Myasthenia gravis is a relatively rare neurological disease that is associated with loss of the acetylcholine receptors that initiate muscle contraction. This results in muscle weakness, which can be life-threatening. The story of how both the physiological basis of the disease and the role of acetylcholine-receptor-specific antibodies were determined is a classic example of the application of basic science to clinical medicine, and it has provided a model for defining other antibody-mediated disorders of the peripheral and central nervous systems.

Unravelling the pathogenesis of myasthenia gravis.

Acute disseminated encephalomyelitis (ADEM) is a monophasic autoimmune demyelinating disease of the central nervous system that typically follows a febrile infection or a vaccination. Children are predominantly affected. A plethora of viral and bacterial pathogens and a number of vaccinations have been associated with ADEM. Experimental animal studies indicate that both primary and secondary autoimmune responses contribute to central nervous system inflammation and subsequent demyelination. The clinical diagnosis of ADEM is strongly suggested by a close temporal relationship between an infectious incident or an immunization and the onset of leukoencephalopathic neurological symptoms. Paraclinical tests may support the diagnosis. Particularly helpful are acute signs of newly developed extensive, multifocal, subcortical white matter abnormalities on magnetic resonance images of the brain. The cerebrospinal fluid may disclose a mild lymphocytic pleocytosis and elevated albumin levels. Oligoclonal bands are not always present in ADEM and, if so, may be transient. The major differential diagnosis of ADEM is multiple sclerosis. Treatment options for ADEM consist of anti-inflammatory and immunosuppressive agents. In general, the disease is self-limiting and the prognostic outcome favorable. In the absence of widely accepted clinical or paraclinical diagnostic guidelines, a number of recently conducted observational case series have substantially broadened our understanding about the clinical phenotype, diagnosis, and prognosis of ADEM.

https://jamanetwork.com/journals/jamaneurology/articlepdf/789775/nnr40041.pdf

Acute disseminated encephalomyelitis: an update.

Summary In 1916, von Economo first described encephalitis lethargica (EL), a CNS disorder presenting with pharyngitis followed by sleep disorder, basal ganglia signs (particularly parkinsonism) and neuropsychiatric sequelae. Since the 1916‐1927 epidemic, only sporadic cases have been described. Pathological studies revealed an encephalitis of the midbrain and basal ganglia, with lymphocyte (predominantly plasma cell) infiltration. The EL epidemic occurred during the same time period as the 1918 influenza pandemic, and the two outbreaks have been linked in the medical literature. However, von Economo and other contemporary scientists thought that the 1918 influenza virus was not the cause of EL. Recent examination of archived EL brain material has failed to demonstrate influenza RNA, adding to the evidence that EL was not an invasive influenza encephalitis. By contrast, the findings of intrathecal oligoclonal bands (OCB) and beneficial effects of steroid treatments have provoked the hypothesis that EL may be immune-mediated. We have recently seen 20 patients with a similar EL phenotype, 55% of whom had a preceding pharyngitis. The patients had remarkable similarity to the historical descriptions of EL: sleep disorder (somnolence, sleep inversion or insomnia), lethargy, parkinsonism, dyskinesias and neuropsychiatric symptoms. CSF examination commonly showed elevated protein and OCB (75 and 69% respectively). Investigation found no evidence of viral encephalitis or other recognized causes of rapid-onset parkinsonism. MRI of the brain was normal in 60% but showed inflammatory changes localized to the deep grey matter in 40% of patients. We investigated the possibility that this phenotype could be a postinfectious autoimmune CNS disorder, and therefore similar to Sydenham’s chorea. Anti-streptolysin-O titres were elevated in 65% of patients. Furthermore, western immunoblotting showed that 95% of EL patients had autoantibodies reactive against human basal ganglia antigens. These antibodies were also present in the CSF in four patients tested. By contrast, antibodies reactive against the basal ganglia were found in only 2‐4% of child and adult controls (n = 173, P < 0.0001). Rather than showing polyspecific binding, these antibodies bound to common neural autoantigens of molecular weight 40, 45, 60 and 98 kDa. Regional tissue comparisons showed that the majority of these autoantigens were specific to or enriched in CNS tissue. Immunohistochemistry with secondary staining localized antibody binding to neurons rather than glial populations. Further investigation is required to determine whether these antibodies affect neuronal function (i.e. whether they are pathogenic anti-neuronal antibodies). Histopathology in one case demonstrated striatal encephalitis with perivenous Band T-lymphocytic infiltration. We believe an EL-like syndrome is still prevalent, and propose that this syndrome may be secondary to autoimmunity against deep grey matter neurons.

Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity

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.

/pdf/antibodies-to-surface-dopamine-2-receptor-in-autoimmune-3akinokp1j.pdf

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

OBJECTIVE. If pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections is a unique clinical entity, we hypothesized that children meeting diagnostic criteria would have more clinical exacerbations temporally linked to bona fide group A β-hemolytic streptococcus infection than matched control subjects (chronic tic and/or obsessive-compulsive disorder with no known temporal relationship to group A β-hemolytic streptococcus infection). PATIENTS AND METHODS. Subjects included 40 matched pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections case-control pairs who were prospectively evaluated with intensive laboratory testing for group A β-hemolytic streptococcus and clinical measures for an average of 2 years. Additional testing occurred at the time of any clinical exacerbations or illness. Laboratory personnel were blinded to case or control status and clinical (exacerbation or not) condition. Clinical raters were blinded to the results of laboratory tests. RESULTS. The cases had a higher clinical exacerbation rate and a higher bona fide group A β-hemolytic streptococcus infection rate than the control group. Only 5 of 64 exacerbations were temporally associated (within 4 weeks) with a group A β-hemolytic streptococcus infection, and all occurred in cases. The number (5.0) was significantly higher than the number that would be expected by chance alone (1.6). Yet, ≥75% of the clinical exacerbations in cases had no observable temporal relationship to group A β-hemolytic streptococcus infection. CONCLUSIONS. Patients who fit published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections seem to represent a subgroup of those with chronic tic disorders and obsessive-compulsive disorder who may be vulnerable to group A β-hemolytic streptococcus infection as a precipitant of neuropsychiatric symptom exacerbations. Group A β-hemolytic streptococcus infection is not the only or even the most common antecedent event associated with exacerbations for these patients. Additional intensive studies are needed to determine whether there is clinical or scientific evidence to support separating out subgroups of tic disorder and/or obsessive-compulsive disorder patients based on specific symptom precipitants.

Streptococcal Infection and Exacerbations of Childhood Tics and Obsessive-Compulsive Symptoms: A Prospective Blinded Cohort Study

Antibasal ganglia antibodies (ABGA) are associated with Sydenham's chorea and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. We present 10 patients with acute disseminated encephalomyelitis (ADEM) associated with Group A beta hemolytic streptococcal infection. The clinical phenotype was novel, with 50% having a dystonic extrapyramidal movement disorder, and 70% a behavioral syndrome. None of the patients had rheumatic fever or Sydenham's chorea. Enzyme-linked immunosorbent assay, Western immunoblotting, and immunohistochemistry were used to detect ABGA. Neurological (n = 40) and streptococcal (n = 40) controls were used for comparison. Enzyme-linked immunosorbent assay results showed significantly elevated ABGA in the patients with poststreptococcal ADEM. Western immunoblotting demonstrated ABGA reactivity to three dominant protein bands of 60, 67, or 80 kDa; a finding not reproduced in controls. Fluorescent immunohistochemistry demonstrated specific binding to large striatal neurones, which was not seen in controls. Streptococcal serology was also significantly elevated in the poststreptococcal ADEM group compared with neurological controls. Magnetic resonance imaging studies showed hyperintense basal ganglia in 80% of patients with poststreptococcal ADEM, compared to 18% of patients with nonstreptococcal ADEM. These findings support a new subgroup of postinfectious autoimmune inflammatory disorders associated with Group A beta hemolytic streptococcus, abnormal basal ganglia imaging, and elevated ABGA.

Elizabeth Goddard

Papers

Poststreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto-reactive antibasal ganglia antibodies.