Summary Autism is a syndrome characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recent epidemiological studies suggest that autism may affect 1 in 150 U. S. children. Exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative added to many vaccines, has become a major source of mercury in children who, within their first two years, may have received a quantity of mercury that exceeds safety guidelines. A review of medical literature and U.S. government data suggests that

Introduction Autistic Spectrum Disorder (ASD) is a neurodevelopmental syndrome with onset prior to age 36 months. Diagnostic criteria consist of impairments in sociality and communication plus repetitive and stereotypic behaviors (1). Traits strongly associated with autism include movement disorders and sensory dysfunctions (2). Although autism may be apparent soon after birth, most autistic children experience at least several months, even a year or more of normal development -- followed by regression, defined as loss of function or failure to progress (2,3,4).

The neurotoxicity of mercury (Hg) has long been recognized (5). Primary data derive from victims of contaminated fish (Japan - Minamata Disease) or grain (Iraq, Guatemala, Russia); from acrodynia (Pink Disease) induced by Hg in teething powders; and from individual instances of mercury poisoning (HgP), many occurring in occupational settings (e.g., Mad Hatter's Disease). Animal and in vitro studies also provide insights into the mechanisms of Hg toxicity. More recently, the Food and Drug Administration (FDA) and the American Academy of Pediatrics (AAP) have determined that the typical amount of Hg injected into infants and toddlers via childhood immunizations has exceeded government safety guidelines on an individual (6) and cumulative vaccine basis (7). The mercury in vaccines derives from thimerosal (TMS), a preservative which is 49.6% ethylmercury (eHg) (7).

Past cases of HgP have presented with much inter-individual variation, depending on the dose, type of mercury, method of administration, duration of exposure, and individual sensitivity. Thus, while commonalities exist across the various instances of HgP, each set of variables has given rise to a different disease manifestation (8,9,10,11). It is hypothesized that the regressive form of autism represents another form of mercury poisoning, based on a thorough correspondence between autistic and HgP traits and physiological abnormalities, as well as on the known exposure to mercury through vaccines. Furthermore, other phenomena are consistent with a causal Hg-ASD relationship. These include (a) symptom onset shortly after immunization; (b) ASD prevalence increases corresponding to vaccination increases; (c) similar sex ratios of affected individuals; (d) a high heritability rate for autism paralleling a genetic predisposition to Hg sensitivity at low doses; and (e) parental reports of autistic children with elevated Hg.

Trait Comparison ASD manifests a constellation of symptoms with much inter-individual variation (3,4). A comparison of traits defining, nearly universal to, or commonly found in autism with those known to arise from mercury poisoning is given in Table I. The characteristics defining or strongly associated with autism are also more fully described.

Autism has been conceived primarily as a psychiatric condition; and two of its three diagnostic criteria are based upon the observable traits of

Differential diagnosis may include childhood schizophrenia, depression, obsessive-compulsive disorder (OCD), anxiety disorder, and other neuroses. Related behaviors commonly found in ASD individuals are irrational fears, poor eye contact, aggressive behaviors, temper tantrums, irritability, and inexplicable changes in mood (1,2,12-17). Mercury poisoning, when undetected, is often initially diagnosed as a psychiatric disorder (18). Commonly occurring symptoms include

Neuroses, including schizoid and obsessive-compulsive traits, problems in inhibition of perseveration, and stereotyped behaviors, have been reported in a number of cases; and lack of eye contact was observed in one 12 year old girl with mercury vapor poisoning (18-35).

In many cases of ASD, verbal IQ is lower than performance IQ (3). Similarly, mercury-exposed children and adults show a marked difficulty with speech (9,19,37). In milder cases scores on language tests may be lower than those of unexposed controls (31,38). Iraqi children who were postnatally poisoned developed articulation problems, from slow, slurred word production to an inability to generate meaningful speech; while Iraqi babies exposed prenatally either failed to develop language or presented with severe language deficits in childhood (23,24,39). Workers with Mad Hatter's disease had word retrieval and articulation difficulties (21).

Nearly all cases of ASD and HgP involve disorders of physical movement (2,30,40). Clumsiness or lack of coordination has been described in many higher functioning ASD individuals (41). Infants and toddlers later diagnosed with autism may fail to crawl properly or may fall over while sitting or standing; and the movement disturbances typically occur on the right side of the body (42). Problems with intentional movement and imitation are common in ASD, as are a variety of unusual stereotypic behaviors such as toe walking, rocking, abnormal postures, choreiform movements, spinning; and hand flapping (2,3,43,44). Noteworthy because of similarities to autism are reports in Hg literature of

The presence of flapping motions in both diseases is of interest because it is such an unusual behavior that it has been recommended as a diagnostic marker for autism (46).

Virtually all ASD subjects show a variety of sensory abnormalities (2). Auditory deficits are present in a minority of individuals and can range from mild to profound hearing loss (2,47). Over- or under-reaction to sound is nearly universal (2,48), and deficits in language comprehension are often present (3). Pain sensitivity or insensitivity is common, as is a general aversion to touch; abnormal sensation in the extremities and mouth may also be present and has been detected even in toddlers under 12 months old (2,49). There may be a variety of visual disturbances, including sensitivity to light (2,50,51,52). As in autism, sensory issues are reported in virtually all instances of Hg toxicity (40). HgP can lead to mild to profound hearing loss (40); speech discrimination is especially impaired (9,34,). Iraqi babies exposed prenatally showed exaggerated reaction to noise (23), while in acrodynia, patients reported noise sensitivity (45). Abnormal sensation in the extremities and mouth is the most common sensory disturbance (25,28). Acrodynia sufferers and prenatally exposed Iraqi babies exhibited excessive pain when bumping limbs and an aversion to touch (23,24,45,53). A range of visual problems has been reported, including photophobia (18,23,34).

