Summary: The use of selective serotonin reuptake inhibitors (SSRIs, such as Prozac®, Celexa®, Lexapro®, Luvox® and Paxil®) taken during pregnancy—especially the first trimester—appears to increase the risk of autism spectrum disorders. There are evidence-based alternatives to SSRIs that support brain health without putting the fetus at risk.

A study recently published in the journal Archives of General Psychiatry draws attention to a risk of autism spectrum disorders (ASDs) born to mothers who took SSRI antidepressants during their pregnancy. The authors observe:

“The prevalence of autism spectrum disorders (ASDs) has increased over recent years. Use of antidepressant medications during pregnancy also shows a secular increase in recent decades, prompting concerns that prenatal exposure may contribute to increased risk of ASD.”

Therefore they set out to…

“…systematically evaluate whether prenatal exposure to antidepressant medications is associated with increased risk of ASD.”

In order to do so they compared the data for 298 children with ASD to 1507 randomly selected control children, along with the data for both their mothers. Their findings support a cautionary approach to the prenatal use of SSRIs:

“Prenatal exposure to antidepressant medications was reported for 20 case children (6.7%) and 50 control children (3.3%). In adjusted logistic regression models, we found a 2-fold increased risk of ASD associated with treatment with selective serotonin reuptake inhibitors by the mother during the year before delivery (adjusted odds ratio, 2.2), with the strongest effect associated with treatment during the first trimester (adjusted odds ratio, 3.8).”

In other words, the increase in risk for the whole year before delivery was 220%, but limiting the investigation to the first trimester it was 380%. Interestingly…

“No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors.”

Meaning that it wasn’t a history of mental health treatment the year before delivery but specifically the use of SSRIs that accounted for the increased risk of ASDs. The authors conclude:

“Although the number of children exposed prenatally to selective serotonin reuptake inhibitors in this population was low, results suggest that exposure, especially during the first trimester, may modestly increase the risk of ASD. The potential risk associated with exposure must be balanced with the risk to the mother or fetus of untreated mental health disorders.”

This would be a troubling dilemma were it not for the fact that therapies supporting brain health are available to treat depression. Serotonin production and signaling, when indicated, can be supported in a physiological and sustainable manner that promotes the brain health of mother and fetus. A categorization and description of key resources that applies to adults as well as children is available in the Parents’ Guide To Brain Health.

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While celiac disease often goes undiagnosed, failure to recognize the non-celiac manifestations of gluten sensitivity is widespread. The neurological effects can contribute to disorders of learning, behavior and neurodevelopment even in the absence of intestinal symptoms. The authors of a study published in the Journal of Attention Disorders observe:

“Several studies report a possible association of celiac disease (CD) with psychiatric and psychological disturbances, such as ADHD.”

They examined 132 subjects affected by CD for ADHD symptoms by behavioral scale before and 6 months after a gluten-free diet was started, and found that:

“The overall score improved significantly as well as most of the ADHD-like symptomatology specific features (Bonferroni-corrected, paired-sample t tests).”

They state in their conclusion:

“The data indicate that ADHD-like symptomatology is markedly overrepresented among untreated CD patients and that a gluten-free diet may improve symptoms significantly within a short period of time. The results of this study also suggest that CD should be included in the list of diseases associated with ADHD-like symptomatology.”

Remember, as the authors of a paper published by GeneReviews state:

“Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than nonclassic celiac disease, characterized by absence of gastrointestinal symptoms.”

The report on a study published in the journal Psychosomatics begins with the observation:

“A high prevalence of depressive symptoms, hypothetically related to serotonergic dysfunction, has been reported among adults with celiac disease. The authors used semistructured psychiatric interviews and symptom measurement scales to study mental disorders in 29 adolescents with celiac disease and 29 matched comparison subjects.

The also observe in review of the existing evidence:

“Patients with celiac disease may suffer from neurological symptoms, such as peripheral neuropathy, ataxia, intellectual deterioration, brain atrophy, and epilepsy…In addition to neurological manifestations, a significantly higher prevalence of depressive symptoms (30–69%) and depressive disorders (42%) has been reported in adult celiac disease patients, compared to medical and normal comparison subjects…Improvement in depressive disorders has been described in some celiac disease patients after they started a gluten-free diet.“

What did their findings show specifically in regard to adolescents?

“We found that celiac disease was associated with higher lifetime prevalences of major depressive disorder and disruptive behavior disorder in adolescents…at least in some of these patients major depression and disruptive behavior disorder were related to celiac disease and alleviated by treatment of celiac disease with a gluten-free diet.”

The clinical implications of the data are summarized in their conclusion:

“Celiac disease is associated with increased prevalence of depressive and disruptive behavior disorders in adolescents, particularly in the phase before diet treatment. In some cases psychiatric symptoms appear to improve after the patient starts a gluten-free diet. The possibility of undiagnosed celiac disease should be taken into account in the differential diagnosis of these disorders, since the diet treatment is essential.“

Interestingly, in light of the reports that follow, they also make this observation:

“The risk of psychological disorders is substantially higher in children with a chronic disease and, for unknown reasons, particularly in patients with inflammatory bowel disease.“

What are the mechanisms by which gluten sensitivity can contribute to neurodevelopmental disorders? A study published in the Journal of Clinical Immunology examines gut mucosal immunopathology in relation to regressive autism:

“Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features…”

The authors undertook a detailed analysis of mucosal infiltrate with flow cytometry (inspected the cellular components of gut lining secretions) and intestinal biopsies, and…

“…found a prominent mucosal eosinophil [allergen-reactive white blood cell] infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet… The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.”

Antibodies to neuronal tissues, signaling molecules and key enzymes can also play a role in neurological disorders associated with gluten sensitivity. The authors of a paper published in the journal Acta Neurologica Scandinavica state:

“The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases.”

GAD is glutamic acid decarboxylase, aka glutamate decarboxylase. Most clinicians reading this are aware that GAD is a target for autoantibodies in type 1 diabetes, but may not recall that it is required to convert glutamate into GABA, our most abundant inhibitory (calming) neurotransmitter. Functional deficiencies of GABA can manifest as anxiety, restlessness, disorganized attention, inner excitability and tension with difficulty relaxing, feeling overwhelmed, worry, etc. The authors used ELISA assays for anti-GAD and for serological markers of gluten sensitivity in patients recruited from clinics based at the Royal Hallamshire hospital, Sheffield, UK. Those with gluten sensitivity were followed up after the introduction of a gluten-free diet. Their data painted a compelling picture:

“Six of seven (86%) patients with SPS were positive for anti-GAD…This compared with 9/90 (11%) patients with idiopathic sporadic ataxia…16/40 (40%) patients with gluten ataxia…and 6/10 patients with type 1 diabetes only…The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity. The same was observed in patients with gluten ataxia and anti-GAD antibodies. This was also associated with clinical improvement.“

Parents of patients and the practitioners caring for them should bear their conclusion in mind:

“These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.”

