Autism Spectrum Disorders and Allergy: Observation from a Pediatric Allergy/immunology Clinic

Harumi Jyonouchi

Disclosures

Expert Rev Clin Immunol. 2010;6(3):397-411. 

In This Article

Possible Effects of Allergic & Nonallergic Disorders on Cognition & Behavioral Symptoms

Allergic and nonallergic diseases causing chronic airway and gut mucosal inflammation may induce or aggravate psychiatric conditions. This may be due to disease-associated stress, pain, discomfort and sleep deprivation that will be discussed in this section. Studies addressing such aspects of allergic and nonallergic diseases are scant. Nevertheless, the limited data available and our clinical findings indicate the importance of recognizing underlying allergic/nonallergic conditions in association with behavioral symptoms.

Neuropsychiatric Effects of Allergic & Nonallergic Diseases in the General Population

Allergic Rhinitis Two studies examined young individuals with seasonal AR due to pollen allergy.[77,78] The results indicated impaired cognitive learning as well as impaired memory in allergic patients. Symptoms such as fatigue were also attributed to the use of antihistamines with sedative effects.[78] However, AR patients given placebo also experienced fatigue and impaired cognitive learning.[78] Another case–control study involving 1814 students (aged 15–17 years) evaluated school performance during the grass pollen season.[79] The results supported previous findings showing a significant risk of lower national examination test scores in the presence of symptomatic AR and/or with the use of sedative antihistamines.[79] Other studies involving smaller numbers of subjects also revealed similar results.[80]

In addition to the negative effects of AR on cognitive activity, impaired sleep is a well-recognized complication.[80] It is not unusual for AR patients to complain of a lack of 'a good night's sleep'. A study that examined the quality of sleep in adult AR patients showed that there was a positive correlation between disturbed sleep and the severity of AR.[81]

The effects of AR on behavioral symptoms, such as irritability, have been recognized by practitioners. One study reported a high prevalence of AR in patients with ADHD, indicating a role of AR in aggravating ADHD symptoms.[82] In this study, AR was validated by examining skin-prick test reactivity. Another study, analyzing healthcare claims databases indicated higher rates of depression and anxiety disorders in AR patients.[83] However, it should be noted that in this study, validation of AR diagnosis was not undertaken.

Asthma Practicing physicians have long suspected that asthma has an effect on mental illnesses and/or behavioral symptoms. Epidemiological studies indicate an increased frequency of anxiety and panic symptoms/disorders in asthma patients.[84] In a study using a large community sample (n = 4181 including 236 asthma patients aged 18–65 years), patients with physician-diagnosed asthma and current (within 4 weeks) asthma symptoms revealed an increased likelihood of any anxiety disorders, specific phobia, panic disorder and panic attacks.[85] A high prevalence of panic attacks in asthma patients in both adults and children was also reported in multiple studies that utilized both clinical and community samples.[84,86–89] In studies focused on populations without documented psychological disorders, asthma was positively associated with later development of internalizing symptoms and panic disorders.[90–92]

How does asthma affect the previously described mental disorders? The etiology of this association is probably very complex and varies with each individual. Proposed theories regarding the association between asthma and mental conditions include somatic effects of hyperventilation, hypersensitivity of CO2 receptors in the brain, the effects of asthma medications, and mutual genetic/environmental factors predisposing for asthma and panic/anxiety disorders such as maladaptation to stress.[84]

Autism spectrum disorder children who are referred to our pediatric allergy/immunology clinic often have many of the previously described behavioral symptoms. The presence of rhinitis and asthma probably aggravates behavioral symptoms in ASD children, as seen in patients with other psychiatric disorders. Therefore, from our experience,[10] we believe that these common medical conditions should be kept in check when providing medical care for ASD children, although prospective studies addressing this assumption are necessary.

GI Disorders An association between IgE-mediated FA and the development of mental disorders is not well documented. However, it has been our observation that children with atopic dermatitis (AD) and FA are often irritable and exhibit a short attention span. Constant pruritus and GI irritation seem to be associated with such behaviors in the patients we have treated in our clinic (see cases 1 and 2 described later). In a population study, atopic eczema was associated with ADHD,[13,93] although a negative association between childhood eczema and ADHD has also been reported.[94,95]

In inflammatory bowel diseases, chronic GI inflammation, caused by autoimmune conditions, is often associated with behavioral symptoms as well as impaired cognitive activity. Interestingly, it was reported that in 35 ASD children with language regression, there was a positive association with both GI symptoms and family history of autoimmune diseases.[96] At this point, I will discuss neuropsychiatric symptoms observed in two GI conditions, CD and NFA, since they are frequently implicated with GI symptoms observed in ASD children.