The biological abnormalities commonly found in autism are listed in Table II, along with the corresponding pathologies arising from mercury exposure. Especially noteworthy similarities are described.

Autism is a neurodevelopmental disorder which has been characterized as "a disorder of neuronal organization, that is, the development of the dentritic tree, synaptogenesis, and the development of the complex connectivity within and between brain regions" (54). Depressed expression of neural cell adhesion molecules (NCAMs), which are critical during brain development for proper synaptic structuring, has been found in one study of autism (55). Organic mercury, which readily crosses the blood-brain barrier, preferentially targets nerve cells and nerve fibers (56); primates accumulate the highest Hg-levels in the brain relative to other organs (40). Furthermore, although most cells respond to mercurial injury by modulating levels of glutathione (GSH), metallothionein, hemoxygenase, and other stress proteins, neurons tend to be "markedly deficient in these responses" and thus are less able to remove Hg and more prone to Hg-induced injury (56). In the developing brain, mercury interferes with neuronal migration, depresses cell division, disrupts microtubule function, and reduces NCAMs (28, 57-59).

While damage has been observed in a number of brain areas in autism, many nuclei and functions are spared (36). HgP's damage is similarly selective (40). Numerous studies link autism with neuronal atypicalities within the amygdala, hippocampi, basal ganglia, the Purkinje and granule cells of the cerebellum, brainstem, basal ganglia, and cerebral cortex (36,60-69). Each of these areas can be affected by HgP (10,34,40,70-73). Migration of Hg, including eHg, into the amygdala is particularly noteworthy, because in primates this brain region has neurons specific for eye contact (74) and it is implicated in autism and in social behaviors (65,66,75).

Autistic brains show neurotransmitter irregularities which are virtually identical to those arising from Hg exposure: both high or low serotonin and dopamine, depending on the subjects studied; elevated epinephrine and norepinephrine in plasma and brain; elevated glutamate; and acetylcholine deficiency in hippocampus (2,21,76-83).

Gillberg and Coleman (2) estimate that 35-45% of autistics eventually develop epilepsy. A recent MEG study reported epileptiform activity in 82% of 50 regressive autistic children; in another study, half the autistic children expressed abnormal EEG activity during sleep (84). Autistic EEG abnormalities tend to be non-specific and have a variety of patterns (85). Unusual epileptiform activity has been found in a number of mercury poisoning cases (18,27,34,86-88). Early mHg exposure enhances tendencies toward epileptiform activity with a reduced level of seizure-discharge amplitude (89), a finding consistent with the subtlety of seizures in many autism spectrum children (84,85). The fact that Hg increases extracellular glutamate would also contribute to epileptiform activity (90).

Some autistic children show a low capacity to oxidize sulfur compounds and low levels of sulfate (91,92). These findings may be linked with HgP because (a) Hg preferentially binds to sulfhydryl molecules (-SH) such as cysteine and GSH, thereby impairing various cellular functions (40), and (b) mercury can irreversibly block the sulfate transporter NaSi cotransporter NaSi-1, present in kidneys and intestines, thus reducing sulfate absorption (93). Besides low sulfate, many autistics have low GSH levels, abnormal GSH-peroxidase activity within erythrocytes, and decreased hepatic ability to detoxify xenobiotics (91,94,95). GSH participates in cellular detoxification of heavy metals (96); hepatic GSH is a primary substrate for organic-Hg clearance from the human (40); and intraneuronal GSH participates in various protective responses against Hg in the CNS (56). By preferentially binding with GSH, preventing absorption of sulfate, or inhibiting the enzymes of glutathione metabolism (97), Hg might diminish GSH bioavailability. Low GSH can also derive from chronic infection (98,99), which would be more likely in the presence of immune impairments arising from mercury (100). Furthermore, mercury disrupts purine and pyrimidine metabolism (97,10). Altered purine or pyrimidine metabolism can induce autistic features and classical autism (2,101,102), suggesting another mechanism by which Hg can contribute to autistic traits.

Autistics are more likely to have allergies, asthma, selective IgA deficiency (sIgAd), enhanced expression of HLA-DR antigen, and an absence of interleukin-2 receptors, as well as familial autoimmunity and a variety of autoimmune phenomena. These include elevated serum IgG and ANA titers, IgM and IgG brain antibodies, and myelin basic protein (MBP) antibodies (103-110). Similarly, atypical responses to Hg have been ascribed to allergic or autoimmune reactions (8), and genetic predisposition to such reactions may explain why Hg sensitivity varies so widely by individual (88,111). Children who developed acrodynia were more likely to have asthma and other allergies (11); IgG brain autoantibodies, MBP, and ANA have been found in HgP subjects (18,111,112); and mice genetically prone to develop autoimmune diseases "are highly susceptible to mercury-induced immunopathological alterations" even at the lowest doses (113). Additionally, many autistics have reduced natural killer cell (NK) function, as well as immune-cell subsets shifted in a Th2 direction and increased urine neopterin levels, indicating immune system activiation (103,114-116). Depending upon genetic predisposition, Hg can induce immune activation, an expansion of Th2 subsets, and decreased NK activity (117-120).

