Food allergy and autism spectrum disorder - Journal of Food Allergy [PDF]

Journal of Food Allergy, Vol. 04 Suppl (1): 4-17, July-December, 2015

Food allergy and autism spectrum disorder

JOURNAL OF FOOD ALLERGY

Journal of Food Allergy, Vol. 04 Suppl (1): 4-17, July-December, 2015 EDITORIAL Revista O cial da Sociedade Brasileira de Alergia Alimentar - SBBA EDITORCHEFE Prof. Dr. Aderbal Sabrá Universidade Unigrario, Rio de Janeiro, Brasil EDITORES CONSULTORES Katie Allen University of Melbourne, Melbourne, Australia Jaime Ramirez Mayans Instituto Nacional de Pediatría, S.S, Mexico Joseph A. Bellanti Georgetown University Medical Center, USA Jorge Amil Dias Centro Hospitalar S. Joao, Portugal

John Walker-Smith Emeritus Prof of Paediatric Gastroenterology University of London, Londo, United Kingdom Marcello Barcinski FIOCRUZ, Rio de Janeiro, Brazil Mauro Batista Morais Paulista School of Medicine, Sao Paulo, Brazil Simon Murch Warwick Medical School, United Kingdom

Jorge Kalil School of Medicine USP and Instituto Butantan, São Paulo, Brazil

Annamaria Staiano University of Naples, Federico II, Italy

Giuseppe Iacono Di Cristina Hospital, Italy

Maria Del Carmen Toca University of Buenos Aires, Argentina

Glenn Furuta Univ. of Colorado Denver School of Medicine, USA Olivier Goulet University of Paris 5 René Descartes, Paris, France

Neil Shah Great Ormond Street Hospital Institue of Child Health University College London, United Kingdom

Harland Winter Harvard Medical School, USA

Journal of Food Allergy Address: Visconde de Piraja, 330 / 311, 22410-001, Rio de Janeiro, Brazil Telephone: + 55 21 2513-2161 E-mail: contact@journaloffoodallergy.com Website: www.journaloffoodallergy.com

Journal of Food Allergy, Vol. 04 Suppl (1): 4-17, July-December, 2015 CONTENTS

Food allergy and autism spectrum disorder............................................................................ 004

Aderbal Sabrá 1, Luciana Corsini 2, Issac Tenório 2, Selma Sabrá 3, João Marcelo Nemer 2, Aderbal Sabra Filho 4 1 Prof. of Food Allergy School of Medicine, UNIGRANRIO 2 Fellow in Food Allergy at UNIGRANRIO 3 Prof. of Pediatric Endoscopy and Food Allergy at UFF and UNIGRANRIO 4 Internship of Food Allergy School of Medicine, UNIGRANRIO

EDITOR COMMENTS Journal of Food Allergy is proud to announce the supplement 2015 devoted to Autistic Spectrum Disorder (ASD) and Food Allergy (FA). e recent discovery of lymphatic system in the central nervous system published in Nature June 1 2015, with this nal sentence “e discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroin ammatory and neurodegenerative diseases associated with immune system dysfunction” entitled Prof Aderbal Sabra to publish his 15 years of research in this area, showing the association between Food Allergy and Autistic Spectrum Disorder. ese two original articles published in the Journal of Food Allergy supplement will be remembered as the turning point for the future of the patients with ASD. e aetiology and the treatment of this disease are the major subjects of the two articles written by Professor Sabra. ese ndings bring new light on immune system dysfunction produced by FA as the cause of the neuroin ammatory disease of ASD.

Journal of Food Allergy, Vol. 04 Suppl (1): 4-17, July-December, 2015

Original Article

FOOD ALLERGY AND AUTISM SPECTRUM DISORDER Aderbal Sabrá, Luciana Corsini, Issac Tenório, Selma Sabrá, João Marcelo Nemer, Aderbal Sabra Filho

ABSTRACT is work shows clinical and laboratory evidences that link food allergy (FA) to Autism Spectrum Disorder (ASD). FA occurred in all autistic patients before the onset of ASD and most of them had at least two Mucosa Associated Lymphoid Tissues (MALT) affected by FA. In the patients with ASD we may point out the prevalence of involvement of the Gut Associated Lymphoid Tissue (GALT).

