Neural Autoantibodies Research Articles

The Frequency of Serum Neural Autoantibodies in Suspected Autoimmune Epilepsy (P6.284)

The Frequency of Serum Neural Autoantibodies in Suspected Autoimmune Epilepsy (P6.284)

Psychiatric Autoimmunity: N-Methyl-d-Aspartate Receptor IgG and Beyond

Descriptions of psychiatric autoimmunity beyond N-methyl-D-aspartate (NMDA) receptor encephalitis are sparse. To report the autoimmune psychiatric spectrum currently recognized in Mayo Clinic practice. Medical record review, testing of stored serum and cerebrospinal fluid for IgGs reactive with synaptic receptors and ion channels, neuronal nuclear and cytoplasmic antigens (including glutamic acid decarboxylase 65-kDa isoform) and case-control comparison were conducted. Patients were categorized into group 1, all adult psychiatric inpatients tested for neural autoantibodies (2002-2011; n = 213), and group 2, all Mayo NMDA receptor IgG-positive patients (2009-2013; n = 13); healthy control subjects were also included (n = 173). In group 1, at least 1 serum autoantibody (but not NMDA receptor IgG) was detected in 36 of 213 psychiatric inpatients. In total, 12 patients were determined retrospectively to have high-likelihood autoimmune encephalitic diagnoses. The most commonly detected autoantibody specificities were voltage-gated potassium channel ([Kv1] VGKC) complex (6) and calcium channel (P/Q type or N type; 5). Symptoms seen were as follows: depressive (8), anxious (7), psychotic (7), disorganized (5), suicidal (3), manic (1) and catatonic (1). In group 2, among 13 NMDA receptor IgG-positive patients, 12 had encephalitis; their psychiatric symptoms were as follows: depressive (9), catatonic (9), disorganized (8), anxious (8), psychotic (7), manic (6), and suicidal (3). Catatonic symptoms were more common in the 12 NMDA receptor IgG-positive patients than in the 12 group 1 patients with high likelihood of encephalitis (p = 0.002). Antibody positivities were usually low positive in value among healthy controls (12 of 16 vs 3 of 12 group 1 encephalitis cases, p = 0.025). NMDA receptor IgG was not detected in any healthy control subject. A spectrum of psychiatric autoimmunity beyond NMDA-R IgG may be under-recognized. Diagnosis is facilitated by combining results of comprehensive psychiatric, laboratory, radiologic, and electrophysiologic evaluations.

The detection of neural autoantibodies in patients with antiepileptic-drug-resistant epilepsy predicts response to immunotherapy.

The detection of antibodies binding neural antigens in patients with epilepsy has led to the definition of 'autoimmune epilepsy'. Patients with neural antibodies not responding to antiepileptic drugs (AEDs) may benefit from immunotherapy. Aim of this study was to evaluate the frequency of autoantibodies specific to neural antigens in patients with epilepsy and their response to immunotherapy. Eighty-one patients and 75 age- and sex-matched healthy subjects (HS) were enrolled in the study. Two groups of patients were included: 39 patients with epilepsy and other neurological symptoms and/or autoimmune diseases responsive to AEDs (group 1) and 42 patients with AED-resistant epilepsy (group 2). Patients' serum and cerebrospinal fluid were evaluated for the presence of autoantibodies directed to neural antigens by indirect immunofluorescence on frozen sections of mouse brain, cell-based assays and a radioimmunoassay. Patients with AED-resistant epilepsy and neural autoantibodies were treated with immunotherapy and the main outcome measure was the reduction in seizure frequency. Neural autoantibodies were detected in 22% of patients (18/81), mostly from the AED-resistant epilepsy group (P = 0.003), but not in HS. Indirect immunofluorescence on mouse brain revealed antibodies binding to unclassified antigens in 10 patients. Twelve patients received immunotherapy and nine (75%) achieved >50% reduction in seizure frequency. A significant proportion of patients with AED-resistant epilepsy harbor neural-specific autoantibodies. The detection of these antibodies, especially of those binding to synaptic antigens, may predict a favorable response to immunotherapy, thus overcoming AED resistance.

Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility.