In most affected children, autistic symptoms emerge gradually, although there are cases of sudden onset (3). The earliest abnormalities have been detected in 4 month olds and consist of subtle movement disturbances; subtle motor-sensory disturbances have been observed in 9 month olds (49). More overt speech and hearing difficulties become noticeable to parents and pediatricians between 12 and 18 months (2). TMS vaccines have been given in repeated intervals starting from infancy and continuing until 12 to 18 months. While HgP symptoms, may arise suddenly in especially sensitive individuals (11), usually there is a preclinical "silent stage" in which subtle neurological changes are occuring (121) and then a gradual emergence of symptoms. The first symptoms are typically sensory- and motor-related, which are followed by speech and hearing deficits, and finally the full array of HgP characteristics (40). Thus, both the timing and nature of symptom emergence in ASD are fully consistent with a vaccinal Hg etiology. This parallel is reinforced by parental reports of excessive amounts of mercury in urine or hair from younger autistic children, as well as some improvement in symptoms with standard chelation therapy (122).

The discovery and rise in prevalence of ASD mirrors the introduction and spread of TMS in vaccines. Autism was first described in 1943 among children born in the 1930s (123). Thimerosal was first introduced into vaccines in the 1930s (7). In studies conducted prior to 1970, autism prevalence was estimated, at 1 in 2000; in studies from 1970 to 1990 it averaged 1 in 1000 (124). This was a period of increased vaccination rates of the TMS- containing DPT vaccines among children in the developed world. In the early 1990s, the prevalence of autism was found to be 1 in 500 (125), and in 2000 the CDC found 1 in 150 children affected in one community, which was consistent with reports from other areas in the country (126). In the late 1980s and early 1990s, two new TMS vaccines, the HIB and Hepatitis B, were added to the recommended schedule (7).

Nearly all US children are immunized, yet only a small proportion develop autism. A pertinent characteristic of mercury is the great variability in its effects by individual, so that at the same exposure level, some will be affected severely while others will be asymptomatic (9,11,28). An example is acrodynia, which arose in the early 20th Century from mercury in teething powders and afflicted only 1 in 500-1000 children given the same low dose (28). Studies in mice as well as humans indicate that susceptibility to Hg effects arises from genetic status, in some cases including a propensity to autoimmune disorders (113,34,40). ASD exhibits a strong genetic component, with high concordance in monozygotic twins and a higher than expected incidence among siblings (4); autism is also more prevalent in families with autoimmune disorders (106).

Additionally, autism is more prevalent among boys than girls, with the ratio estimated at 4:1 (2). Mercury studies in mice and humans consistently report greater effects on males than females, except for kidney damage (57). At high doses, both sexes are affected equally; at low doses only males are affected (38,40,127).

We have shown that every major characteristic of autism has been exhibited in at least several cases of documented mercury poisoning. Recently, the FDA and AAP have revealed that the amount of mercury given to infants from vaccinations has exceeded safety levels. The timing of mercury administration via vaccines coincides with the onset of autistic symptoms. Parental reports of autistic children with measurable mercury levels in hair and urine indicate a history of mercury exposure. Thus the standard primary criteria for a diagnosis of mercury poisoning - observable symptoms, known exposure at the time of symptom onset, and detectable levels in biologic samples (11,31) - have been met in autism. As such, mercury toxicity may be a significant etiological factor in at least some cases of regressive autism. Further, each known form of HgP in the past has resulted in a unique variation of mercurialism - e.g., Minamata disease, acrodynia, Mad Hatter's disease - none of which has been autism, suggesting that the Hg source which may be involved in ASD has not yet been characterized; given that most infants receive eHg via vaccines, and given that the effect on infants of eHg in vaccines has never been studied (129), vaccinal thimerosal should be considered a probable source. It is also possible that vaccinal eHg may be additive to a prenatal mercury load derived from maternal amalgams, immune globulin injections, or fish consumption, and environmental sources.

The history of acrodynia illustrates that a severe disorder, afflicting a small but significant percentage of children, can arise from a seemingly benign application of low doses of mercury. This review establishes the likelihood that Hg may likewise be etiologically significant in ASD, with the Hg derived from thimerosal in vaccines rather than teething powders. Due to the extensive parallels between autism and HgP, the likelihood of a causal relationship is great. Given this possibility, TMS should be removed from all childhood vaccines, and the mechanisms of Hg toxicity in autism should be thoroughly investigated. With perhaps 1 in 150 children now diagnosed with ASD, development of HgP-related treatments, such as chelation, would prove beneficial for this large and seemingly growing population.

Table I: Summary Comparison of Traits of Autism & Mercury Poisoning
(ASD references in bold; HgP references in italics)

Table II: Summary Comparison of Biological Abnormalities
in Autism & Mercury Exposure

