Brain Autoimmune Diseases Research Articles

Disease Course and Response to Immunotherapy in Children With Childhood Disintegrative Disorder: A Retrospective Case Series.

Childhood disintegrative disorder is a poorly understood neurobehavioral disorder of early childhood characterized by acute to subacute profound regression in previously developed language, social behavior, and adaptive functions. The etiology of childhood disintegrative disorder remains unknown and treatment is focused on symptomatic management. Interest in neuroinflammatory mechanisms has grown with the increased recognition of autoimmune brain diseases and similarities between the presenting symptoms of childhood disintegrative disorder and pediatric autoimmune encephalitis. Importantly, a diagnosis of pediatric autoimmune encephalitis requires evidence of inflammation on paraclinical testing, which is absent in childhood disintegrative disorder. Here we report 5 children with childhood disintegrative disorder who were initially diagnosed with possible autoimmune encephalitis and treated with immunotherapy. Two children had provocative improvements, whereas 3 did not change significantly on immunotherapy. Additionally, a sixth patient with childhood disintegrative disorder evaluated in our Autoimmune Brain Disease Clinic showed spontaneous improvement and is included to highlight the variable natural history of childhood disintegrative disorder that may mimic treatment responsiveness.

Nodding syndrome is unlikely to be an autoimmune reaction to leiomodin-1 after infection by Onchocerca volvulus

Nodding syndrome is a neurological disease of children in northern Uganda. Infection with the nematode parasite Onchocerca volvulus has been epidemiologically implicated as the cause of the disease. It has been proposed that an autoantibody directed against the human protein leiomodin-1 cross reacts with a tropomyosin-like nematode protein, thus suggesting that nodding syndrome is an autoimmune brain disease due to extra-cerebral parasitism. This hypothesis is dependent on constitutive neuronal expression of leiomodin-1. We tested this hypothesis by studying the distribution of leiomodin-1 in the normal human brain and other human tissues using immunohistochemistry. We found that immunostaining for leiomodin-1 follows a smooth muscle cell specific pattern. In the brain, it is confined to the smooth muscle cells of cerebral blood vessels and is not generally present in neurons or glia. However, immunoreactivity was identified in human Purkinje cell membrane and the body wall of C. elegans (as a proxy for Onchocerca volvulus) but only when immunostained with an antibody recognizing the N-terminal of leiomodin-1. Homology between leiomodin-1 and tropomodulin, specifically at the N-terminus, could explain why leiomodin-1 antibody cross reactivity between human Purkinje cells and C. elegans. However, we cannot provide proof confirming that the immunoreactivity in the membranes of Purkinje cells is specifically caused by the expression of tropomodulin. To overcome this limitation, further investigations using additional immunohistochemical and biochemical studies are required to corroborate our findings and provide more comprehensive evidence. Nevertheless, our findings do not support to the autoimmunity hypothesis involving Onchocerca volvulus and leiomodin-1. To gain a more comprehensive understanding of the cause and pathogenesis of NS, it is essential to explore alternative hypotheses.

Progress in the mechanism of neuronal surface P antigen modulating hippocampal function and implications for autoimmune brain disease.

The aim of this study was to present a new regulation system in the hippocampus constituted by the neuronal surface P antigen (NSPA) and the tyrosine phosphatase PTPMEG/PTPN4, which provides mechanistic and therapeutic possibilities for cognitive dysfunction driven by antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE). Mice models lacking the function of NSPA as an E3 ubiquitin ligase show impaired glutamatergic synaptic plasticity, decreased levels of NMDAR at the postsynaptic density in hippocampus and memory deficits. The levels of PTPMEG/PTPN4 are increased due to lower ubiquitination and proteasomal degradation, resulting in dephosphorylation of tyrosines that control endocytosis in GluN2 NMDAR subunits. Adult hippocampal neurogenesis (AHN) that normally contributes to memory processes is also defective in the absence of NSPA. NSPA function is crucial in memory processes controlling the stability of NMDAR at PSD through the ubiquitination of PTPMEG/PTPN4 and also through AHN. As anti-P autoantibodies reproduce the impairments of glutamatergic transmission, plasticity and memory performance seen in the absence of NSPA, it might be expected to perturb the NSPA/PTPMEG/PTPN4 pathway leading to hypofunction of NMDAR. This neuropathogenic mechanism contrasts with that of anti-NMDAR antibodies also involved in lupus cognitive dysfunction. Testing this hypothesis might open new therapeutic possibilities for cognitive dysfunction in SLE patients bearing anti-P autoantibodies.

Reader Response: Clinical Significance of Anti-NMDAR Concurrent With Glial or Neuronal Surface Antibodies.

Martinez-Hernandez et al.1 systematically explored the co-occurrence of anti-NMDAR with other cell surface neuronal antibodies or glial antibodies (MOG, AQP4). Anti-NMDAR encephalitis is an autoimmune brain disease characterized by psychosis, memory loss, dystonia, catatonia, seizures, and coma.2 Ovarian teratoma triggers about half of cases but other tumors are rare. Anti-NMDAR encephalitis is usually not associated with other types of brain autoimmunity. However, a small group of patients may have co-existing neuromyelitis optica, MOG antibody syndrome, or additional CNS synaptic antibodies.3,4

Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease

Astrocytes constantly adapt their ramified morphology in order to support brain cell assemblies. Such plasticity is partly mediated by ion and water fluxes, which rely on the water channel aquaporin-4 (AQP4). The mechanism by which this channel locally contributes to process dynamics has remained elusive. Using a combination of single-molecule and calcium imaging approaches, we here investigated in hippocampal astrocytes the dynamic distribution of the AQP4 isoforms M1 and M23. Surface AQP4-M1 formed small aggregates that contrast with the large AQP4-M23 clusters that are enriched near glutamatergic synapses. Strikingly, stabilizing surface AQP4-M23 tuned the motility ofastrocyte processes and favors glutamate synapse activity. Furthermore, human autoantibodies directed against AQP4 from neuromyelitis optica (NMO) patients impaired AQP4-M23 dynamic distribution and, consequently, astrocyte process and synaptic activity. Collectively, it emerges that the membrane dynamics of AQP4 isoform regulate brain cell assemblies in health and autoimmune brain disease targeting AQP4.

SUN-285 Autoimmune Brain Disease Associated with Severe Obesity and Progressive Hypothalamic and Pituitary Dysfunction

Hypothalamic dysfunction can lead to rapidly progressive severe obesity, which has been observed in the pediatric age group after an insult to the hypothalamus, such as tumors, trauma, inflammatory disease, or surgical treatment. We present here the progression of hypothalamic and pituitary dysfunction associated with severe obesity due to a primary inflammatory process in the brain and the therapeutic effect of immunosuppressants and aggressive weight management. The patient presented with new onset focal epilepsy refractory to anti-epileptic medications at age 6 years 8 months (illness month 0) at 23.6 kg and BMI-Z of -0.07. At month 2, he had a 2 kg weight gain thought to be due to anti-epileptics. At month 7 (35.6 kg, BMI-Z 2.10), he had gained 12 kg, precocious puberty was noted and he was started on a GnRH agonist. He was also having behavioral changes, including decreased cognition, hyperphagia, and difficulty sleeping. At month 10 (45.5 kg, BMI-Z 2.57), a brain biopsy showing lymphocytic infiltration confirmed the primary diagnosis of autoimmune brain disease as the cause of hypothalamic dysfunction and seizure disorder; therefore, a methylprednisone burst was started at month 11 (48.2 kg, BMI-Z 2.63), followed by monthly cyclophosphamide and a 7 month oral prednisone taper. By month 12, he developed respiratory symptoms requiring hospital admission. Indirect calorimetry revealed resting energy expenditure of 802 kcal/day; topiramate was initiated, and he was discharged home on a 1200 kcal/day diet. At month 13, central hypothyroidism was diagnosed (TSH 0.34, free T4 0.61) and levothyroxine started. At month 13.5, he was at maximum weight (60.1 kg, BMI-Z 2.88, 36.5 kg total gain) and he again had worsened respiratory distress requiring admission; at this time phentermine was started, CPAP was initiated, diet was decreased to 1000 kcal/day and changed to ketogenic. From months 13 to 18, he had his first weight reduction of 5.5 kg with a noted decrease in appetite. He was continued on monthly cyclophosphamide and IV methylprednisone through month 16 when a brain MRI was showed improvement; cyclophosphamide discontinued and prednisone weaned. Adrenal insufficiency was found, although it was unclear if iatrogenic or central. By month 19 (57.1 kg, BMI-Z 2.73) off immunosuppression, he had worsened hyperphagia and seizure activity and decreased cognitive abilities, possibly suggestive of a flare of the brain inflammation; thus aggressive immunosuppression was reinitiated. This case demonstrates severe obesity related to progressive hypothalamic and pituitary dysfunction secondary to inflammatory brain disease. The management of weight gain for this patient remains difficult due to hyperphagia related to behavior dysregulation and low basal metabolic rate, in addition to continued need for immunosuppressants to treat the underlying autoimmune condition. Funding: NIDDK K23

16.4 Treatment Approaches in the Management of Autoimmune Encephalopathy

This presentation will focus on the treatment of autoimmune encephalopathies (AEs), including immunomodulatory treatments and supportive therapies. AE is a broad category of autoimmune brain disease, representing numerous diagnoses, with a range of symptoms and severity. As a result, there are different treatment recommendations based on the clinical features and specific diagnosis. It is important for all providers to recognize the heterogeneity in treatment responses across the spectrum of AE and across immunomodulatory therapies. Understanding the expected timeline for improvement after different therapies is essential to accurately assessing effectiveness of treatment and determining which supportive therapies may be necessary.

Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

BackgroundDespite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications.AimTo study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis.MethodsWe measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups.ResultsIn descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97–1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis showed similar clustering of cytokine/chemokine molecules in immune mediated encephalitis (ADEM and anti-NMDAR E). Th1 and B cell (CXCL13 and CXCL10) molecules clustered together in patients with severe encephalopathy at admission and worse disability at follow up in all encephalitis. There was no correlation between CSF neopterin and IFN-γ or IFN-α.ConclusionA combination panel of cytokine/chemokines consisting of CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 measured using multiplex immunoassay may be used to diagnose and monitor intrathecal inflammation in the brain. Given their association with worse outcome, certain key chemokines (CXCL13, CXCL10) could represent potential therapeutic targets in encephalitis.

Tissue hypoxia in autoimmune brain disease: A Columbian discovery?

Tissue hypoxia in autoimmune brain disease: A Columbian discovery?

Reversible cerebellar ataxia with thyrotoxicosis: An autoimmune brain disease in remission due to Graves′ disease

We hereby report a patient with seizure disorder who was on long term carbamazepine, admitted with features of thyrotoxicosis and cerebellar dysfunction. Anticonvulsant medications are cerebellar toxins; but in this case, reversal of cerebellar dysfunction was noted upon treatment of thyrotoxicosis with antithyroid drugs.

Long Lasting Local and Systemic Inflammation after Cerebral Hypoxic ischemia in Newborn Mice

BackgroundHypoxic ischemia (HI) is an important cause of neonatal brain injury and subsequent inflammation affects neurological outcome. In this study we performed investigations of systemic and local activation states of inflammatory cells from innate and adaptive immunity at different time points after neonatal HI brain injury in mice.Methodology/Principal FindingsWe developed a multiplex flow cytometry based method combined with immunohistochemistry to investigate cellular immune responses in the brain 24 h to 7 months after HI brain injury. In addition, functional studies of ex vivo splenocytes after cerebral hypoxic ischemia were performed. Both central and peripheral activation of CD11b+ and CD11c+ antigen presenting cells were seen with expression of the costimulatory molecule CD86 and MHC-II, indicating active antigen presentation in the damaged hemisphere and in the spleen. After one week, naïve CD45rb+ T-lymphocytes were demonstrated in the damaged brain hemisphere. In a second phase after three months, pronounced activation of CD45rb− T-lymphocytes expressing CD69 and CD25 was seen in the damaged hemisphere. Brain homogenate induced proliferation in splenocytes after HI but not in controls.Conclusions/SignificanceOur findings demonstrate activation of both local and systemic immune responses months after hypoxic ischemic neonatal brain injury. The long term immune activation observed is of general importance for future studies of the inflammatory response after brain injury as most previous studies have focused on the first few weeks after damage, while the effects of the late inflammation phase may be missed. Furthermore, the self-reactive component raises the question if there is a correlation with development of autoimmune brain disease later in life.

Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells

Relapses and disease exacerbations are vexing features of multiple sclerosis. Osteopontin (Opn), which is expressed in multiple sclerosis lesions, is increased in patients' plasma during relapses. Here, in models of multiple sclerosis including relapsing, progressive and multifocal experimental autoimmune encephalomyelitis (EAE), Opn triggered recurrent relapses, promoted worsening paralysis and induced neurological deficits, including optic neuritis. Increased inflammation followed Opn administration, whereas its absence resulted in more cell death of brain-infiltrating lymphocytes. Opn promoted the survival of activated T cells by inhibiting the transcription factor Foxo3a, by activating the transcription factor NF-kappaB through induction of phosphorylation of the kinase IKKbeta and by altering expression of the proapoptotic proteins Bim, Bak and Bax. Those mechanisms collectively suppressed the death of myelin-reactive T cells, linking Opn to the relapses and insidious progression characterizing multiple sclerosis.

El estreptococo piógenes y el cerebro: viviendo con el enemigo

Streptococcus pyogenes (or group A beta hemolytic streptococcus) is a pathogenic bacterium that can give rise to a range of invasive and autoimmune diseases, although it is more widely known as the cause of tonsillitis. It is particularly interesting to note that this germ only causes disease in humans. For many years it has been acknowledged that it can cause an autoimmune brain disease (Sydenham s chorea). Yet, the spectrum of post streptococcal brain disorders has recently been extended to include other movement disorders such as tics or dystonia. A number of systematic psychiatric studies have shown that certain emotional disorders generally accompany the movement disorder (particularly, obsessive compulsive disorder). The proposed pathogenetic mechanism is that of a neuronal dysfunction in which antibodies play a mediating role. The antibodies that are produced after the streptococcal infection cross react with neuronal proteins, and more especially so in individuals with a propensity. This represents a possible model of immunological mimicry and its potential importance with respect to certain idiopathic disorders such as Tourette syndrome and obsessive compulsive disorder.