KEY WORDS: Autism Spectrum Disorder; Food Allergy; Allergy and Immunology

J FOOD ALLERGY. 2015; SUPPL 1 417

INTRODUCTION

e autism spectrum disorder (ASD) is characterized by disorders of the neurological development, typically diagnosed within the rst 4 years of life, which presents itself clinically with impairments in the social interaction, de cits of verbal and non-verbal communication and repetitive stereotypic behavior without any purpose (1-3). It occurs in one every 68 individuals and may affect any child, regardless of sex, race or socio-economical condition, being four to ve times more frequent in the male sex (4). Patients with ASD present their own characteristics of communication, social interaction, behavior, intelligence and learning. e clinical condition varies within the spectrum of the disease, from severe cases, with self-aggression, isolation and less than one hour of sleep per day, to children with few alterations in the behavior and that still can interact socially. Patients with ASD may show comorbidities such as anxiety disorder, attention de cit and hyperactivity disorder (ADHD) and depression. Asperger’s Syndrome, presently included in the clinical spectrum of ASD, presents also global disorders usually less compromised in the development and obsession for speci c areas of knowledge with cognition and verbal skills relatively preserved (5-10). In the literature indexed up to this moment, ASD does not have a de ned etiology and the involved pathophysiological mechanisms still remain unknown. Present studies on these mechanisms and of the etiopathogeny have investigated the genetic and environmental causes and immunizations. Due to this lack of Pag. 4

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information relative to ASD, its treatment becomes unpredictable and continues being a fallacy (11). ETIOPATHOGENY AND GENETIC FACTORS e epidemiological ndings show that, among brothers, if one has ASD the chance of the other to develop the disorder is of 35%. In identical twins, if one has ASD the other has 90% of chance of being also affected. Some genetic and/or chromosomic alterations can increase the risk of developing ASD, such as Tuberous Sclerosis and the Fragile X Chromosomic Syndrome. However, the majority of patients have no family history of ASD, suggesting that its origin can be random or depend on epigenetic. In order to understand better how the genetic factors could contribute for the genesis of the disorder, the family history of all patients with ASD treated at the Gastroenterology and Allergy Service of the Unigranrio University (S.G.A.U.U.) was analyzed. e collected data corroborate with those described in the literature (Figure 1), showing that the minority (24%) have a family history for ASD, ADHD (Attention De cit Hyperactivity Disorder) and/ or Asperger Syndrome. On the other hand, the family history of food allergy (FA) and respiratory and skin allergies was positive in more than 80% of the cases, suggesting that the genetic factors involved in the etiopathogeny of allergies may be in uencing the development of ASD.

ETIOPATHOGENY AND ENVIRONMENTAL FACTORS

Figure 1 - Family history of patients with ASD.

changes or mutations in certain genes (12).

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Several environmental factors are related to the development of FA and, possibly, of ASD, considering the important link between etiopathogeny of both which will be discussed in this article; they are: socio-economic condition, reduction of the number of family members, family health, age of parents, exposure to toxins, environmental contamination, excess hygiene, indiscriminate use of antimicrobials and proton pump inhibitors, modi cation of the diet caused by the expansion of food industry. obesity, de ciency of Vitamin D, immunizations, climatic changes, cigarette smoking and other pollutants in the environmental air and in the water for drinking and bathing (11, 13). ETIOPATOGENY AND INMUNIZATIONS All over the world, the age group that is most exposed to immunization is from zero to 2 years, and it is possible to analyze the impact of this practice, observing the drastic reduction of the number and/or severity of the respective transmissible diseases. As ASD onset increases in the same group of age, an expressive number of relatives consider vaccines as the cause or inciting factor of ASD. ere is no direct association between ASD and thimerosal (preservative of measles vaccine) and other preservatives of vaccines or of the measles virus. erefore, independently of the elimination of thimerosal from the vaccines, in 2001, the number of autistic patients increases all over the world (14). When quantifying the triggers mentioned by parents and relatives of the patients that have developed ASD and were treated at S.G.A.U.U., we may notice that in 52% it was mentioned that the vaccines were the inciting factor of ASD. In other words, more than half of the parents and relatives that identi ed a trigger for ASD mention that the vaccines were “responsible” for the triggering of the condition. Of 38 patients diagnosed with ASD and FA, 19 mentioned the triggers. Among them, there are the vaccines, weaning, psychic traumas, cranio encephalic trauma (CET), dog bite, upper respiratory tract infections (URTI) and otitis (Figure 2). FA AND ASD Our research in this area began in 1998 with the publication of a previous note in e Lancet, indicating that patients with FA had endoscopic alterations in the biopsies of terminal ileum similar to the ones described by the group of Professor John Walker Smith, performed in patients with ASD (15, 16). In 2003 and 2012, we published that patients with FA and celiac disease present behavior disorders and immunologic 1 response described frequently in patients with ASD in studies of immuno uorescence and of cytochemistry(17-19). And in 2004, pathways of antigens, lymphocytes and immunoglobulins, aer the immune activation in Peyer´s Platches (PP) of the GALT system searching for their homing site. e selected homing may be in the BALT (bronchial associated lymphoid tissue), NALT (nasal associated lymphoid tissue), SALT (skin associated lymphoid tissue), returning to GALT or CNSALT (central nervous system associated lymphoid tissue), affected in ASD. e de nition of which target organ will be involved is in uenced by genetic inheritance, of environmental factors and of other factors of in ammatory nature(20). is interaction between the mucosa associated lymphoid tissues and the lymphatic and blood systems, through which they are interconnected, is shown in Figure 3. In 2006, we made a multi centric study in Rio de Janeiro, in Venezuela with the participation of Dr. Lenny Gonzalez and in Washington DC with the participation of Prof. Joseph Bellanti in patients with ASD and gastrointestinal symptoms. e alterations in their immunologic responses identi ed in the peripheral blood, the immune histochemistry alterations in their biopsies, besides the ndings on gastrointestinal endoscopy observed

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Figure 2 - Triggers mentioned by the relatives of patients with ASD. Total: 19 patients. CET: cranio encephalic trauma, URTI: upper respiratory tract infections.

Figure 3 - Interaction between MALTs and the Lymphatic and Blood systems through which they are connected.

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in more than one hundred patients with ASD, were identical to the ones found in patients with FA (21). In 2008, participating in a multicentric meeting held in Harvard under the guidance of Pros. Harland Winter and Timoty Buie, we could identify gastrointestinal alterations, common to most patients with ASD, that led these patients to present the stereotyped behavior of the disease (22-24). ese ndings of the gastrointestinal alterations in patients with ASD, submitted and discussed in this meeting, are compatible with FA. By working and researching, during the last 20 years, exclusively in the FA area, we have performed the analysis of more than one thousand cases, selected randomly, and that were within the classic criteria for the diagnosis of FA. In this manner, the rst clinical score was structured for the diagnosis of FA, published in the Journal of Food Allergy in 2012, that standardizes the diagnostic research and served also as a tool in this present study (25). By studying patients with FA, it is possible to notice that genetic and environmental factors as well as immunizations, are also present, in different

moments, in expressive numbers. e genetic predisposition, which in this case determines the capacity to answer with allergy to non-pathogenic antigens, is of main importance for the genesis of the allergic disease and is also present in ASD. Children of parents that both are allergic have 80% chance to be allergic and, as described before, we have noticed that in more than 85% of the patients with ASD, there was a family history of respiratory and food allergy. Food allergy is a multifactorial disease that develops in the presence of factors such as improper breastfeeding, health of the mother and of her gastrointestinal tract during pregnancy and breastfeeding, enteromammary cycle disease, deliveries with serious complications and sterile (caesarean) and early exposure to cow’s milk and, less frequently, to wheat and soy bean (11). In Figure 4 we have included all 44 patients with ASD previously diagnosed, cared at S.G.A.U.U. One hundred per cent of these patients were diagnosed with FA by the Score for the Diagnosis of FA (25), the thorough physical examination with focus on the identi cation of the multisystemic involvement and the laboratory investigation that identi es the immune

Figure 4 - Pro le of 44 patients with ASD treated at S.G.A.U.U. CM: cow’s milk (early exposure to cow’s milk), EMCD: enteromammary cycle disease, FA: food allergy. Pag. 8

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mediated mechanisms. We have collected data through the review of the records, characterizing this study as retrospective cross sectional study. Some topics of the graphics do not have the same total number of patients, because along the years new anamnesis data were added, according to the literature advances in this area. In this sample, the proportion between male and female sex was of 3:1 and it is possible to notice that most of the patients were born from caesarian delivery and were early exposed to cow’s milk (CM). We have noticed, further, that in 28% the disease of the enteromammary cycle was present and that more than half reported triggers causing the ASD. Although it is accepted that the central nervous system (CNS) receives constant immunologic monitoring, only in June 2015 the presence of lymphatic vessels in the meninges was observed (26-28). is discovery of the lymphatic system in the CNS requires a new revaluation of the basic presumptions of neuro-immunology and brings a new light on the etiology of neurodegenerative and neuro-in ammatory diseases, such as ASD which associates with the disturbs of the immunologic system (29). In ammations, physical and psychic traumas, infections and neurotropic vaccines (Measles, Sabin and Pertussis) cause in ammation in the neurons and have the potencial to make, directly, the Central Nervous System (CNS) the homing or the FA target organ, attracting the circulating lymphocytes and the immunoglobulin that participate in the process (30). e clinical manifestations of FA in the CNS (Central Nervous System) could present as the autistic spectrum disorder, changing clinically as per the affected area and the extent of allergic aggression to this system. ere was the involvement of other mucosa associated lymphoid tissues (MALT), previous to the onset of ASD in all except one previously asymptomatic patient(Figure 5). In 65% of the

patients (Figure 6), the ASD was established as a disease in patients with proper psychomotor development and neurologic past without alterations, but with serious FA. And almost half of the patients articulated the speech within the rst two years of life, lost with the beginning of the clinical features. We have then developed our hypothesis of FA being one of the previous factors in patients that developed ASD, if these patients with FA suffer in ammation of the CNS that could make neurons a target organ or homing site of FA (11,20). All patients with ASD showed a Score above 9 for the Diagnosis of FA, in other words, they were highly consistent with the diagnosis of the pathology in question. erefore, they were duly investigated in order to de ne the immune mechanisms involved in the etiopathogeny so that the proper therapy could be applied. In spite of the common clinical characteristics, we have found different immune mediations. In 78% of the patients, the humoral immune response (IgE) was present, either singularly or associated to the cellular response, characterizing the mixed mediation. In 23% of the patients, we notice alteration in the cellular immunity and in 9% other immune responses were identi ed, among them the ones mediated by eosinophils and NK cells (Figure 7).

CEREBELLUM ALTERATIONS IN ASD Recent studies have shown that the cerebellum, besides participating of the motor coordination, performs also an important role in motricity, cognition and in the emotional processes (31). Motor, cognitive and emotional abnormalities may result from injuries in parts of the cerebellum that extend to motor areas, prefrontal cortex and limbic system, respectively (32-34). ere are also evidences that the cerebellum is related to several cognitive abnormalities and psychopathological manifestations (35). ere is a strong association between abnormalities in the cerebellum and psychiatric diseases, such

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Figure 5 - Number of associated lymphoid tissues affected before the onset of ASD symptoms.

Figure 6 - Articulation of speech and psychomotor development before the onset of ASD symptoms.

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Figure 7 - Immune responses in patients with ASD and FA diagnosis.

as schizophrenia, bipolar disorder, depression, anxiety disorders, ADHD and ASD (36-51). We should point out that there is a strong association between allergic diseases (allergic rhinitis, atopic eczema and asthma) with ADHD and that other psychiatric diseases, such as separation anxiety disorder, obsessive-compulsive disorder and Tourette's syndrome are also found frequently in atopic patients (52-55). Oddly enough, it was found that cerebellum injuries in children may predict the occurrence of autism later, this being another possible trigger for the homing mechanism (56). Presently, there are three known cerebellum abnormalities in patients with ASD: reduction of the Purkinje cells, reduced cerebellum volume and interruption of feedback between the cerebellum and the cortex. e Purkinje cells are of inhibitory nature, and their lack would reduce the inhibition projected by the cerebellum in the cortical and sub cortical areas, causing hyper sensibility in these regions of the brain found in most patients with ASD (57). We have studied the CNS of these patients with ASD, through nuclear magnetic resonance spectroscopy under anesthesia and found, in all of them, a strong indication of in ammation in the cerebellum region. Such injury is followed by accumulation of Glutamine and Glutamate in 100% of the cases (58), corroborating the ndings present in the literature. ASD AND DIET WITHOUT CASEIN AND GLUTEN Presently, the National Institute of Health (NIH) does not recommend the dietetic restriction as primary treatment of the disease, due to the lack of scienti c data that justify and prove the impact of this practice, but even so many children with ASD follow a gluten and casein restrictive diet and some of them restrict soybean s also.22. e success of this diet derives from the great frequency of allergy to milk, wheat and soybean and, therefore, it works only in patients with ASD that are allergic exclusively to these allergens. Some patients will show total improvement, including clinical improvement of ASD while others will not have any bene ts with the restrictive diet. e patients in which the diet does not work are, probably, allergic to other food. Cow’s milk, wheat and soybean are the main and more frequent allergens in patients with FA, but eggs, meat and nuts are also important (59-62). Pag. 11

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Evaluating the sensitization to main food allergens in patients treated at S.G.A.U.U., we notice that the 39 patients submitted to prick test have shown reaction to cow’s milk, more than half reacted also to wheat and approximately 38% to soybean (Figure 8). Now it is possible to understand why the restriction to certain foods works in some patients and does not work in others, in these the FA depends upon other allergens.

Figure 8: positivity in skin prick test to antigens of cow’s milk, wheat and soybean. TREATMENT AND PREVENTION OF ASD ere is no cure or preventive practices currently, however there are medicines and therapies that, when implemented early, may bene t some patients with ASD, reducing their symptoms and increasing their capacities of learning and helping them to advance in their cognitive development. We should point out that there are no data informing that patients with ASD develop the speech aer adopting these practices. e present state of dietetic treatment of ASD is based upon the restrictive diet, without gluten and casein, with no scienti c support up to this moment. We know that this wrong but accepted and practiced conduct, is bene cial to some patients with ASD and does not work in others, as discussed before. e same is noticed with the use of supplementation with vitamins and minerals. TREATMENT OF FA AND IMPROVEMENT OF ASD With these data in our hands, we began the treatment of our patients with previous diagnosis of ASD excluding from their diets the allergens of FA, to which they showed sensitization, resulting in a behavioral improvement in all of them. In general, the laboratory routine is shown in the second visit and, aer that, we guide our patients to a restrictive diet based upon the prick test with food allergens. erefore, we have included in Figure 9 only those patients that have been on a speci c restrictive diet and, therefore, had more than three or more doctor visits. e treatment for ASD and FA should be established, as early as possible, as diet without allergens (formulas of amino acids), while making the investigation of immunologic mediation and the analysis of food allergens involved in theallergic response. It is necessary, also, to check the extension of the brain damage and the staPag. 12

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EVOLUTION IN PATIENTS WITH MORE THAN 3 VISITS REPORT BY THE RELATIVES (Total:19)

Figure 9 - Report by the relatives on the evolution of patients with ASD aer the third doctor visit, which corresponds to the return aer the implementation of guided diet. ging of the motor, cognitive and socio-affective development. e study of the brain damage is made by magnetic nuclear resonance spectroscopy and the staging of the development is evaluated through questionnaires and forms (Brown ADD Scales for Children and Adolescents). With these data we applied a individualized diet to each patient and follow up periodically the evolution of development and clinical improvement. e diet without allergens shall continue while there are clinical and laboratory indicators of food allergy. It is necessary to follow up the cure of FA, even when the patients leave the ASD. is is because FA may always cause in ammation in the patients that have neurotropism for allergic response, with recurrence of the clinical ASD condition. With the FA cure, the neurotropic in ammatory mediators disappear and, with them, the possibility of new immune aggressions to the CNS. e symptoms of ASD improve, new capacities appear, the focus of the eyes with characteristics of affection appear in substitution of the vague and distant look in the eyes and the patients show evident signs of progress in their cognitive functions. Almost 70% have developed the speech aer the treatment and all 9 patients that had difficulty in sleeping and in remaining sleeping improved their situation in respect to sleep (Figure 9). e gain of new motor, cognitive and socio- affective abilities will depend upon the extent of the neuronal lesion at the time of the diagnosis, but all patients undergoing treatment have bene ted and improved their quality of life. PREVENTION OF ASD Some measures can be taken prophylactic in order to avoid the establishment of FA. ey include the stimulus to exclusive breastfeeding of the newborn, eliminating the use of any formulas except the hypoallergenic of amino-acid at the nursery, stimulating the vaginal delivery, avoiding excess hygiene and the indiscriminated use of antibiotics, therefore reducing the risk factors for the development of FA (63-67). In mothers with disease of the enteromammary cycle, it will be inevitable the existence of FA in the infant, but it is possible to prevent the aggression to the CNS through mother’s diet or, in case the restrictions are not possible, the introduction of amino acid formulas (68). If the patient develops FA, we should avoid the concomitant aggression to CNS, eliminating any and all cause of in ammation in the CNS. e prophylaxis will be to avoid the homing for the neurons in these patients with FA, specially during the maturation phase and of natural lack of complete myelination of the CNS. We recommend, in these cases, the continued use of hypoallergenic diet. For patients with ASD genetics, we should also avoid the development of the FA. If FA occurs, with the risk of lesion and possible aggression to CNS, we should immediately establish a hypoallergenic diet, preferably with amino acid formulas, until the resolution of FA and the aggression to the CNS (11). Pag. 13

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