Mercury Exposure	Autism
*Biochemistry*
Binds -SH groups; blocks sulfate transporter in intestines, kidneys (40,93)	Low sulfate levels (91,92)
Reduces glutathione availability; inhibits enzymes of glutathione metabolism; glutathione needed in neurons, cells, and liver to detoxify heavy metals; reduces glutathione peroxidase and reductase (97,100,161,162)	Low levels of glutathione; decreased ability of liver to detoxify xenobiotics; abnormal glutathione peroxidase activity in erythrocytes (91,94,95)
Disrupts purine and pyrimidine metabolism (10,97,158,159)	Purine and pyrimidine metabolism errors lead to autistic features (2,101,102)
Disrupts mitochondrial activities, especially in brain (160,163,164)	Mitochondrial dysfunction, especially in brain (76,172)
*Immune System*
Sensitive individuals more likely to have allergies, asthma, autoimmune-like symptoms, especially rheumatoid-like ones (8,11,18,24,28,31,111,113)	More likely to have allergies and asthma; familial presence of autoimmune diseases, especially rheumatoid arthritis; IgA deficiencies (103,106-109,115)
Can produce an immune response in CNS; causes brain/MBP autoantibodies (18,111,165)	On-going immune response in CNS; brain/MBP autoantibodies present (104,105,109,110)
Causes overproduction of Th2 subset; kills/inhibits lymphocytes, T-cells, and monocytes; decreases NK T-cell activity; induces or suppresses IFNg & IL-2 (100,112,117-120,166)	Skewed immune-cell subset in the Th2 direction; decreased responses to T-cell mitogens; reduced NK T-cell function; increased IFNg & IL-12 (103,108,114-116,173,174)
*CNS Structure*
Selectively targets brain areas unable to detoxify or reduce Hg-induced oxidative stress (40,56,161)	Specific areas of brain pathology; many functions spared (36)
Accummulates in amygdala, hippocampus, basal ganglia, cerebral cortex; damages Purkinje and granule cells in cerebellum; brain stem defects in some cases (10,34,40,70-73)	Pathology in amygdala, hippocampus, basal ganglia, cerebral cortex; damage to Purkinje and granule cells in cerebellum; brain stem defects in some cases (36,60-69)
Causes abnormal neuronal cytoarchitecture; disrupts neuronal migration, microtubules, and cell division; reduces NCAMs (10,28,57-59,161)	Neuronal disorganization; increased neuronal cell replication, increased glial cells; depressed expression of NCAMs (4,54,55)
Progressive microcephaly (24)	Progressive microcephaly and macrocephaly (175)
*Neuro-chemistry*
Prevents presynaptic serotonin release and inhibits serotonin transport; causes calcium disruptions (78,79,163,167,168)	Decreased serotonin synthesis in children; abnormal calcium metabolism (76,77,103,179)
Alters dopamine systems; peroxidine deficiency in rats resembles mercurialism in humans (8,80)	Either high or low dopamine levels; positive response to peroxidine, which lowers dopamine levels (2,177,178)
Elevates epinephrine and norepinephrine levels by blocking enzyme that degrades epinephrine (81,160)	Elevated norepinephrine and epinephrine (2)
Elevates glutamate (21,171)	Elevated glutamate and aspartate (82,176)
Leads to cortical acetylcholine deficiency; increases muscarinic receptor density in hippocampus and cerebellum (57,170)	Cortical acetylcholine deficiency; reduced muscarinic receptor binding in hippocampus (83)
Causes demyelinating neuropathy (22,169)	Demyelination in brain (105)
*Neurophysiology*
Causes abnormal EEGs, epileptiform activity, variable patterns, e.g., subtle, low amplitude seizure activities (27,31,34,86-89)	Abnormal EEGs, epileptiform activity, variable patterns, including subtle, low amplitude seizure activities (2,4,84,85)
Causes abnormal vestibular nystagmus responses; loss of sense of position in space (9,19,34,70)	Abnormal vestibular nystagmus responses; loss of sense of position in space (27,180)
Results in autonomic disturbance: excessive sweating, poor circulation, elevated heart rate (11,18,31,45)	Autonomic disturbance: unusual sweating, poor circulation, elevated heart rate (17,180)

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Autism, a developmental brain disorder, causes severe behavioral problems in children but it lasts a life-long. The cause and treatment of autism is not well known. We have studied autism as an autoimmune disorder. Autoimmunity is an abnormal condition in which a person's immune system goes haywire and reacts abnormally to his/her own organs. Thus autism will involve an autoimmune reaction to brain because brain is the affected organ. We have identified several autoimmune factors such as brain-specific autoantibodies, virus (and/or vaccine) serology, autoimmunity-producing cytokines, and serotonin and serotonin receptor antibodies. These factors are extremely important in identifying a virus-induced autoimmune pathology in autism. Therefore, the laboratory evaluation of these factors is helpful for uncovering a pathogenetic role of autoimmunity in autism and for monitoring patient responses before, during and after experimental immunotherapy that is known to produce significant improvements of clinical symptoms in children with autism.

[NOTE: Initially, I recommend Test numbers #1, #2 and #3 but you can choose whatever you like. All autistic patients (children and adults) should be tested].

Require 2-3 mL of serum for all tests. Draw 4-5 mL of blood (about one teaspoonful) into a red top tube. Spin tube to make clear fluid called serum. Collect serum into a new tube, place cap or stopper, and put some masking tape to secure the cap (this is very important). Then the tube should be wrapped in some padded material like the bubble wrap, and packaged into a shipping box. The package should be sent Monday through Thursday by OVERNIGHT DELIVERY (FedEx/UPS is your choice) to avoid weekend delivery. If it takes more than 24-30 hours for delivery, please include some dry ice in the shipment.

It is absolutely essential that you contact Dr. Singh before scheduling a blood draw or sending a sample.
Dr. Vijendra Singh, PhD
Biotechnology Center
Utah State University
4700 Old Main Hill
Logan, UT 84322-4700, USA
Phone: (435) 797-7193
Fax: (435) 797-2766
Email: singhvk@cc.usu.edu

I am a member of the anesthesiology faculty at Stanford University Hospital, writing in response to the question of autistic children requiring anesthesia for dental procedures.

