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To 1) determine, using contemporary recombinant antigen–based assays, the aquaporin-4 (AQP4)–immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome.

Small-cell lung carcinoma (SCLC) and limbic encephalitis are recognized -aminobutyric acid-B receptor (GABABR) autoantibody accompaniments. We sought to determine in a diagnostic serology laboratory the frequency and accompaniments (neurologic, oncologic, and serologic) of GABABR–immunoglobulin G (IgG).

To determine the characteristics of adult-onset autoimmune chorea, and compare paraneoplastic and idiopathic subgroups.

Autoantibodies targeting voltage-gated potassium channel (VGKC) complexes cause a spectrum of neuronal hyperexcitability disorders. We investigated pain as a manifestation of VGKC-complex autoimmunity.

Neurologic autoimmunity frequently occurs with thymoma, particularly myasthenia gravis and skeletal muscle–specific autoantibodies. Type 1 antineuronal nuclear antibody (ANNA-1/“anti-Hu”), which is recognized as an immunoglobulin G marker of small-cell lung carcinoma, has not been reported with thymoma. The authors identified four patients (three under age 40) with ANNA-1 and a paraneoplastic neurologic complication of thymoma. Retrospective testing of stored serum from 172 patients with thymoma revealed ANNA-1 in 3. This report extends the oncologic implications of ANNA-1 seropositivity.

Autoantibodies specific for the nicotinic acetylcholine receptor (AChR) of skeletal muscle impair neuromuscular transmission in myasthenia gravis (MG). Autoantibodies specific for α3 neuronal AChRs or voltage-gated potassium channels have been reported in patients with Isaacs syndrome, an acquired disorder of continuous muscle fiber activity characterized by neuromyotonia.

The diagnosis of acquired myasthenia gravis (MG) in apparently seronegative individuals is aided by finding immunoglobulin complexed to acetylcholine receptors (AChR) and a reduction in the number of binding sites for a-bungarotoxin (α-BTx) in nerve-muscle biopsies. In this study, we found that anti-AChR antibodies in extracellular fluids can complex with cytoplasmic epitopes of AChR in the process of muscle extraction. When normal muscle was briefly exposed to antibodies (≥0.3 nmol/1) in the initial step of tissue homogenization (before detergent extraction), membranous AChR became complexed with IgG. This was so even with a nonmyasthenogenic monoclonal antibody specific for the α-subunit's presumptive cytoplasmic segment 366–389. We also found that antibodies reactive with AChR's α-BTx binding region can significantly lower apparent yields of α-BTx binding sites extracted from muscle. Thus, the finding of IgG complexed to AChR extracted from biopsied muscle does not necessarily reflect in vivo binding but, nevertheless, is a sensitive indicator of AChR seropositivity in patients suspected to have MG.

Autoantibodies specific for the acetylcholine receptor (AChR) of skeletal muscle (containing the α1 subunit) impair neuromuscular transmission in myasthenia gravis (MG). AChRs mediating fast synaptic transmission through autonomic ganglia are structurally similar to muscle AChR, but contain theα3 subunit. We propose that ganglionic AChR autoimmunity may cause dysautonomia.

Sera from three of four patients with paraneoplastic cerebellar degeneration (PCD) associated with gynecologic cancer had antibodies that stained the cytoplasm of Purkinje cells in a characteristic discrete and coarsely granular pattern. No such antibodies were found in PCD patients with small cell cancer of the lung, in patients with cerebellar degeneration without cancer, in nonneurologic patients with small cell carcinoma or gynecologic cancer, or in normal subjects. Immunoelectron microscopy revealed that the antibodies of PCD bound to clusters of ribosomes, granular endoplasmic reticulum, and the trans-face of the vesicles of the Golgi complex in Purkinje cells. Immunostaining was localized in orderly arrays of stacked parallel cisternae of the endoplasmic reticulum in the perikaryon and dendritic processes. This pattern suggested that at least one autoantigen of PCD may be a glycoprotein specific for cerebellar tissue that is associated with the endoplasmic reticulum. Some patches of Purkinje plasma membrane also were immunostained.