Interestingly, impairment in the ability to digest gliadin (from gluten), a problem which has a genetic basis, can contribute to affective disorders. The authors of a paper published in Behavioral and Brain Functions offer evidence from an investigation of the urine of depressed patients for relevant undigested peptides:

“We find overlapping patterns of peptide peaks in severe depression, but with considerable individuality. Mass spectrometry shows that some of these peptides are probably of dietary origin, because their sequences are found only in certain dietary proteins. Opioids from casein and gliadin are typical examples.“

Their conclusion is part of the rationale for offering specific digestive enzymes (peptidases) to patients with gluten sensitivity:

“Peptide increase in urine is found when break down is deficient, and the data presented agree with reports on peptidase deficiencies in depression.”

Another mechanism by which gluten can promote autoimmune disorders with neurological, behavioral and neurodevelopmental consequences is by causing abnormal permeability (‘leakiness’) of the intestinal mucosal barrier. This causes the gut-associated immune tissue to be abnormally exposed to the intestinal contents. The authors of a paper published recently in the Annals of the New York Academy of Sciences examine the link between intestinal permeability and autoimmune disease:

“Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity.”

In delineating the process by which exposure to antigen in the gut triggers a genetic susceptibility, they note:

“In all cases, increased permeability precedes disease and causes an abnormality in antigen delivery that triggers immune events, eventually leading to a multiorgan process and autoimmunity.”

Moreover…

“Alterations in the intestinal balance between beneficial and potentially harmful bacteria have also been associated with allergy, type 1 diabetes and inflammatory bowel diseases…”

These factors come to a point that disrupts the tight junctions (TJ) of the intestinal barrier by perturbing the production of zonulin, an agent involved in loss of barrier function and autoimmune disease:

“The zonulin upregulation during the acute phase of CD was confirmed by measuring zonulin concentration…Compared to healthy controls, CD subjects showed significantly higher zonulin serum concentrations during the acute phase of the disease that decreased following a gluten-free diet…Similar results were obtained from T1D subjects…Our group has generated evidence that gliadin induces increased intestinal permeability by releasing preformed zonulin…When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability.”

They summarize their findings with this important statement:

“Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to dysfunction of intercellular TJ all seem to be key components in the pathogenesis of autoimmune diseases. Both in CD and T1D gliadin may play a role in causing loss of intestinal barrier function and/or inducing the autoimmune response in genetically predisposed individuals…Since TJ dysfunction allows this interaction, new therapeutic strategies aimed at re-establishing the intestinal barrier function offer innovative, unexplored approaches for the treatment of these devastating diseases.”

Further confirmation of the damage gliadin does to the intestinal epithelial barrier is offered in a paper published in the Scandinavian Journal of Gastroenterology:

“We investigated whether gliadin has any immediate effect on zonulin release and signaling.”

They exposed human intestinal tissue to gliadin and evaluated zonulin release and barrier permeability by PCR (polymerase chain reaction) and immunofluorescence microscopy. They too documented similar effects:

“When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability…”

However, they found that non-celiac patients also exhibited an increased zonulin release that, while not the magnitude of the celiac patients, caused intestinal permeability:

“…biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability…”

This would be an argument in favor of everyone adopting a gluten-free diet. The authors’ conclusion is striking:

“Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.”

The authors of a study published in the journal Gastroenterology add to the body of knowledge by identifying the mechanism by which gluten increases zonulin release and intestinal permeability:

“Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability…We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment.“

They demonstrated that the chemokine receptor CXCR3 binds gliadin by examining CXCR3 protein and gene expression in intestinal epithelial cell lines and biopsy specimens, and gliadin-CXCR3 interaction by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. On a positive note, the observed that…

“Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability…[however] Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet.“

What about evidence that following a gluten-free diet helps with behavioral disorders of children and adolescents? The authors of a study published in BMC (BioMed Central) Psychiatry state:

“Coeliac disease in adolescents has been associated with an increased prevalence of depressive and disruptive behavioural disorders, particularly in the phase before diet treatment. We studied the possible effects of a gluten-free diet on psychiatric symptoms, on hormonal status (prolactin, thyroidal function) and on large neutral amino acid serum concentrations in adolescents with coeliac disease commencing a gluten-free diet.”

Moreover…

“Coeliac disease is an under-diagnosed autoimmune type of gastrointestinal disorder… Non-specific symptoms such as fatigue and dyspepsia are common, but the disease may also be clinically silent….Undetected or neglected, coeliac disease is associated with serious complications…depressive and disruptive behavioural disorders are highly common also among adolescents, particularly in the phase before diet treatment…Recently 73% of patients with untreated coeliac disease – but only 7% of patients adhering to a gluten-free diet – were reported to have cerebral blood flow abnormalities similar to those among patients with depressive disorders.“

They assessed adolescents aged 12 to 16 years with several symptom scales and followed them at intervals after starting a gluten-free diet. What did their data show?

“Adolescent coeliac disease patients with depression had significantly lower pre-diet tryptophan/ competing amino-acid (CAA) ratios and free tryptophan concentrations, and significantly higher biopsy morning prolactin levels compared to those without depression. A significant decrease in psychiatric symptoms was found at 3 months on a gluten-free diet compared to patients’ baseline condition, coinciding with significantly decreased coeliac disease activity and prolactin levels and with a significant increase in serum concentrations of CAAs.”

Parents and clinicians should consider their conclusions:

“…since diet treatment may alleviate psychiatric symptoms, and earlier diagnosis may have beneficial effects on psychological and even on neurobiological vulnerability to depression, the possibility of psychiatric complications of coeliac disease needs to be taken into account in differential diagnosis of depressive and behavioural disorders.”

A paper published in the journal Nutritional Neuroscience suggests similar indications for some children with autism spectrum disorders:

“There is increasing interest in the use of gluten- and casein-free diets for children with autism spectrum disorders (ASDs). We report results from a two-stage, 24-month, randomised, controlled trial incorporating an adaptive ‘catch-up’ design and interim analysis.”

They randomly assigned 72 Danish children to two diets and examined them for inattention and hyperactivity at baseline, 8 and 12 months. At that point there data showed that…

“…there was a significant improvement to mean diet group scores (time*treatment interaction) on sub-domains of ADOS, GARS and ADHD-IV measures. Surpassing of predefined statistical thresholds as evidence of improvement in group A at 12 months sanctioned the re-assignment of group B participants to active dietary treatment.”

The authors state in their conclusion:

“Our results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD.”

