Childhood atopic dermatitis as a precursor for developing attention deficit/hyperactivity disorder.

Atopic dermatitis (AD) is a skin disease characterized by chronic inflammatory condition that shows hallmark presentations in terms of sleep disturbances, pruritus, and psychological stress, and an association with increased attention deficit/hyperactivity disorder (ADHD) risk. A number of studies have suggested for the co-occurrence of the two diseased conditions. In terms of global prevalence, AD and ADHD almost exhibit a parallel increment according to epidemiological data. In addition, recent reports indicate AD to show a temporal association with later onset of ADHD. Although several studies suggest for the potential link between AD and ADHD, currently there is no definitive answer to this regard. Furthermore, epidemiological evidence of co-occurrence does not ascertain a pathophysiological link between the two conditions. The pathophysiological basis behind the association of AD and ADHD also remain poorly elucidated. The objective of this review is to present an extensive account of AD and associated comorbidities with a special attention toward ADHD as well as to elaborate on the mechanisms underlying their association. The review can provide healthcare providers with the recent updates on AD-ADHD association and help them while dealing with such patients. In general, AD and ADHD show a positive association in majority of the cross-sectional studies. However, large longitudinal studies are required to draw any conclusion on the temporal nature of such association.

Parental asthma occurrence, exacerbations and risk of attention-deficit/hyperactivity disorder.

OBJECTIVE: To investigate whether intrauterine exposure to maternal asthma or asthma exacerbations increases the risk of attention-deficit/hyperactivity disorder (ADHD). METHODS: Using Danish register data, this cohort study comprised of 961,202 live singletons born in Denmark during 1997-2012. Children were followed to a maximum of 20.0 years from birth until the first of ADHD-diagnosis/prescription, emigration, death, or 31 December 2016. Cox regression models were used to evaluate the association between maternal or paternal asthma, asthma exacerbations and offspring ADHD. RESULTS: During 11.4 million person-years of follow-up, 27,780 (2.9%) children were identified as having ADHD. ADHD risk was increased among offspring born to asthmatic mothers (hazard ratio (HR) 1.41, 95% CI: 1.36-1.46) or asthmatic fathers (HR 1.13, 95% CI: 1.08-1.18). Antenatal antiasthma medication treatment did not increase offspring ADHD. However, higher risks were observed among offspring of mothers with asthma exacerbations compared with children of asthmatic mothers with no exacerbations: HR 1.12 (95% CI: 1.00-1.25) for pre-pregnancy exacerbations; 1.21 (95% CI: 1.00-1.47) for exacerbations during pregnancy; and 1.25 (95% CI: 1.08-1.44) for exacerbations after delivery. CONCLUSIONS: These results support theories regarding shared genetic and environmental risk factors having a role in the development of ADHD.

Neuroinflammation as a risk factor for attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a persistent, and impairing pediatric-onset neurodevelopmental condition. Its high prevalence, and recurrent controversy over its widespread identification and treatment, drive strong interest in its etiology and mechanisms. Emerging evidence for a role for neuroinflammation in ADHD pathophysiology is of great interest. This evidence includes 1) the above-chance comorbidity of ADHD with inflammatory and autoimmune disorders, 2) initial studies indicating an association with ADHD and increased serum cytokines, 3) preliminary evidence from genetic studies demonstrating associations between polymorphisms in genes associated with inflammatory pathways and ADHD, 4) emerging evidence that early life exposure to environmental factors may increase risk for ADHD via an inflammatory mechanism, and 5) mechanistic evidence from animal models of maternal immune activation documenting behavioral and neural outcomes consistent with ADHD. Prenatal exposure to inflammation is associated with changes in offspring brain development including reductions in cortical gray matter volume and the volume of certain cortical areas -parallel to observations associated with ADHD. Alterations in neurotransmitter systems, including the dopaminergic, serotonergic and glutamatergic systems, are observed in ADHD populations. Animal models provide strong evidence that development and function of these neurotransmitters systems are sensitive to exposure to in utero inflammation. In summary, accumulating evidence from human studies and animal models, while still incomplete, support a potential role for neuroinflammation in the pathophysiology of ADHD. Confirmation of this association and the underlying mechanisms have become valuable targets for research. If confirmed, such a picture may be important in opening new intervention routes.

ADHD pathogenesis in the immune, endocrine and nervous systems of juvenile and maturating SHR and WKY rats.

RATIONALE: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioural disorders with morphological and functional brain abnormalities. However, there is a growing body of evidence that abnormalities in the immune and endocrine systems may also account for the ADHD pathogenesis. OBJECTIVES: To test ADHD pathogenesis in neurological, immune and endocrine systems, this study examined the concentrations of cytokines, chemokines, oxidative stress markers, metabolic parameters, steroid hormones and steroidogenic enzymes in the serum and/or tissues of spontaneously hypertensive rats (SHRs, animal model of ADHD) and Wistar Kyoto rats (WKYs, control animals). Moreover, the volume of the medial prefrontal cortex (mPFC) as well as the density of dopamine 2 (D2) receptor-expressing cells and tyrosine hydroxylase (TH)-positive nerve fibres in it was also elucidated. METHODS: Peripheral blood, spleen and adrenal gland samples, as well as brain sections collected on day 35 (juvenile) and day 70 (maturating) from SHRs and WKYs, were processed by ELISA and immunohistochemistry, respectively. RESULTS: The results show significant increases of serum and/or tissue concentrations of cytokines, chemokines and oxidative stress markers in juvenile SHRs when compared to the age-matched WKYs. These increases were accompanied by a lowered volume of the mPFC and up-regulation of D2 in this brain region. In maturating SHRs, the levels of inflammatory and oxidative stress markers were normalised and accompanied by elevated contents of steroid hormones. CONCLUSIONS: Significant elevations of serum and/or tissue contents of cytokines, chemokines and oxidative stress markers as well as volumetric and neurochemical alterations in the mPFC of juvenile SHRs may suggest the cooperation of neurological and immune systems in the ADHD pathogenesis. Elevated levels of steroid hormones in maturating SHRs may be a compensatory effect involved in reducing inflammation and ADHD symptoms.

Familial association of attention-deficit hyperactivity disorder with autoimmune diseases in the population of Sweden.

AIMS: In the era of genome-wide association studies, familial risks are used to estimate disease heritability and success in gene identification. We wanted to estimate associations of 42 autoimmune diseases with attention-deficit hyperactivity disorder (ADHD) between individuals and family members. PARTICIPANTS AND METHODS: The availability of a Multigeneration Register in Sweden provides reliable access to family data that covers the last century. An open cohort design of the diseases in individual and family members was obtained through linkage to the Hospital Discharge Register. Standardized incidence ratios were calculated as relative risks for ADHD in family members of affected patients compared with those without affected family members. RESULTS: Among a total of 86 493 patients, 18 153 had a family history of autoimmune diseases. ADHD was associated with 14 autoimmune diseases in the first-degree relatives, including ankylosing spondylitis (standardized incidence ratio:1.13), celiac disease (1.16), Crohn's disease (1.07), diabetes mellitus type 1 (1.19), discoid lupus erythematosus (1.26), glomerular nephritis chronic (1.13), Hashimoto/hypothyroidism (1.11), lupoid hepatitis (1.44), multiple sclerosis (1.11), psoriasis (1.18), Reiter's disease (1.38), rheumatoid arthritis (1.07), Sjögren's syndrome (1.21), and ulcerative colitis (1.05). CONCLUSION: Familial associations with several autoimmune diseases suggest genetic sharing and challenge to gene identification.

A Review on the Role of Inflammation in Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition that impairs quality of life in social, academic, and occupational contexts for both children and adults. Although a strong neurobiological basis has been demonstrated, the pathophysiology of ADHD is still poorly understood. Among the proposed mechanisms are glial activation, neuronal damage and degeneration, increased oxidative stress, reduced neurotrophic support, altered neurotransmitter metabolism, and blood-brain barrier disruption. In this way, a potential role of inflammation has been increasingly researched. However, evidence for the involvement of inflammation in ADHD is still scarce and comes mainly from (1) observational studies showing a strong comorbidity of ADHD with inflammatory and autoimmune disorders; (2) studies evaluating serum inflammatory markers; and (3) genetic studies. A co-occurrence of ADHD with inflammatory disorders has been demonstrated in a large number of subjects, suggesting a range of underlying mechanisms such as an altered immune response, common genetics, and environmental links. The evaluation of serum inflammatory markers has provided mixed results, likely due to the small sample sizes and high heterogeneity between biomarkers. However, there is evidence that increased inflammation during the early development may be a risk factor for ADHD symptoms. Although genetic studies have demonstrated a potential role for inflammation in this disorder, there is no clear evidence. To sum up, inflammation may be an important mechanism in ADHD pathophysiology, but more studies are still needed for a more precise conclusion.