Anti-acetylcholine receptor (AChR) autoantibodies are a marker of acquired myasthenia gravis (MG). Some of these antibodies cause muscle weakness. Striational autoantibodies (Str Ab) also are a marker of MG. They are most prevalent in older patients and patients with thymoma. Here we describe a reproducible enzyme immunoassay (AChR-EIA) for detecting antibodies reactive with human muscle AChR, using antigens concentrated on plastic by prior sequential application of a biotinylated carrier, avidin, and biotinylated monoclonal IgG against AChR. There was significant correlation between values for antibodies assayed by AChR-EIA and by immunoprecipitation of AChR complexed with 125I-α-bungarotoxin. Unexpectedly, AChR-EIA and StrAb values also were significantly correlated. Further studies revealed a significant and unprecedented correlation for StrAb and AChR precipitating antibodies. A plausible explanation for these findings is that some StrAb may react with cytoskeletal proteins that associate and copurify with AChR. The AChR-EIA offers a nonradioactive method for detecting two autoantibodies that are relatively restricted to patients with acquired MG.

Experimental autoimmune myasthenia gravis (EAMG) was passively transferred with immunoglobulin from rats with chronic EAMG to normal recipients. IgG and C3 were localized on terminal expansions of junctional folds of end-plates by 6 hours. Segments of folds rich in acetylcholine receptor (AChR) and coated with IgG and C3 were shed into the synaptic space by 24 hours, resulting in AChR deficiency of the postsynaptic membrane. Many sensitized postsynaptic regions were destroyed by macrophages by day 2, but effective nerve-muscle contacts were reestablished by day 5. On day 10, end-plates were still structurally abnormal and showed AChR deficiency, but the animals were clinically recovered. On day 54, postsynaptic regions were still reduced in size, with slight reduction of postsynaptic AChR. Throughout the study, the miniature end-plate potential amplitude tended to vary directly with morphometric estimates of the abundance of the postsynaptic membrane reacting for AChR. Complement-mediated injury to the junctional folds and opsonization of the postsynaptic region can explain the morphologic changes. It is not yet known why phagocytic invasion of the end-plate occurs in acute EAMG and in passively transferred EAMG induced by chronic EAMG immuglobulin, but not in chronic EAMG and only rarely in the human disease.

Elevated amounts of antibodies specific for acetylcholine receptors were detected in 87 percent of sera from 71 patients with myasthenia gravis but not in 175 sera from individuals without myasthenia gravis, including those with other neurologic or autoimmune diseases. Antireceptor antibodies were not directed at the acetylcholine binding site of the receptor. Presence or titer of antibody did not appear to correlate with age, sex, steroid therapy, or duration of symptoms. Myasthenia gravis patients with only ocular symptoms had lower antibody titers, while the majority of titers in myasthenia gravis patients with thymoma exceeded the median titer of the myasthenia gravis group as a whole. Assay of antireceptor antibody should prove a useful test in the diagnosis of myasthenia gravis.

Peroxidase-conjugated α-bungarotoxin (P-BGT) was used for the ultrastructural localization of the acetylcholine receptor in end-plates in external intercostal muscles of four patients with myasthenia gravis, in forelimb digit extensor muscles of rats with advanced chronic experimental autoimmune myasthenia gravis, and in suitable human and rat controls. In control end-plates, the previously reported localization of acetylcholine receptor on the terminal expansions of the postsynaptic folds and, in traces, on the presynaptic membrane was confirmed. By contrast, in myasthenia gravis some postsynaptic regions bound no P-BGT; in other regions, the folds displayed only faint traces of the reaction product, or only some segments of the postsynaptic membrane showed the reaction product; finally, in some regions there was no apparent decrease in reaction product. In general, those postsynaptic regions showing the greatest decrease in P-BGT binding were also the simplest or showed the most degenerative changes, and the presynaptic staining was decreased in proportion to the decrease in the adjacent postsynaptic P-BGT binding. In the experimental animals, the abnormalities in the amount and distribution of the acetylcholine receptor were essentially like those in the more severely affected patients. Morphometric estimates of the postsynaptic acetylcholine receptor surface correlated well with the patients' clinical status and linearly with the miniature end-plate potential amplitude.

