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• W2912951552 abstract "Epidemiological studies, animal models, and case–control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive–compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4–15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. Los estudios epidemiológicos, los modelos animales y los estudios de casos y controles indican que la activación inmune materna puede ser un factor importante involucrado en la expresión de la enfermedad del trastorno del espectro autista (TEA), el síndrome de Tourette y el trastorno obsesivo compulsivo (TOC). Informamos ocho niños (edad media 6 años de edad y 6 meses [rango 4-15 años]; 6 varones y 2 mujeres) remitidos durante un período de 2 años con al menos uno de estos trastornos del desarrollo neurológico más un historial materno de autoinmunidad tiroidea. Siete de ocho niños presentaron un inicio brusco de síntomas neuropsiquiátricos (TOC [n = 6], tics [n = 5] y / o psicosis [n = 1]), asociados con una regresión autista o global. Cuatro niños tenían un diagnóstico preexistente de TEA. Seis presentaciones fueron precedidas por infección, y los síntomas siguieron un curso de recaídas y remisiones en siete niños. Todos los niños respondieron al tratamiento inmunomodulador según lo indicado por una reducción en los síntomas psiquiátricos, y siete niños también fueron tratados con tratamiento convencional con una mejora adicional. Proponemos que la autoinmunidad materna puede activar la microglía fetal o alterar la transcripción de la vulnerabilidad del desarrollo neurológico y / o los genes inmunes en el útero, y es un factor ambiental que aumenta la expresión y la gravedad de los problemas del desarrollo neurológico, y la susceptibilidad a deterioros después de estímulos infecciosos o estresantes. Estudos epidemiológicos, modelos animais, e estudos de caso-controle indicam que a ativação imune materna pode ser um importante fator envolvido na expressão de doenças do transtorno do espectro autista (TEA), síndrome de Tourette, e transtorno obsessivo compulsivo (TOC). Reportamos oito crianças (média de idade 6a 6m [variação 4–15a]; 6 do sexo masculino e 2 do sexo feminino) encaminhadas em um período de 2 anos com pelo menos uma desordem neurodesenvolvimental e história de auto-imunidade tireóide materna. Sete das oito crianças apresentaram início agudo de sintomas neuropsiquiátricos (TOC [n=6], tiques [n=5], e/ou psicose [n=1]), associados com regressão autística ou global. Quatro crianças tinham diagnóstico pré-existente de TEA. Seis apresentações foram precedidas por infecção, e os sintomas seguiram um curso recorrência-remisão em sete crianças. Todas as crianças responderam ao tratamento imunomodulatório, indicado pela redução nos sintomas psiquiátricos, e sete crianças também foram abordadas com tratamento convencional, com melhora adicional. Nós propomos que a autoimunidade maternal pode ativar a microglia fetal ou alterar a transcrição de genes de vulnerabilidade neurodesenvolvimental e/ou imunes, e um fator ambiental pode aumentar a expressão e severidade de problemas neurodesenvolvimentais e suscetibilidade a deterioração após estímulo infeccioso ou estresse. This article is commented on by Scola on page 866 of this issue. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the abstract to view the translations. Autism spectrum disorder (ASD), Tourette syndrome, and obsessive–compulsive disorder (OCD) are common conditions of childhood, and the aetiology includes both genetic and environmental factors.1, 2 Epidemiological studies have reported a higher rate of maternal autoimmunity in children with ASD and Tourette syndrome.3, 4 It has been hypothesized that maternal autoimmunity and other maternal immune factors may pose a risk to the fetus through ‘maternal immune activation’,5, 6 whereby the inflammatory milieu in utero is thought to result in epigenetic alteration of expression of genes involved in neuronal development and/or activation of the resident immune cells of the brain, the microglia.7, 8 Although there is robust animal model support for the maternal immune activation hypothesis, evidence in humans is lacking, and longitudinal studies are required. We report a case series of children with neurodevelopmental and neuropsychiatric disorders whose mothers have chronic autoimmune thyroiditis (Hashimoto's thyroiditis), in addition to autoimmunity in other first-degree and second-degree family members. These children typically had an unusual clinical trajectory with an acute, mostly infection-provoked, onset of neuropsychiatric symptoms, often associated with autistic and motor regression, which followed a relapsing-remitting course. The paediatric patients were among 180 new patients referred to the neurology service with Tourette syndrome, OCD, and/or ASD at The Children's Hospital at Westmead, Sydney, Australia, over a 2-year period from June 2016 to June 2018. ASD was diagnosed by child development units, using the Autism Diagnostic Observation Schedule and DSM-IV/DSM-5 criteria. OCD, Tourette syndrome, and comorbidities fulfilled DSM-5 criteria.9 OCD was often the dominant therapeutic target and was monitored with the Children's Yale-Brown Obsessive Compulsive Scale. A family history of autoimmunity, neurodevelopmental, and neuropsychiatric disorders was elicited for first-degree and second-degree family members by clinical interview, followed by a routine clinical history and assessment. Antibiotics were prescribed for their immunomodulating properties if children had abrupt-onset of symptoms, an infection-provoked relapsing-remitting course, and/or a family or personal history of autoimmune disease. Corticosteroids and immunoglobulin were reserved for children who were severely affected and did not respond to conventional symptomatic therapy. Ethical approval was granted by the Sydney Children's Hospital Network Human Research Ethics Committee (HREC/18/SCHN/227). Parental informed written consent for reporting the clinical cases was obtained. Each case is outlined in Table SI (online supporting information) and three cases illustrating the breadth of presentations are reported in Appendix S1 (online supporting information). We describe eight index children born to eight mothers (mean age 10y at latest follow-up, range 6–16y; six males and two females). Four children had a diagnosis of ASD before the onset of their new acute neuropsychiatric symptoms. All but one mother (n=7) had a history of Hashimoto thyroiditis, diagnosed before the child's presentation to our centre. Of this group, five had clinical and biochemical hypothyroidism needing thyroxine replacement. One mother tested positive for thyroid autoantibodies after our assessment because of her strong family history of autoimmunity (case 1). Hashimoto thyroiditis was diagnosed before pregnancy with the described index patient in three mothers, during pregnancy in two mothers, and after pregnancy in three mothers. Of the two mothers diagnosed with Hashimoto thyroiditis during pregnancy, one was symptomatic. All mothers with hypothyroidism received thyroxine replacement, and thyroid hormone levels were stable during pregnancy. Two mothers had additional autoimmune disorders (vitiligo and rheumatoid arthritis) diagnosed before pregnancy, and three of the mothers had generalized anxiety disorder diagnosed by their general practitioners. Autoimmune diseases in other first-degree and second-degree family members were present in seven families: Hashimoto thyroiditis (seven members in four families), rheumatoid arthritis (five members in four families), primary biliary cirrhosis (one family member), and ulcerative colitis (one family member). Two index children were reported to have one brother each with high-functioning ASD, one of whom also had comorbid anxiety and depression. The remaining eight siblings (mean age 10y at end of study reporting, range 3–20y; two males and six females) were well without reported neurodevelopmental or neuropsychiatric disorders or autoimmune conditions. Of the 18 children born to the eight mothers, eight of the 10 males had a neurodevelopmental or neuropsychiatric disorder, compared to only two of the eight females. Interestingly, both index females with neurodevelopmental/psychiatric disorders had evidence of autoimmunity themselves, with the first having positive thyroid autoantibodies (case 8), and the second developing vitiligo at 8 years of age (case 5). Seven of the eight index children had abrupt onset of their neuropsychiatric symptoms with severe change in function within 2 weeks of symptom onset (mean age 6y 6mo, range 4–15y). The children had autistic (n=5) and motor (n=7) regression, including the four children with a pre-existing diagnosis of ASD. The most common neuropsychiatric presentations were new-onset OCD (n=6), sensory symptoms (n=6), tics (n=5), anxiety (n=5), and psychosis (n=1). Two children presented to an emergency department within 2 weeks of symptom onset. Only one child (case 7) had no regression and a more insidious symptom onset. Six children had an infection in the month before their acute neuropsychiatric presentation. All but one child (case 7) had a relapsing-remitting course with symptom exacerbations associated with infections in five children. The length of follow-up from the time at onset of neuropsychiatric symptoms ranged from 6 months to 7 years (median 2y). All children positively responded to empiric immunomodulatory treatment (antibiotics, steroids, and/or intravenous immunoglobulin), as indicated by a reduction in psychiatric symptoms reported by parents/teachers, evident on clinical review and measured using the Children's Yale-Brown Obsessive Compulsive Scale in five of the six children with OCD. Six children had additional improvement from psychotropic medications and psychotherapy. All children are now stable on conventional and/or immunomodulatory treatment (either regularly or as required; Table SI, Fig. 1a,b). We present eight children, seven of whom had acute-onset, complex neuropsychiatric symptoms associated with autistic and motor regression. The regression periods were not pure autistic regressions focused only on social and language behaviours, as there was additional loss of motor function such as loss of ambulation or fine motor skills. The mothers of the eight children all had Hashimoto thyroiditis, five of whom had biochemical hypothyroidism, plus there was a high rate of other autoimmune diseases in the child, mother, and other first-degree and second-degree family members. Seven of the eight index children had an unusually dynamic clinical course with relapsing-remitting neuropsychiatric symptomatology, and six of these children's initial presentations were associated with infection, with five children having subsequent infection-associated exacerbations. These patients lacked any peripheral or central markers of inflammation with typically normal brain magnetic resonance imaging, blood and cerebrospinal fluid findings including cerebrospinal fluid neopterin, a sensitive marker of central nervous system inflammation.10 All children responded empirically to immunological approaches combined with conventional therapy with antipsychotics, selective serotonin reuptake inhibitors, and psychological therapy when needed. Indeed, some patients responded to antibiotics, but conventional selective serotonin reuptake inhibitors seemed to have a more sustained benefit on OCD symptoms and anxiety (Fig. 1a). In three patients who were incapacitated by their symptoms despite conventional therapies, empirical trials of corticosteroids and intravenous immunoglobulin were effective. Some of the children had a clinical course compatible with paediatric acute neuropsychiatric syndrome, although this entity (and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) remains controversial and a recent critical review questioned the existence of the entity.11 Interestingly, of the 18 children (8 index and 10 siblings) born to the eight mothers, there was a higher rate of neurodevelopmental or psychiatric symptoms in the male children, compared to females. This is consistent with male:female ratios in ASD and Tourette syndrome, and, if our hypothesis is true, suggests males are more vulnerable to the environmental effects of immune activation, as has been demonstrated in animal models.12 Moreover, the two female index cases in our series had evidence of autoimmunity in themselves, suggesting a greater degree of exposure to a dysregulated immune environment. Epidemiological data demonstrate that children of mothers with autoimmune disease have a higher risk of ASD (34%; 95% confidence interval [CI]=1.23–1.46), Tourette syndrome (22%; 95% CI=1.01–1.48), and childhood epilepsy.3, 4, 13 Maternal infection, asthma, and allergy have also been associated with ASD in offspring.3, 14, 15 One report has suggested that children with OCD and/or tics have a higher rate of maternal autoimmunity than the general population, with the highest rate in children with acute-onset neuropsychiatric symptoms.16 Interestingly, a study from a tertiary autism clinic found that patients with autistic regression were more likely to have a maternal history of autoimmunity, compared to patients without autistic regression.17 Host autoimmunity and atopy are reported more frequently in children with ASD, and an association with paternal autoimmunity has also been studied but results are conflicting.18 Animal models of maternal immune activation have demonstrated that offspring of dams exposed to polyinosinic:polycytidylic acid and lipopolysaccharide, mimics of viral and bacterial infections respectively, show abnormal communication, socialization, anxiety, and repetitive behaviours, in addition to neuropathological findings similar to those seen in ASD.5, 6 In humans, maternal interleukin-6 levels are associated with altered neuronal connectivity and working memory in newborn infants, and elevated maternal mid-gestational levels of interleukin-4, interleukin-5, and interferon-gamma have been associated with autism in offspring.19, 20 The transfer of