Chronic gastrointestinal dysmotility greatly impacts the quality of life. Treatment options are limited and generally symptomatic. Neural autoimmunity is an under-recognized etiology. We evaluated immunotherapy as an aid to diagnosing autoimmune gastrointestinal dysmotility (AGID). Twenty-three subjects evaluated at the Mayo Clinic for suspected AGID (August 2006-February 2014) fulfilled the following criteria: (1) prominent symptoms of gastrointestinal dysmotility with abnormalities on scintigraphy-manometry; (2) serological evidence or personal/family history of autoimmune disease; (3) treated by immunotherapy on a trial basis, 6-12 weeks (intravenous immune globulin, 16; or methylprednisolone, 5; or both, 2). Response was defined subjectively (symptomatic improvement) and objectively (gastrointestinal scintigraphy/manometry studies). Symptoms at presentation: constipation, 18/23; nausea or vomiting, 18/23; weight loss, 17/23; bloating, 13/23; and early satiety, 4/23. Thirteen patients had personal/family history of autoimmunity. Sixteen had neural autoantibodies and 19 had extra-intestinal autonomic testing abnormalities. Cancer was detected in three patients. Preimmunotherapy scintigraphy revealed slowed transit (19/21 evaluated; gastric, 11; small bowel, 12; colonic, 11); manometry studies were abnormal in 7/8. Postimmunotherapy, 17 (74%) had improvement (both symptomatic and scintigraphic, five; symptomatic alone, eight; scintigraphic alone, four). Nine responders re-evaluated had scintigraphic evidence of improvement. The majority of responders who were re-evaluated had improvement in autonomic testing (six of seven) or manometry (two of two). This proof of principle study illustrates the importance of considering an autoimmune basis for idiopathic gastrointestinal dysmotility and supports the utility of a diagnostic trial of immunotherapy.

Neural Autoantibody Clusters Aid Diagnosis of Cancer

Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer. Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil). Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P < 0.0001). In the validation cohorts, many tumor-associated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin response-mediator protein-5 autoantibodies). Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patient's cancer risk and type.

Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.

To evaluate a trial of immunotherapy as an aid to diagnosis in suspected autoimmune epilepsy. We reviewed the charts of 110 patients seen at our autoimmune neurology clinic with seizures as a chief complaint. Twenty-nine patients met the following inclusion criteria: (1) autoimmune epilepsy suspected based on the presence of ≥ 1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and (2) initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IV immune globulin (IVIg), or both. Patients were defined as responders if there was a 50% or greater reduction in seizure frequency. Eighteen patients (62%) responded, of whom 10 (34%) became seizure-free; 52% improved with the first agent. Of those receiving a second agent after not responding to the first, 43% improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 vs 22 months; p = 0.048). Responders included 14/16 (87.5%) patients with antibodies to plasma membrane antigens, 2/6 (33%) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33%) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85%). These retrospective findings justify consideration of a trial of immunotherapy in patients with suspected autoimmune epilepsy. This study provides Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIg, or both improve seizure control.

Autoimmune Encephalitis—Antibody Targets and Their Potential Pathogenicity in Immunotherapy-responsive Syndromes

Autoimmune encephalitis (AIE) associated with neural autoantibodies is increasingly recognised as a cause of subacute onset amnesia, confusion and seizures. In the past decade, several key antibody targets have been identified in AIE. These include the N-methyl D-aspartate (NMDA) receptors, voltage-gated potassium channel complexes – in particular leucine-rich glioma inactivated 1 (LGI1) and glutamic acid decarboxylase (GAD). There is accumulating clinical and laboratory evidence that antibodies targeting the extracellular domains of cell surface molecules are directly pathogenic. Each antibody target associates with a spectrum of clinical features and relative response to immunotherapies. These immunotherapies have been shown to improve short- and long-term clinical outcomes in affected patients. AIE is an important differential diagnosis to consider in patients presenting with symptoms of encephalitis as early diagnosis can lead to successful treatment.

Cramp‐fasciculation syndrome in patients with and without neural autoantibodies

We investigated the clinical, electrophysiological and neural autoantibody characteristics in cramp-fasciculation syndrome (CFS) patients. We reviewed Mayo Clinic records from 2000 to 2011 to identify clinically defined CFS patients who underwent neural autoantibody testing. Stored sera of patients who tested positive for antibodies to voltage-gated potassium channel complex (VGKC complex) were analyzed further for leucine-rich glioma-inactivated 1 (LGI1) or contactin-associated protein-2 immunoglobulin G (CASPR2-IgG) antibodies. Thirty-seven patients were identified. Twelve were seropositive for neural autoantibodies. Clinical manifestations were similar in seropositive and seronegative patients, although central and autonomic neuronal hyperexcitability symptoms were more common in seropositive cases. No patients had a malignancy. Repetitive tibial nerve stimulation at 10 Hz revealed longer afterdischarges in seropositive patients. Two of 7 patients with VGKC-complex autoimmunity demonstrated LGI1 or CASPR2-IgG antibodies. Only 2 of 12 seropositive patients required immunotherapy. VGKC-complex autoimmunity occurs in a minority of CFS patients. Antibody positivity was associated with extramuscular manifestations, typically without malignancy. Target antigens within the VGKC complex remain unknown in most patients.

Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System

The recent report on “Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System” is very interesting.1 Dr McKeon noted that “comprehensive serological and cerebrospinal fluid (CSF) evaluation for neural autoantibodies may permit a focused cancer evaluation.”1 In fact, the serological and CSF evaluation for autoantibodies might be a useful tool for disease assessment.1,2 Nevertheless, there are several concerns regarding such testing. First, the method of antibody testing is very important. Sometimes, the titer might be low and can be detected only by some methods (such as indirect immunofluorescence tests).3 In addition, using insensitive methods might result in false-negative results.3,4 The possibility of a false-positive antibody result should always be kept in mind when interpreting the result. For example, in the case of P/Q-type voltage-gated calcium channel (VGCC) antibodies, false positives can be seen in upto 6% of patients with paraneoplastic syndromes and the true rate of false positives in the general population is unknown.5 Since the availability of the gold standard test, immunohistochemical staining on brain tissue sections combined with confirmation by immunoblotting using recombinant purified proteins, is difficult, a development of a reliable and readily available assay is needed.6

Neural autoantibodies and immunotherapy-responsive epilepsy: A prospective study

Neural autoantibodies and immunotherapy-responsive epilepsy: A prospective study

Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System

As a result of the burgeoning growth of disease-specific neural autoantibody markers available for diagnostic patient evaluation, there has been increasing awareness of autoimmune central nervous system (CNS) disorders in hospital practice. Hospital-based neurologists have also taken great interest in these disorders since many occur in the setting of an occult systemic cancer which can be detected and treated at an early stage, and many affected patients are responsive to immunotherapy. Associated neurological disorders are typically subacute in onset, some are common or classic (eg, limbic encephalitis, cerebellar degeneration), but others have atypical or multifocal presentations. For patients with a suspected paraneoplastic disorder, many and costly oncological evaluations may be required for diagnosis. Comprehensive serological and cerebrospinal fluid (CSF) evaluation for neural autoantibodies may permit a focused cancer evaluation (eg, antineuronal nuclear antibody type 1 [ANNA-1] is associated with small cell lung carcinoma), and in some circumstances may indicate the likelihood of a good response to therapy (eg, voltage-gated potassium channel complex antibody) or poor neurological prognosis (eg, purkinje cell cytoplasmic antibody type 1 [antiYo]). Positron-emission tomography-computed tomography (PET-CT) imaging of trunk may increase the diagnostic yield for certain cancers where other modalities have been negative. For some patients, rapid treatment with immunotherapy may facilitate marked improvement, or full recovery; multiple sequential trials of one or more of steroids, intravenous immunoglobulin or plasma exchange, or combination therapy are often required. For patients with N-methyl-d-aspartate receptor antibody encephalitis, early treatment with immunosuppressants and weeks or months of supportive intensive care may additionally be required. One or more of clinical examination, electroencephalogram (including video telemetry), and imaging provide objective parameters to which posttreatment outcomes can be compared.

Cramp-Fasciculation Syndrome in Patients with and without Neural Autoantibodies (PD1.005)

Cramp-Fasciculation Syndrome in Patients with and without Neural Autoantibodies (PD1.005)

Autoimmune Encephalitis—Antibody Targets and Their Potential Pathogenicity in Immunotherapy-responsive Syndromes

Autoimmune encephalitis (AIE) associated with neural autoantibodies is increasingly recognized as a cause of subacute onset amnesia, confusion, and seizures. In the past decade, several key antibody targets have been identified in AIE. These include the N-methyl D-aspartate (NMDA) receptors, voltage-gated potassium channel complexes—in particular leucine-rich glioma inactivated 1 (LGI1) and glutamic acid decarboxylase (GAD). There is accumulating clinical and laboratory evidence that antibodies targeting the extracellular domains of cell-surface molecules are directly pathogenic. Each antibody target associates with a spectrum of clinical features and relative response to immunotherapies. These immunotherapies have been shown to improve short- and long-term clinical outcomes in affected patients. AIE is an important differential diagnosis to consider in patients presenting with symptoms of encephalitis as early diagnosis can lead to successful treatment.