Celiac Disease It is now known that the clinical manifestations of CD are highly variable and can manifest as neurological or psychiatric symptoms. Some neuropsychiatric manifestations may be explained by malnutrition or a deficiency in micronutrients that results from chronic GI inflammation. However, certain neuropsychiatric symptoms appear to occur without notable nutrient deficiency. In studies involving 71 adult CD patients without detectable nutrient deficiency, 21 of these patients were shown to have neurological/psychiatric complications, including headache, depression, entrapment syndromes, peripheral neuropathy and epilepsy.[97] On the other hand, in a study evaluating a large number of CD children (n = 835), only 15 of them (1.79%) were noted to have neurologic/psychiatric problems, including epilepsy (n = 4), febrile seizures (n = 3), nonsyndromatic mental retardation (n = 2), chronic nonprogressive headache (n = 2) and bipolar disorders (n = 3).[69] Based on these results, it appears that neuropsychiatric manifestations may be low in CD children. However, it is important to keep in mind that other autoimmune conditions that are frequently seen in CD children,[98,99] as well as micronutrient deficiency, can cause neurological and psychiatric manifestations.[98,99]

Non-IgE-mediated FA As noted previously, severe NFA (food protein-induced enterocolitis syndrome) can lead to FTT and malnutrition.[73] Therefore, as with CD children, FTT and malnutrition may explain the worsening neuropsychiatric symptoms in NFA children. However, in our experience, NFA patients without notable nutrient deficiency often exhibit irritability, hyperactivity and a short attention span, similar to what is seen in children with atopic eczema. Such behavioral symptoms generally resolve or improve after implementation of a restricted diet that avoids the offending food.[73] In children treated in our clinic, parents of NFA children often comment that he/she is a 'different child' after implementation of the restricted diet.

Few published data exist regarding behavioral changes in non-ASD children with NFA. As part of one of our previous studies, behavioral changes in non-ASD children with NFA (n = 6; 2–4 years of age) were examined using an Aberrant Behavior Checklist (ABC) questionnaire[100] prior to and 3 months after implementation of the restricted diet. These non-ASD/NFA children were studied as NFA controls when studying behavioral changes in ASD/NFA children following dietary intervention.[101] Our results revealed a noticeable reduction in ABC subscales I (irritability) and IV (hyperactivity) in non-ASD/NFA children after implementation of the restricted diet (Figure 1). These results suggest that NFA-induced GI symptoms can impact behavioral symptoms (mainly irritability and hyperactivity) in children who do not have ASD. This may well also be the case in ASD children.[101]

Figure 1.

Changes in scores in each Aberrant Behavior Checklist subscale before and 3 months after dietary intervention in non-autism spectrum disorder children with non-IgE-mediated food allergy. ABC subscales: I (irritability), II (lethargy), III (stereotypy), IV (hyperactivity), V (inappropriate speech).
*Lower than values prior to dietary intervention (Wilcoxon signed ranks test).
Error bars denote standard deviations.
ABC: Aberrant Behavior Checklist.
Data obtained from USA Institutional Review Board-approved investigations in our clinic.

Effects of Chronic Medical Conditions in ASD Children

Individuals with developmental disabilities are likely to be at a greater risk of developing chronic and acute medical conditions than the general population, partly owing to poor communication skills. This has been demonstrated in several published studies, which will now be described.

A Swedish study examined subjects with developmental disabilities admitted to the hospital.[102] The results revealed that study subjects had at least one chronic medical condition and a threefold higher rate of hospital admissions than the general population.[102] Similar results were obtained in studies conducted in Australia and England. The Australian study revealed higher rates of medical consultations and hospital admissions in subjects with developmental disabilities (mental retardation) (aged 20–50 years; n = 202) than controls.[103] The English study showed that older individuals with developmental disabilities (aged >65 years; n = 134) had a higher frequency of medical conditions than controls.[104]

It should be noted that these studies focused on individuals with mental retardation, not necessarily ASD. However, these results provide evidence that similar issues may also apply to individuals with ASD. As previously noted, in our experience, diagnoses of common childhood diseases are more difficult in ASD children than normally growing children. Therefore, when caring for an ASD child, it is imperative to keep common medical conditions in check, despite the difficulties associated with examining these children. The idea that allergic and nonallergic medical conditions, as described previously in this review, can affect behavioral symptoms in ASD children, is not really surprising, especially considering their effects on the general population. However, only a few studies have examined the effects of medical conditions on behavioral symptoms in ASD children and even fewer are of substantial quality in their research methodologies.

A number of studies have examined minimally verbal subjects, many of whom were autistic. It has been reported that in individuals with minimal verbal skills, problem behaviors such as aggression, self-injury and temper tantrums can vary with concurrent medical conditions.[105,106] Sleep deprivation and active allergic symptoms negatively affected problematic behaviors in individuals of 13, 15 and 18 years of age with mental retardation, aggression and self-injurious behaviors.[107] In Chiladiti's syndrome (interposition of the colon between the liver and the diaphragm), adult patients with mental retardation were found to exhibit GI symptoms (e.g., nausea, pain, vomiting, anorexia, abdominal distension and constipation) similar to those observed in the pediatric population, although this syndrome is generally asymptomatic in adults with normal cognitive activity.[108] In addition, an association between self-injurious behaviors and premenstrual syndrome was also reported in seven out of nine women with mental retardation.[109]

As with normal individuals, proper medical intervention will probably lead to the improvement of behavioral symptoms caused by acute or chronic medical conditions in individuals with ASD and other mental disabilities. However, published data examining the effectiveness of medical intervention on problematic behaviors in individuals with developmental disabilities are extremely limited.[106,110] Carr et al. attempted to develop quantitative measures for assessing pain in minimally verbal individuals (n = 11; nine out of 11 diagnosed with autism) using questionnaires.[106] Results from the use of these questionnaires indicated significant behavioral changes with pain or discomfort in the study subjects.[106] In addition to changes in behavior, it may also be likely that underlying medical conditions affect cognitive activities in ASD children, as was observed in normal children with allergic disorders.[79]

Using the pain scale developed by Carr et al., as well as ABC questionnaires, we observed significant changes in the ABC scores of a few ASD children in our clinic when they experienced flare-ups of common childhood medical conditions (e.g., AR, asthma, NFA, CRS and recurrent ear infection). Three representative cases will now be described.

Case 1. An 8-year-old ASD Child with Severe IgE & Non-IgE-mediated FA, AD & AR This child was diagnosed with pervasive developmental disorder – not otherwise specified and is high functional when his allergic conditions (food allergen-induced eczema, allergic rhinoconjunctivitis and non-IgE-mediated delayed-type FA) are under control. However, when experiencing a flare-up of seasonal allergy symptoms or when an accidental exposure to offending food occurs, his behavioral symptoms worsen markedly, affecting his school performance. Figure 2 illustrates how the ABC scores worsen when his medical conditions flare-up (i.e., when he was sick). In parallel to changes in the ABC score, his total pain scale became as high as 23 when he was sick as opposed to 0 when he is well.

Figure 2.

Changes in scores in each Aberrant Behavior Checklist subscale when this autism spectrum disorder child is sick or well in case 1. ABC subscales: I (irritability), II (lethargy), III (stereotypy), IV (hyperactivity), V (inappropriate speech).
ABC: Aberrant Behavior Checklist.
Data obtained from USA Institutional Review Board-approved investigations in our clinic.

Case 2. A 5-year-old ASD Child with NFA This child was diagnosed with autism with impaired expressive language but good receptive language. His behavioral symptoms, especially hyperactivity and irritability, were significantly worse with recurrence of NFA symptoms following accidental exposure to offending food. This is evidenced by changes of the ABC score (Figure 3).

Figure 3.

Changes in scores in each Aberrant Behavior Checklist subscale when this autism spectrum disorder child is sick or well in case 2. ABC subscales: I (irritability), II (lethargy), III (stereotypy), IV (hyperactivity), V (inappropriate speech).
ABC: Aberrant Behavior Checklist.
Data obtained from USA Institutional Review Board-approved investigations in our clinic.

Case 3. A 7-year-old Child with Nonverbal Autism & Untreated Chronic Sinusitis This nonverbal autistic child was diagnosed with recurrent OM and treated with frequent but short courses of antibiosis by his general pediatrician. His behaviors have been problematic, with extreme irritability and hyperactivity as well as self-injurious behaviors (e.g., biting hands, hitting and banging head). Placement of a pressure equalization tube did not relieve his ear symptoms. This child was revealed to have pansinusitis by sinus CT scan, despite being afebrile. He was treated with a prolonged course of intravenous and oral antibiotics, which rendered significant improvement in his behavioral symptoms, as evidenced by changes in the ABC score (Figure 4). His pain scale was high at 45 when he was sick and is at 11 now that he is well. In summary, changes in his ABC scores reflect behavioral changes affected by his illness.

Figure 4.

Changes in scores in each Aberrant Behavior Checklist subscale when this autism spectrum disorder child is sick or well in case 3. ABC subscales: I (irritability), II (lethargy), III (stereotypy), IV (hyperactivity), V (inappropriate speech).
ABC: Aberrant Behavior Checklist.
Data obtained from USA Institutional Review Board-approved investigations in our clinic.

These three cases described in the previous paragraphs illustrate the potential effects of underlying common allergic and nonallergic medical conditions on behavioral symptoms in ASD children. In addition, such observations point out the importance of and need for practicing physicians to consider how sickness can affect individuals with ASD. However, it is important to note that, although our clinic treats a significant numbers of ASD children, our observations are based on a limited numbers of patients, and larger prospective studies are urgently needed to further address the effects of common medical conditions in these ASD children.

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