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ObjectivesTo report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients.MethodsArchived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen.ResultsIgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25–87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration.ConclusionsThis study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.

IMPORTANCE: Recognizing the presenting and immunopathological features of Kelch-like protein-11 immunoglobulin G seropositive (KLHL11 IgG+) patients may aid in early diagnosis and management. OBJECTIVE: To describe expanding neurologic phenotype, cancer associations, outcomes, and immunopathologic features of KLHL11 encephalitis. DESIGN, SETTING, AND PARTICIPANTS: This retrospective tertiary care center study, conducted from October 15, 1998, to November 1, 2019, prospectively identified 31 KLHL11 IgG+ cases in the neuroimmunology laboratory. Eight were identified by retrospective testing of patients with rhomboencephalitis (confirmed by tissue-based-immunofluorescence and transfected-cell-based assays). MAIN OUTCOMES AND MEASURES: Outcome variables included modified Rankin score and gait aid use. RESULTS: All 39 KLHL11 IgG+ patients were men (median age, 46 years; range, 28-73 years). Initial clinical presentations were ataxia (n = 32; 82%), diplopia (n = 22; 56%), vertigo (n = 21; 54%), hearing loss (n = 15; 39%), tinnitus (n = 14; 36%), dysarthria (n = 11; 28%), and seizures (n = 9; 23%). Atypical neurologic presentations included neuropsychiatric dysfunction, myeloneuropathy, and cervical amyotrophy. Hearing loss or tinnitus preceded other neurologic deficits by 1 to 8 months in 10 patients (26%). Among patients screened for malignancy (n = 36), testicular germ-cell tumors (n = 23; 64%) or testicular microlithiasis and fibrosis concerning for regressed germ cell tumor (n = 7; 19%) were found in 83% of the patients (n = 30). In 2 patients, lymph node biopsy diagnosed metastatic lung adenocarcinoma in one and chronic lymphocytic leukemia in the other. Initial brain magnetic resonance imaging revealed T2 hyperintensities in the temporal lobe (n = 12), cerebellum (n = 9), brainstem (n = 3), or diencephalon (n = 3). Among KLHL11 IgG+ patients who underwent HLA class I and class II genotyping (n = 10), most were found to have HLA-DQB1*02:01 (n = 7; 70%) and HLA-DRB1*03:01 (n = 6; 60%) associations. A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell–predominant inflammation and nonnecrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and 2 autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early active inflammation and later extensive neuronal loss. Compared with nonautoimmune control peripheral blood mononuclear cells, cluster of differentiation (CD) 8+ and CD4+ T cells were significantly activated when patient peripheral blood mononuclear cells were cultured with KLHL11 protein. Most patients (58%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [n = 10] or improved [n = 9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer. Long-term outcomes in KLHL11-IgG+ patients were similar to Ma2 encephalitis. CONCLUSIONS AND RELEVANCE: Kelch-like protein-11 IgG is a biomarker of testicular germ-cell tumor and paraneoplastic neurologic syndrome, often refractory to treatment. Described expanded neurologic phenotype and paraclinical findings may aid in its early diagnosis and treatment.

To characterize the cardiorespiratory abnormalities in patients with necrotizing autoimmune myopathy (NAM).

Neurologic autoimmune disorders in the context of systemic cancer reflect antitumor immune responses against onconeural proteins that are autoantigens in the nervous system. These responses observe basic principles of cancer immunity and are highly pertinent to oncological practice since the introduction of immune checkpoint inhibitor cancer therapy. The patient’s autoantibody profile is consistent with the antigenic composition of the underlying malignancy. A major determinant of the pathogenic outcome is the anatomic and subcellular location of the autoantigen. IgGs targeting plasma membrane proteins (eg, muscle acetylcholine receptor -IgG in patients with paraneoplastic myasthenia gravis) have pathogenic potential. However, IgGs specific for intracellular antigens (eg, antineuronal nuclear antibody 1 [anti-Hu] associated with sensory neuronopathy and small cell lung cancer) are surrogate markers for CD8+T lymphocytes targeting peptides derived from nuclear or cytoplasmic proteins. In an inflammatory milieu, those peptides translocate to neural plasma membranes as major histocompatibility complex class I protein complexes. Paraneoplastic neurologic autoimmunity can affect any level of the neuraxis and may be mistaken for cancer progression. Importantly, these disorders generally respond favorably to early-initiated immunotherapy and cancer treatment. Small cell lung cancer and thymoma are commonly associated with neurologic autoimmunity, but in the context of checkpoint inhibitor therapy, other malignancy associations are increasingly recognized.

IMPORTANCE: Recent studies have reported a higher relapse rate following an initial inflammatory demyelinating disorder in pediatric patients with persistent seropositivity of antibodies targeting myelin oligodendrocyte glycoprotein (MOG-IgG1). To date, the clinical implications of longitudinal MOG-IgG1 seropositivity using live cell assays with IgG1 secondary antibodies in adults after acute disseminated encephalomyelitis (ADEM) are unknown. OBJECTIVE: To determine whether MOG-IgG1 serostatus (transient vs persistent) and titer change over time provide clinical utility in predicting the likelihood of relapse after ADEM. DESIGN, SETTING, AND PARTICIPANTS: This cohort study identified patients with an initial diagnosis of ADEM evaluated at a single referral center between January 1, 1990, and October 1, 2017. Fifty-one patients were included, including 31 children and 20 adults. Longitudinal serologic testing was performed detecting autoantibodies targeting aquaporin 4 (AQP4-IgG) and MOG-IgG1 with clinically validated fluorescence-activated cell sorting assays. Patients were divided into 3 cohorts: persistent seropositivity, transient seropositivity, and seronegativity. MAIN OUTCOMES AND MEASURES: Clinical demographic characteristics, longitudinal AQP4-IgG and MOG-IgG1 serostatus, titers, relapses, use of immunotherapy, and Expanded Disability Status Scale score at follow-up. RESULTS: Of 51 patients presenting with an initial diagnosis of ADEM, 20 (39%) were adult, 24 (47%) were female, and ages ranged from 12 months to 57 years. Seventeen patients fulfilled criteria for persistent seropositivity; of those, 8 of 9 children (89%) and 7 of 8 adults (88%) had at least 1 relapse after median (range) follow-up periods of 75 (15-236) months and 39 (9-161) months, respectively. Eight patients (16%), including 4 adults, fulfilled criteria for transient seropositivity; of those, no children and 1 of 4 adults (25%) relapsed after median (range) follow-up periods of 32 (24-114) months and 16 (13-27) months, respectively. Of 24 patients with AQP4-IgG and MOG-IgG seronegativity, 6 of 17 children (35%) and 2 of 7 adults (29%) had at least 1 relapse after median (range) follow-up periods of 36 (3-203) months and 34 (15-217) months, respectively. There were only 2 patients, including 1 adult, with AQP4-IgG seropositivity, and both relapsed. The hazard ratio for relapses in those with persistent MOG-IgG1 positivity compared with AQP4-IgG and MOG-IgG1 seronegativity was 3.1 (95% CI, 1.1-8.9; P = .04) in children and 5.5 (95% CI, 1.4-22.5; P = .02) in adults. Immunotherapy was used in 5 of 9 children (56%) and 6 of 8 adults (75%) with persistent seropositivity and in 3 of 17 children (18%) and 1 of 7 adults (14%) with AQP4-IgG and MOG-IgG seronegativity. CONCLUSIONS AND RELEVANCE: Relapse occurred in 15 of 17 patients (88%) with persistent MOG-IgG1 seropositivity after ADEM; only 1 patient with transient seropositivity experienced relapse. Our data extend the clinical utility of MOG-IgG1 serological testing to adult patients and highlights that longitudinal serologic evaluation of MOG-IgG1 could help predict disease course and consideration of immunotherapy.