Chronic pain as a manifestation of potassium channel-complex autoimmunity

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. We reviewed the prevalence and characteristics of pain in VGKC-complex-immunoglobulin G (IgG)-seropositive patients in 25 months of comprehensive service testing for neural autoantibodies, subtyped positive sera for LGI1-IgG and CASPR2-IgG specificities, and reviewed pain prevalence in autoimmune control patients. VGKC-complex-IgG was identified in 1,992 patients of 54,853 tested (4%). Of 316 evaluated neurologically at Mayo Clinic, 159 (50%) had pain, in isolation (28%) or with accompanying neurologic manifestations (72%), and not attributable to alternative cause. Pain was subacute in onset, chronic in course, neuropathic, nociceptive, regional, or diffuse and sometimes attributed to fibromyalgia (6%) or psychogenic cause (13%). Most patients had normal peripheral nervous system function, measured by neuropathy impairment scores and nerve conduction. Evidence of neuronal hyperexcitability (hyperhidrosis, quantitative heat-pain hyperalgesia, or electromyographic excitability) was 25-fold more common in pain patients. Pain management required multiple medications in 70% (narcotics, 30%); 13 of 16 patients reported pain relief with immunotherapy. Pain was significantly associated with CASPR2-IgG-positivity (16% positive with pain, 7% without pain; p = 0.014) but not with LGI1-IgG. Less than 10% of 167 patients with neural autoantibodies other than VGKC-complex-IgG reported pain. Chronic idiopathic pain is a syndromic manifestation of VGKC-complex autoimmunity. Hyperexcitability of nociceptive pathways is implicated. CASPR2-IgG significantly associates with pain, but in most patients the antigenic VGKC-complex molecule remains to be determined. VGKC-complex autoimmunity represents an important new direction for pain research and therapy.

Autoimmune Epilepsy

To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. Observational, retrospective case series. Mayo Clinic Health System. Thirty-two patients with an exclusive (n=11) or predominant (n=21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more antiepileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response- mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each. Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclophosphamide. Seizure frequency. After a median interval of 17 months (range, 3-72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody-positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody-positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone. When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.

Objective and Symptomatic Reversal of Autoimmune Gastrointestinal Dysmotility with Immunotherapy (P05.208)

Objective: To report the utility of scintigraphy as a marker of improvement in autoimmune gastrointestinal dysmotility. Background Autoimmune gastrointestinal dysmotility (AGID) is an under-recognized cause of abnormal gastrointestinal transit, in part because of limited diagnostic tests and a lack of documented evidence of improvement after treatment. Design/Methods: We included five female patients evaluated at Mayo Clinic from 2008 – 2011 with suspected AGID and in whom scintigraphy pre and post immunotherapy demonstrated improvement. Results: Symptom onset occurred at a median age of 48 years (range, 34-70), was subacute (≤8 weeks) in 2 of 5 patients and insidious (>8 weeks) in 3. Four presented with symptoms of constipation; 3 bloating; 2 severe weight loss; 2 nausea/vomiting; 2 diarrhea; 1 early satiety, and 1 abdominal pain. Symptoms in 2 arose in the setting of pandysautonomia; in 2 as a component of multifocal neurological disease, and in 1 were isolated. Neural-specific autoantibodies were detected in 3 patients (ganglionic AChR, 2; peripherin, 1). Pre-immunotherapy scintigraphy revealed abnormally slow gastrointestinal transit in all 5 patients. Invasive manometric tests performed in two patients revealed neuropathic abnormalities. The median delay to AGID diagnosis was 12 months (range, 11-18 months). Clues to this diagnosis included: presence of neural autoantibodies in 3; evidence of a multifocal neurological disorder in 3; pandysautonomia in 2; coexisting organ-specific autoimmunity in 3; and multilevel GI dysmotility in 2. Immunotherapies included: intravenous methylprednisolone, 3, and intravenous immune globulin, 2. Four of the five patients reported symptom improvement. Scintigraphy post-immunotherapy revealed improvements in all five patients in the following regions: gastric emptying, 2; small-bowel transit, 3; and colonic-motility, 4. Conclusions: This report provides objective evidence that AGID is reversible by immunotherapy. Scintigraphy is a useful aid for confirming the diagnosis, detecting subclinical improvements and thus identifying patients who may benefit from longer-term immunosuppression. Disclosure: Dr. Flanagan has nothing to disclose. Dr. Saito has nothing to disclose. Dr. Lennon has nothing to disclose. Dr. Fealey has nothing to disclose. Dr. Pittock has received research support from Alexion Pharmaceuticals, Inc.