We tested thymus cells from 119 patients with acquired myasthenia gravis(MG) for in vitro production of acetylcholine receptor (AChR) binding antibodies (Ab); 109 were seropositive, of which 82 (75%) secreted AChRAb in vitro. As noted in earlier studies, thymus cell secretion of AChRAb paralleled serum Ab levels (ρs= 0.503; p< 0.0001; n = 119). Striational Ab secretion also correlated with the patients' serologic status. AChRAb secretion in vitro predicted the secretory activity of thymus cells implanted in severe combined immune deficiency(SCID) mice. Thymocytes from patients treated with corticosteroids made significantly less AChRAb than thymocytes from untreated patients(p< 0.005). Of particular note: (1) AChRAb was secreted by thymocytes from two of five nonimmunosuppressed patients who had generalized MG but who were seronegative for AChR binding autoantibodies; and (2) AChRAb secretion from both thymic and nonthymic sources was documented in a patient with noninvasive thymoma whose first signs of MG appeared 7 months after thymectomy. We conclude that the thymus in a majority of patients with acquired MG is the principal but not the sole reservoir of immunocytes that specifically react with muscle antigens.

Type 1 antineuronal nuclear autoantibody (ANNA-1, also known as "anti-Hu") is a marker of neurologic autoimmunity that is highly associated with small-cell lung carcinoma (SCLC). To determine the spectrum of symptoms and signs as well as the frequency of cancer in adult patients who are seropositive for ANNA-1, we reviewed 162 sequential patients (67% female) identified as ANNA-1-positive in a comprehensive immunofluorescence screening test. In 21% of these patients, the antibody test requested by the physician was not ANNA-1. By the end of the follow-up period, cancer had been found in 142 patients (88%). Ten of these lacked evidence of SCLC (4 had prostate carcinoma, 3 breast carcinoma, 1 both prostate carcinoma and melanoma, 1 lymphoma, and 1 squamous-cell lung carcinoma). Of the 132 patients(81%) with proven SCLC, 17 had one or more coexisting malignant neoplasms (6 had renal carcinoma, 4 another lung primary carcinoma, 3 prostate carcinoma, 3 breast carcinoma, and 4 assorted neoplasms). The diagnosis of SCLC in 128 patients(97%) followed the onset of paraneoplastic symptoms. SCLC was identified in 10 patients by chest MRI after an equivocal chest radiograph or CT; in 28 by bronchoscopy, mediastinoscopy, or thoracotomy; and in 7 at autopsy. Neurologic signs in decreasing frequency were neuropathy (sensory> mixed somatic > autonomic > cranial [especially cranial nerve VIII] > motor), cerebellar ataxia, limbic encephalitis, polyradiculopathy, associated Lambert-Eaton myasthenic syndrome, myopathy, myelopathy, opsoclonus/myoclonus, motor neuronopathy, brachial plexopathy, and aphasia. Nineteen patients had a solely gastrointestinal initial presentation, including gastroparesis, pseudo-obstruction, esophageal achalasia, or other dysmotility. We conclude that seropositivity for ANNA-1 can expedite the diagnosis and treatment of otherwise occult cancer in patients, especially tobacco abusers, with varied neurologic and gastroenterologic presentations. The search for SCLC should not end on discovering a different neoplasm.

We investigated specificities of acetylcholine receptor (AChR) antibodies in 100 seropositive patients with myasthenia gravis (MG). Antibodies in 74 of these sera were inhibited by more than 50 from binding to human muscle AChR by a rat monoclonal antibody (mAb) of “main immunogenic region” (MIR) specificity. The mAb inhibition was not explainable by epitope competition because (1) the mAb was reactive with both Torpedoand human AChR, but antibodies in 85 of the MG sera did notbind to TorpedoAChR, and (2) the mAb blocked binding of rat anti-peptide antibodies to an a subunit region of the human AChR unrelated antigenically to the designated MIR region. Individual patients' sera had evidence of extensive antibody heterogeneity and revealed interspecies polymorphisms in AChR antigenicity, near and remote from the neurotransmitter-binding region. The data challenge the concept that a MIR of the AChR is the principal stimulus for antibody production in MG, and emphasize a potential pitfall in assuming seronegativity in MG on the basis of a single assay system.