The etiology of statin intolerance is hypothesized to be due to genetic variants that impact statin disposition and clearance. We sought to determine whether genetic variants were associated to statin intolerance. The studied cohort consisted of hyperlipidemic participants (n  90) clinically diagnosed with statin intolerance by a cardiologist and matched controls without statin intolerance. Creatine kinase activity, lipid profiles and genetic analyses were performed on genes involved in statin metabolism and included UGT1A1and UGT1A3sequencing and targeted analyses of CYP3A422, CYP3A53, SLCO1B15and 1b, ABCB1c.3435C>T, ABCG2c.421C>A and GATMrs9806699. Although lipids were higher in cases, genetic variant minor allele frequencies were similar between cases and controls, except for UGT1A128, which was less prevalent in cases than controls.

IMPORTANCE: A novel astrocytic autoantibody has been identified as a biomarker of a relapsing autoimmune meningoencephalomyelitis that is immunotherapy responsive. Seropositivity distinguishes autoimmune glial fibrillary acidic protein (GFAP) meningoencephalomyelitis from disorders commonly considered in the differential diagnosis. OBJECTIVE: To describe a novel IgG autoantibody found in serum or cerebrospinal fluid that is specific for a cytosolic intermediate filament protein of astrocytes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of the medical records of seropositive patients identified in the Mayo Clinic Neuroimmunology Laboratory from October 15, 1998, to April 1, 2016, in blinded comprehensive serologic evaluation for autoantibody profiles to aid the diagnosis of neurologic autoimmunity (and predict cancer likelihood). MAIN OUTCOMES AND MEASURES: Frequency and definition of novel autoantibody, the autoantigen’s immunochemical identification, clinical and magnetic resonance imaging correlations of the autoantibody, and immunotherapy responsiveness. RESULTS: Of 103 patients whose medical records were available for review, the 16 initial patients identified as seropositive were the subject of this study. Median age at neurologic symptom onset was 42 years (range, 21-73 years); there was no sex predominance. The novel neural autoantibody, which we discovered to be GFAP-specific, is disease spectrum restricted but not rare (frequency equivalent to Purkinje cell antibody type 1 [anti-Yo]). Its filamentous pial, subventricular, and perivascular immunostaining pattern on mouse tissue resembles the characteristic magnetic resonance imaging findings of linear perivascular enhancement in patients. Prominent clinical manifestations are headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor, and cerebellar ataxia. Cerebrospinal fluid was inflammatory in 13 of 14 patients (93%) with data available. Neoplasia was diagnosed within 3 years of neurologic onset in 6 of 16 patients (38%): prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenoma, and teratoma. Neurologic improvement followed treatment with high-dose corticosteroids, with a tendency of patients to relapse without long-term immunosuppression. CONCLUSIONS AND RELEVANCE: Glial fibrillary acidic protein–specific IgG identifies a distinctive, corticosteroid-responsive, sometimes paraneoplastic autoimmune meningoencephalomyelitis. It has a lethal canine equivalent: necrotizing meningoencephalitis. Expression of GFAP has been reported in some of the tumor types identified in paraneoplastic cases. Glial fibrillary acidic protein peptide–specific cytotoxic CD8+ T cells are implicated as effectors in a transgenic mouse model of autoimmune GFAP meningoencephalitis.

IMPORTANCE: Thymoma is commonly recognized in association with paraneoplastic autoimmune myasthenia gravis (MG), an IgG–mediated impairment of synaptic transmission targeting the nicotinic acetylcholine receptor of muscle. Newly identified synaptic autoantibodies may expand the serological profile of thymoma. OBJECTIVE: To investigate the frequency of potentially pathogenic neural synaptic autoantibodies in patients with thymoma. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with histopathologically confirmed thymoma and serum available to test for synaptic autoantibodies (collected 1986-2014) at the Mayo Clinic Neuroimmunology Laboratory. We identified and classified 193 patients with thymoma into 4 groups: (1) lacking neurological autoimmunity (n = 43); (2) isolated MG (n = 98); (3) MG plus additional autoimmune neurological manifestations (n = 26); and (4) neurological autoimmunity other than MG (n = 26). MAIN OUTCOMES AND MEASURES: Clinical presentation and serum profile of autoantibodies reactive with molecularly defined synaptic plasma membrane proteins of muscle, peripheral, and central nervous systems. RESULTS: Of the 193 patients with thymoma, mean patient age was 52 years and did not significantly differ by sex (106 women) or group. Myasthenia gravis was the most prevalent clinical manifestation (64%) followed by dysautonomia (16 patients [8%]) and encephalopathy (15 patients [8%]); 164 patients (85%) had at least 1 synaptic autoantibody, and 63 of these patients (38%) had at least 1 more. Muscle acetylcholine receptor was most frequent (78%), followed by ganglionic acetylcholine receptor (20%), voltage-gated Kv1 potassium channel-complex (13%), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (5%). Less frequent were aquaporin-4, voltage-gated Kv1 potassium channel-complex related proteins (leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2), glycine receptor, and γ-aminobutyric acid-A receptor. Synaptic autoantibodies were significantly more frequent in patients with neurological autoimmunity than in those without and were most frequent in patients with neurological manifestations other than or in addition to MG. CONCLUSIONS AND RELEVANCE: Synaptic autoantibodies, particularly those reactive with ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily (namely α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, glycine, and γ-aminobutyric acid-A receptors), were prevalent in patients with thymoma. Autoantibodies of this extended spectrum may enhance autoimmune serological testing as an aid to preoperative thymoma diagnosis. Detection of currently known synaptic autoantibody specificities absent from this profile have potential algorithmic usefulness as negative predictors for thymoma (as recognized for neuronal voltage-gated calcium channel autoantibodies).

IMPORTANCE: Necrotizing autoimmune myopathy (NAM) is characterized pathologically by necrotic muscle fibers with absent or minimal inflammation. It is often accompanied by statin therapy, connective tissue diseases, cancer, and autoantibodies specific for signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR). Data are limited concerning differences among etiologic subgroups and treatment outcomes in NAM. OBJECTIVES: To describe the clinical, serologic, and electrophysiologic characteristics of NAM, compare patient subgroups, and determine clinical outcome predictors. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective review of medical records for 63 adult Mayo Clinic patients assigned the clinical and histopathologic diagnosis of NAM from January 1, 2004, through December 31, 2013. Patients were stratified by presumed cause and autoantibody status. MAIN OUTCOMES AND MEASURES: Clinical, electrophysiologic, and pathologic characteristics were collected and compared among patient subgroups. Predictors of response to treatment were identified by univariate logistic regression. RESULTS: Lower extremity weakness predominated (46 [73%]). Distal weakness (26 [41%]), dysphagia (22 [35%]), and dyspnea (23 [37%]) were common. Twenty-two patients (35%) were receiving a statin medication at onset, 6 had cancer, and 3 had a connective tissue disease. The median creatine kinase level was 5326 U/L. In 13 patients (24%), SRP-IgG was detected, and in 17 patients (34%), HMGCR-IgG was detected (one-third of whom had not received statin medication). One patient was dual seropositive. Facial weakness was more common in SRP-IgG–positive patients. Myotonic discharges were more common in statin-associated NAM. Prednisone monotherapy was insufficient to control disease in most patients; 30 (90%) of 32 patients required 2 or more immunotherapeutic agents. Relapse occurred in 16 (55%) of 29 patients during immunosuppressant taper or discontinuation. Predictors of favorable outcome were male sex and use of 2 or more immunotherapeutic agents within 3 months of onset. CONCLUSIONS AND RELEVANCE: Necrotizing autoimmune myopathy was idiopathic in half of this cohort with clinical and histopathologically defined disease. In the remainder, NAM was associated with statin medication, cancer, or connective tissue disease. One in 4 patients was SRP-IgG positive, and 1 in 3 was HMGCR-IgG positive. The disease was usually not controlled by corticosteroid monotherapy. Presentation, course, and outcomes did not differ significantly in seropositive, seronegative, and statin-associated cases. Early aggressive immunosuppressant therapy improved outcomes, and risk of relapse was high during medication dose reduction or withdrawal.