What is the practical bottom line for parents and practitioners? There is mounting scientific evidence that the possibility of gluten sensitivity should not be overlooked when investigating the contributing causes to childhood disorders of learning, behavior and neurodevelopment. Given that celiac disease can be ‘silent’, and that we are particularly concerned with the non-celiac neurological manifestations of gluten sensitivity, testing for the genetic susceptibility in addition to anti-gliadin antibodies is a clinically prudent course of action.

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Evidence continues to accumulate regarding the important role of vitamin D in brain development and immune regulation. As such vitamin D is considered a neurosteroid. The authors of a paper published recently in the journal Psychoneuroendocrinology state:

“There is now clear evidence that vitamin D is involved in brain development.“

The specific focus of their study is schizophrenia as a developmental disorder. This is of interest to all parents and clinicians because the same mechanisms may be involved for neurodevelopmental disorders on a lower end of the spectrum of intensity including problems of learning and behavior.

“The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia…”

The authors developed an animal model to study the effects of vitamin D deficiency on brain development that included removing vitamin D from the diet during gestation while being sure to maintain normal calcium levels. The effects were dramatic:

“The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing.”

The summarize their findings by stating:

“Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that vitamin D acts as a neurosteroid with direct effects on brain development.“

The authors of a paper published in the FASEB Journal (The Journal of the Federation of American Societies for Experimental Biology) report their review of the scientific evidence for the link between vitamin D and brain dysfunction. The examination included:

“1) biological functions of vitamin D relevant to cognition and behavior; 2) studies in humans and rodents that directly examine effects of vitamin D inadequacy on cognition or behavior; and 3) immunomodulatory activity of vitamin D relative to the proinflammatory cytokine theory of cognitive/behavioral dysfunction.”

The data over a wide range of topics was mixed, but the overall weight of evidence significant:

“We conclude there is ample biological evidence to suggest an important role for vitamin D in brain development and function…While mechanistic and biological evidence strongly suggests that calcitriol is involved in brain development and critical brain functions, it has proved more difficult experimentally to demonstrate obvious effects of vitamin D inadequacy on cognitive or behavioral endpoints…Despite residual uncertainty, we believe the evidence overall suggests that supplementation to ensure adequacy is prudent…”

Consider also a paper published a few months ago in Acta Neurologica Scandinavica that further examines the role of vitamin D in the central nervous system:

“Epidemiological and experimental evidence suggest that vitamin D deficiency is a risk factor for multiple sclerosis and other autoimmune diseases…Hypovitaminosis D is also associated with several other neurological diseases that is less likely mediated by dysregulated immune responses, including Parkinson’s disease and Alzheimer’s disease, schizophrenia and affective disorders, suggesting a more diverse role for vitamin D in the maintenance of brain health.”

Moreover…

“…both the vitamin D receptor and the enzymes necessary to synthesize bioactive 1,25-dihydroxyvitamin D are expressed in the brain, and hypovitaminosis D is associated with abnormal development and function of the brain.”

They offer insight into why studying the effects of vitamin D in the brain may not be as simple as presumed—specifically the difference between the levels in peripheral blood and intrathecal levels (in the cerebrospinal fluid around the spinal cord and brain):

“We here review current knowledge on the intrathecal vitamin D homeostasis in heath and disease, highlighting the need to assess vitamin D in the intrathecal compartment.”

What other evidence is there for a link between low levels of vitamin D and psychiatric diagnoses? A recent paper published in The Journal of Steroid Biochemistry and Molecular Biology examines the association between low vitamin D and psychiatric diagnoses in a group of Swedish patients. For 117 subjects serum 25-hydroxy-vitamin D (25-OHD) and plasma intact parathyroid hormone (iPTH) was collected, together with demographic data and psychiatric diagnoses.

“Their median 25-OHD was considerably lower than published reports on Swedish healthy populations. Only 14.5% had recommended levels…Patients with ADHD had unexpectedly low iPTH levels…having a diagnosis of autism spectrum disorder or schizophrenia predicted low 25-OHD levels. Hence, the diagnoses that have been hypothetically linked to developmental (prenatal) vitamin D deficiency, schizophrenia and autism, had the lowest 25-OHD levels in this adult sample, supporting the notion that vitamin D deficiency may not only be a predisposing developmental factor but also relate to the adult patients’ psychiatric state.”

And their data yielded another very relevant observation:

“This is further supported by the considerable psychiatric improvement that coincided with vitamin D treatment in some of the patients whose deficiency was treated.”

But how prevalent is vitamin D deficiency among American children? A paper published in the journal Pediatrics last year should serve as a reminder to both parents and doctors. The authors set out to…

“…determine the prevalence of 25-hydroxyvitamin D (25[OH]D) deficiency and associations between 25(OH)D deficiency and cardiovascular risk factors in children and adolescents.”

What did the data show? Even using a low reference range thatand is presently considered too low by most labs and has been updated:

“Overall, 9% of the pediatric population, representing 7.6 million US children and adolescents, were 25(OH)D deficient and 61%, representing 50.8 million US children and adolescents, were 25(OH)D insufficient.”

Even by outdated standards that amounts to 70% of the pediatric population in the US. Hence their conclusion:

“25(OH)D deficiency is common in the general US pediatric population and is associated with adverse cardiovascular risks.”

We can see from the above that the risks include brain health and development as well. How do you find out if your child’s (and your) vitamin D level is sufficient? Since individual genetic and circumstantial needs can vary so greatly, taking out the guesswork with a serum 25(OH)D (25-hydroxy vitamin D) test is best.

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Can gastrointestinal pathology be a contributing factor in neurodevelopmental disorders? Consider this study published in the American Journal of Gastroenterology in which the authors begin:

“Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls.”

They performed ileocolonoscopies and biopsies on 60 children whose diagnoses included Developmental diagnoses were autism (50 patients), Asperger’s syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). The tissue specimens were reviewed by three pathologists and compared with 22 well children and 2o with ulcerative colitis. Their data for GI pathology in the affected cohort were striking:

“Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls . Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls. Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls.”

Considering the impact of the enteric (gut) immune and nervous systems on the brain these findings are not a surprise. “When the gut is inflamed the brain is inflamed.” The authors conclude by stating:

“A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.”

A paper published last year in the Canadian Journal of Gastroenterology adds to the discussion of this topic in regard to autism. The authors state:

“There have been several reports of a link between autism and chronic gastrointestinal symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability and unfavourable gut microflora.”

