopenia during therapy with DMSA.
Prior to starting therapy, it is important that a complete blood count (CBC) with platelet count be 9 checked, both to provide a baseline as well as to detect any pre-existing abnormalities. Blood levels of liver transaminases (ALT and AST) are also important for the same reasons. DMSA is primarily excreted in the urine19, so kidney dysfunction will cause it to accumulate in the blood.
To prevent serious toxicity, it is important to detect any decreased renal function prior to starting therapy. In the absence of any signs or symptoms of renal insufficiency, blood urea nitrogen (BUN) and creatinine levels should be adequate to document normal renal function. If there are any reasons to suspect renal insufficiency, creatinine clearance should be measured.
Periodic checks of blood urea nitrogen and creatinine should also be performed when other blood studies are done. Several investigators have found that autistic children are typically low in blood zinc and high in blood copper. Many other minerals, such as selenium and magnesium, are often low as well.
The body stores of these minerals can be estimated by measuring the red blood cell mineral content. Serum copper and plasma zinc levels are considered to be the most accurate reflections of total body content of these two minerals, but not many laboratories can perform this assay consistently. Other options are platelet and erythrocyte copper and zinc levels.
Practitioners who decide to use copper and zinc levels routinely are advised to closely monitor their analytical laboratory and to perform periodic quality-control checks with known samples.
Detoxification Of the chelating agents available at present, DMSA (succimer, Chemet®) provides the optimal combination of safety and efficacy. DMSA has been used extensively for nearly fifty years and is approved by the USFDA to treat lead poisoning in children; its safety record is exemplary20.
There is far less experience using DMPS, especially in children, and the adult experience with it has shown that it is significantly more toxic than DMSA. DMPS is currently not approved for any use by the USFDA.
Several animal studies have shown that DMSA is capable of removing a portion of the mercury bound in the brain21,22. Some of these studies have also shown that, months after exposure, mercury still moves between the blood and brain in both directions23.
It should be noted that, to date, no studies have definitively shown any chelating agent capable of removing mercury from the human brain, no doubt due to the reluctance of human subjects to have their brains removed for analysis. One autopsy study has demonstrated that, despite urine and blood mercury levels in the normal range, mercury will persist in the brain and other organs for many years without adequate chelation therapy24.
DMSA should be given in doses of no more than 10 mg/kg/dose and no more than 30 mg/kg/day with a maximum dose of 500 mg (1500 mg/day maximum). Exceeding these limits has been associated with a significantly higher incidence of side effects and toxicity.
The dosing interval can be any convenient period, as long as the dose limits are not exceeded. There is no convincing evidence to suggest that dosing intervals shorter than eight hours provide any inherent benefit, although a lower dose given more frequently may help to reduce troublesome side effects.
In addition, the subset of children who experience improvement only while receiving DMSA may benefit from more frequent dosing. Clinical experience supporting 3- or 4-hour dosing intervals is matched by equally good results with 8-hour dosing. As always, the dosing interval should be based on the clinical response of the individual patient. 10 DMSA is usually given orally but it can, if necessary, be given intravenously.
There is also some experience with rectal administration via suppository. Despite the sulfurous smell, most children will take it if it is mixed with a suitable masking liquid, such as orange juice or other sweet beverage. One study has shown that mercury-intoxicated rats prefer water containing DMSA to pure water, while the control animals would shun the water with DMSA25; this phenomenon has been seen in some children as well.
Acidic or neutral liquids are best to maintain the activity of the DMSA while in solution. DMSA will retain approximately 80% of its activity after 24 hours in solution, but prolonged storage in solution may result in significant degradation and loss of effectiveness26. If the child will swallow capsules, the whole issue of taste and smell can be neatly bypassed.
The treatment period can last from three to five days with a "rest period" of at least as long as the treatment period. A treatment of three days followed by a rest period of eleven days provides adequate time for bone marrow suppression to resolve and yet is short enough for rapid removal of tissue mercury. A three-day treatment period allows the drug to be administered over the weekend (Friday evening through Monday morning), which can be a tremendous convenience.
Common side effects of DMSA are nausea, diarrhea, anorexia, flatulence and fatigue. If these become serious enough, reducing the dose will usually make the symptoms tolerable. Occasionally, patients develop a maculopapular rash during treatment; this should not to be confused with an allergic reaction27. Some autistic children are reported to experience a transient regression in language and behavior during and shortly after treatment. Reducing the dose may also make these symptoms less bothersome.
Clinical experience suggests that most children who experience regression at the start of therapy will have less regression with each subsequent cycle of treatment. Serious side effects of DMSA are extremely rare and include allergic reaction, toxic epidermal necrolysis (TEN) and erythema multiforme (Stevens-Johnson syndrome)a. Potentially dangerous neutropenia and thrombocytopenia may also occur28. While reducing the dose may reduce the severity of the neutropenia and thrombocytopenia, truly dangerous reductions in cell count are a contraindication to continued therapy without a compelling reason to do so.
Obviously, allergic a No cross-sensitivity between DMSA and the sulfa antibiotics has been reported. If the patient has a history of sensitivity or allergy to other dithiol chelating agents (e.g. DMPS, DMPA, dimercaprol/BAL), they may not be a candidate for DMSA therapy, depending on the severity of the reaction. If the reaction was mild or ambiguous, a small test dose can help resolve the issue. Toxic epidermal necrolysis and erythema multiforme occur without predictable pattern and their etiologies are poorly understood. Both may occur with the initial treatment or may appear after several months of therapy.
Both have been reported only a few times in connection with DMSA even though tens of thousands of children have received the drug. Erythema multiforme (Stevens-Johnson syndrome) is a selflimited inflammatory disorder of the skin and mucous membranes. It is thought to be induced by immune complexes and mediated by lymphocytes. It is characterized by distinctive target-shaped skin lesions, sore throat, mucous ulcers and fever. It usually begins a week or more after therapy starts and will usually resolve spontaneously if the inciting medication is stopped.
Toxic epidermal necrolysis (TEN) is the most serious cutaneous drug reaction and may be fatal if not recognized. Its onset is generally very acute and characterized by epidermal necrosis without significant dermal inflammation. Its pathology is poorly understood but it also usually resolves when the inciting agent is stopped. There are no other specific treatments other than supportive therapy and symptom relief. 11 reaction, TEN and Stevens-Johnson syndrome are absolute contraindications to continued therapy.
More beneficial "side effects" reported with DMSA therapy in autistic children include rapid progression of language ability, improved social interaction, improved eye contact, and decreased self-stimulatory behaviors ("stimming"). Children with motor problems have experienced significant improvement in both strength and coordination.
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