Thymic B lymphocyte clones from patients with myasthenia gravis secrete monoclonal striational autoantibodies reacting with myosin, alpha actinin, or actin.

Striational autoantibodies (StrAb), which react with elements of skeletal muscle cross-striations, occur frequently in patients with thymoma associated with myasthenia gravis (MG). Dissociated thymic lymphocytes from 22 of 72 MG patients secreted StrAb when cultured with PWM. A high yield of EBV-transformed B cell lines was established from thymus, thymoma, and peripheral blood of seven patients with MG, but clones secreting StrAb arose only from the three patients who had StrAb in their sera. The monoclonal StrAb bound to A bands or I bands in skeletal muscle of human, rat, and frog. One bound to mitochondria in addition to myofibrillar I bands. None bound to nuclei, smooth muscle, or gastric mucosal cells. In immunoblot analyses and ELISAs the monoclonal StrAb bound to muscle and nonmuscle isotypes of myosin, alpha actinin, and/or actin. All bound to contractile proteins common to thymus and muscle, and one selectively immunostained epithelial cells of the thymic medulla. From these antigenic specificities we suggest that StrAb might arise as an immune response directed against the cytoskeletal anchoring proteins associated with nicotinic acetylcholine receptors in thymic epithelial cells undergoing neoplastic transformation to thymoma.

Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs.

Immunization of animals with acetylcholine receptor (AChR) protein from the electric organs of Electrophorus electricus and Torpedo californica induces an autoimmune response to the AChR of mammalian skeletal muscle. Rats and guinea pigs develop experimental autoimmune myasthenia gravis (EAMG) after a single inoculation with small quantities of AChR and adjuvant. The indicence and severity of disease appears to depend on the dose of AChR and stability of the emulsion. EAMG is strikingly similar to myasthenia gravis (MG) of man in its clinical picture and its electrophysiological abnormalities. The presence of antibodies to syngeneic rat muscle AChR in the serum of rats with EAMG documents the existence of autoimmunity in the experimental disease. A common immunopathogenesis is suggested for both EAMG and mg.

Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis.

An acute phase of experimental autoimmune myasthenia gravis (EAMG) occurs transiently early in the immune response of Lewis rats to nicotinic acetylcholine receptors (AChR) when Bordetella pertussis is used as adjuvant. It is characterized by a destructive cellular attack directed at the postsynaptic membranes of muscle. Acute EAMG can be passively transferred to normal rats by IgG from serum of rats with chronic EAMG. In the present study, acute EAMG, induced either by passive transfer of syngeneic antibodies or by active immmunization, was inhibited in rats depleted of complement by treatment with cobra venom factor (CoF). Furthermore, passive transfer of antibodies in excess of the muscle's content of AChR was without any measurable effect in rats treated with CoF. Although 60% of the muscle's AChR was complexed with antibody, there was no reduction in the muscle's content of AChR, and neuromuscular transmission was not compromised as judged electromyographically by curare sensitivity. These data imply that redistribution, accelerated degradation, and impairment of the ionophore function of AChR, effects of antibodies described in vitro on extrajunctional AChR, do not play a significant role in vivo in impairing neuromuscular transmission in an intact neuromuscular junction. Complement appears to be a critical mediator of anti-AChR antibodies' pathogenicity in vivo.

Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis.

Immunization of Lewis rats with acetylcholine receptor (AChR) purified from either Electrophorus electricus electric organ or syngeneic rat muscle induced experimental autoimmune myasthenia gravis (EAMG). This was demonstrated by clinical signs of weakness and by electromyographic evidence of imparied neuromuscular transmission. The amount of rat AChR required to induce an autoimmune response was comparable to the amount of eel AChR required. In vitro complexing of rat AChrR with antibody reduced its immunogenicity. Autoantibody to muscle AChR was present in serum and complexed with AChR in muscle. Antibody was not bound to the ACh binding site of AChR, since antibody-AChR complexes extracted from muscle could still bind 125I-alpha-bungarotoxin. The amount of AChR extracted from muscle of rats with EAMG was diminished. The amount of AChR and antibody-AChR complexes in muscle was measured at intervals after immunization with eel AChR. The amount of AChR decreased in rats with acute EAMG, then transiently increased to more than normal amounts during remission, and finally decreased to only about 20% of normal in rats with chronic EAMG. At least half of the AChR remaining in animals with chronic EAMG was complexed with antibody. Thus, both a decrease in amount of AChR and the formation of antibody-AChR complexes contribute to impairment of neuromuscular transmission in rats with EAMG. The possible mechanisms involved in the changes in AChR content are discussed.

Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies.

Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.