The authors examined two autism spectrum disorder patients with chronic intestinal symptoms and abnormal endoscopies and reviewed relevant background studies. Their findings inspired this conclusion:

“While genetic susceptibility is an important contributor in ASDs, the exact etiology of these pervasive developmental disorders remains unclear and is most likely multi-factorial…Be it an immune-mediated connection, versus a ‘brain-gut axis’ interplay such as seen in irritable bowel syndrome, the increased prevalence of GI symptoms in this group of patients cannot be denied, nor the added distress that these symptoms could have on an individual who is already communicatively challenged…a heightened awareness and lower threshold for work-up and management of GI symptoms may help improve quality of life of these patients who may be suffering in silence.”

The authors of a paper published in the Journal of Neuroimmunology consider lymphocyte subsets and inflammatory cytokines in the gut in relation to autism:

“Gastrointestinal pathology, characterized by lymphoid nodular hyperplasia and entero-colitis, has been demonstrated in a cohort of children with autistic spectrum disorder (ASD).”

They assessed inflammation in the intestines of ASD children in comparison with well controls and children with Crohn’s disease by examining inflammatory cytokines present in CD3+ lymphocytes (T helper and cytotoxic T cells):

“In both peripheral blood and mucosa, CD3+ TNFα+ and CD3+ IFNγ+ [pro-inflammatory cytokines] were increased in ASD children compared with NIC [non-inflamed controls] and reached levels similar to CD [Crohn's disease]. In contrast, peripheral and mucosal CD3+ IL-10+ [anti-inflammatory cytokine] were markedly lower in ASD children with GI symptoms compared with both NIC and CD controls. In addition, mucosal CD3+ IL-4+ [pro-inflammatory] cells were increased in ASD compared with NIC.”

Again we see a marked pattern of gastrointestinal inflammation distinguishing the ASD group. The authors conclude:

“There is a unique pattern of peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines, which is consistent with significant immune dysregulation, in this ASD cohort.”

Disorders of learning, behavior and neurodevelopment in childhood and adolescence are a heterogenous group with multiple possible causes so it would be an error to expect that all children with ASD have GI pathology and a principal or accessory cause. But it would be an equal error to fail to confirm whether or not it is a contributing factor in each individual case.

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Brain development, structure and function can suffer from a number of adverse environmental influences. A paper published in the journal Acta Pædiatrica review some of the environmental risk factors for ADHD.

“Converging evidence from epidemiologic, neuropsychology, neuroimaging, genetic and treatment studies shows that ADHD is a valid medical disorder…The majority of studies performed to assess genetic risk factors in ADHD have supported a strong familial nature of this disorder…However, several biological and environmental factors have also been proposed as risk factors for ADHD, including food additives/diet, lead contamination, cigarette and alcohol exposure, maternal smoking during pregnancy, and low birth weight.“

The authors review numerous studies that examine some these extraneous risk factors. They conclude by stating:

“Although a substantial fraction of the aetiology of ADHD is due to genes, the studies reviewed in this article show that many environmental risk factors and potential gene–environment interactions also increase the risk for the disorder.”

A study published in the journal Neuropediatrics investigates specifically the association between blood levels of mercury and ADHD in Hong Kong children:

“Fifty-two children with ADHD aged below 18 years diagnosed by DSM IV criteria without perinatal brain insults, mental retardation or neurological deficits were recruited from a developmental assessment center. Fifty-nine normal controls were recruited from a nearby hospital. Blood mercury levels were measured by cold vapor atomic absorption spectrophotometry.”

The authors uncovered a significant difference in blood mercury levels between the children with ADHD and the controls (‘normal’ children) which remained apparent after adjusting for age, gender and parents’ occupations:

“Children with blood mercury level above 29 nmol/L had 9.69 times higher risk of having ADHD after adjustment for confounding variables.”

The average blood mercury levels were higher for both the inattentive and combined subtypes of ADHD. Let’s bear in mind that this is one possible causal factor among many, not ‘THE’ cause. The authors conclude by stating:

“High blood mercury level was associated with ADHD. Whether the relationship is causal requires further studies.”

We can see a similar biological mechanism at play when we consider research recently published in Pediatric Allergy and Immunology that examines the association of heavy metals and Tourette syndrome. The authors state:

“Tourette syndrome (TS) is a childhood-onset and relapsing disorder characterized by involuntary simple or complex tics and high co-morbidity with behavioral anomalies…We investigated immunologic alternations and serum heavy metal levels in patients with TS to elucidate the unclarified mechanisms.”

Their findings illuminate a key point:

“In exacerbation, there were reverse CD4/CD8 (in two), higher percentages of natural killer cells (in five) and memory T cells (in eight), diminished lymphocyte activation CD69 marker (in three) and impaired NK cytotoxicity (in six) that showed a trend of lower inhibitory CD94 (NKG2A), activating NKp46, and perforin expression compared to those of patients with stable TS and healthy controls…Serum ASLO, mycoplasma antibody and the levels of heavy metals were not significantly different.”

In other words, the levels of heavy metals were pretty much the same but the immune system reaction to them was different. This is why it is impossible to make absolute statements about sub-acute levels of any heavy metal or toxin. Whether it elicits a dysregulated immune response leading to brain inflammation depends on the individual. The authors note this in their conclusion:

“Our study demonstrated that, in some patients with TS, consistently higher memory T cells and lower cytotoxicity in exacerbation status reflect immune alterations and underscore the potential for immunomodulation or immunosuppressive treatment.”

A paper published not long ago in Annals of Clinical Psychiatry carries the point further. The authors summarize the laboratory findings and other data in evidence for an autoimmune pathogenesis for autism:

“ Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay.”

Their findings certainly revealed the fire behind the smoke:

“Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)—salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants—a marker of systemic inflammation.”

Here again we see why it is impossible to argue for an environmental factor (heavy metal, virus, vaccine) as an absolute cause for autism or any other condition. Children at risk are those whose immune system is dysregulated and predisposed to an autoimmune triggering agent.

The authors state in their conclusion:

“The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy.”

We can also consider mild traumatic brain injury as a kind of ‘environmental risk factor’ for disorders neurodevelopment, learning and behavior. A study just published in the journal Pediatrics tests the link between postconcussion syndrome (PCS) and brain injury:

“Much disagreement exists as to whether postconcussion syndrome (PCS) is attributable to brain injury or to other factors such as trauma alone, preexisting psychosocial problems, or medicolegal issues. We investigated the epidemiology and natural history of PCS symptoms in a large cohort of children with a mild traumatic brain injury (mTBI) and compared them with children with an extracranial injury (ECI).”

The authors followed 670 children with mTBI and 197 children with ECI (non-cranial injury) and used the the Post Concussion Symptom Inventory, Rivermead Postconcussion Symptom Questionnaire, Brief Symptom Inventory, and Family Assessment Device to determine outcomes. Their data led to this conclusion:

“Among school-aged children with mTBI, 13.7% were symptomatic 3 months after injury. This finding could not be explained by trauma, family dysfunction, or maternal psychological adjustment. The results of this study provide clear support for the validity of the diagnosis of PCS in children.“

Environmental factors can be so severe that anyone would be affected. For most, however, the response depends on the individual. A skilled and experienced clinician knows when and where to focus suspicion. In the functional medicine model there are numerous resources available to test objectively when a question about environmental factors needs an answer, followed by the appropriate therapies when indicated.