There are no data that any anesthetic drug(s) cause or worsen autism, nor are there any published data on preferred drugs for anesthetizing autistic children.

Dental anesthesia is usually performed in the dentist's office. The mandatory requirements are:

If the child has serious medical problems (e.g., heart problems, breathing problems, seizures, or airway problems) it is sometimes unsafe to give anesthesia care in the dental office, and the dentist will need to do the procedure in a hospital room setting. This decision is made by the anesthesiologist.

Our standard of care is to make a preoperative phone call to the parent(s), both to obtain information on the child's medical history, and also to describe the anesthetic planned for the child.

The preferred technique for dental office anesthesia is 'deep sedation,' where the child is asleep, without awareness of pain, is breathing spontaneously, and has stable vital signs. The anesthesiologist is in constant attendance.

The anesthetic begins by sedating the child so that an intravenous (IV) can be inserted.

The monitors of vital signs are applied to the child, including the pulse oximeter, the electrocardiogram, the blood pressure cuff, and a stethoscope. Additional sedation is added via the IV as needed to maintain the deep sedation state safely. Typically we add narcotic pain relievers such as meperidine (Demerol), or the short acting sedative propofol. Local anesthetic is sometimes injected by the dentist.

When the dental procedure is finished, the child stays at the facility until safely aware. This usually requires a minimum of 30 minutes.

Post-anesthesia side effects are sleepiness, sometimes nausea, and in some children, aggressive behavior or agitation.

When dental sedation is done by an experienced anesthesiologist with modern monitoring equipment and medications, the rate of major complications should be low. The risk of driving in the car to the dental office should exceed the anesthetic risk.

Please refer to our anesthesia website at www.aamgpaloalto.com, particularly the sections on dental anesthesia and pediatric anesthesia. Email response is provided.

Richard John Novak, M.D.
Clinical Associate Professor
Stanford Department of Anesthesiology

In recent years, biological aspects of autism-spectrum disorders are becoming documented, researched, and treated. Much of the credit goes to Bernie Rimland and the DAN! docs, as well as to pioneers such as Paul Shattock, Andy Wakefield, Bill Shaw, and the persevering folks at the Great Smokies lab -- and to the parents and interested physicians who ordered lab-tests and who continually conduct their own research, whether "at home", via PubMed and the Internet, or via wading into whole-text articles or, in some cases, actually launching clinical studies (1) .

As I survey the growing amount of biological data about autism-spectrum kids, several categories of biological information are apparent. Generally speaking, the new data arise from six primary categories of information; there is some overlap among the categories; and, for most kids whose lab-test data are available, one major category is missing. Here is a general way to refer to the 6 categories of data already established for autism-spectrum kids:

I believe that biological aspects of autism-spectrum disorders will not have a firm foundation until thorough immune-panels become part of the overall autism-spectrum database (3). Furthermore, for each specific child, the thorough immune panel may enhance the parents' and physician's understanding of etiologically significant factors for that specific child; and this knowledge ought augment avoiding treatments that may be harmful while aiding in the design of positive treatments for that child.

At the Orlando conference (4), the importance of immune and infectious contributions was conveyed most clearly by Dr. Luigina Romani, who focused upon immune- and infection-related factors that can shift immunity and thereby contribute to persistent or recurring Candida -- an infection that not only is worthy of treating but also is a symptom of the underlying immune shift whose symptoms, signs, and causes need be addressed. Her lecture complemented my own interest and early findings in immunological and infectious profiles of autism-spectrum children.

In recent years a parents of autism-spectrum kids have been sending me the child's immune-panel, often accompanied by other lab reports, occasionally including an entire medical history. As previously mentioned, the most thorough immune panels were ordered by Hugh Fudenberg, MD (5); and most of these reports demonstrate at least one, often two, and occasionally three signs of atypical chronic infection and/or immune atypicality. Importantly, these infectious and immunological signs cannot be identified and delineated by data-sets A thru F in the above list. Instead, to fully comprehend the biological aspects of many (probably most, I'd now say) autism-spectrum kids, immune-panel data are necessary.

[Here it is important to note that Bill Shaw's Great Plains lab is now offering a number of immune-related tests, and immune tests not offered by Bill and crew can be obtained by other labs (9)]

Because *most* of the thorough immune panels I've perused contain obvious atypicalities (10a), and because the work of Reed Warren, Roger Burger and others implicates infectious etiologies and immune aspects as significant, I believe that, for many autism-spectrum children (10b-10i), a thorough list of initial immune-panel tests is needed.

Parents occasionally query the autism-list and other lists asking "What immune tests?" My suggested answer to that question emerges as follows: in a high percentage of kids representing the still small number of immune panels I've perused, *nearly *every *child has signs of a percolating infection or several, far beyond reference ranges. The words underlying, chronic, and atypical are appropriate. In several cases these elevations are accompanied by an obvious immune impairment, eg, no response to a common antigen such as tetanus, mumps, or varicella. That these atypicalities occur suggests that information from a thorough immune panel is extremely important for many and perhaps most autism- spectrum children and would augment their treatment protocols if and as significant data are obtained.

In the context of credit due Hugh Fudenberg, Reed Warren, and VK Singh, an immune-panel my research shows to be significant is presented below.