Defining Autoimmune Epilepsy

The goal of this study was to identify clinical characteristics and response to treatment of autoimmune epilepsy. The authors retrospectively reviewed data from 32 patients followed in a specialty autoimmune neurology clinic. The authors define autoimmune epilepsy as (1) epilepsy as the exclusive or predominant symptom, and (2) a suspected autoimmune pathogenesis based on detection of neural autoantibodies, inflammatory cerebrospinal fluid (CSF) findings (leukocytosis or …

Paraneoplastic encephalomyelopathies: pathology and mechanisms

The last three decades have seen major advances in the understanding of paraneoplastic and idiopathic autoimmune disorders affecting the central nervous system (CNS). Neural-specific autoantibodies and their target antigens have been discovered, immunopathology and neuroimaging patterns recognized and pathogenic mechanisms elucidated. Disorders accompanied by autoantibody markers of neural peptide-specific cytotoxic effector T cells [such as anti-neuronal nuclear antibody type 1 (ANNA-1, aka anti-Hu), Purkinje cell antibody type 1 (PCA-1, aka anti-Yo) and CRMP-5 IgG] are generally poorly responsive to immunotherapy. Disorders accompanied by neural plasma membrane-reactive autoantibodies [the effectors of synaptic disorders, which include antibodies targeting voltage-gated potassium channel (VGKC) complex proteins, NMDA and GABA-B receptors] generally respond well to early immunotherapy. Here we describe in detail the neuropathological findings and pathophysiology of paraneoplastic CNS disorders with reference to antigen-specific serology and neurological and oncological contexts.

CSF complements serum for evaluating paraneoplastic antibodies and NMO-IgG

The detection of neural-reactive immunoglobulin G (IgG) autoantibodies aids the diagnosis of organ-specific autoimmune neurologic disorders. Many paraneoplastic autoantibodies reliably predict a particular cancer type and are accompanied by varied neurologic presentations of subacute onset.1 The detection of neuromyelitis optica (NMO)–IgG predicts a relapsing inflammatory demyelinating disorder predominated by optic neuritis and transverse myelitis.2 When an autoimmune neurologic disorder is suspected, serologic testing of serum is frequently undertaken before more invasive CSF evaluation. However, CSF evaluation can complement testing of serum when suspicion for an autoimmune etiology persists despite a negative serum result. Here we report, for a 25-year period of testing by standardized indirect immunofluorescence protocols, the frequency of neural autoantibody detection in serum and CSF. ### Methods. The immunofluorescence protocols we used were validated in this laboratory for detection of paraneoplastic antibodies (anti-neuronal nuclear antibody [ANNA]-1; ANNA-2; ANNA-3; Purkinje cell cytoplasmic antibody [PCA]-1; PCA-2; PCA-Tr; collapsin response-mediator protein [CRMP]-5-IgG; amphiphysin antibody; antiglial/neuronal nuclear antibody [AGNA]-1; NMDA receptor antibody) and NMO-IgG. We searched the Mayo Clinic Neuroimmunology Laboratory database (January 1986 to March 2010) for all patient samples …

Neural autoantibody evaluation in functional gastrointestinal disorders: a population-based case-control study.

Our goal is to investigate the serum profile of neural autoantibodies in community-based patients with irritable bowel syndrome (IBS) or functional dyspepsia. The pathogenesis of functional gastrointestinal (GI) disorders, including IBS and dyspepsia, are unknown. Theories range from purely psychological to autoimmune alterations in GI tract neuromuscular function. The study subjects, based in Olmsted County, MN, reported symptoms of functional dyspepsia or IBS (n = 69), or were asymptomatic controls (n = 64). Their coded sera were screened for antibodies targeting neuronal, glial, and muscle autoantigens. The prevalence of neural autoantibodies with functional GI disorders did not differ significantly from controls (17% vs. 13%; P = 0.43). In no case was a neuronal or glial nuclear autoantibody or enteric neuronal autoantibody identified. Neuronal cation channel antibodies were identified in 9% of cases (voltage-gated potassium channel [VGKC] in one dyspepsia case and one IBS case, ganglionic acetylcholine receptor [AChR] in four IBS cases) and in 6% of controls (ganglionic AChR in one, voltage-gated calcium channel [VGCC], N-type, in two and VGKC in one; P = 0.36). The frequency of glutamic acid decarboxylase-65 (GAD65) autoantibodies was similar in cases (10%) and controls (5%; P = 0.23). Our data do not support neural autoimmunity as the basis for most IBS or functional dyspepsia cases.