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Numerous micro and macronutrients are required to grow and sustain a human brain in both structure and function. A paper published in the Journal of Nutrition, Health & Aging presents evidence for some of the key micronutrients:

“…most micronutrients (vitamins and trace-elements) have been directly evaluated in the setting of cerebral functioning. For instance, to produce energy, the use of glucose by nervous tissue implies the presence of vitamin B1; this vitamin modulates cognitive performance…Vitamins B6 and B12, among others, are directly involved in the synthesis of some neurotransmitters…Supplementation with cobalamin…frequently improves the functioning of factors related to the frontal lobe, as well as the language function of those with cognitive disorders. Adolescents who have a borderline level of vitamin B12 develop signs of cognitive changes.“

Revisiting the importance of iron for the brain:

“Iron is necessary to ensure oxygenation and to produce energy in the cerebral parenchyma (via cytochrome oxidase), and for the synthesis of neurotransmitters and myelin; iron deficiency is found in children with attention-deficit/hyperactivity disorder. Iron concentrations in the umbilical artery are critical during the development of the foetus, and in relation with the IQ in the child; infantile anaemia with its associated iron deficiency is linked to perturbation of the development of cognitive functions.“

Moreover, even subclinical deficiencies of micronutrients can have profound effects:

“…the full genetic potential of the child for physical growth and mental development may be compromised due to deficiency (even subclinical) of micronutrients.”

Macronutrients for the brain are addressed by the same author in an accompanying paper, starting with another look at fats:

“DHA (docosahexaenoic acid) is one for the major building structures of membrane phospholipids of brain and absolutely necessary for neuronal function…ALA acid deficiency alters the course of brain development…the nature of polyunsaturated fatty acids (in particular omega-3, ALA and DHA) present in formula milks for infants (premature and term) conditions the visual, neurological and cerebral abilities, including intellectual…Low fat diet may have adverse effects on mood.“

Regarding protein:

“The nature of the amino acid composition of dietary proteins contributes to cerebral function; taking into account that tryptophan plays a special role. In fact, some indispensable amino acids present in dietary proteins participate to elaborate neurotransmitters (and neuromodulators).”

The importance of blood sugar stability cannot be overstated:

“The regulation of glycaemia (thanks to the ingestion of food with a low glycaemic index ensuring a low insulin level) improves the quality and duration of intellectual performance, if only because at rest the brain consumes more than 50% of dietary carbohydrates, approximately 80% of which are used only for energy purpose. In infants, adults and aged, as well as in diabetes, poorer glycaemic control is associated with lower performances, for instance on tests of memory. At all ages…some cognitive functions appear sensitive to short term variations in glucose availability.”

The author concludes:

“[A] number of findings show that dietary factors play major roles in determining whether the brain ages successfully or experiences neurodegenerative disorders.”

Research recently presented in Psychosomatic Medicine (Journal of Biobehavioral Medicine) investigates:

“……the association between dietary folate, riboflavin, vitamin B-6, and vitamin B-12 and depressive symptoms in a group of adolescents.“

The authors correlated data on dietary intake with scores for depressive symptoms in 3,067 boys and 3,450 girls aged 12 to 15 years as defined by the Center of Epidemiologic Studies Depression Scale. What were the results?

“The prevalence of depressive symptoms was 22.5% for boys and 31.2% for girls. Folate intake was inversely associated with depressive symptoms in both boys and girls. Vitamin B-6 intake was inversely associated with depressive symptoms in both boys and girls. Riboflavin intake was inversely associated with depressive symptoms in girls, but not in boys. No clear association was seen between vitamin B-12 intake and depressive symptoms in either sex.”

Other studies have show an association between low vitamin B12 and depression in adults. We can speculate that this may be due to declining gastric digestive and absorptive capacity with age.

The authors conclude:

“This study suggests that higher intake of dietary B vitamins, particularly folate and vitamin B-6, is independently associated with a lower prevalence of depressive symptoms in early adolescence.“

There is interesting evidence for the importance of zinc in the clinical management of ADHD in a paper published in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry. The authors state:

“Some studies suggest that deficiency of zinc play a substantial role in the aetiopathogenesis of ADHD. Therefore, to assess the efficacy of zinc sulfate we conducted treatment trial.”

They examined the effect of double-blind treatment with zinc sulfate or placebo on 72 girls and 328 boys with a diagnosis of ADHD. Efficacy was assessed with a triad of rating scales. What did the data show?

“Zinc sulfate was statistically superior to placebo in reducing both hyperactive, impulsive and impaired socialization symptoms, but not in reducing attention deficiency symptoms, as assessed by ADHDS. However, full therapeutic response rates of the zinc and placebo groups remained 28.7% and 20%, respectively. It was determined that the hyperactivity, impulsivity and socialization scores displayed significant decrease in patients of older age and high BMI score with low zinc and free fatty acids (FFA) levels.“

The benefit of carnitine has been investigated for ADHD in boys and presented in a paper published in the journal Prostaglandins, Leukotrienes and Essential Fatty Acids:

“The ADHD behavior was observed by parents completing the Child Behavior Checklist (CBCL) and by teachers completing the Conners teacher-rating score, in a randomized, double-blind, placebo-controlled double-crossover trial.”

Significant improvements in behavior at home and at school were documented:

“Before treatment, the CBCL total and sub-scores were significantly different from those of normal Dutch boys. Responders showed a significant improvement of the CBCL total scores compared to baseline…responders showed higher levels of plasma-free carnitine and acetylcarnitine.“

The authors state in their conclusion:

“Treatment with carnitine significantly decreased the attention problems and aggressive behavior in boys with ADHD.“

An important paper also published in Progress in Neuro-Psychopharmacology and Biological Psychiatry disruption of the metabolism of tryptophan by inflammation can contribute to major depressive disorder (MDD) in adolescents. For background the authors state:

“Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins…The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho…”

The authors employed high resolution proton magnetic resonance spectroscopic imaging to examine fourteen adolescents with MDD, seven of whom had melancholic features, and six healthy controls.

“Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate and the left putamen, respectively…These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD.“

In other words, the authors’ evidence shows that for the melancholic subset of adolescents with major depressive disorder, pro-inflammatory cytokines are disrupting the metabolism of tryptophan into serotonin. This brings into focus special considerations for the management of diet and nutritional precursor supplementation.

Environmental toxins also place a burden on brain metabolism that can disrupt neurodevelopment. A paper published in the journal Neurotoxicology describes the importance of the redox/methylation pathways in the brain. The authors state:

“Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase.”

Methionine synthase activity is required for the dopamine metabolic activity and dopamine receptor function that promotes neuronal synchronization and attention (synchrony is impaired in autism).

“Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects…oxidative stress, initiated by environment factors in genetically vulnerable individuals, [can lead] to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.”

Here we see the possibility of environment conditions demanding extraordinary metabolic support to prevent disruption of developing neural networks.

None of the research presented here implies that a specific nutritional or metabolic intervention is correct for any given individual. In all cases the parents and clinician should keep in mind the possibility that any of these factors may play a role. However, a “try this, try that” approach should be avoided in favor of objectively determining the needs of the individual with the appropriate laboratory tests. While the experienced clinician will have an abundant toolbox, the urinary assessment of organic acids is an indispensable resource.

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There is a large and growing body of evidence for the role of brain inflammation due to immune dysregulation in disorders of learning, behavior and autism. A study recently published in the journal Biological Psychiatry shows how the microglia (immune cells in the brain) are activated and increased in the prefrontal cortex in autism:

“In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates.”

The authors used advanced immunochemistry and nuclear imaging techniques to compare microglial activation and volume in autistic and normal brains. Their conclusion:

“Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients.”

Autoimmune activity may manifest through a variety of autoantibodies to neural tissues in autistic spectrum disorders, epilepsy, Landau-Kleffner Syndrome (infantile acquired aphasia), etc. An earlier paper in Biological Psychiatry documents abnormal immune markers in the serum in association with these disorders:

“Brain derived neurotrophic factor (BDNF) elevation in newborn sera predicts intellectual/social developmental abnormalities. Other autoantibodies (AAs) to endothelial cells (ECs) and myelin basic protein (MBP) are also elevated in some children. We tested relationships between BDNF, BDNF AAs, and other AAs in children with these disorders.“

The authors measured these immune ‘attack molecules’ in measured in children with autism, childhood disintegrative disorder (CDD), pervasive developmental delay-not otherwise specified (PDD-nos), acquired epilepsy, Landau-Kleffner syndrome (LKS); healthy children (HC), and children with non-neurological illnesses (NNI). The data showed significant elevations. Their conclusion:

“Children with developmental disorders and epilepsy have higher AAs to several neural antigens compared to controls. The presence of both BDNF AAs and elevated BDNF levels in some children with autism and CDD suggests a previously unrecognized interaction between the immune system and BDNF.”

Immune dysregulation can manifest on a spectrum of developmental dysfunction from very mild development and learning disorders to full-blown autism. A recent paper in the same journal presents the evidence for immune dysfunction in healthy siblings of autistic kids:

“Endophenotypes are simple biological aspects of a disease that can be observed in unaffected relatives…an “autism endophenotype” justifies the observation that a mild reduction in ideational fluency and nonverbal generativity might be observed in healthy, unaffected relatives of children with autism…we examined whether the “autism endophenotype” would extend its effects on the immune system.“

The authors tested multiple immune parameters in autistic kids and their siblings in comparison to healthy ‘controls’ without a family history for autism and came to this conclusion:

“Results of this pilot study indicate that a complex immune dysfunction is present both in autistic children and in their non-autistic siblings and show the presence of an “autism endophenotype” that expands its effects on immunologic functions.”

An early paper published in Pediatric Neurology provides evidence of neuroinflammation in the cerebrospinal fluid in autism:

“In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders.”

Neopterin and biopterin are easily measured in the urine. What did the data show?

“In cerebrospinal fluid from 12 children with autism, quinolinic acid and neopterin were decreased, and biopterin was elevated, compared with control subjects.”

Subsequent research published in the same journal revealed the role of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in cases of autism that became worse:

“Recent reports implicating elevated cytokines in the central nervous system in a small number of patients studied with autism have reported clinical regression.”

The authors’ measurements of TNF-α in the serum and CSF of autistic children resulted in data that painted this picture:

“Elevation of cerebrospinal fluid levels of tumor necrosis factor-alpha was significantly higher than concurrent serum levels in all of the patients studied. The ratio of the cerebrospinal fluid levels to serum levels averaged 53.7:1…This observation may offer a unique insight into central nervous system inflammatory mechanisms that may contribute to the onset of autism and may serve as a potential clinical marker.”

Research just published in the journal Brain, Behavior, and Immunity reports the role of other pro-inflammatory cytokines in worsening cases of autistic spectrum disorder.

“A potential role for immune dysfunction has been suggested in Autism spectrum disorders (ASD). To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2 to 5 year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism.”

The data painted an unmistakable and compelling picture:

“Observations indicate significant increases in plasma levels of a number of cytokines, including IL-1β, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls. Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in ASD children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors.“

Their conclusion is important for every clinician and parent to bear in mind:

“In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD.”

We can also be informed by a fascinating study published in Biological Psychiatry confirming that behavioral abnormalities are associated with autoimmune attack on hormones in the brain and periphery. The authors set out to resolve the biological mechanism involved in aggressive behavior:

“Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior…We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects.”

Assays for antibodies revealed a definite pattern for both conduct disorder and prisoners groups leading the authors to conclude:

“High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.”

We can also appreciate the evidence presented the Journal of Neuroimmunology that autism is characterized by a deficit in the ability to dampen autoimmune attack on the brain by the cytokine transforming growth factor beta-1 (TGFβ1):

“Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. There is evidence of both immune dysregulation and autoimmune phenomena in autism. We examined the regulatory cytokine transforming growth factor beta-1 (TGFβ1) because of its role in controlling immune responses.”

The authors compared plasma levels of active TGFβ1 were in 75 children with ASD to 68 controls, finding that they were significantly lower in the ASD group. Moreover…

“…there were significant correlations between psychological measures and TGFβ1 levels, such that lower TGFβ1 levels were associated with lower adaptive behaviors and worse behavioral symptoms. The data suggest that immune responses in autism may be inappropriately regulated due to reductions in TGFβ1.”

Their findings likely apply to a range of developmental, learning and behavioral disorders:

“Such immune dysregulation may predispose to the development of possible autoimmune responses and/or adverse neuroimmune interactions during critical windows in development.“

Along these lines, a paper published in Biological Psychiatry describes the impaired immune tolerance due to deficiencies in regulatory T cells, another critical immune regulating factor in children with Tourette Syndrome. The authors state:

“Since regulatory T (T reg) cells play a major role in preventing autoimmunity, we hypothesized that a defect in T reg cells may be present in children with Tourette syndrome (TS).”