By presenting a comprehensive list of immune-panel tests, parents and cooperative docs can have a useful starting point for evaluating an autism-spectrum child. Later, if and as biological treatments are enacted, the initial test data will provide a baseline measure for evaluating subsequent therapies.

That biological analyses of autism-spectrum kids usually have not included Fudenberg-like immune panels is ironic, given that the Reed Warren et al findings about immune-impairments in autism-spectrum children have been known for so long.

In other words, if these kids have acquired and/or genetic immune- impairments, let's evaluate their viral load and their immune function -- along with the Category A thru F measures already pioneered; and I can't help but think that, in some and perhaps many autism-spectrum kids, the atypicalities measured by Great Smokies, Great Plains, and other labs may well be due to some of the same viral critters and immune-shifts I'm noticing in the Fudenberg-like panels I've seen thus far.

Many autism-spectrum and/or LKS kids are prescribed steroids such as Prednisone, which many parents describe as "it really helped, for a while" and/or "my child's deterioration occurred while on Prednisone".

Importantly, Prednisone is known to be an immune suppressant. Based upon what I've seen in the through immune panels I've perused, I no longer know how a neurologist or other doctor can dare to prescribe Prednisone without first ordering an extensive immune/infectious workup that would indicate whether or not any infectious and/or immune atypicalities are present, especially given the increasingly documented link between certain pathogens and seizures. For instance, Herpes simplex virus (HSV) is now implicated in a goodly percentage of seizure disorders (eg, 11-13); and Predisone's immunosuppressive effects are well known (14).

My opinion as a non-MD researcher is that, for autism-spectrum kid, category G hereinabove -- the thorough immune panel -- needs be obtained by parents and docs. Will the thorough immune panel offer clues for every child? Probably not, but the only way to determine that is to obtain and evaluate the results of the data.

Immune panel data augment findings from the other categories of lab data, and vice versa. Without the thorough immune panel, the pilot is flying with a high degree of blindness.

In most *thorough* immune-panel reports that I've perused on behalf of parents of autism-spectrum kids (n<15), tests in the Basic Panel have revealed atypical elevations of EBV, CMV, and/or HHV6; co-occurring infections are common; and other immune atypicalities are seen in some of the panels, including -- even in this small initial sampling and with much variation from child to child:

If a parent purchases a thorough immune evaluation, he or she is not guaranteed that meaningful results will come forth. There is no way of knowing what the tests will show, although the child's and the family's medical history can provide clues as to what tests ought not be omitted. For some parents, the money invested in the tests will have been wasted. Furthermore, the data from such an immune panel may place the child and the parents at the forefront of medical research and treatment, which means that data and observations from recent research will have to be utilized (5, 12a-12b).

At one prominent lab, tests constituting what I think of as the "Basic Panel" would cost slightly less than $1500.

The following list sets forth a minimum of tests I believe necessary for an initial evaluation of the child's immunity. There is an emphasis upon herpes class viruses because

A viral screen is important, especially for IgG antibodies, which would indicate an atypical chronic infection. EBV provides an exception, because it has a variety of proteins that, if reactivated, can generate IgM antibodies; thus for EBV, both IgM and IgG are suggested. Also, if the child has recently experienced a regression, then adding IgM antibodies might be instructive in some cases.

	IgG	HSV1, HSV2, varicella, CMV, HHV6
IgM and	IgG	for an EBV screen
	IgG	measles
	IgG	rubella
	IgG	rubeola
	IgG	coxsackie
	IgG	vaccinal antigens, eg, diptheria, tetanus, mumps
	IgG	for Myelin Basic Protein (16)

The following is offered as a set of tests and mimics much of the data presented in the charts I've evaluated:

The tests listed above provide an excellent overview of many aspects of the child's immunity. However, pathogen-specific assays are *specific*, ie, they don't provide information about other pathogens. However, the last six tests listed above provide an overview that can reflect pathogens not studied in the pathogen-specific tests.

The work of numerous researchers, augmented and expanded by the immunity and infection lab-tests ordered by a few physicians, demonstrate that immune- impairments (whether acquired and/or genetic) appear to play a causal and (in some cases) an ongoing role in a goodly subset of autism-spectrum children. The information from a thorough immune panel is an important contribution to a child's diagnostic profile and treatment options.

1. Bolte ER. Autism and Clostridium tetani. Med Hypotheses 1998 51(2):133-44.
2. Paul Shattock and colleagues have been finding atypical IAG levels in a substantial percentage of autism-spectrum children. Here is a preliminary citation about their work:
J Chromatogr B Biomed Sci Appl 1998 Aug 7;712(1-2):51-8
Rapid analysis of low levels of indolyl-3-acryloylglycine in human urine by high-performance liquid chromatography.
Mills MJ, Savery D, Shattock PE
Autism Research Unit, School of Health Sciences, University of Sunderland, UK.
3. Hugh Fudenberg, MD, is one of the 20th Century's preeminent immunologists.
Immune panels ordered by Dr. Fudenberg are the examples I have in mind when I write the phrase "thorough immune panels".
4. Biological Treatments for Autism and PDD. Orlando Conference, May 8- 9, 1999.
5. Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism:
a pilot study. Biotherapy 1996;9(1-3):143-7.