Antagonism of voltage-gated calcium channels in small cell carcinomas of patients with and without Lambert-Eaton myasthenic syndrome by autoantibodies omega-conotoxin and adenosine.

The Lambert-Eaton myasthenic syndrome (LES) is an autoimmune presynaptic disorder of peripheral cholinergic neurotransmission in which there is often an associated small cell lung carcinoma (SCC). SCC lines established from patients with and without LES exhibit a Ca2+ influx response to depolarization by K+ that is consistent with the presence of voltage-gated Ca2+ channels. Autoantibodies antagonistic to SCC Ca2+ channel activity were found exclusively in patients with LES, independent of cancer status. Depolarization-induced uptake of 45Ca2+ by SCC lines was reduced maximally after 3-4 days of exposure to serum immunoglobulins from 14 of 19 LES patients, while 53 control immunoglobulins (including patients with SCC, other tumors, other paraneoplastic syndromes, and other neurological and autoimmune diseases) were without effect. The snail neurotoxin omega-conotoxin of subtype GVIA, which is a specific antagonist of presynaptic Ca2+ channels, inhibited K+-stimulated Ca2+ uptake in a dose-dependent manner that was essentially irreversible. Adenosine, reported to be a specific antagonist of neuronal Ca2+ channels, also impaired voltage-stimulated Ca2+ influx in SCC. Use of LES patients' IgG and omega-conotoxin in further studies of SCC may facilitate identification and purification of the LES antigen(s) and yield a quantitative serological test for diagnosing this autoimmune paraneoplastic syndrome.

Remyelination by oligodendrocytes stimulated by antiserum to spinal cord.

The new synthesis of myelin and the proliferation of oligodendrocytes was stimulated by serum from syngeneic mice immunized with homogenized spinal cord (SCH). Treatment with this antiserum produced a 10-fold increase in the area of remyelination in spinal cords that had become demyelinated previously as a result of infection by Theiler's murine encephalomyelitis virus. Inflammation was decreased in regions of white matter that showed remyelination. Oligodendrocytes exposed to anti-SCH in vitro incorporated three to five times more [3H]thymidine than resting cells did and expressed more myelin basic protein in their cytoplasm, suggesting stimulation of myelinogenesis. Thus, there is a factor present in anti-SCH antiserum that stimulates central nervous system-type remyelination. This finding may provide clues for the therapy of patients with demyelinating disorders such as multiple sclerosis.

Ultrastructural localization of immune complexes (IgG and C3) at the end-plate in experimental autoimmune myasthenia gravis.

Rats immunized with purified torpedo acetylcholine receptor (AChR) plus adjuvants developed chronic experimental autoimmune myasthenia gravis (EAMG) after day 28. Forelimb muscles from EAMG rats 29 to 103 days after immunization and from control animals were used for the ultrastructural localization of IgG and C3. IgG was demonstrated with rabbit anti-rat IgG followed by treatment with peroxidase-labeled staphylococcal protein A; and C3 with peroxidase-labeled rabbit anti-rat C3, or with unlabeled rabbit anti-rat C3 followed by peroxidase-labeled protein A. In EAMG rats both IgG and C3 were localized on the terminal expansions of the junctional folds, where AChR is known to be located, and on detached, degenerated parts of the folds in the synaptic space. Background staining was negligible. The findings provide unambiguous evidence for a destructive autoimmune reaction involving the postsynaptic membrane in EAMG, implicate the complement system in this reaction and show that detachment of the tips of the junctional folds is one way by which immune complexes, and AChR, are eliminated from the postsynaptic membrane. The immuno-electron microscopic findings in chronic EAMG closely resemble those described in human myasthenia gravis.

Experimental autoimmune myasthenia gravis: a sequential and quantitative study of the neuromuscular junction ultrastructure and electrophysiologic correlations.

Neuromuscular junction ultrastructure in rat forelimb digit extensor muscle was sequentially and quantitatively investigated in experimental autoimmune myasthenia gravis (EAMG). Experimental animals were immunized with highly purified eel electroplax acetylcholine receptor protein plus complete Freund's adjuvant and B pertussis vaccine; control animals received only adjuvant and vaccine. During the first 7 days (latent period) after immunization end-plate structure and neuromuscular transmission remained normal in the experimental group. Between day 7 and 11 (acute phase) mononuclear cells infiltrated those regions of muscle where the end-plates were located and there was intense degeneration of the postsynaptic regions with splitting away of abnormal junctional folds from the underlying muscle fibers. Macrophages entered the gaps thus formed and removed the degenerating folds by phagocytosis. The nerve terminals were displaced from their usual location but maintained their structural integrity. Neuromuscular transmission was blocked in many muscle fibers. Miniature end-plate potentias (MEPPs), detectable in only a few fibers, were of abnormally low amplitude. After day 11 (chronic phase) the nerve terminals returned to the highly simplified postsynaptic folds became reconstituted and again degenerated. Immature junctions with poorly differentiated postsynaptic regions and nerve sprouts near end-plates were also observed. In two animals relapsing during the chronic phase degeneration of the postsynaptic folds was more intense than in the other chronic-phase animals. The posysynaptic membrane length and length per unit area and the MEPP amplitudes were significantly decreased in all chronic phase animals and the decreases were greater in the relapsing than in the non-lapsing animals. Minor morphometric alterations were also observed in the nerve terminals. These might have been secondary to the postsynaptic changes. The postsynaptic region is the primary target of the autoimmune reaction in EAMG. The ultrastructural, morphometric and electrophysiological abnormalities of the end-plate in chronic EAMG resemble those which have been observed in human myasthenia gravis.