Descriptions of psychiatric autoimmunity beyond N-methyl-d-aspartate (NMDA) receptor encephalitis are sparse.

IMPORTANCE: Short transverse myelitis (STM; <3 vertebral segments) is considered noncharacteristic of neuromyelitis optica (NMO) spectrum disorders (NMOSDs). Nonappreciation of the potential for STM to occur in NMOSD may lead to increased disability from delay in diagnosis and appropriate treatment. OBJECTIVES: To determine the frequency of short lesions at the initial myelitis manifestation of NMOSD and to compare the demographic, clinical, and radiological characteristics of aquaporin-4-IgG (AQP4-IgG) seropositive and seronegative STM. DESIGN, SETTING, AND PARTICIPANTS: We reviewed the records and images of patients at the Mayo Clinic who were identified as AQP4-IgG positive from 1996 to 2014. Inclusion criteria were first STM episode, magnetic resonance imaging performed 90 days or less from symptom onset, spinal cord T2-hyperintense lesion less than 3 vertebral segments, AQP4-IgG seropositivity, and a final diagnosis of NMO or NMOSD. Patients with an initial longitudinally extensive transverse myelitis were excluded (n = 151). Patients with STM who were seronegative for AQP4-IgG among an Olmsted County population–based cohort of inflammatory demyelinating disorders of the central nervous system were used as a control group. MAIN OUTCOMES AND MEASURES: Delay to diagnosis in months, clinical and radiological characteristics, and disability measured by ambulatory status. RESULTS: Twenty-five patients who were AQP4-IgG seropositive with an initial STM represented 14% of initial myelitis episodes among patients with NMOSD. The STM episode was defined as the first manifestation of NMOSD in 10 patients (40%) preceded by optic neuritis in 13 patients (52%) and preceded by a nausea and vomiting episode in 2 patients (8%). In comparison with the excluded patients with NMOSD who had an initial longitudinally extensive transverse myelitis, delay to diagnosis/treatment was greater when initial lesions were short (P = .02). In AQP4-IgG–positive STM cases, subsequent myelitis episodes were longitudinally extensive in 92%. Attributes more common in patients with AQP4-IgG–positive STM than in 27 population-based patients with AQP4-IgG–negative STM included the following: nonwhite race/ethnicity; tonic spasms; coexisting autoimmunity; magnetic resonance imaging (central cord lesions, T1 hypointensity, and a brain inconsistent with multiple sclerosis); and cerebrospinal fluid (oligoclonal bands lacking). CONCLUSIONS AND RELEVANCE: Short transverse myelitis is not uncommon in NMOSD and, when it is present, delays diagnosis and treatment. Clinical and radiological characteristics identified in this study may help select patients with STM who are at the highest risk for an NMOSD. Short transverse myelitis does not exclude consideration of AQP4-IgG testing or NMOSD diagnosis.

IMPORTANCE: Using an aquaporin-4 (AQP4) M1-isoform–specific enzyme-linked immunosorbent assay (ELISA) and a fixed transfected cell-based assay (CBA), we tested AQP4-IgG in a northern California population representative cohort of 3293 potential cases with multiple sclerosis (MS). Seropositive cases were tested additionally by fluorescence-activated cell sorting, a live transfected cell-based assay. OBSERVATIONS: Sera samples were available in 1040 cases; 7 yielded positive results, 4 by ELISA alone and 3 by both ELISA and CBA. Clinical data (episodes of optic neuritis and longitudinally extensive transverse myelitis [reported on at least 1 magnetic resonance imaging spine]) supported the alternative diagnosis of neuromyelitis optica for 2 patients as seropositive by both ELISA and CBA. These 2 patients alone tested positive by a fluorescence-activated cell-sorting assay. The diagnosis of MS was considered correct in the other 5 patients. Thus, 5 ELISA results and 1 fixed CBA result were false positive. CONCLUSIONS AND RELEVANCE: Sensitive serological evaluation for AQP4-IgG in this large population-representative cohort of predominantly white non-Hispanic patients with MS reveals that neuromyelitis optica spectrum disorder is rarely misdiagnosed as MS in contemporary US neurological practice (0.2%). The frequency of a false-positive result for ELISA and CBA in this MS cohort were 0.5% and 0.1%, respectively. This finding reflects the superior specificity of CBA and justifies caution in interpreting AQP4-IgG results obtained by ELISA.

IMPORTANCE: Documentation of muscle pathology compatible with targeting of sarcolemmal aquaporin-4 (AQP4) by complement-activating IgG implies involvement of organs beyond the central nervous system in neuromyelitis optica spectrum disorders. OBSERVATIONS: We report on a 51-year-old woman who had relapsing optic neuritis, transverse myelitis, AQP4-IgG seropositivity, and recurrent myalgias with hyperCKemia. A muscle biopsy revealed scattered myofibers with internal nuclei, atrophy, and regeneration but no necrosis. Mild inflammatory exudates, in endomysial and perivascular spaces, consisted of lymphocytes, histiocytes, and scattered eosinophils. The sarcolemma exhibited loss of AQP4 and deposition of IgG and complement activation products, characteristics not seen in control biopsy samples of healthy muscle and immune-mediated myopathies. CONCLUSIONS AND RELEVANCE: Recurrent hyperCKemia accompanying AQP4-IgG seropositivity reflects targeting of skeletal muscle AQP4 by pathogenic IgG. The entity of autoimmune AQP4 myopathy extends the neuromyelitis optica spectrum beyond the central nervous system.

IMPORTANCE Reports of neuromyelitis optica spectrum disorder (NMOSD) occurring in the setting of neoplasia suggest that aquaporin-4 autoimmunity may in some cases have a paraneoplastic basis. OBSERVATIONS In this case report, we describe a patient with NMOSD whose test results were seropositive for aquaporin-4 IgG and who had a hepatic metastasis from a small-bowel neuroendocrine tumor. The tumor cells expressed aquaporin-4 immunoreactivity. She presented to the Neurology Department at Wayne State University with bilateral leg weakness, ascending paresthesias, and decreased sensation. CONCLUSIONS AND RELEVANCE This case extends the context of NMOSD as a paraneoplastic disorder.