ab: 40 infantile autistic patients were studied. They ranged from 6 years to 15 years of age at entry. 22 were cases of classical infantile autism; whereas 18 lacked one or more clinical defects associated with infantile autism ("pseudo-autism"). Of the 22 with classic autism, 21 responded to transfer factor (TF) treatment by gaining at least 2 points in symptoms severity score average (SSSA); and 10 became normal in that they were main-streamed in school and clinical characteristics were fully normalized. Of the 18 remaining, 4 responded to TF, some to other therapies. After cessation of TF therapy, 5 in the autistic group and 3 of the pseudo-autistic group regressed, but they did not drop as low as baseline levels. PMID: 8993773, UI: 97146917
6. Puccetti P, Romani L, Bistoni F. A TH1-TH2-like switch in candidiasis: new perspectives for therapy. Trends Microbiol 1995 Jun;3(6):237-40.
7. Romani L et al. T helper cell dichotomy to Candida albicans: implications for pathology, therapy, and vaccine design. Immunol Res 1995;14(2):148-62.
8. acquired immune-impairment monograph
9. Four labs among many:
Antibody Assays Laboratory
Great Plains Laboratory
Immunosciences Lab Inc
Lab of VK Singh, PhD, c/o U of Michigan
10a. atypical chronic infection in autism-spectrum children:
chronic infection
10b. Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A et al.
Strong association of the third hypervariable region of HLA-DR beta 1 with autism. J Neuroimmunol 1996 Jul;67(2):97-102.
Center for Persons with Disabilities, Utah State University, Logan 84322, USA. medlab@cc.usu.edu
10c. Warren RP et al. Immunogenetic studies in autism and related disorders.
Mol Chem Neuropathol 1996 May-Aug;28(1-3):77-81
10d. Warren RP, Yonk J, Burger RW, Odell D, Warren WL. DR-positive T cells in autism: association with decreased plasma levels of the complement C4B protein. Neuropsychobiology 1995;31(2):53-7.

10e. Warren RP, Burger RA, Odell D, Torres AR, Warren WL. Decreased plasma concentrations of the C4B complement protein in autism. Arch Pediatr Adolesc Med 1994 Feb;148(2):180-3.
10f. Warren RP et al. Increased frequency of the null allele at the complement C4b locus in autism. Clin Exp Immunol 1991 Mar;83(3):438-40.
10g. Yonk LJ, Warren RP, Burger RA et al. CD4+ helper T cell depression in autism. Immunol Lett 1990 Sep;25(4):341-5.
10h. Warren RP et al. Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism. Immunol Invest 1990 Jun;19(3):245-51.
10i. Warren RP, Foster A, Margaretten NC. Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry 1987 May;26(3):333-5.
10j. Warren RP et al. Immune abnormalities in patients with autism. J Autism Dev Disord 1986 Jun;16(2):189-97.
ab: We have begun an investigation on the immune systems of patients with autism in attempt to determine if immune mechanisms are involved in the development of this severe developmental disorder. A study of 31 autistic patients has revealed several immune-system abnormalities, including reduced responsiveness in the lymphocyte blastogenesis assay to phytohemagglutinin, concanavalin A, and pokeweed mitogen; decreased numbers of T lymphocytes; and an altered ratio of helper to suppressor T cells...
11. Sanders VJ et al. Presence of herpes simplex DNA in surgical tissue from human epileptic seizure foci detected by polymerase chain reaction:
preliminary study. Archives of Neurology 54.8.954-60 1997.
12. Cornford ME, McCormick GF. Adult-onset temporal lobe epilepsy associated with smoldering herpes simplex 2 infection. Neurology 1997 Feb;48(2):425-30.
ab: A 40-year-old man with chronic genital herpes simplex infection developed partial complex temporal lobe seizures of insidious onset, with EEG and MRI evidence of a unilateral temporal lobe destructive, atrophic process.
Extensive workup did not reveal an infectious etiology. Three years of escalating number and severity of daily seizures with memory loss led to temporal lobectomy. Histologic study revealed active, low-level viral infection in the resected hippocampus and temporal lobe cortex, with immunohistochemical evidence for infection by herpes simplex 2, principally in neurons. In situ hybridization confirmed the presence of herpes simplex virus in neurons.
Anticonvulsant-resistant seizure episodes began to recur several times daily soon after surgery, but the addition of acyclovir to the treatment regimen resulted in a substantial reduction in seizure occurrence, maintained for the subsequent 2.5 years.
12b. Kitchingman GR, Rooney C. Cytotoxic T cells and immunotherapy. Pediatr Radiol 1998 Jul;28(7):489-91.
Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105, USA.
ab: Promising immunotherapies for viral infections and malignancies reflect the successful, rapid translation of laboratory findings into clinical practice. Fletcher et al. [1] present imaging studies of Epstein-Barr virus (EBV)-associated lymphomas before and after immunotherapy. Here, we briefly review the scientific bases of such novel therapies, which have evolved from advances in understanding of immune effector cells, of the cytokines that drive immune responses, and of the mechanisms underlying cell death.
13. Neurologic aspects of Herpes simplex virus:
neurologic HSV
14. Steroids as immunosuppressants:
steroids
15. Kitchingman GR, Rooney C. Cytotoxic T cells and immunotherapy. Pediatr Radiol 1998 Jul;28(7):489-91.
Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105, USA.
ab: Promising immunotherapies for viral infections and malignancies reflect the successful, rapid translation of laboratory findings into clinical practice. Fletcher et al. [1] present imaging studies of Epstein-Barr virus (EBV)-associated lymphomas before and after immunotherapy. Here, we briefly review the scientific bases of such novel therapies, which have evolved from advances in understanding of immune effector cells, of the cytokines that drive immune responses, and of the mechanisms underlying cell death. Comment on: Pediatr Radiol 1998 Jul;28(7):492-6
16. VK Singh, PhD, is among the pioneers of autoimmune aspects of autism- spectrum disorders. His lab offers several assays, including anti-MBP antibodies. His lab is currently providing several assays significant in autism spectrum children, including but not limited to anti-MBP antibodies, anti- measles antibodies, etc. Here are *some* of his published articles:
16a. Singh VK et al. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol 1998 Oct;89(1):105-8.
College of Pharmacy, University of Michigan, Ann Arbor,
Michigan, 48109-1065, USA.
16b. Singh VK, Warren R, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol 1997 Jul;17(1):88-90.
Department of Psychiatry, University of Michigan, Ann Arbor 48109-1065, USA.
16c. Singh VK, Singh EA, Warren RP. Hyperserotoninemia and serotonin receptor antibodies in children with autism but not mental retardation. Biol Psychiatry 1997 Mar 15;41(6):753-5.
16d. Singh VK. Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. J Neuroimmunol 1996 May;66(1- 2):143-5.
16e. Singh VK et al. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun 1993 Mar;7(1):97-103.