maternal autoantibodies may also be relevant, considering maternal contactin-associated protein-2 (CASPR2) and thyroid peroxidase antibodies have been associated with adverse neurodevelopmental and neuropsychiatric outcomes.21-23 It can be hypothesized that maternal immune activation affects neurodevelopment of the offspring in utero by multiple mechanisms, including epigenetic alteration of neurodevelopmental vulnerability genes in the offspring, the direct effect of maternal immune molecules such as proinflammatory cytokines or autoantibodies on neurogenesis and synaptic formation, and priming of microglia affecting synaptic development and potential further activation ex utero by stress or infection.5, 24 We hypothesize that such fetal brain priming (epigenetically or immunologically) provides a plausible explanation for the infection provoked relapsing-remitting course evident in the majority of the cases described in this report, and a different theoretical mechanistic model of what has been called paediatric acute neuropsychiatric syndrome.11 The speed of deterioration and response to immune therapies was notably faster than that seen in autoantibody-associated disease and seems more compatible with an innate immune disorder or an alternate process such as cell signalling dysfunction. Similarly, we propose that the immunomodulation treatments could be having direct brain effects, by modifying microglia function, altering gene expression, or modifying cell signalling,25 rather than a ‘classic immune suppression’ of peripheral immune molecules. Hypothyroidism is well recognized to adversely affect neurocognitive development in offspring, but thyroid hormone levels were stable in pregnancy when measured, and the dynamic clinical course and response to immunomodulatory treatments are difficult to explain by remote exposure to abnormal thyroid hormone and thyrotropin levels.26 There is some evidence for microglial activation in Tourette syndrome, OCD, and ASD.27, 28 Ribonucleic acid transcriptomes from the basal ganglia of patients with Tourette syndrome demonstrate upregulation in immune-related genes consistent with microglial activation, and neuroimaging studies demonstrate microglial activation in adults with OCD, and children with Tourette syndrome and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection.29-31 However, these studies have limitations, and further studies are required to explore this hypothesis.11 We acknowledge that the case series is selected and therefore open to bias, or coincidental association. Indeed, autoimmune thyroid disease is the second most frequent autoimmune disease, with an estimated incidence of autoimmune hypothyroidism in females of 350 per 100 000 per year, and the prevalence in the general population is 1% to 2%, with highest rates in elderly females.32, 33 However, thyroid peroxidase antibodies have been shown to be more common in pregnant mothers who subsequently had children with autism and are associated with lower motor and intellectual development, independent of maternal thyroid hormone levels.21, 26 In our series, three mothers tested positive for thyroid autoantibodies postpartum and the onset of autoimmune thyroid disease in those patients is not clear, yet their propensity to autoimmunity is manifest. A further limitation is the assessment of therapeutic responses, and although five children had prospectively collected conventional measurements (Children's Yale-Brown Obsessive Compulsive Scale for OCD), and reports were corroborated by teachers and other health professionals, the therapeutic effect was not controlled and therefore open to bias. There is a need for biomarkers in mothers and offspring that may help inform the biological process and treatment of putative immune mechanisms, which at the moment is empirical and understandably criticized.11 However our hypothetical model, based on our clinical observations and other literature, follows the ‘gene plus environment’ model of ASD and associated neurodevelopmental and psychiatric disorders, involving vulnerability genes plus environmental modifiers or exacerbating factors of disease expression, via epigenetic or immunological mechanisms.8 The members of the Immune-Neurodevelopment (Imm-Nd) Study Group are as follows: Margherita Nosadini, Ubaid Shah, John Down, Wendy Gold, and Markus J Hofer. The authors have stated that they had no interests that might be perceived as posing a conflict or bias. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2912951552 title "Maternal thyroid autoimmunity associated with acute‐onset neuropsychiatric disorders and global regression in offspring" @default.
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