IMPORTANCE Studies focused on recurrent longitudinally extensive transverse myelitis (rLETM) are lacking. OBJECTIVES To determine the aquaporin 4 (AQP4) IgG detection rate using recombinant human APQ4-based assays in sequential serum specimens collected from patients with rLETM categorized as negative by first-generation tissue-based indirect immunofluorescence (IIF) assay and to define the clinical characteristics and motor disability outcomes in AQP4-IgG–positive rLETM. DESIGN, SETTING, AND PARTICIPANTS A search of the Mayo Clinic computerized central diagnostic index (October 1, 2005, through November 30, 2011), cross-linked with the Neuroimmunology Laboratory database, identified 48 patients with rLETM, of whom 36 (75%) were positive and 12 (25%) negative for neuromyelitis optica (NMO) IgG (per IIF of serial serum specimens). Stored serum specimens from “seronegative” patients were retested with recombinant human AQP4-based assays, including enzyme-linked immunosorbent, transfected cell-based, and fluorescence-activated cell-sorting assays. Control patients included 140 AQP4-IgG–positive patients with NMO, of whom a subgroup of 20 initially presented with 2 attacks of transverse myelitis (rLETM-onset NMO). MAIN OUTCOMES AND MEASURES AQP4-IgG serostatus, clinical characteristics, and Expanded Disability Status Scale score. RESULTS Six patients with negative IIF results were reclassified as AQP4-IgG positive, yielding an overall AQP4-IgG seropositivity rate of 89%. Fluorescence-activated cell-sorting, cell-based, and enzyme-linked immunosorbent assays improved the detection rate to 89%, 85%, and 81%, respectively. The female to male ratio was 2:3 for AQP4-IgG–negative rLETM and 5:1 for AQP4-IgG–positive patients. The AQP4-IgG–positive patients with rLETM or rLETM-onset NMO were similar in age at onset, sex ratio, attack severity, relapse rate, and motor disability. From Kaplan-Meier analyses, 36% of AQP4-IgG–positive patients with rLETM are anticipated to need a cane to walk within 5 years after onset. For patients with rLETM-onset NMO, the median time from onset to first optic neuritis attack (54 months) was similar to the median disease duration for AQP4-IgG–positive patients with rLETM (59 months). The median number of attacks was 3 for AQP4-IgG–positive patients with rLETM (range, 2-22), and the first optic neuritis attack for those with rLETM-onset NMO followed a median of 3 myelitis attacks (range, 2-19). Immunosuppressant therapy reduced the relapse rate in both AQP4-IgG–positive and AQP4-IgG–negative patients with rLETM. CONCLUSIONS AND RELEVANCE Recombinant antigen–based assays significantly increase AQP4-IgG detection in patients with rLETM, and AQP4-IgG–negative adults with rLETM are rare. Evolution to NMO can be anticipated in AQP4-IgG–positive patients. Early initiation of immunotherapy may result in a more favorable motor outcome.

IMPORTANCE: Reports of pediatric-onset stiff-man syndrome (SMS) are rare. This may be an underrecognized disorder in child neurology practice. OBJECTIVE: To describe patients with disorders in the SMS spectrum beginning in childhood. DESIGN, SETTING, AND PARTICIPANTS: This study was a medical record review and serological evaluation conducted at child and adult neurology clinics at the Mayo Clinic, Rochester, Minnesota. Systematic review of the literature was conducted of patients who presented from 1984-2012 with onset of symptomatic SMS occurring at age 18 years or younger. MAIN OUTCOMES AND MEASURES: Response to symptomatic and immunotherapies, patient and physician reported, including modified Rankin scale. RESULTS: We identified 8 patients with childhood-onset SMS, representing 5% of patients with SMS evaluated at Mayo Clinic during a period of 29 years (4 were girls). The median age at symptom onset was 11 years (range, 1-14 years). The diagnosis in 3 patients was not established until adulthood (median symptom duration at diagnosis, 14 years; range, 0-46 years). The phenotypes encountered were: classic SMS (n = 5, involving the low back and lower extremities), variant SMS (n = 2, limited to 1 limb [with dystonic posture] or back), and progressive encephalomyelitis with rigidity and myoclonus (n = 1). Initial misdiagnoses included functional movement disorder (n = 2), generalized dystonia and parkinsonism (n = 1), and hereditary spastic paraparesis (n = 1). Six patients had 1 or more coexisting autoimmune disorders: type 1 diabetes mellitus (n = 4), thyroid disease (n = 2), and vitiligo (n = 2). Serologic study results revealed glutamic acid decarboxylase 65–IgG in all cases (median value, 754 nmol/L; range, 0.06-3847 nmol/L; normal value, ≤0.02 nmol/L) and glycine receptor antibody in 3 cases. Improvements were noted with symptomatic therapy (diazepam, 6 of 6 patients treated, and oral baclofen, 3 of 3 treated) and immunotherapy (intravenous immune globulin, 3 of 4 treated and plasmapheresis, 3 of 4 treated). The 3 patients with glycine receptor antibody all improved with immunotherapy. At last follow-up, 4 patients had mild or no symptoms, but 4 had moderate or severe residual symptoms and required maintenance symptomatic therapy (n = 5) and immunotherapy (n = 4). Ten of 12 pediatric SMS cases identified by literature review had a severe whole-body phenotype resembling progressive encephalomyelitis with rigidity and myoclonus. CONCLUSIONS AND RELEVANCE: Childhood-onset SMS is a rare but underrecognized and treatable disorder. Serological and electrophysiological testing aid diagnosis.

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.

OBJECTIVE To determine, in patients identified as seropositive for neuronal voltage-gated potassium channel (VGKC) complex autoantibodies, the spectrum of clinical presentations and frequency of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as defined antigenic neuronal targets in the VGKC macromolecular complex. DESIGN Retrospective cohort study. SETTING Clinical practice, Mayo Clinic Neuroimmunology Laboratory and Department of Neurology. PATIENTS A total of 54 853 patients were evaluated, of whom 1992 were found to be VGKC complex IgG positive. RESULTS From June 1, 2008, to June 30, 2010, comprehensive service serologic evaluation performed on 54 853 patients with unexplained neurologic symptoms identified 1992 patients (4%) who were positive for VGKC complex IgG (values ≥0.03 nmol/L). Among 316 seropositive patients evaluated clinically at our institution, 82 (26%) were seropositive for LGI1 IgG and/or CASPR2 IgG. Of these 82 patients, 27% had low (0.03-0.09 nmol/L), 51% had medium (0.10-0.99 nmol/L), and 22% had high (≥1.00 nmol/L) VGKC complex IgG values. Leucine-rich glioma-inactivated protein 1 IgG positivity was associated with higher VGKC complex IgG values (P < .001) and cortical presentations (P < .001); CASPR2 IgG was associated with peripheral motor excitability (P = .009). However, neither autoantibody was pathognomonic for a specific neurologic presentation or correlated significantly with cancer. Neurologic phenotypes were diverse. Cerebrocortical manifestations (including cognitive impairment and seizures) were recorded in 76% of patients with LGI1 IgG alone (n = 46) and 29% with CASPR2 IgG alone (n = 28). Peripheral motor hyperexcitability was found in 21% of patients with CASPR2 IgG alone and 6.5% of patients with LGI1 IgG alone. CONCLUSIONS The study emphasizes diverse and overlapping neurologic phenotypes across a range of VGKC complex IgG values and varying LGI1 IgG and CASPR2 IgG specificities. The frequent occurrence of LGI1 IgG and CASPR2 IgG in serum samples with low and medium VGKC complex IgG values supports the clinical significance of low values in clinical evaluation. Additional antigenic components of VGKC macromolecular complexes remain to be defined.

OBJECTIVES To determine whether glycine receptor α1 subunit-specific autoantibodies (GlyRα1-IgG) occur in a broader spectrum of brainstem and spinal hyperexcitability disorders than the progressive encephalomyelitis with rigidity and myoclonus phenotype recognized to date, and to ascertain disease specificity. DESIGN Retrospective, case-control study. SETTINGS Mayo Clinic, Rochester, Minnesota, and University of Barcelona, Spain. PATIENTS Eighty-one patients with stiff-man syndrome phenotype, 80 neurologic control subjects, and 20 healthy control subjects. INTERVENTION Glycine receptor α1–transfected cells to test serum or cerebrospinal fluid from cases and control subjects. MAIN OUTCOME MEASURES Frequency of GlyRα1-IgG positivity among stiff-man syndrome phenotype cases and control subjects. Comparison of GlyRα1-IgG seropositive and seronegative cases. RESULTS Seropositive cases (12% of cases) included 9 with stiff-man syndrome (4 classic; 5 variant; 66% were glutamic acid decarboxylase 65–IgG positive) and 1 with progressive encephalomyelitis with rigidity and myoclonus. Immunotherapy responses were noted more frequently in GlyRα1-IgG–positive cases (6 of 7 improved) than in seronegative cases (7 of 25 improved; P = .02). The single seropositive control patient had steroid-responsive vision loss and optic atrophy with inflammatory cerebrospinal fluid. CONCLUSIONS Glycine receptor α1–IgG aids identification of autoimmune brainstem/spinal cord hyperexcitability disorders and may extend to the glycinergic visual system.