Parents often ask the Autism Research Institute for any available information on anesthesia when their autistic child needs a surgical or dental procedure. In response, we published a request for input from anesthesiologists in a recent Autism Research Review International newsletter. We are delighted to be able to post this excellent article from anesthesiologist, Louise Kirz, M.D. who has two autistic sons. Bernard Rimland, Ph.D.

Your child needs a surgical procedure and an anesthetic. This can be a frightening experience for any parent and their child. Add to this the special needs of a child with autism and many of us throw up our hands and say, "How in the world am I going to get (us) through this one!" As a parent of two autistic boys I understand what you are going through. There is always one more thing that we need to get our child through. As a board-certified anesthesiologist, I also understand the problems faced by trying to anesthetize one of our special children. Here is a partial list of suggestions and information for parents and anesthesiologists.

Anesthesia can be broken down into three basic types: general anesthesia, regional anesthesia and sedation anesthesia. (Otherwise known as MAC anesthesia or monitored anesthesia care.)

I will focus a little more on general anesthesia since most of you will be facing this option. I will discuss the process your child will probably go through, and some of the choices you and your child's anesthesiologist will have to make.

This is where your child will change into a hospital gown, meet the anesthesiologist (again ?!) and have any last minute questions answered. This is where a sedative may be given. The use of preoperative sedative is a good thing to discuss prior to the day of surgery. Preoperative sedatives are not an absolutely necessary item in doing a general anesthetic. However the majority of anesthesiologists who work with young children (6 and under) often use some type of medication to allow an easier transition from parents to operating room. The use of preoperative sedation is very common prior to surgery for adults as well. No matter how well prepared your child is, a small amount of medication may be necessary to transition into the operating room. My concern in this area as a parent and an anesthesiologist is that sometimes the medication can be used in place of preparing the child ahead of time and instead of talkng to the child in the preoperative area. Because of our children's communication difficulties we (parents and professionals) too often assume that the children do not understand what is happening.

In your place, I would discuss with my child's anesthesiologist the need for the sedation. I would also inform the anesthesiologist of any unusual reactions my child has had with any medications.

This generally occurs in the operating room with you now pacing in the waiting room. Some hospitals have induction rooms, which allow the parents to be present at the induction of anesthesia for their child. (I was present during the induction of anesthesia for one of my boys ... to be honest I am not sure I would do that again). Induction of anesthesia can occur in one of two ways, by mask with the child breathing an anesthetic gas or by an intravenous injection of a sedative drug followed by the child breathing the anesthetic gas. This is absolutely one of those areas you need to discuss with the anesthesiologist prior to surgery. For children younger than about 5 years old, typical or autistic, most anesthesiologists would opt for a mask induction. (Child breathes the anesthetic gas.) Over the age of about 7 to 9 years in a typical child many of us opt for placing an intravenous line in the holding area and inducing anesthesia through that line. For those of us with autistic 8+ year olds we have some choices. My bias is that with the use of EMLA R cream (a local anesthetic cream applied directly to site where the intravenous line is to be placed) many of our slightly older autistic children would tolerate an intravenous line placement in the holding area. This of course depends very much on you and your child and of course your child's anesthesiologist. My practice in this area varies from child to child. The advantage to a mask anesthetic induction is that the child can be asleep before the IV (intravenous line) is placed. The disadvantage to a mask anesthetic is that it can be very unpleasant for the child and the child can become very agitated.

A combination of medications given either intravenously (placed after the child is asleep if a mask induction is done) and inhaled. Most general anesthetics require the placement of some sort of tube in your child mouth and throat to protect his lungs and deliver the anesthetic gas. This could be an endotracheal tube or an LMA (laryngeal mask airway). The choices of what to use, how much to give and when to give it are the topics for an anesthesia training program and ongoing medical education. You may want to emphasize with your child's anesthesiologist that you think your child will do better if he can be awake, alert and back to normal for him as quickly as possible.

Whatever medications used to continue the anesthesia are allowed to wear off, are reversed, or are turned off and exhaled.

Specially training nurses monitor your child until he is awake and out from under most of the influences of the general anesthetic. Pain medications will be given if needed. This is an area of concern, as even a typical child may wake up confused or disoriented. Ask when you can be with your child to help get him reoriented. What your anesthesiologist wants to know: