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BACKGROUND/OBJECTIVE: We reported that 43% of patients with Lambert-Eaton myasthenic syndrome (LEMS) and small cell lung cancer (SCLC) had an antibody called anti-glial nuclear antibody (AGNA), defined by the immunoreaction with the nuclei of the Bergmann glia of the cerebellum. This study was undertaken to identify the antigen recognized by AGNA and to confirm the association with paraneoplastic LEMS in a larger series. METHODS: We probed a fetal brain cDNA library with AGNA-positive sera. The presence of antibodies against the isolated antigen was detected by immunoblot of phage plaques from two positive clones. We studied 105 patients with LEMS (55 with SCLC), 50 with paraneoplastic neurologic syndromes, SCLC, and Hu antibodies, and 50 with only SCLC. RESULTS: Probing of the fetal brain expression library with AGNA sera resulted in the isolation of SOX1, a highly immunogenic tumor antigen in SCLC. IgG eluted from SOX1 clones produced the same cerebellar immunoreactivity as of AGNA sera. SOX1 antibodies were present in 64% of patients with LEMS and SCLC but in none of the 50 with idiopathic LEMS (p < 0.0001). Compared with paraneoplastic LEMS, the frequency of SOX1 antibodies was significantly lower in patients with Hu antibodies (32%, p = 0.002) and in those with only SCLC (22%). CONCLUSIONS: SOX1 is the antigen recognized by anti-glial nuclear antibody-positive sera. The detection of SOX1 antibodies in patients with Lambert-Eaton myasthenic syndrome (LEMS) predicts the presence of small cell lung cancer and may be used to follow more closely those LEMS patients with no evidence of cancer at the initial workup.

Lambert-Eaton myasthenic syndrome is a rare, but reasonably well-understood, antibody-mediated autoimmune disease that is caused by serum auto-antibodies and results in muscle weakness and autonomic dysfunction. One half of the patients have an idiopathic form, the other half a tumour-associated form of the disease. Three randomised trials and a large number of smaller clinical studies have resulted in a number of drugs becoming available for the treatment of Lambert-Eaton myasthenic syndrome. Several drugs are available for the symptomatic treatment of the disease, including guanidine, aminopyridines or acetylcholinesterase inhibitors. Other therapies aim to deplete the serum autoantibodies or to suppress the immune system. For this purpose, immunomodulating strategies, such as intravenous immunoglobulins or plasmapheresis, or several immunosuppressive agents are available. Chemotherapy has successfully ameliorated the course of disease in Lambert-Eaton myasthenic syndrome patients with an underlying tumour.

There has been a rapid increase in the characterization of encephalitis associated with antibodies to cell surface or synaptic proteins,1 starting with the report of 4 patients with prominent psychiatric symptoms who rapidly progressed into hypoventilation and coma.2 The disorder was subsequently identified as anti-NMDA receptor (NMDAR) encephalitis, now the best characterized and most frequently recognized autoimmune encephalitis,3 demonstrating that “newly identified” does not always mean “infrequent” or “rare.” In addition to frequency, 2 reasons for the sharp increase in the identification of patients with this syndrome are the characteristic clinical features that facilitate its recognition on clinical grounds and the specificity of the diagnostic test that when properly used leaves no margin for error.4 The latter is straightforward: examine the patient's CSF with HEK cells expressing GluN1 or GluN1/2 subunits of the NMDAR (the cell-based assay [CBA] used commercially or in research laboratories). If only serum is used, there is a risk (∼15%) of false-negative or false-positive results5; this risk decreases if the serum is examined with an additional confirmatory test, such as immunohistochemistry with rat brain tissue. If these criteria are not used, the specificity of the test decreases and the presumed “spectrum” of symptoms enlarges.

Antibodies to NMDA receptor, blood–brain barrier disruption and schizophrenia: a theory with unproven links

IMPORTANCE: Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis often develop prominent psychiatric manifestations. The frequency and type of isolated psychiatric episodes (pure psychiatric symptoms without neurological involvement) either as initial presentation of the disease or as relapse are unknown. OBJECTIVE: To determine the frequency, symptoms, and outcome of isolated psychiatric episodes in a cohort of patients with anti-NMDAR encephalitis. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort of patients diagnosed during a 5-year period (median follow-up, 2 years). A total of 571 patients with IgG antibodies against the NR1 subunit of the NMDAR were included in the study. Antibody studies were performed at the University of Pennsylvania and the University of Barcelona, and clinical information was obtained by us or referring physicians. MAIN OUTCOMES AND MEASURES: Frequency, type of symptoms, and outcome of patients with anti-NMDAR encephalitis and isolated psychiatric manifestations. RESULTS: Of 571 patients, 23 (4%) developed isolated psychiatric episodes, 5 at disease onset and 18 during relapse. For all 23 patients, age (median, 20 years), sex (91%female), and tumor association (43%; ovarian teratoma in all cases) were similar to the population at large. Predominant symptoms included delusional thinking (74%), mood disturbances (70%, usually manic), and aggression (57%). Brain magnetic resonance imaging findings were abnormal in 10 of 22 patients (45%) and cerebrospinal fluid analysis showed pleocytosis in 17 of 22 patients (77%). Eighty-three percent of the patients had full or substantial recovery after immunotherapy and tumor resection when appropriate. After relapse, 17 of 18 patients (94%) returned to a similar or better prerelapse functional level. CONCLUSIONS AND RELEVANCE: Isolated psychiatric episodes are rare but can occur as initial onset or relapse of anti-NMDAR encephalitis. Recognition of these episodes is important because they respond to immunotherapy. In patients with new-onset psychosis, having a history of encephalitis, subtle neurological symptoms, and/or abnormal results on ancillary tests should prompt screening for NMDAR antibodies.