Evaluation of the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume as inflammatory markers in children with attention-deficit hyperactivity disorder.

AIM: The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), and mean platelet volume (MPV) have recently been used as indicators of a systemic inflammatory response. The aim of this study was to investigate the relations of the NLR, PLR, MLR, and MPV with attention-deficit hyperactivity disorder (ADHD). METHODS: The study group consisting of 82 children diagnosed with ADHD was compared with a healthy control (HC) group of 70 age-, sex-, and body-mass-index-matched subjects. The NLR, PLR, MLR, and MPV were measured according to the complete blood count. RESULTS: The NLR, PLR, MLR, MPV, and neutrophil count of the ADHD group were significantly higher than those of the HC group. The lymphocyte counts of the patients were significantly lower than those of the HC group. CONCLUSION: Inflammation might play a role in the etiopathogenesis of ADHD. The NLR, PLR, MLR, and MPV may be potential inflammation markers for ADHD in children.

Rationale for Dietary Antioxidant Treatment of ADHD.

Increasing understanding arises regarding disadvantages of stimulant medication in children with ADHD (Attention-Deficit Hyperactivity Disorder). This review presents scientific findings supporting dietary antioxidant treatment of ADHD and describes substantial alterations in the immune system, epigenetic regulation of gene expression, and oxidative stress regulation in ADHD. As a result, chronic inflammation and oxidative stress could develop, which can lead to ADHD symptoms, for example by chronic T-cell-mediated neuroinflammation, as well as by neuronal oxidative damage and loss of normal cerebral functions. Therefore, modulation of immune system activity and oxidant-antioxidant balance using nutritional approaches might have potential in ADHD treatment. The use of natural antioxidants against oxidative conditions is an emerging field in the management of neurodegenerative diseases. Dietary polyphenols, for example, have antioxidant capacities as well as immunoregulatory effects and, therefore, appear appropriate in ADHD therapy. This review can stimulate the development and investigation of dietary antioxidant treatment in ADHD, which is highly desired.

Anti-Basal Ganglia Antibodies and Streptococcal Infection in ADHD.

OBJECTIVE: Group A Streptococcus has been associated with ADHD, tic disorders (TD), and obsessive-compulsive disorder (OCD) through anti-basal ganglia antibodies (ABGA). METHOD: We investigated the association between ABGA and streptococcal exposure with behavioral, motor, and cognitive measures in 38 children with ADHD not comorbid to OCD or TD (nc-ADHD) and in 38 healthy children. An additional group of 15 children with TD and/or OCD was examined. RESULTS: ABGA titers were present in 3% of nc-ADHD patients and controls but in 27% of TD and/or OCD patients. Evidence of streptococcal exposure was similar between ADHD patients and controls living in the same urban area. Behavioral, motor, and cognitive measures were not associated with anti-streptococcal antibodies. CONCLUSION: ABGA do not distinguish nc-ADHD from controls. The differences in the frequency of streptococcal exposure in previous studies are determined by the dynamic nature of the infection rather than the behavioral phenotype of ADHD.

Transient Isolated Lower Bulbar Palsy With Elevated Serum Anti-GM1 and Anti-GD1b Antibodies During Aripiprazole Treatment.

BACKGROUND: Transient bulbar palsy without involvement of the facial or extraocular muscles is a rare presentation. It is considered a form of cranial polyneuropathy, a variant of Guillain-Barré syndrome that is related to the autoimmune mechanisms induced by preceding infections or vaccinations. However, drug-induced cranial polyneuropathy has not previously been reported. We describe a boy with isolated bulbar palsy and positive serum antiganglioside antibodies during aripiprazole treatment. PATIENT DESCRIPTION: This 12-year-old boy was admitted with a seven-day history of dysarthria, tongue discomfort, and tinnitus. Three weeks before symptom onset, aripiprazole was added to the patient's medications for attention-deficit hyperactivity disorder. On examination, he showed curtaining of the pharyngeal wall, tongue fasciculation and deviation, and a weak gag reflex. Cranial magnetic resonance imaging suggested lower cranial nerve involvement. Serum anti-GM1 IgG and anti-GD1b IgG antibodies were positive. After stopping aripiprazole, his bulbar symptoms improved. However, on readministration of aripiprazole seven weeks later, dysarthria recurred and again resolved after stopping the drug. CONCLUSION: We describe the first patient with anti-GM1 IgG and anti-GD1b IgG antibodies-associated transient cranial polyneuropathy presenting as isolated bulbar palsy. These findings could be an adverse effect of aripiprazole treatment.

Effect of Pycnogenol® on attention-deficit hyperactivity disorder (ADHD): study protocol for a randomised controlled trial.

BACKGROUND: Methylphenidate (MPH), the first choice medication for attention-deficit hyperactivity disorder (ADHD), is associated with serious adverse effects like arrhythmia. Evidence on the association of ADHD with immune and oxidant-antioxidant imbalances offers potential for antioxidant and/or immunomodulatory nutritional supplements as ADHD therapy. One small randomised trial in ADHD suggests, despite various limitations, therapeutic benefit from Pycnogenol®, a herbal, polyphenol-rich extract. METHODS: This phase III trial is a 10-week, randomised, double-blind, placebo and active treatment controlled multicentre trial with three parallel treatment arms to compare the effect of Pycnogenol® to MPH and placebo on the behaviour of 144 paediatric ADHD and attention-deficit disorder (ADD) patients. Evaluations of behaviour (measured by the ADHD-Rating Scale (primary endpoint) and the Social-emotional Questionnaire (SEQ)), immunity (plasma cytokine and antibody levels, white blood cell counts and faecal microbial composition), oxidative stress (erythrocyte glutathione, plasma lipid-soluble vitamins and malondialdehyde and urinary 8-OHdG levels, as well as antioxidant enzyme activity and gene expression), serum zinc and neuropeptide Y level, urinary catecholamines and physical complaints (Physical Complaints Questionnaire) will be performed in week 10 and compared to baseline. Acceptability evaluations will be based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account. DISCUSSION: This trial takes into account comorbid behavioural and physical symptoms, as well as a broad range of innovative immune and oxidative biomarkers, expected to provide fundamental knowledge on ADHD aetiology and therapy. Research on microbiota in ADHD is novel. Moreover, the active control arm is rather unseen in research on nutritional supplements, but of great importance, as patients and parents are often concerned with the side effects of MPH. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT02700685 . Registered on 18 January 2016. EudraCT 2016-000215-32 . Registered on 4 October 2016.

Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases.

BACKGROUND: Prenatal inflammatory mechanisms may play a role in the pathogenesis of psychiatric disorders and could be relevant for attention-deficit/hyperactivity disorder (ADHD). We investigated maternal chronic somatic diseases with immune components as possible risk factors for ADHD in offspring. METHODS: We performed a population-based nested case-control study by linking data from longitudinal Norwegian registers. We included all individuals born during the period 1967-2008 and alive at record linkage (2012). Individuals receiving ADHD medication during the years 2004-2012 were defined as patients with ADHD (N = 47,944), and all remaining individuals (N = 2,274,713) were defined as control subjects. The associations between maternal diseases and ADHD in offspring were analyzed using logistic regression models. RESULTS: The following chronic diseases with immune components were related to ADHD in offspring: multiple sclerosis (adjusted odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.2-2.5), rheumatoid arthritis (adjusted OR = 1.7; 95% CI = 1.5-1.9), type 1 diabetes (adjusted OR = 1.6; 95% CI = 1.3-2.0), asthma (adjusted OR = 1.5; 95% CI = 1.4-1.6), and hypothyroidism (adjusted OR = 1.2; 95% CI = 1.1-1.4). In contrast, chronic hypertension and type 2 diabetes showed no significant associations. Estimates were almost unchanged with additional adjustment for parental ADHD, infant birth weight, and gestational age. Although point estimates for male and female offspring were different for some diseases (e.g., maternal asthma [adjusted OR = 1.7; 95% CI = 1.5-1.8 for female offspring and adjusted OR = 1.5; 95% CI = 1.4-1.6 for male offspring]), none of the associations differed significantly by offspring sex. CONCLUSIONS: Several maternal somatic diseases with immune components were found to increase the risk of ADHD in offspring. The associations could involve several causal pathways, including common genetic predisposition and environmental factors, and increased insight into the mechanisms behind these relationships could enhance our understanding of the etiology of ADHD.

Paraneoplastic syndrome-associated neuronal antibodies in adult ADHD.

A high seroprevalence of Yo antibodies targeting cerebellar Purkinje cells was recently reported in children with attention deficit/hyperactivity disorder (ADHD). We investigated the presence of 8 paraneoplastic neurological syndrome (PNS)-associated antibodies including anti-Yo in 169 adult ADHD patients. No associations between ADHD and serum Yo antibodies or other antibodies associated with PNS were found. However, 10 out of 48 ADHD patient sera analyzed by immunofluorescence presented antibodies targeting cerebellar Purkinje cells. This reactivity probably represents the presence of low levels of antibodies against multiple cellular hitherto unknown antigens with little to no clinical significance.

Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation.

PURPOSE: Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. METHODS: Articles were identified with a search of Medline (starting in 1980) by using the key words anxiety, attention-deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, and stress. FINDINGS: Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic-pituitary-adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. IMPLICATIONS: Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation, and flavonoids are discussed.

Immunization with DISC1 protein in an animal model of ADHD influences behavior and excitatory amino acids in prefrontal cortex and striatum.

The Disrupted-in-schizophrenia 1 (DISC1) gene is involved in vulnerability to neuropsychiatric disorders. Naples high-excitability (NHE) rat model neuropsychiatric problems characterized by an unbalanced mesocortical dopamine system. Here, we assessed behavioral and neurochemical effects of immunization against multimeric rat DISC1 protein in adult NHE rats, an animal model of attention-deficit hyperactivity disorder and their Random-Bred (NRB) controls. Males of both lines received subcutaneous injections of vehicle (PB), adjuvant only (AD) or recombinant rat DISC1 protein purified from E. coli, suspended in AD (anti-DISC1) at age of 30, 45 and 60 postnatal days (pnd). At 75 pnd, the rats were exposed to a Làt maze and 2 days later to an Olton eight-arm radial maze, and horizontal (HA) and vertical activities (VA) were monitored. Non-selective (NSA) and selective spatial attention (SSA) were monitored in the Làt and in the Olton maze by duration of rearings and working memory, respectively. Post mortem neurochemistry in the prefrontal cortex (PFc), dorsal (DS) and ventral (VS) striatum of L-Glutamate, L-Aspartate and L-Leucine was performed. All immunized rats showed a clear humoral IgM (but not IgG) immune response against the immunogen, indicating that immunological self-tolerance to DISC1 can be overcome by immunization. NHE rats exhibited a higher unspecific IgM response to adjuvant, indicating an immunological abnormality. The sole anti-DISC1 immunization-specific behavioral in the NHE rats was an increased horizontal activity in the Làt maze. Adjuvant treatment increased vertical activity in both lines, but in the NRB controls it increased rearing and decreased horizontal activity. Liquid chromatography/tandem mass spectrometry analysis of soluble or membrane-trapped neurotransmitters aspartate, glutamate and leucine revealed increased soluble aspartate levels in the ventral striatum of NRB controls after anti-DISC1 immunization. Immune activation by adjuvant independent of simultaneous DISC1 immunization led to other specific changes in NHE and control NRB rats. In DISC1-immunized NHE rats, horizontal activity in Lat maze correlated with membrane-trapped glutamate in PFc and in the NRB rats, duration of rearing in Olton maze correlated with membrane-trapped glutamate in PFc and aspartate in dorsal striatum. In addition to non-specific immune activation (by AD), the postnatal anti-DISC1 immune treatment led to behavioral changes related to mechanisms of activity and attention and had influenced amino acids and synaptic markers in striatum and neocortex in the adult NHE as well as control animals.

Antibasal Ganglia Antibodies and Antistreptolysin O in Noncomorbid ADHD.

OBJECTIVE: An association between streptococcal infections, ABGA positivity, and no comorbidity ADHD (nc-ADHD) has been little investigated. The aim of this study was to evaluate the streptococcal infection frequency, defined entitled serum antistreptolysin O (ASO), and frequency of serum ABGA positivity in a sample of patients with nc-ADHD. METHOD: In all 40 participants were investigated the ASO titer and ABGA. RESULTS: The results showed that ABGA positivity was statistically significantly higher in patients affected by ADHD than in patients of a control group, and pathological values of ASO were statistically more frequent in the ADHD group than the control group. CONCLUSION: These data suggest that streptococcal infections and autoimmune reactions against the basal ganglia are more frequent in ADHD patients than patients in a control group.

Is atopy in early childhood a risk factor for ADHD and ASD? a longitudinal study.

OBJECTIVE: Previous studies have found a temporal concordance in the increased prevalence of atopic diathesis/atopic diseases, attention-deficit hyperactivity disorder (ADHD), and autistic spectrum disorder (ASD) worldwide. But, the temporal association among these 3 distinct diseases is unknown. METHOD: 14,812 atopic subjects diagnosed with any atopic disease (asthma, atopic dermatitis, allergic rhinitis, or allergic conjunctivitis) before the age of 3 (atopic cohort) and 6944 non-atopic subjects with no lifetime atopic disease (non-atopic cohort), born between 1997 and 2000, were enrolled and followed to December 31, 2010 to identify the development of ADHD and ASD. RESULTS: The presence of any atopic disease in early childhood increased the risk of developing ADHD (hazard ratio [HR]: 1.97) and ASD (HR: 3.40) in later life. Greater numbers of atopic comorbidities (4 comorbidities: ADHD: HR: 2.53; ASD: HR: 4.29) were significantly related to a greater risk of developing ADHD and ASD. DISCUSSION: Atopic diathesis in early childhood elevated the risk of developing ADHD and ASD in later life, with the dose-dependent relationship of more atopic comorbidities with a greater likelihood of ADHD and ASD.

Subclinical immune reactions to viral infections may correlate with child and adolescent diagnosis of attention-deficit/hyperactivity disorder: a preliminary study from Turkey.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neuro-developmental disorders of childhood and adolescence. Studies focusing on the relationship of infectious agents and ADHD are scarce. It is also known that cerebellar injury may lead to hyperactive behavior. This study aimed to evaluate the relationship between viral agents of cerebellitis and the diagnosis of ADHD. METHODS: The study group was formed of 60 consecutive ADHD patients and 30 healthy children. IgG levels for VZV; HSV-1, CMV, Measles, Mumps, Rubella and EBV were evaluated. RESULTS: Males were significantly higher among patients with ADHD (65% vs. 40%, p=0.025). Patients with ADHD displayed significantly higher positivity for measles IgG (80% vs. 60%, p=0.044). When patients with ADHD were classified according to their pubertal status, adolescents with ADHD displayed higher positivity for mumps (100% vs. 74.4%, p=0.043). Most of the patients were diagnosed with ADHD-Combined or Hyperactive/Impulsive Subtypes (56.6%) while 43.3% were diagnosed with ADHD-predominantly inattentive type. When patients with subtypes of ADHD were compared in terms of seropositivity, it was found that patients with ADHD-Combined/ Hyperactive-Impulsive subtypes had significantly elevated reactions for Rubella (100% vs. 88.5%, p=0.044). CONCLUSION: Although limited to a single center and may be prone to sampling biases, our results may support the notion that immune reactions may be related with ADHD among children and adolescents. Further, prospective studies from multiple centers are needed to support our findings and establish causality.

Nutrition, immunological mechanisms and dietary immunomodulation in ADHD.

Attention-deficit hyperactivity disorder (ADHD) etiology is not completely understood, but common comorbid dysfunction of the gastrointestinal and immune system suggests that these systems may be affected by a common genetic background and molecular mechanisms. For example, increased levels of specific cytokines were observed in ADHD. Moreover, ADHD has a high comorbidity with both Th1- and Th2-mediated disorders like ear infections, eczema and asthma. A common pathophysiological mechanism was suggested to underlie both asthma and ADHD, while several genes that are linked to ADHD have immune functions. Furthermore, immunological recognition of food provoking ADHD-like behavior was suggested. An immune imbalance, probably requiring a predisposing genetic background, is therefore suggested to contribute to ADHD etiology, with immune dysregulation being more likely than a single subcellular defect. However, next to allergic mechanisms, also pharmacological mechanisms (especially in case of food additives) might be involved. In addition, though cellular (cytokine-related) rather than antibody-mediated immune mechanisms seem involved, specific immune-inflammatory markers other than antibodies have not been systematically studied in ADHD. Substantial alterations implicated in ADHD apparently occur in the immune system and epigenetic regulation of gene expression. As a result, chronic inflammation and oxidative stress could develop, which can lead to ADHD symptoms, for example by chronic T-cell-mediated neuroinflammation. If immune pathways contribute to ADHD, both its diagnosis and treatment should be reconsidered. Modulation of immune system activity might have potential in ADHD treatment, for example by nutritional approaches providing safe and low-cost ADHD therapy, but further research in these fields is implicated.