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.

OBJECTIVE To determine the sex and age distribution of aquaporin-4 (AQP4) autoimmunity using data derived from clinical service laboratory testing of 56 464 patient samples. DESIGN Observational analysis. SETTING Mayo Clinic Neuroimmunology Laboratory. PATIENTS Between October 1, 2005, and January 4, 2011, 56 464 patients were tested for AQP4-IgG; 2960 (5.2%) patients were seropositive. MAIN OUTCOME MEASURE Seropositivity for AQP4-IgG. RESULTS Patients seropositive for AQP4-IgG were older than seronegative patients (mean [SD] age, 46 [16] vs 42 [15] years, respectively; P < .001). More females than males were tested (37 662 vs 16 810, respectively; P < .001). Among 2743 seropositive patients, 146 (5.3%) were pediatric (aged ≤18 years) and 333 (12.1%) were elderly (aged ≥65 years). The sex distribution of seropositive patients was 2465 females and 306 males (absolute female:male ratio, 8.1:1; P < .001). After adjusting for the number of females tested, an excess of females persisted (adjusted female:male ratio, 3.6:1). Female predominance for AQP4-IgG was more striking in adults (absolute female:male ratio, 8.4:1; adjusted female:male ratio, 3.5:1) than in pediatric patients (absolute female:male ratio, 4.3:1; adjusted female:male ratio, 2.9:1) (P < .001). Elderly women were more likely to be seropositive than individuals in other age categories (13.1% vs 6.0%, respectively; P < .001). The proportion of AQP4-IgG–seropositive individuals (detection rate), defined by decade of age, increased exponentially in women after age 50 years. CONCLUSIONS Seropositivity for AQP4-IgG occurs predominantly in females, particularly in individuals older than 18 years. Among seropositive patients, 1 in 6 is in the extremes of age. The detection rate of AQP4-IgG increased in women after age 50 years.

OBJECTIVE To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. DESIGN Observational, retrospective case series. SETTING Mayo Clinic Health System. PATIENTS 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. INTERVENTION Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclophosphamide. MAIN OUTCOME MEASURE Seizure frequency. RESULTS 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. CONCLUSION When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.

BACKGROUND Little information is available about the incidence of stiff-man syndrome (SMS) (the classic form or its variants) or about long-term treatment responses and outcomes. OBJECTIVE To comprehensively describe the characteristics of a cohort of patients with SMS. DESIGN Observational study. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS Ninety-nine patients with classic SMS vs variants of the disorder, both glutamic acid decarboxylase 65 kD isoform (GAD65) antibody seropositive and seronegative. MAIN OUTCOME MEASURES Neurological, autoimmune, serological, and oncological findings; treatments; and outcomes between January 1984 and December 2008. RESULTS The median follow-up duration was 5 years (range, 0-23 years). Seventy-nine patients (59 having classic SMS, 19 having partial SMS, and 1 having progressive encephalomyelitis with rigidity and myoclonus [PERM]) were GAD65 antibody seropositive. Sixty-seven percent (53 of 79) of them had at least 1 coexisting autoimmune disease, and 4% (3 of 79) had cancer. GAD65 antibody values at initial evaluation were significantly higher among patients with classic SMS (median value, 623 nmol/L) than among patients with partial SMS (median value, 163 nmol/L) (P < .001). The initial GAD65 antibody value was positively correlated with the last follow-up Rankin score (P = .03). Among 20 patients who were GAD65 antibody seronegative (6 with classic SMS, 12 with partial SMS, and 2 with PERM), 15% (3 of 20) had at least 1 coexisting autoimmune disease, and 25% (5 of 20) had cancer (3 with amphiphysin autoimmunity and breast carcinoma and 2 with Hodgkin lymphoma). Excluding patients with PERM, all patients but 1 had sustained improvements with at least 1 γ-aminobutyric acid agent, usually diazepam; the median dosage for patients with classic SMS was 40.0 mg/d. Additional improvements occurred among 14 of 34 patients (41%) who received immunotherapy (intravenous immune globulin, azathioprine, prednisone, mycophenolate mofetil, or cyclophosphamide). Sixteen of 25 patients (64%) with extended follow-up duration remained ambulatory. CONCLUSIONS Recognition of classic SMS vs variants is important because appropriate therapy improves symptoms in most patients. Classification by anatomical extent and by GAD65 antibody serostatus gives important diagnostic and prognostic information.

OBJECTIVE To investigate the full extent of Purkinje cell cytoplasmic autoantibody type 1 autoimmunity (classically associated with paraneoplastic cerebellar degeneration) from clinical, immunohistochemical, and neuropathological perspectives. DESIGN Case series. SETTING Mayo Clinics, 3 sites (Minnesota, Arizona, and Florida). PATIENTS Of 133 138 patients tested over a 21-year period, 83 (0.06%) were identified as seropositive for Purkinje cell cytoplasmic autoantibody type 1 IgG. MAIN OUTCOME MEASURES The frequency of cerebellar and noncerebellar disorders and the clinical outcomes (neurological and oncological) of the patients. RESULTS All patients were women. At initial presentation, 64 patients (77%) had a cerebellar disorder, and 19 patients (23%) had an extracerebellar disorder. Over the clinical course, neurological symptoms and signs were multifocal in 50 patients (60%), and they involved the cerebellum (89% of patients), the pyramidal tract (30%), the brainstem (13%), and the spinal anterior horn cells or peripheral nerve (10%; frequently upper limb predominant); 11% of patients did not develop cerebellar ataxia. Serological and neuropathological findings were observed in the cerebellum, the brainstem, the spinal cord, the anterior horn, and the dorsal root ganglion that paralleled the diversity of clinical signs. After a median follow-up of 18 months, 1 or more carcinomas had been detected in 88% of patients: ovarian epithelial cancer (53%), breast cancer (22%), fallopian tubal cancer (11%), primary peritoneal cancer (5%), metastases of unknown primary cancer (4%), and other cancers (4%). Sustained improvement was reported in 15% of patients following oncological or immunological therapies. Voltage-gated calcium channel antibodies coexisted in 23 patients (28%). CONCLUSIONS Purkinje cell cytoplasmic autoantibody type 1 autoimmunity most commonly affects the cerebellum, but the spectrum of neurological symptoms and presentations is broad. Neurological outcomes are usually poor, even when cancer remission is achieved.

OBJECTIVES To report the clinical, laboratory, and radiographic features and the response to plasmapheresis in a patient with encephalopathy, opsoclonus, and myoclonus whose cerebrospinal fluid was positive for N-methyl-D-aspartate receptor–IgG. DESIGN Case report. SETTING St Marys Hospital, Rochester, Minnesota. PATIENT A 27-year-old woman with a history of episodic migraine developed subacute progressive myoclonus, opsoclonus, and encephalopathy. RESULTS Magnetic resonance imaging demonstrated nodular leptomeningeal enhancement in the superior cerebellar folia and subsequent T2 hyperintensities in the periventricular regions and amygdala. A positron emission tomographic scan of the head demonstrated predominantly frontotemporoparietal cortical hypometabolism with sparing of the primary sensory and motor cortices. Cerebrospinal fluid examination revealed a lymphocytic pleocytosis, mildly elevated protein level, elevated IgG index, and positive oligoclonal banding. Autoimmune cerebrospinal fluid screening revealed a neural-specific IgG that bound to synapse-rich regions of mouse hippocampus and cerebellar granular layer; the neural-specific IgG was confirmed to be N-methyl-D-aspartate receptor specific. No neoplasm was detected by physical examination or by whole-body computed tomography and positron emission tomography. A 5-day course of high-dose intravenous methylprednisolone sodium succinate yielded limited improvement, and the patient subsequently required intensive care unit admission following a pulseless electrical activity arrest associated with pulmonary embolism. The encephalopathy improved dramatically after plasmapheresis. CONCLUSIONS This case highlights opsoclonus and myoclonus as manifestations of autoimmune N-methyl-D-aspartate receptor encephalitis in the setting of a novel appearance on positron emission tomography, and it shows a remarkable clinical response to plasmapheresis.