They analyzed the peripheral blood of TS kids compared to matched control subjects on multiple occasions to determine the numbers of CD4+CD25+CD69− T reg cells. The results were clear:

“A significant decrease in T reg cells was observed in patients with moderate to severe TS symptoms compared with healthy age-matched control children. A decrease in T reg cell number was also noted during symptom exacerbations in five out of six patients.”

Their conclusion affirms the role of autoimmunity in Tourette syndrome:

“These data support our hypothesis that at least some TS patients may have a decreased capacity to inhibit autoreactive lymphocytes through a deficit in T reg cells. Interactions of host T cell immunity and microbial factors may also contribute to the pathogenesis of TS.”

Early evidence for the role of autoimmunity in autism was presented in the journal Neuroscience Letters. The authors state:

“It is well established that increased neopterin levels are associated with activation of the cellular immune system and that reduced biopterins are essential for neurotransmitter synthesis. It has been suggested that some autistic children may be suffering from an autoimmune disorder.”

They measured these pterins in the urine of pre-school autistic children, their siblings and age-matched control children and found:

“Both urinary neopterin and biopterin were raised in the autistic children compared to controls and the siblings showed intermediate values. This supports the possible involvement of cell-mediated immunity in the aetiology of autism.”

The finding for the non-autistic siblings shows again that brain autoimmunity can manifest on a wide spectrum.

Yet more evidence for autoimmune dysfunction in both kids with autism and their siblings was offered in a study published in the Journal of Neuroimmunology on antibrain antibodies:

“Serum autoantibodies to human brain, identified by ELISA and Western immunoblotting, were evaluated in 29 children with autism spectrum disorder (22 with autistic disorder), 9 non-autistic siblings and 13 controls.”

The authors sum up the abnormalities found by concluding:

“Results suggest that children with autistic disorder and their siblings exhibit differences compared to controls in autoimmune reactivity to specific epitopes located in distinct brain regions.”

No discussion of autoimmunity and the brain would be complete without considering the role of the gut, the site of 60-80% of all the immune system tissue in the body. A paper published in the Journal of Clinical Immunology describes the corresponding autoimmune intestinal inflammation in children with autism.

“A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children.”

The authors performed duodenal biopsies and measured CD3+ lymphocytes in the colonic mucosa for the presence of the pro-inflammatory cytokines TNF-α, IL-2, IL-4, IFN-γ and the anti-inflammatory IL-10. Again we see a clear expression of autoimmunity:

“Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls. In the duodenum…epithelial TNF-α+ cells in ASD children [were] significantly greater compared with noninflamed controls but not coeliac disease controls…IL-10+ cells were fewer in ASD children than in noninflamed controls. In the colon,TNF-α+ and CD3+IFN-γ+ were more frequent in ASD children than in noninflamed controls.”

Note the similar findings for ASD and celiac disease. In striking accordance with with the authors found:

“There was a significantly greater proportion of TNF-α+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet. There is a consistent profile of lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities.”

It would be a shame for any clinician or parent to be unaware of their conclusion:

“The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.“

Regarding the link between autoimmune inflammation in the gut and brain it’s important to remember that the classical IgE-mediated food allergy diagnosed by skin prick is not usually the concern. Two papers published the Annals of Allergy, Asthma & Immunology illustrate the point. In IgE and non-IgE food allergy the authors note that:

“Food allergy (FA) is characterized by an abnormal immunologic reactivity to food proteins. The gastro-intestinal tract serves not only a nutritive function but also is a major immunologic organ. Although previously thought to be triggered primarily by an IgE-mediated mechanism of injury, considerable evidence now suggests that non-IgE mechanisms may also be involved in the pathogenesis of FA.”

The authors gathered extensive data on a range of disorders including attention-deficit-hyperactivity disorder and behavioral disorders, and correlated them with immunologic deviations to Th1 or Th2 mechanisms of FA. Their conclusion is crucial knowledge for anyone treating food allergy mediated disorders:

“The results of this review allow the construction of a central, unifying hypothesis for a new classification of FA as follows: the clinical manifestations of FA, expressed in affected target organs, may be the result of immunologic injury mediated by interaction of food antigens with contiguous elements of mucosal associated lymphoid tissue. These appear to be modulated by relative imbalances of the Th1/Th2 paradigm, which may be the ultimate determinant governing the expression of FA as IgE-mediated, non-IgE-mediated, or mixed forms of IgE/non-IgE mechanisms of FA.”

This is critically important because Th1 and Th2 imbalances require different interventions; it also offers a partial explanation of why antibody tests for food allergy are not reliable. The recent post on why autoimmune and allergic diseases are on the rise is of interest in this context. We also see in the same issue of Annals of Allergy, Asthma & Immunology a paper on the link between non-IgE-mediated food allergies and the inflamed lymphoid intestinal tissue that was described above in the report on mucosal immune activation and autism. Here the authors conclude:

“These studies suggest that abnormalities in Th1 function may not only play a role in some patients with non—IgE-mediated FA in whom decreased Th1 function is seen, but also in patients with celiac disease in whom an increased Th1 function is seen. The studies also suggest that lymphonodular hyperplasia may be a hallmark histologic lesion in patients with non—IgE-mediated FA.”

What does lymphonodular hyperplasia feel like? Sometimes nothing more than a little bloating. All of this helps us to appreciate the significance of neurologic disorders with gluten sensitivity. This was explored in a paper published in the journal Pediatrics more than six years ago:

“During the past 2 decades, celiac disease (CD) has been recognized as a multisystem autoimmune disorder. A growing body of distinct neurologic conditions such as cerebellar ataxia, epilepsy, myoclonic ataxia, chronic neuropathies, and dementia have been reported, mainly in middle-aged adults. There still are insufficient data on the association of CD with various neurologic disorders in children, adolescents, and young adults, including more common and “soft” neurologic conditions, such as headache, learning disorders, attention-deficit/hyperactivity disorder (ADHD), and tic disorders. The aim of the present study is to look for a broader spectrum of neurologic disorders in CD patients, most of them children or young adults.”

The authors found that kids with CD were far more likely to develop neurologic disorders than the control subjects, including hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia. Thus their conclusion:

“This study suggests that the variability of neurologic disorders that occur in CD is broader than previously reported and includes “softer” and more common neurologic disorders, such as chronic headache, developmental delay, hypotonia, and learning disorders or ADHD.”

Research published in the journal Nutritional Neuroscience clarifies one of the mechanisms behind autoimmune reaction to nervous system antigens in autism:

“We assessed the reactivity of sera from 50 autism patients and 50 healthy controls to specific peptides from gliadin and the cerebellum. A significant percentage of autism patients showed elevations in antibodies against gliadin and cerebellar peptides simultaneously.“

The authors employed detailed antigen-antibody probes with confirmation by sophisticated DOT-immunoblot and inhibition studies to reach their conclusion:

“We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells [a type of brain cell] and gliadin peptides, which may be responsible for some of the neurological symptoms in autism. “

Gliadin is the immunoreactive antigen contained in gluten.

Mention should also be made of the ability of infections to sometimes trigger an autoimmune disorder as discussed in a study published in the Journal of Child Psychology and Psychiatry on PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections).

“…(PANDAS) is a recently recognized syndrome in which pre-adolescent children have abrupt onsets of tics and/or obsessive-compulsive symptoms, a recurring and remitting course of illness temporally related to streptococcal infections, and associated neurologic findings including adventitious movements, hyperactivity and emotional lability.

The authors undertook a search for clinical and laboratory evidence and found consistent clinical findings have been described in a large case series, including magnetic resonance imaging that shows inflammatory changes in the basal ganglia, along with anti-basal ganglia antibodies have been found in some acute cases that were similar to those against streptococcal antigens. They note in their conclusion:

“PANDAS…has stimulated new research endeavors into the possible links between bacterial pathogens, autoimmune reactions, and neuropsychiatric symptoms.”

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This review just published in the journal Current Opinion in Pediatrics doesn’t attempt a comprehensive analysis of the multiple contributing causes of autism. It is, however, an important proposal by a respected authority in the field. He strongly asserts that environmental neurotoxins be more carefully investigated than they have up to this time. The author notes that genetic factors…

“…account for only a small fraction of cases, and do not easily explain key clinical and epidemiological features.” He further states that “Indirect evidence for an environmental contribution to autism comes from studies demonstrating the sensitivity of the developing brain to external exposures such as lead, ethyl alcohol and methyl mercury. But the most powerful proof-of-concept evidence derives from studies specifically linking autism to exposures in early pregnancy – thalidomide, misoprostol, and valproic acid; maternal rubella infection; and the organophosphate insecticide, chlorpyrifos.”

The author concludes by summarizing:

“Children today are surrounded by thousands of synthetic chemicals. Two hundred of them are neurotoxic in adult humans, and 1000 more in laboratory models. Yet fewer than 20% of high-volume chemicals have been tested for neurodevelopmental toxicity. I propose a targeted discovery strategy focused on suspect chemicals, which combines expanded toxicological screening, neurobiological research and prospective epidemiological studies.”

Many of you reading this may already know that I am using laboratory tools to objectively assess for toxic exposure and metabolism, along with evidence-based physiological interventions that protect and support the capacity of the body to break down and eliminate these ubiquitous poisons.

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There is a connection between how well you can smell, brain damage from autoimmune inflammation, and psychiatric disease. Consider this fascinating paper published in the journal Clinical Immunology in which the authors discuss the “inter-relationship between olfactory impairment, autoimmunity and neurological/psychiatric symptoms in several diseases affecting the central nervous system (CNS) such as Parkinson, Alzheimer’s disease, autism, schizophrenia, multiple sclerosis and neuropsychiatric lupus erythematosus. We suggest that common manifestations are not mere coincidences. Current data from animal models show that neuropsychiatric manifestations are intimately associated with smell impairment, and autoimmune dysregulation, via autoantibodies…”

In another paper published in the journal Autoimmunity Reviews the authors note that “Research in the field of immunology as well as in various brain illnesses is beginning to indicate the increasing relevance of smell in pathophysiology.” They further state “…evidence exists that there may be something unique about the olfactory system that is inextricably related to immunological function. In addition, accumulating evidence confirms the existence of olfactory dysfunction in brain disease, much of which appears at early stages including multiple sclerosis, Alzheimer’s Disease, Parkinson’s Disease, schizophrenia and depression…under certain circumstances, olfactory abnormalities may be associated with autoimmune conditions. Since the organization of the olfactory system is so sensitive, impairment may be noted at an early stage. This may become important in the prediction of certain brain illnesses.”

This paper recently published in the International Journal of Neuroscience focuses specifically on the link between olfaction, autoimmunity and Parkinson’s Disease. They first describe “the immune alterations observed in PD patients…the increase in the innate immune components including complement and cytokines within their substantia nigra and cerebrospinal fluid (CSF). These alterations extended to the adaptive immune response with the elevation of T cells and autoantibodies…in the peripheral blood and CSF of PD patients.” (Just the kinds of things we test for in the functional medicine approach.) They then describe the link between PD, autoimmunity and olfaction: “Smell deficit is one of the earliest signs of PD and a unique observation suggesting olfactory declines to be a consequence of autoimmune mechanisms.”

And the authors of this study published recently in the journal Autoimmunity observe that “Psychiatric diseases are often associated with mild alterations in immune functions (e.g., schizophrenia) as well as autoimmune features. Recent evidence suggests that autoimmune diseases (AD) demonstrate a higher prevalence of psychiatric disorders, such as depression and psychosis, than in the normal population. Patients with AD often have an olfactory impairment as well, based on smell studies… ” They report that olfactory gene receptors have brain functions in addition to smell, and go on to describe the genetic polymorphisms (variations) that link autoimmunity, psychiatric disorders and smell impairment.

The paper that concludes this post is tantalizingly entitled Olfaction—A Window to the Mind. Published not long ago in The Israel Medical Association Journal, it is available here in its entirety. The authors comment that “The sense of smell can provide a natural window to the brain. This window provides an opportunity to examine neural mechanisms and brain function in a non-invasive way.” They then undertake a fascinating review of the field of olfactory studies encompassing aspects ranging from autoimmunity and neuropsychiatric disease to sexual function, addiction, social behavior and the discrimination of self from non-self. Their conclusion is worth bearing in mind: “…assessment of the sense of smell and olfactory impairments is usually overlooked by patients and their clinicians. Given the clinical data reviewed here, clinicians should be encouraged to screen for olfactory impairments, which can help in the early diagnosis of CNS diseases such as Parkinson, dementia and schizophrenia, as well as CNS-autoimmune diseases such as neuropsychiatric lupus.”

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This research  on the safety and efficacy of oral DMSA (dimercapto succinic acid) therapy for children with autistic spectrum disorders was recently published in BMC Clinical Pharmacology in two parts:

1. Part A—Medical results
2. Part B—Behavioral results

The authors conclude in Part A: “Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC glutathione, and effective in normalizing platelet counts. Only 1 round (3 days) was sufficient to improve glutathione and platelets. Additional rounds increased excretion of toxic metals.”

They further state in their conclusion to Part B: “Overall, both one and seven rounds of DMSA therapy seems to be reasonably safe in children with ASD who have high urinary excretion of toxic metals, and possibly helpful in reducing some of the symptoms of autism in those children.” [RBC = red blood cell; ASD = autistic spectrum disorder]

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