Autonomic dysfunction is a recognized feature of the Lambert-Eaton myasthenic syndrome (LES). However, the characteristic pattern of dysautonomia has not been clearly documented and its pathophysiologic basis is not known. We therefore abstracted autonomic symptomatology and results of quantitative tests for salivation, and vasomotor, cardiovagal, and sudomotor reflexes from records of 30 LES patients. Dry mouth (77%) and impotence (45% of men) were the most common symptoms. Composite Autonomic Scoring Scale results were abnormal in 93% of patients, and autonomic failure was severe in 20%. The frequency of specific test abnormalities were the following: sudomotor function, 83%; cardiovagal reflexes, 75%; salivation, 44%; and adrenergic function, 37%. Although voltage-gated N-type calcium (Ca2+) channels are implicated in autonomic transmission, the low frequency of serum antibodies to N-type Ca2+channels found in the patients of this study(31% positive) argues against a pathogenic role in mediating LES-related dysautonomia. In contrast, 93% of the patients were seropositive for P/Q-type Ca2+channel antibodies. A subset of these antibodies is thought to impair neuromuscular transmission. Autoantibodies of thyrogastric or glutamic acid decarboxylase specificity (markers of predisposition to type 1 diabetes mellitus) were found in 45% of patients, and type 1 antineuronal nuclear antibody (or anti-Hu, a marker of autoimmune neuropathy associated with small-cell lung carcinoma) was found in 3%. No autoantibody correlated with autonomic dysfunction severity. Sensorimotor neuropathy was documented in five patients, and was not significantly associated with autonomic neuropathy. Autonomic failure was most severe in older subjects with cancer (p= 0.02, age by cancer interaction).

We followed 21 patients with sensory neuronopathy without evidence of cancer for up to 23 years. All were seronegative for type 1 antineuronal nuclear antibodies (ANNA-1, also called “anti-Hu”). We additionally studied 67 seropositive patients with sensory neuronopathy or a related neurologic syndrome. Ninety-one percent of the seropositive patients had a small-cell lung carcinoma. One, with a normal chest x-ray, had been followed for 7 years for sensory neuronopathy of indeterminate cause before serologic testing for ANNA-1 led to the discovery of the tumor by CT. We conclude that ANNA-1 seropositivity in a patient with sensory neuronopathy is strong evidence for an underlying small-cell lung cancer.

Encephalitis is a significant cause of morbidity and mortality, yet a causative factor is identified in <50% of cases.1The most common causes are infectious (particularly herpes simplex virus [HSV]) and autoimmune.2Diagnosis of the latter potentially treatable cause is aided by the detection in serum or CSF of an informative profile of autoantibodies against neuronal intracellular proteins and plasma membrane proteins (e.g., voltage-gated potassium channel [VGKC] complex and calcium channels [VGCC, P/Q-type or N-type] and a growing list of glutamate receptors [R] and other autoantibodies of synaptic specificity).3,4Neural autoantibodies, particularly NMDA-R-IgG, have recently been reported in the setting of viral encephalitides.5,6Herein, we report a unique case of N-type VGCC autoantibody temporally associated with HSV encephalitis.

Article abstract— In rats with experimental autoimmune myasthenia gravis, light and electron microscopic evaluation of proximal and distal radial and distal phrenic nerve trunks was done to see whether a morphologic abnormality was present in alpha motor axons. No significant difference was found in density of myelinated fibers between nerves of experimental and control animals.

An infant with transient neonatal myasthenia gravis had a double-blood-volume exchange transfusion because of maternal-fetal blood group incompatibility. This seemed to accelerate both decline in antiacetylcholine antibody titer and clinical improvement.

Elevated amounts of antibodies specific for acetylcholine receptors were detected in 87 percent of sera from 71 patients with myasthenia gravis but not in 175 sera from individuals without myasthenia gravis, including those with other neurologic or autoimmune disease. Antireceptor antibodies were not directed at the acetylcholine binding site of the receptor. Presence or titer of antibody did not appear to correlate with age, sex, steroid therapy, or duration of symptoms. Myasthenia gravis patients with only ocular symptoms had lower antibody titers, while the majority of titers in myasthenia gravis patients with thymoma exceeded the median titer of the myasthenia gravis group as a whole. Assay of antireceptor antibody should prove a useful test in the diagnosis of myasthenia gravis.

We tested the hypothesis that immunoglobulins directed against a CNS autoantigen, myelin basic protein, may promote remyelination in the course of a chronic, immune-mediated demyelinating disease SJL/J mice infected chronically with Daniel's strain of Theiler's virus served as an experimental model of MS. The spinal cords of these mice exhibit extensive primary demyelination and inflammation with minimal spontaneous remyelination. Treatment with whole antiserum or affinity-purified mouse immunoglobulins directed against rat or rabbit myelin basic protein increased new myelin synthesis as measured by quantitative morphometry. Electron microscopy revealed numerous oligodendrocytes in remyelinated CNS lesions and a relative lack of inflammatory cells. Viral antigen persisted in the spinal cord despite enhanced CNS-type remyelination. These findings indicate that immunoglobulins reactive with myelin autoantigens have the potential to promote myelin repair.