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Objectives: To extend the symptomatic spectrum of acute neurologic syndrome associated with dopamine-2 receptor (D2R) antibodies., Methods: A 13-year-old adolescent boy was admitted to the Neurology Department with abnormal jaw movements. The initial evaluation included laboratory examinations of blood, chest radiography, brain MRI, EEG, and neuropsychologic tests. Serum and CSF samples were collected for immunologic studies. The clinical outcome of the patient was followed up for 18 months after the first hospitalization., Results: Paroxysmal jaw clonus, blepharospasm, and sialorrhea were observed in the patient with a history of Tourette syndrome and obsessive-compulsive disease and with an acute neurologic syndrome associated with D2R antibodies. The symptoms responded to IV methylprednisolone (IVMP), relapsed twice during prednisone reduction, and, finally, improved after the combined treatment of IVMP and IV immunoglobulin., Discussion: Recognizing paroxysmal jaw clonus (possibly with blepharospasm and sialorrhea) and considering the relationship between these episodes and D2R antibodies will be helpful in the early diagnosis and treatment of immune neurologic syndromes., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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 Sydenham's chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourette's 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.

Schizophrenia shares several genetic features with diseases known to be autoimmune and could therefore be an autoimmune disease itself. Antipsychotic drugs, which are effective in treating the psychotic symptoms of schizophrenia, have one property in common--they block dopamine receptors in the central nervous system. This observation has led to the hypothesis that overactivity of dopaminergic pathways is the cause of the psychotic symptoms, but a seeming anomaly is that the turnover of dopamine is not increased in schizophrenia. Dopamine-receptor-stimulating autoantibodies are postulated to cause the dopaminergic hyperactivity, thereby accounting for the anomaly.

Autoantibodies against dopamine receptors in schizophrenic patients have been postulated. IgG was fractionated from sera of 15 schizophrenic patients (DSM III) in an acute episode. However, 3H-spiperone binding to dopamine receptors was not inhibited by this fraction.

Clinical and neuropharmacological evidence indicates the involvement of dopaminergic mechanisms in Parkinson's disease and schizophrenia, as well as in iatrogenic Parkinsonism and drug-induced schizophrenia-like syndrome. The evidence hitherto presented stresses the existence of a reversed relationship between Parkinson's disease and schizophrenia and implicates the possibility that dysfunction of dopamine-receptors may be a central phenomenon in both diseases. In view of the recent demonstration of two separate dopamine-receptors, it is postulated that a striatal receptor blockade may cause Parkinson's disease, whereas a limbic receptor blockade may result in schizophrenia. The recent discovery that several autoimmune diseases, such as myasthenia gravis, are the result of an immunopharmacological block at receptor sites, together with several observations of immunological disorders in Parkinson's disease and schizophrenia, suggests the possibility that certain types of Parkinson's disease and schizophrenia might be the consequence of an autoimmune blockade of striatal or limbic dopamine-receptors, respectively.