The differential diagnosis of inflammatory myelopathies is broad. Autoimmune myelopathies represent a heterogeneous but significant portion of inflammatory myelopathies. The discovery of serologic biomarkers of autoimmune myelopathies (including aquaporin-4 and collapsin response-mediator protein-5 CRMP-5 immunoglobulin IgGs) supports the concept of an autoimmune attack targeting the spinal cord. Neuroimaging, in particular MRI, may reveal distinctive patterns of signal abnormality suggesting an autoimmune etiology, such as longitudinally extensive transverse myelitis in neuromyelitis optica spectrum disorders or tract-specific changes in paraneoplastic disorders. IgG biomarkers of autoimmune myelopathies enable more precise disease classification and have the potential to direct a cancer search, predict outcome, guide therapeutic decision making, and lead to future development of antigen-specific targeted therapies. The goal of initial immunotherapy is to reverse or halt progression. Long-term immunotherapy aims to maintain remission and prevent relapse.

BACKGROUND Plasma exchange (PLEX) is a beneficial rescue therapy for acute, steroid-refractory central nervous system inflammatory demyelinating disease (CNS-IDD). Despite the approximately 45% PLEX response rate reported among patients with CNS-IDD, determinants of interindividual differences in PLEX response are not well characterized. OBJECTIVE To perform an exploratory analysis of clinical, radiographic, and serological features associated with beneficial PLEX response. DESIGN Historical cohort study. SETTING Neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota. PATIENTS All Mayo Clinic patients treated with PLEX between January 5, 1999, and November 12, 2007, for a steroid-refractory CNS-IDD attack. MAIN OUTCOME MEASURE The PLEX response in attack-related, targeted neurological deficit(s) assessed within the 6-month period following PLEX. RESULTS We identified 153 patients treated with PLEX for a steroid-refractory CNS-IDD, of whom 90 (59%) exhibited moderate to marked functional neurological improvement within 6 months following treatment. Pre-PLEX clinical features associated with a beneficial PLEX response were shorter disease duration (P = .02) and preserved deep tendon reflexes (P = .001); post-PLEX variables included a diagnosis of relapsing-remitting multiple sclerosis (P = .008) and a lower Expanded Disability Status Scale score (P < .001) at last follow-up. Plasma exchange was less effective for patients with multiple sclerosis who subsequently developed a progressive disease course (P = .046). Radiographic features associated with a beneficial PLEX response were presence of ring-enhancing lesions (odds ratio = 4.00; P = .03) and/or mass effect (odds ratio = 3.00; P = .02). No association was found between neuromyelitis optica–IgG serostatus and PLEX response. CONCLUSIONS We have identified clinical and radiographic features that may aid in identifying patients with fulminant, steroid-refractory CNS-IDD attacks who are more likely to respond to PLEX.

OBJECTIVE To identify the spectrum of sleep disorders associated with autoantibodies reactive with voltage-gated potassium channel (VGKC) complexes. DESIGN Case series of all patients with neurologic disorders of VGKC autoimmunity evaluated in the Mayo Clinic Center for Sleep Medicine (Rochester, Minnesota) between January 1, 1994, and February 1, 2010. SETTING Academic referral center. PATIENTS Fifteen consecutive patients were identified with limbic encephalitis (n = 5), Morvan syndrome (n = 4), and overlapping features (n = 6). INTERVENTION Ten patients received immunotherapy (corticosteroids, cyclophosphamide, or mycophenolate mofetil). MAIN OUTCOME MEASURE Response to immunotherapy. RESULTS The median VGKC autoantibody value at presentation was 1.51 nmol/L (range, 0.09-4.86 nmol/L). Neoplasms were discovered in 5 patients (33%) (thymoma [n = 2], prostate adenocarcinoma, colon adenocarcinoma, and melanoma). In 14 patients (93%), serious sleep disturbances were identified (insomnia, dream enactment behavior, suspected nocturnal epilepsy, and hypersomnia). Severe insomnia occurred in 9 patients (60%), regardless of neurologic presentation. Polysomnography at presentation (7 patients) revealed a mean sleep efficiency of 19% (4 patients had complete absence of sleep). Dream enactment behavior occurred in 8 patients (53%), including 3 of 5 with limbic encephalitis and all 4 with Morvan syndrome. Two of 7 polysomnograms demonstrated loss of rapid eye movement sleep muscle atonia; absent or minimal rapid eye movement sleep precluded interpretation in 4 patients. Sleep disorders resolved completely or almost completely in 8 of 10 patients who received immunotherapy. CONCLUSIONS Sleep disorders are cardinal manifestations of VGKC complex autoimmunity in association with a spectrum of neurologic presentations. They may respond favorably to immunotherapy.Arch Neurol. 2011;68(6):733-738--

Video electroencephalography (vEEG) has proven to be a valuable tool in the differentiation of pseudoseizures or psychogenic non-epileptic seizures (PNES) from epileptic seizures. Clinicians should, however, be aware of a number of conditions that may be misdiagnosed as pseudoseizures.

BACKGROUND Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma. OBJECTIVE To describe clinically (with a video) ANNA-2–associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes. DESIGN Retrospective case series with prospective clinical follow-up. SETTING Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota. PATIENTS Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990. MAIN OUTCOME METHODS Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed. RESULTS Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8+ T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset. CONCLUSIONS Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8+ T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization.Arch Neurol. 2010;67(9):1109-1115--

The diagnosis of an autoimmune dementia requires the detection of objective improvements in cognitive decline (usually subacute in onset with a fluctuating course) after a course of immunotherapy. Serum and CSF antibody markers of autoimmunity (particularly those with neural antigen specificity) as well as other CSF markers of inflammation increase the suspicion for an autoimmune cause. The detection of neural autoantibodies should raise concern for a paraneoplastic etiology and may inform a targeted oncologic evaluation (eg, NMDA receptor antibodies are associated with teratoma). MRI, EEG, functional imaging, and neuropsychological evaluations provide objective evidence of neurologic dysfunction by which the success of immunotherapy may be measured. Most treatment information emanates from retrospective case series and expert opinion. Nonetheless, early intervention allows reversal of deficits in many patients. Chronic treatment is often required to maintain remission.

OBJECTIVE To evaluate the cancer detection rate of whole-body positron emission tomography–computed tomography (PET-CT) in a paraneoplastic neurologic context. DESIGN Retrospective medical record review. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS Fifty-six consecutive patients with clinically suspected paraneoplastic neurologic disorders who underwent PET-CT after negative standard evaluations, including CT. MAIN OUTCOME MEASURE Rate of cancer detection. RESULTS Abnormalities suggestive of cancer were detected using PET-CT in 22 patients (39%); 10 patients (18%) had cancer confirmed histologically. Cancers detected (limited stage in 9 of 10 patients and extratruncal in 4) were as follows: 2 thyroid papillary cell carcinomas, 3 solitary lymph nodes with unknown primary (2 adenocarcinomas and 1 small cell carcinoma), 1 tonsil squamous cell carcinoma, 3 lung carcinomas (1 adenocarcinoma, 1 small cell, and 1 squamous cell), and 1 colon adenocarcinoma. Detection of a well-characterized neuronal nuclear or cytoplasmic paraneoplastic autoantibody was associated with a successful PET-CT–directed cancer search (P < .001). Detection of limited-stage cancer facilitated early initiation of oncologic treatments and immunotherapy; cancer remission was reported in 7 patients, and sustained improvements in neurologic symptoms were reported in 5 (median follow-up, 11 months; range, 2-48 months). Combined data from 2 previous studies using conventional PET alone (123 patients) revealed that 28% of patients had a PET abnormality suggestive of cancer and that 12% had a cancer diagnosis. CONCLUSION In a paraneoplastic neurologic context, PET-CT improves the detection of cancers when other screening test results are negative, particularly in the setting of seropositivity for a neuronal nuclear or cytoplasmic autoantibody marker of cancer.Published online January 11, 2010 (doi:10.1001/archneurol.2009.336).Arch Neurol. 2010;67(3):322-329--

BACKGROUND Recent reports support a pathogenic role in neuromyelitis optica (NMO) for the aquaporin-4 (AQP4)–specific autoantibody (NMO-IgG). Neuromyelitis optica is an inflammatory demyelinating central nervous system disease, usually relapsing, that causes variable degrees of attack-related disability. The NMO-IgG binds in vitro to the extracellular domain of AQP4, activates complement, and causes astrocyte lesioning. OBJECTIVE To compare the prognostic utility of NMO-IgG titer and quantitative measures of complement-mediated injury to AQP4-expressing cells in NMO attacks. DESIGN, SETTING, AND PARTICIPANTS A retrospective clinical-serological correlative study at Mayo Clinic's Neuroimmunology Laboratory was undertaken. Over an 18-month period, we identified NMO-IgG–seropositive patients in whom sufficient serum and adequate clinical information pertaining to NMO attacks (6 severe, 6 mild) were available to analyze clinical-serological correlations. Sera from 9 patients with multiple sclerosis and 9 healthy subjects (all NMO-IgG seronegative) served as controls. Complement activation was measured by quantifying the number of green fluorescent protein–AQP4–transfected HEK 293 cells permeable to the viability dye propidium iodide after exposure to patient serum and active complement. MAIN OUTCOME MEASURES Attack severity (mild or severe), percentage of AQP4-transfected cells lesioned, and NMO-IgG titer. RESULTS The median percentage of AQP4-transfected cells lesioned by complement in the presence of serum from patients with NMO was 14% for patients with mild attacks and 54% for patients with severe attacks (P = .005). Median complement activation values for sera from healthy subjects and patients with multiple sclerosis were 8% and 12%, respectively. Patients with mild NMO attacks and patients with severe NMO attacks did not differ significantly with respect to NMO-IgG titer (P = .089). CONCLUSIONS A laboratory measure of complement-mediated cell injury may serve as a prognostic biomarker in NMO. Larger prospective studies are required to validate this observation.Arch Neurol. 2009;66(9):1164-1167--

OBJECTIVE To compare the sensitivity and specificity of immunofluorescence (IF) and immunoprecipitation (IP) assays using green fluorescent protein–tagged aquaporin-4 (AQP4) in 6335 patients for whom serological evaluation was requested on a service basis. DESIGN Case-control study. SETTING Mayo Clinic Neuroimmunology Laboratory (Rochester, Minnesota) and Departments of Neurology (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida). PATIENTS Group 1, 835 Mayo Clinic patients, 100 with a neuromyelitis optica (NMO) spectrum disorder diagnosis and 735 without NMO spectrum disorder; group 2, 5500 non–Mayo Clinic patients. MAIN OUTCOME MEASURE Sensitivity and specificity of each assay for NMO or NMO spectrum disorder, individually and combined. RESULTS In group 1, the sensitivity rates for NMO were IF, 58%; IP, 33%; and combined assays, 63%. The sensitivity rates for relapsing longitudinally extensive transverse myelitis were IF, 29%; IP, 6%; and combined assays, 29%. The specificity rates for NMO and relapsing longitudinally extensive transverse myelitis were IF, 99.6%; IP, 99.3%; and combined assays, 99.2%. In group 2, NMO-IgG was detected by IF in 498 of 5500 patients (9.1%) and by IP in 331 patients (6.0%); 76 of the 331 patients seropositive by IP (23%) were negative by IF. Clinical information was available for 124 patients (including 16 of those seropositive by IP only); 123 had a definite NMO spectrum disorder and 1 was at risk for NMO (monophasic optic neuritis). CONCLUSIONS In this large, clinical practice-based study, NMO-IgG detected by IF or IP was highly specific for NMO spectrum disorders. The IP assay was significantly less sensitive than IF. Combined testing improved sensitivity by 5%.Arch Neurol. 2009;66(9):1134-1138--

OBJECTIVE To describe the clinical utility of the nicotinic ganglionic acetylcholine receptor (α3-AChR) autoantibody as a marker of neurological autoimmunity and cancer. DESIGN Case-control study. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS A total of 15 000 patients seen at Mayo Clinic (2005-2007) and evaluated on a service basis for paraneoplastic neurological autoimmunity for whom clinical information was obtained retrospectively by medical record review as well as 457 neurologically asymptomatic patients or control subjects of whom 173 were healthy, 245 had lung cancer, and 39 had systemic lupus erythematosus or Sjögren syndrome. OUTCOME MEASURES Neurological, oncological, and serological associations of α3-AChR autoantibody seropositivity. RESULTS Of 15 000 patients tested on a service basis, 1% were seropositive (median, 0.12 nmol/L; range, 0.03-18.8 nmol/L; normal, ≤0.02 nmol/L), 55% were male, and the median age was 65 years. Cancer was found (new or by history) in 24 of 78 patients evaluated for cancer while at Mayo Clinic (30%); 43% had adenocarcinoma (more patients had breast cancer than prostate, lung, and gastrointestinal cancers; each of the latter groups had about the same number of patients). Of 12 patients with high antibody values (≥1.00 nmol/L), 83% had pandysautonomia. Of 85 patients with medium antibody values (0.10-0.99 nmol/L), neurological presentations were more diverse and included peripheral neuropathies (36%), dysautonomia (20%, usually limited), and encephalopathy (13%). Of 58 patients with low antibody values (0.03-0.09 nmol/L), 54% had a nonautoimmune neurological disorder or no neurological disorder. Of 245 control patients with lung cancer, 7.8% were seropositive. Only 1 of 212 control patients without cancer (0.5%) was seropositive (P < .001). CONCLUSION The detection of α3-AChR autoantibody aids the diagnosis of neurological autoimmunity and cancer. Arch Neurol. 2009;66(6):735-741--

OBJECTIVE To describe reversible extralimbic paraneoplastic encephalopathies with large, lobar lesions on magnetic resonance imaging (MRI). DESIGN Case series. SETTING Autoimmune Neurology Clinic, Mayo Clinic, Rochester, Minnesota. RESULTS Three patients had large confluent areas of signal abnormality on T2-weighted MRI, including frontal in 2 and frontal and occipital in 1. Patient 1, a woman aged 63 years, experienced hemiparesis with hemianopia 3 years after a diagnosis of adenocarcinoma of the breast. Nine years later, rapidly progressive dementia developed. Patient 2, a woman aged 79 years, presented with monoparesis and epilepsia partialis continua, 1 year after a diagnosis of adenocarcinoma of the breast. Patient 3, a man aged 65 years, had paraneoplastic sensory neuronopathy, limbic encephalitis, antineuronal nuclear autoantibody type 1 (ANNA-1), and squamous cell carcinoma of the lung. He was stable for 3 years after treatment. Subacute onset of aphasia, delirium, worsening seizures, and rising ANNA-1 titers led to a diagnosis of recurrent limited carcinoma. Brain MRI abnormalities in all patients improved dramatically after immunotherapy. Two patients had sustained clinical remission. CONCLUSION Recognition of paraneoplastic extralimbic lobar encephalopathies is important because these disorders and their underlying cancers are treatable.Arch Neurol. 2009;66(2):268-271--

BACKGROUND Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody–associated encephalopathy. OBJECTIVE To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity. DESIGN Observational, prospective case series. SETTING Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. PATIENTS A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review. MAIN OUTCOME MEASURES Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy. RESULTS All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients' conditions (92%) improved after immunomodulatory therapy. CONCLUSIONS Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody–associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases.Arch Neurol. 2008;65(10):1341-1346--

BACKGROUND The neuromyelitis optica IgG autoantibody (NMO-IgG) is a validated biomarker for NMO and an emerging spectrum of inflammatory central nervous system–demyelinating disorders. Its antigen is the astrocytic water channel aquaporin-4; NMO-IgG has not been described in a cancer context. OBJECTIVES To report (1) neurologic and oncologic correlates for patients incidentally identified as NMO-IgG seropositive in a blinded evaluation for paraneoplastic autoantibodies and (2) the frequency of cancer in NMO-IgG–seropositive patients. DESIGN Observational, retrospective case series. SETTING Neuroimmunology Laboratory and Neurology Clinical Practice, Mayo Clinic College of Medicine. PATIENTS AND METHODS From 1998 to 2007, we detected NMO-IgG in 2 patient groups: (1) 31 patients (88% female) identified incidentally among 180 000 patients evaluated for paraneoplastic autoantibodies and (2) 141 patients identified through physician-requested serological evaluation for a suspected NMO-spectrum disorder. RESULTS In the first group, clinical information was available for 28 patients (90%). An NMO-spectrum disorder was diagnosed in 26 patients (93%), of whom 6 had a neoplasm (5 carcinomas [2 breast, 1 lung, 1 thymic, and 1 uterine cervical] and 1 B-cell lymphoma) and 1 had monoclonal gammopathy. In 4 patients, NMO-related symptoms followed neoplasia detection (median, 14 [range 3-18] months), and in 2 patients, symptoms preceded neoplasia detection (by 5 and 3 months). Two patients had carcinoma (1 breast and 1 lung) without neurological evidence of an NMO-spectrum disorder. In the second group, neoplasms were recorded in 7 seropositive patients (5.0%) with a clinically diagnosed NMO-spectrum disorder: 3 carcinomas (all breast), 1 thyroid Hürthle cell, 1 carcinoid, 1 pituitary somatotropinoma, and 1 B-cell lymphoma. An eighth patient had monoclonal gammopathy. CONCLUSIONS Aquaporin-4–specific IgG in some cases of NMO may reflect a paraneoplastic immune response. The clinical utility of this autoantibody as a cancer marker warrants prospective investigation.Arch Neurol. 2008;65(5):629-632--

BACKGROUND Neuromyelitis optica (NMO) is often associated with other clinical or serological markers of non–organ-specific autoimmunity. OBJECTIVE To evaluate the relationship between NMO spectrum disorders (NMOSDs), including NMO, longitudinally extensive transverse myelitis, and recurrent optic neuritis, and autoimmune disease. We concentrated on the association with systemic lupus erythematosus (SLE), Sjögren syndrome (SS), or serological evidence of these disorders, which commonly is a source of diagnostic confusion. DESIGN Retrospective blinded serological survey. SETTING Mayo Clinic College of Medicine, Rochester, and Centre Hospitalier Régional Universitaire de Lille. METHODS Group 1 included 153 US patients with NMOSDs (78 with NMO and 75 with longitudinally extensive transverse myelitis) and 33 control subjects with SS/SLE. Group 2 included 30 French patients with SS/SLE, 14 with NMOSDs (6 with NMO, 6 with longitudinally extensive transverse myelitis, and 2 with recurrent optic neuritis), 16 without NMOSDs, and 4 with NMO without SS/SLE. RESULTS For group 1, NMO-IgG was detected in 66.7%, antinuclear antibodies in 43.8%, and Sjögren syndrome A (SSA) antibodies in 15.7% of patients with NMO and longitudinally extensive transverse myelitis. Five NMO-IgG–seropositive patients with NMOSDs had coexisting SLE, SS, or both. Antinuclear antibodies and SSA antibodies were more frequent in NMO-IgG–seropositive patients than in NMO-IgG–seronegative patients (P = .001). For group 2, NMO-IgG was detected in 5 of 14 patients (35.7%) with NMOSDs and SS/SLE and in 2 of 4 patients (50.0%) with NMO without SS/SLE (P = .59). We detected NMO-IgG only in patients with NMOSDs and not in 49 controls with SS/SLE but without optic neuritis or myelitis from the 2 cohorts (P = .01). CONCLUSION Neuromyelitis optica spectrum disorders with seropositive findings for NMO-IgG occurring with SS/SLE or non–organ-specific autoantibodies is an indication of coexisting NMO rather than a vasculopathic or other complication of SS/SLE.Arch Neurol. 2008;65(1):78-83--

BACKGROUND Acquired generalized repetitive myoclonus may be mistaken for tremor. Distinguishing myoclonus has etiologic and therapeutic implications. OBJECTIVE To describe isolated generalized polymyoclonus and the outcomes of etiologic evaluations at the time of diagnosis. DESIGN Computer search of the Mayo Movement Neurophysiology Laboratory database and medical records linkage system. SETTING Department of Neurology, Mayo Clinic. PATIENTS Nineteen adults with generalized repetitive myoclonus confirmed using surface electromyography (burst duration <50 milliseconds), and other neurologic features minimal or absent. INTERVENTIONS Treatment of myoclonus and underlying causes. MAIN OUTCOME MEASURES Clinical presentation and underlying etiologies. RESULTS We identified 19 patients with isolated generalized polymyoclonus resembling whole-body tremor. Onset was most often subacute (12 patients), mean symptom duration was 1.8 years, and mean age at onset was 55 years. Referral diagnoses or patient complaints were tremor, tremulousness, or shaking in all but 5 patients. All the patients had repetitive myoclonus of all limbs, impairing gait in 14 patients. Surface electromyography confirmed nonperiodic muscle burst durations of less than 50 milliseconds, typical of myoclonus. Clinical and serologic screening for cancer and autoimmunity revealed metastatic breast cancer in 2 patients (1 positive for ganglionic acetylcholine receptor antibody) and antibody profiles implicating neurologic autoimmunity in 3 patients (CRMP-5 IgG or neuronal voltage-gated potassium channel antibodies). Medications known to occasionally trigger myoclonus (opioids, selective serotonin reuptake inhibitors, and a serotonin-norepinephrine reuptake inhibitor) were being taken by 7 patients. Myoclonus resolved after discontinuation of selective serotonin reuptake inhibitor therapy in 1 patient; drug discontinuation was declined and follow-up was inadequate in the other 6. CONCLUSIONS Isolated whole-body tremulousness should raise the suspicion of generalized polymyoclonus, confirmed using routine surface electromyography. Recognition is important because the differential diagnosis includes autoimmunity and drug-induced myoclonus.Arch Neurol. 2007;64(9):1318-1322 --

BACKGROUND Neuromyelitis optica (NMO)–IgG is a specific autoantibody marker for NMO. It binds selectively to aquaporin 4 (AQP4), which is highly concentrated in astrocytic foot processes at the blood-brain barrier and is not restricted to optic nerve and spinal cord. Although it is conventionally believed that the brain is spared, brain imaging abnormalities are not uncommon in patients with NMO. OBJECTIVE To investigate the location of brain lesions that are distinctive for NMO with respect to the localization of AQP4 in mammalian brain. DESIGN Observational, retrospective case series. SETTING Clinical serologic cohort of patients tested for NMO-IgG for whom brain MRI images were available. PATIENTS We identified 120 patients seropositive for NMO-IgG for whom brain magnetic resonance images were available. MAIN OUTCOME MEASURE Magnetic resonance imaging abnormalities. RESULTS In 8 patients we observed recurring and distinctive magnetic resonance imaging abnormalities in the hypothalamic and periventricular areas that corresponded to brain regions of high AQP4 expression. CONCLUSION The distribution of NMO-characteristic brain lesions corresponds to sites of high AQP4 expression.Arch Neurol. 2006;63:964-968 --