Evidence against acetylcholine receptor having a main immunogenic region as target for autoantibodies in myasthenia gravis.

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 Torpedo and human AChR, but antibodies in 85 of the MG sera did not bind to Torpedo AChR, and (2) the mAb blocked binding of rat anti-peptide antibodies to an alpha 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.

Acetylcholine receptor autoantibody secretion by thymocytes: relationship to myasthenia gravis.

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 (rho s = 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.

Enzyme immunoassay of anti-human acetylcholine receptor autoantibodies in patients with myasthenia gravis reveals correlation with striational autoantibodies.

Anti-acetylcholine receptor (AChR) autoantibodies are a marker of acquired myasthenia gravis (MG). Some of these antibodies cause muscle weakness. Striational autoantibodies (StrAb) 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-alpha-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.

Immunoglobulins reactive with myelin basic protein promote CNS remyelination.

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.

Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies.

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.

Muscle acetylcholine receptors complexed with autologous IgG reflect seropositivity but not necessarily in vivo binding.

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 alpha-bungarotoxin (alpha-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 (greater than or equal to 0.3 nmol/l) 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 alpha-subunit's presumptive cytoplasmic segment 366-389. We also found that antibodies reactive with AChR's alpha-BTx binding region can significantly lower apparent yields of alpha-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.

Exchange transfusion in neonatal myasthenia gravis.

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.

Autonomic dysfunction in the Lambert-Eaton myasthenic syndrome: serologic and clinical correlates.

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).

Autoimmune paraneoplastic cerebellar degeneration: ultrastructural localization of antibody-binding sites in Purkinje cells.

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 cerebellar tissue that is associated with the endoplasmic reticulum. Some patches of Purkinje plasma membrane also were immunostained.

Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes.

BACKGROUND: Autoantibodies specific for the acetylcholine receptor (AChR) of skeletal muscle (containing the alpha1 subunit) impair neuromuscular transmission in myasthenia gravis (MG). AChRs mediating fast synaptic transmission through autonomic ganglia are structurally similar to muscle AChR, but contain the alpha3 subunit. We propose that ganglionic AChR autoimmunity may cause dysautonomia. OBJECTIVE: To test serum of patients with autonomic neuropathy for autoantibodies of neuronal ganglionic AChR specificity. METHODS: We developed an immunoprecipitation radioassay by complexing epibatidine (125I-labeled high affinity agonist) to a Triton X-100-solubilized AChR antigen from peripheral neuroblastoma membranes. Monoclonal rat immunoglobulins (IgG) specific for muscle or neuronal AChRs validated the assay's specificity. We tested serum from 52 healthy subjects, 12 patients with subacute autonomic neuropathy, and 248 patients with other neurologic disorders. RESULTS: Twelve patients had antibodies that bound unequivocally to ganglionic AChR. Five had subacute autonomic neuropathy, and three (of six tested) had Isaacs' syndrome; four of these eight had a carcinoma (lung, bladder, rectum, thyroid). The remaining four seropositive patients (two Lambert-Eaton syndrome, one dementia, one sensory neuronopathy) all had Ca2+ channel antibodies and three had small cell lung carcinoma. No healthy subject had ganglionic AChR antibodies, nor did 62 patients with MG and muscle AChR antibodies. CONCLUSION: Neuronal AChR antibodies are a novel serologic marker of neurologic autoimmunity. The pathogenicity of neuronal AChR autoantibodies in autonomic neuropathy, Isaacs' syndrome, or other neurologic disorders remains to be shown, as has been demonstrated for muscle AChR antibodies in MG. An autoimmune and potentially paraneoplastic etiology is implicated in seropositive patients.

Seronegativity for type 1 antineuronal nuclear antibodies ('anti-Hu') in subacute sensory neuronopathy patients without cancer.

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 neuropathy 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.