Sekhar Pillai

Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders

Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. Despite these developments, many cases of encephalitis remain unexplained. We have previously described a basal ganglia encephalitis with dominant movement and psychiatric disease, and proposed an autoimmune aetiology. Given the role of dopamine and dopamine receptors in the control of movement and behaviour, we hypothesized that patients with basal ganglia encephalitis and other putative autoimmune basal ganglia disorders harboured serum autoantibodies against important dopamine surface proteins. Basal ganglia encephalitis sera immunolabelled live surface cultured neurons that have high expression of dopamine surface proteins. To detect autoantibodies, we performed flow cytometry cell-based assays using human embryonic kidney cells to express surface antigens. Twelve of 17 children (aged 0.4-15 years, nine males) with basal ganglia encephalitis had elevated immunoglobulin G to extracellular dopamine-2 receptor, compared with 0/67 controls. Immunofluorescence on wild-type mouse brain showed that basal ganglia encephalitis sera immunolabelled microtubule-associated protein 2-positive neurons in striatum and also in cultured striatal neurons, whereas the immunolabelling was significantly decreased in dopamine-2 receptor knock-out brains. Immunocytochemistry confirmed that immunoreactivity localized to the surface of dopamine-2 receptor-transfected cells. Immunoabsorption of basal ganglia encephalitis sera on dopamine-2 receptor-transfected human embryonic kidney cells decreased immunolabelling of dopamine-2 receptor-transfected human embryonic kidney cells, neurons and wild-type mouse brain. Using a similar flow cytometry cell-based assay, we found no elevated immunoglobulin G binding to dopamine 1, 3 or 5 receptor, dopamine transporter or N-methyl-d-aspartate receptor. The 12 dopamine-2 receptor antibody-positive patients with encephalitis had movement disorders characterized by parkinsonism, dystonia and chorea. In addition, the patients had psychiatric disturbance with emotional lability, attention deficit and psychosis. Brain magnetic resonance imaging showed lesions localized to the basal ganglia in 50% of the patients. Elevated dopamine-2 receptor immunoglobulin G was also found in 10/30 patients with Sydenhams chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourettes syndrome. No dopamine-1 receptor immunoglobulin G was detected in any disease or control groups. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders.

N-Methyl-D-Aspartate Receptor Antibodies in Pediatric Dyskinetic Encephalitis Lethargica

Encephalitis lethargica (EL) describes an encephalitis with psychiatric, sleep, and extrapyramidal movement disorders. Dyskinetic and Parkinsonian forms have been described. EL shares clinical features with the anti–N‐methyl‐D‐aspartate receptor (NMDAR‐Ab) encephalitis. We studied 20 sera from pediatric patients with contemporary EL. Ten sera (from 2 males and 8 females, aged 1.3–13 years) and 6/6 cerebrospinal fluid samples were positive for NMDAR‐Ab. NMDAR‐Ab–positive patients had dyskinesias, agitation, seizures, and insomnia, whereas Parkinsonism and somnolence dominated in the NMDAR‐Ab–negative children. We were unable to identify any tumors. The dyskinetic form of EL is an NMDAR‐Ab encephalitis and can affect very young children. Ann Neurol 2009;66:704–709

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor

Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N‐methyl‐D‐aspartate receptor (NMDAR).

Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome

BACKGROUND AND OBJECTIVES: Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. METHODS: By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). RESULTS: An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. CONCLUSIONS: We have defined clinical and radiologic phenotypes of infectious and immune-mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/autoantibody-associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority.

Early relapse risk after a first CNS inflammatory demyelination episode: examining international consensus definitions

The International Pediatric Multiple Sclerosis Study Group (IPMS) has recently proposed consensus definitions for paediatric multiple sclerosis (MS) and related disorders. The term‘acute disseminated encephalomyelitis’(ADEM) has been used previously to describe any monophasic episode of disseminated demyelination. The study group now propose that ADEM must be multifocal, polysymptomatic, and include encephalopathy (as an essential requirement). An alternative diagnosis for a first acute inflammatory event is‘clinically isolated syndrome’(CIS). A CIS event may be either monofocal (such as isolated optic neuritis) or multifocal, but cannot include encephalopathy. As with adults, children with two or more discrete demyelinating events separated in time and space meet criteria for MS. In children with MS, the demyelination events must not meet ADEM criteria. To test the usefulness of these new criteria, a new cohort of 40 patients (18 males, 22 females; mean age 8y [SD 4y 4mo]) with central nervous system (CNS) demyelination were studied. Using IPMS definitions, the presenting diagnosis was ADEM in 12 patients and CIS in 28 patients. At presentation, patients with CIS were more likely to have intrathecal synthesis of oligoclonal bands and fulfil KIDMUS MS magnetic resonance imaging criteria, compared with patients with ADEM (p<0.025). Patients were followed‐up for a mean of 2 years 2 months. Only one of 12 patients with ADEM went on to develop MS during the study period, whereas 13 of 28 patients with CIS relapsed and fulfilled a diagnosis of MS (p<0.025). The new diagnostic criteria for ADEM may be criticized for being overly restrictive (particularly with encephalopathy being an essential criterion), and it is suspected that many practising physicians will be of the opinion that these new criteria will underdiagnose ADEM, and overdiagnose MS at the expense of multiphasic ADEM. However, it is hoped that these new criteria may improve prognostic specificity and provide uniformity to future paediatric CNS demyelination research.

Cortical hypometabolism demonstrated by PET in relapsing NMDA receptor encephalitis.

N-methyl-d-aspartate (NMDA) receptor encephalitis is a newly defined type of autoimmune encephalitis. Two girls (age 3 years, case 1, and 7 years, case 2) with relapsing NMDA receptor encephalitis each had the classic clinical features of encephalopathy, movement disorders, psychiatric symptoms, seizures, insomnia, and mild autonomic dysfunction. Both patients had persistent neuropsychiatric disability, despite immune therapies. Positron emission tomography (PET) scans were performed during clinical relapse at 6 weeks (case 1) and 5 months (case 2). In both cases, the scans demonstrated reduced fluorodeoxyglucose metabolism in the cerebral cortex, with the temporal regions being most affected. PET imaging was more sensitive than magnetic resonance imaging in these patients. In contrast, the one previous report of acute NMDA receptor encephalitis indicated cortical hypermetabolism. Thus, NMDA receptor encephalitis may be associated with variable PET findings, possibly dependent upon the timing of the study, or other factors. Future studies should investigate whether cortical hypometabolism is associated with a relapsing course, and whether it is predictive of a poorer outcome in NMDA receptor encephalitis.

A prospective study of acute movement disorders in children.

Aim  The purpose of this study was to report a prospective cohort of children with acute‐onset movement disorders.

Movement disorders in children with anti‐NMDAR encephalitis and other autoimmune encephalopathies

Accurate recognition of movement disorder phenomenology may differentiate children with anti‐N‐methyl D‐aspartate receptor (NMDAR) encephalitis, autoimmune basal ganglia encephalitis (BGE), and Sydenhams chorea (SC). Three neurologists blinded to the diagnoses recorded dominant and associated movement disorders seen on videos of 31 patients with anti‐NMDAR encephalitis (n = 10), BGE (n = 12), and SC (n = 9). Stereotypy was only seen in anti‐NMDAR encephalitis (8/10) and not in BGE and SC (P < 0.001). Perseveration was only seen in anti‐NMDAR encephalitis (5/10) and not in BGE and SC (P < 0.001). Akinesia was more commonly seen in BGE (5/12) than in anti‐NMDAR encephalitis (1/10, P = 0.097). Tremor was more commonly seen in BGE (5/12) than in anti‐NMDAR encephalitis (1/10, P = 0.097). Chorea was seen in all groups: anti‐NMDAR encephalitis (4/10), BGE (3/12), and SC (9/9). Likewise, dystonia was seen in all groups: anti‐NMDAR encephalitis (6/10), BGE (7/12), and SC (2/9). Stereotypies or perseveration are suggestive of anti‐NMDAR encephalitis, whereas their absence and the presence of akinesia and tremor is more suggestive of BGE. Chorea and dystonia are least discriminating.

Symptomatic treatment of children with anti-NMDAR encephalitis

We performed the first study on the perceived benefit and adverse effects of symptomatic management in children with anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis.

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

Background Despite 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. Aim To study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis. Methods We 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. Results In 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. Conclusion A 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.