Objective To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Study design Review of clinical data, long-term follow-up, and immunologic studies performed in a single center in Spain in the last 4 years. Results The median age of the patients was 13 years (range, 8 months-18 years), 70% were female. In 12 patients (60%), the initial symptoms were neurologic, usually dyskinesias or seizures, and in the other 40% psychiatric. One month into the disease, all patients had involuntary movements and alterations of behavior and speech. All patients received steroids, intravenous immunoglobulin or plasma exchange, and 7 rituximab or cyclophosphamide. With a median follow up of 17.5 months, 85% had substantial recovery, 10% moderate or severe deficits, and 1 died. Three patients had previous episodes compatible with anti-NMDAR encephalitis, 2 of them with additional relapses after the diagnosis of the disorder. Ovarian teratoma was identified in 2 patients, 1 at onset of encephalitis and the other 1 year later. Two novel observations (1 patient each) include, the identification of an electroencephalographic pattern (“extreme delta brush”) considered characteristic of this disorder, and the development of anti-NMDAR encephalitis as post herpes simplex encephalitis choreoathetosis. Conclusions The initial symptoms of pediatric anti-NMDAR encephalitis vary from those of the adults (more neurologic and less psychiatric in children), the development of a mono-symptomatic illness is extremely rare (except in relapses), and most patients respond to treatment. Our study suggests a link between post herpes simplex encephalitis choreoathetosis and anti-NMDAR encephalitis.

Objective: To provide the clinical features and suggest treatment guidelines for anti-NMDA-receptor encephalitis. Background Anti-NMDA-receptor encephalitis is the most common and best characterized antibody-mediated encephalitis. We provide the clinical features, treatment, and follow-up of 500 patients. Design/Methods: Cohort study, analysis of demographics, onset, treatment, and long-term follow-up. Results: 82% were female. Median age was 21 years (range 1-85; 36% 45 years). 42% had a tumor (95% teratomas). 55% of females >12 years had ovarian teratoma(s) versus 8% 3 of the following: psychiatric symptoms, memory, speech disorders, seizures, dyskinesias, decreased level of consciousness, autonomic instability, or hypoventilation. Within the first month, movement disorders and ataxia were more frequent in children (92% and 17% vs 70% and 2%, p Conclusions: Anti-NMDA-receptor encephalitis is a severe but treatable disorder of predominantly young individuals. Prompt treatment improves outcome. If initial immunotherapy fails, second-line treatment is usually effective. 75% of patients have full/substantial improvement although the process of recovery can take >24 months. Supported by: In part by grants from the National Institutes of Health and National Cancer Institute RO1CA89054 (Dalmau), 1RC1NS068204-01 (Balice-Gordon and Dalmau), a McKnight Neuroscience of Brain Disorders award (Balice-Gordon and Dalmau), a KWF fellowship 2009-4451 of the Dutch Cancer Society (Titulaer), and a grant from the Fondo de Investigaciones Sanitarias, FIS, Spain (Martinez-Hernandez). Disclosure: Dr. Titulaer has nothing to disclose. Dr. McCracken has nothing to disclose. Dr. Gabilondo Cuellar has nothing to disclose. Dr. Martinez-Hernandez has nothing to disclose. Dr. Graus has nothing to disclose. Dr. Balice-Gordon has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity for Up To Date, Inc.Dr. Dalmau has received research support from Euroimmun.

Recent studies have identified antibodies to the SOXB1 group of proteins in patients with paraneoplastic disorders (PNDs) associated with small-cell lung cancer (SCLC), particularly Lambert-Eaton myasthenic syndrome (LEMS), but rarely in non-tumour LEMS, indicating that these antibodies may be useful paraneoplastic biomarkers. We aimed to establish if SOX antibodies could be used to identify underlying tumours in a range of PNDs, including control tumour groups. We established a SOX2 ELISA with high test-retest reproducibility. Positivity to SOX2 in control patients without neurological symptoms was 77/259 (30%) in SCLC, but only 15/238 (6%) in non-SCLC, 0/75 in breast cancer, 3/104 (3%) in ovarian cancer, and 12/414 (3%) in age matched healthy controls. Antibodies to SOX2 were detected in 39/71 (55%) patients with LEMS-SCLC, and 7/105 (6.6%) patients with non-tumour LEMS (p 90%) markers for SCLC, but not other tumours, in patients with PNDs, particularly LEMS with or without ataxia.

Sample Group O D @ 6 5 0 n m The Presence of Autoantibodies to Tumour-Associated Antigens can Predate Clinical Diagnosis of Lung Cancer Caroline Chapman(1), D Isenberg(2), A Murray(3), A Thorpe(1), J McElveen(3), J Allen(3), J Robertson(1) (1) Division of Surgery, School of Clinical Sciences, University of Nottingham, Nottingham UK. (2) Centre For Rheumatology, University of London, UK. (3) Oncimmune Ltd, Nottingham City Hospital, Nottingham, UK. email: caroline.chapman@nottingham.ac.uk

Background: Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible. Objectives: An overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability. Methods: Many studies with class IV evidence were available; one study reached level III evidence. No evidence-based recommendations grade A–C were possible, but good practice points were agreed by consensus. Recommendations: The nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT-thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3–6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy.