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Summary: Background: Complement activation after binding of an IgG autoantibody to aquaporin 4 (AQP4) is thought to be a major determinant of CNS inflammation and astrocytic injury in neuromyelitis optica. The aim of this study was to investigate the use of eculizumab—a therapeutic monoclonal IgG that neutralises the complement protein C5—in neuromyelitis optica spectrum disorders. Methods: Between Oct 20, 2009, and Nov 3, 2010, we recruited patients from two US centres into an open-label trial. Patients were AQP4-IgG-seropositive, aged at least 18 years, had a neuromyelitis optica spectrum disorder, and had at least two attacks in the preceding 6 months or three in the previous 12 months. Patients received meningococcal vaccine at a screening visit and 2 weeks later began eculizumab treatment. They received 600 mg intravenous eculizumab weekly for 4 weeks, 900 mg in the fifth week, and then 900 mg every 2 weeks for 48 weeks. The coprimary endpoints were efficacy (measured by number of attacks [new worsening of neurological function lasting for more than 24 h and not attributable to an identifiable cause]) and safety. Secondary endpoints were disability (measured by expanded disability status scale), ambulation (Hauser score), and visual acuity. At follow-up visits (after 6 weeks and 3, 6, 9, and 12 months of treatment; and 3 and 12 months after discontinuation), complete neurological examination was undertaken and an adverse event questionnaire completed. This trial is registered with ClinicalTrials.gov, number NCT00904826. Findings: We enrolled 14 patients, all of whom were women. After 12 months of eculizumab treatment, 12 patients were relapse free; two had had possible attacks. The median number of attacks per year fell from three before treatment (range two to four) to zero (zero to one) during treatment (p<0·0001). No patient had worsened disability by any outcome measure. Median score on the expanded disability status scale improved from 4·3 (range 1·0–8·0) before treatment to 3·5 (0–8·0) during treatment (p=0·0078). Two patients improved by two points and three improved by one point on the Hauser score; no change was recorded for the other patients. Visual acuity had improved in at least one eye by one point in four patients, and by two points in one patient; no change was recorded for other patients. One patient had meningococcal sepsis and sterile meningitis about 2 months after the first eculizumab infusion, but resumed treatment after full recovery. No other drug-related serious adverse events occurred. Eight attacks in five patients were reported within 12 months of eculizumab withdrawal. Interpretation: Eculizumab seems to be well tolerated, significantly reduce attack frequency, and stabilise or improve neurological disability measures in patients with aggressive neuromyelitis optica spectrum disorders. The apparent effects of eculizumab deserve further investigation in larger, randomised controlled studies. Funding: Alexion Pharmaceuticals. [Copyright &y& Elsevier]

Background & Aims: Antibodies against the water channel protein aquaporin (AQP)-4 cause a spectrum of inflammatory, demyelinating, central nervous system disorders called neuromyelitis optica spectrum disorders (NMOSDs); these primarily affect the optic nerves and spinal cord but also the brain. Symptoms of intractable nausea, vomiting, and hiccups reflect involvement of AQP4 in the brainstem area postrema and account for gastroenterological presentations. We investigated the frequency of intractable nausea, vomiting, or hiccups in patients with NMOSD who tested positive for immunoglobulin G against AQP4 (AQP4-IgG). We also analyzed sera from patients with idiopathic nausea or vomiting for the presence of AQP4-IgG. Methods: We reviewed the Mayo Clinic AQP4-IgG positive NMOSD database (n = 70) to identify patients who presented with vomiting, focusing on results from gastroenterological evaluations. We also tested serum samples (from the Gastroparesis Clinical Research Consortium repository) from patients who presented with idiopathic nausea or vomiting for AQP4-IgG (controls, n = 318 with gastroparesis and 117 without gastroparesis). Results: Ten AQP4-IgG–positive patients diagnosed with NMOSD (14% of patients in the database) initially presented with intractable vomiting. Extensive gastroenterological evaluation was noninformative. AQP4-IgG was not detected in any of the controls. Conclusions: Although NMOSDs are rare, tests for AQP4-IgG should be considered for patients who present with unexplained, intractable vomiting. Detection of the antibody before the development of optic neuritis or transverse myelitis allows patients to receive immunosuppressive therapy before the development of neurologic disabilities. [ABSTRACT FROM AUTHOR]

Summary: Background: Between November, 2006, and May, 2008, a subacute neurological syndrome affected workers from two swine abattoirs in Minnesota and Indiana who had occupational exposure to aerosolised porcine brain. We aimed to describe the pathogenic and immunological characteristics of this illness. Methods: All patients from two abattoirs who presented or were referred to the Mayo Clinic (Rochester, MN, USA) with neurological symptoms were included. We recorded details of exposure to aerosolised brain tissue and did comprehensive neurological, laboratory, neuroimaging, electrophysiological, pathological, and autoimmune serological assessments. Healthy controls were recruited from the community and from workers at the plant in Minnesota. Findings: 24 patients were identified (21 from Minnesota, three from Indiana). The shortest duration from first exposure to symptom onset was 4 weeks. No infectious agent that could trigger disease was identified. All patients developed polyradiculoneuropathy, which was usually sensory predominant and painful. Two patients had initial CNS manifestations: transverse myelitis and meningoencephalitis. Nerve conduction studies localised abnormalities to the most proximal and distal nerve segments. Quantitative sensory and autonomic testing revealed involvement of large and small sensory fibres and sweat fibres. MRI showed prominent abnormalities of roots and ganglia. Nerve biopsies identified mild demyelination, axonal degeneration, and perivascular inflammation. Protein concentrations were high in the CSF of 18 (86%) of 21 patients. Sera from all patients and 29 (34%) of 85 unaffected workplace controls (but none of 178 community controls) had a distinctive neural-reactive IgG; 75% of patients'' sera contained an IgG specific to myelin basic protein. Seropositivity correlated directly with exposure risk in patients and controls. 17 patients required immunomodulatory therapies, six improved spontaneously, and one was lost to follow-up after exposure stopped. Interpretation: The neurological disorder described is autoimmune in origin and is related to occupational exposure to multiple aerosolised porcine brain tissue antigens. The pattern of nerve involvement suggests vulnerability of nerve roots and terminals where the blood–nerve barrier is most permeable. Funding: Mayo Clinic Foundation; Minnesota Department of Health; Centers for Disease Control and Prevention. [Copyright &y& Elsevier]

Background & Aims: Autoimmune gastrointestinal dysmotility is a limited autoimmune dysautonomia occurring idiopathically or in the context of an anatomically remote neoplasm, previously documented or unsuspected. Here we report 24 Mayo Clinic patients in whom the profile of serum autoantibodies aided this diagnosis. Methods: All patients were ascertained serologically in the course of service evaluation for autoantibodies consistent with neurologic autoimmunity. Review of their histories, motility studies, and laboratory findings revealed that all had presented with subacute gastrointestinal dysmotility. Results: Recorded motility abnormalities included esophageal dysmotility 8 (6 had achalasia), delayed gastric emptying 12, slow small intestinal transit 7, slow colonic transit 4, and pelvic floor dyssynergia 4. Four patients underwent abdominal surgery; 2 commenced total parenteral nutrition. Plasma membrane cation channel autoantibodies were detected in 23 patients: neuronal voltage-gated calcium channel (5 N-type and 1 P/Q-type), acetylcholine receptor (11 ganglionic-type and 4 muscle-type), and neuronal voltage-gated potassium channel autoantibodies (4). Two patients had antineuronal nuclear autoantibodies, type 1. Approximately half of the patients had neural autoantibodies (including skeletal muscle striational and glutamic acid decarboxylase, 65kd isoform) or other antibody markers of organ-specific autoimmunity (thyroid or gastric parietal cell specificities). Neoplasia was diagnosed in 11 patients (9 recent, 2 remote): lung, breast and endometrial, gastrointestinal and thymoma. Moderate to dramatic improvement in gastrointestinal symptoms was reported after immunotherapy in 4 of 4 patients treated and after pyridostigmine treatment in 2 of 2 patients treated. Conclusions: Autoimmune serology aids the diagnosis of autoimmune gastrointestinal dysmotility, both paraneoplastic and idiopathic, and might guide management. [Copyright &y& Elsevier]

Summary: Neuromyelitis optica (also known as Devic''s disease) is an idiopathic, severe, demyelinating disease of the central nervous system that preferentially affects the optic nerve and spinal cord. Neuromyelitis optica has a worldwide distribution, poor prognosis, and has long been thought of as a variant of multiple sclerosis; however, clinical, laboratory, immunological, and pathological characteristics that distinguish it from multiple sclerosis are now recognised. The presence of a highly specific serum autoantibody marker (NMO-IgG) further differentiates neuromyelitis optica from multiple sclerosis and has helped to define a neuromyelitis optica spectrum of disorders. NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica. The knowledge gained from further assessment of the exact role of NMO-IgG in the pathogenesis of neuromyelitis optica will provide a foundation for rational therapeutic trials for this rapidly disabling disease. [Copyright &y& Elsevier]

Background & Aims: Autoimmune gastrointestinal dysmotility (AGID) is a limited form of autoimmune autonomic neuropathy occurring idiopathically or in a paraneoplastic context. This disorder is considered rare, but is underrecognized as a cause for GI dysmotilities of varying anatomic extent, severity, and duration. We describe the diagnosis and management of an instructive case. Methods: A 60-year-old (nondiabetic) woman presented with a 15-year history of severe isolated gastroparesis. Paraneoplastic autoantibody evaluation aided the diagnosis of AGID. This included indirect immunofluorescence (neuronal nuclear and cytoplasmic antibodies), radioimmunoprecipitation assays (neuronal and muscle plasma membrane cation channel antibodies), and enzyme-linked immunosorbent assay (muscle striational antibodies). Results: Serologic testing revealed both ganglionic neuronal acetylcholine receptor and N-type voltage-gated calcium channel autoantibodies. This profile was consistent with AGID and, despite the long history, raised the possibility of lung, breast, or ovarian carcinoma or thymoma. An underlying neoplasm was excluded by appropriate investigations. In a 1-month trial of oral pyridostigmine therapy, the patient’s GI symptoms improved and her weight stabilized. Pyridostigmine was continued at a low dose, and was supplemented by tegaserod. Conclusions: Autoimmune serology is a valuable adjunct to the diagnosis and guide to management of patients with AGID. The favorable response to acetylcholinesterase inhibitors, despite a 15-year history, suggests an immunopharmacologic rather than an inflammatory cytotoxic pathology. Immunomodulatory therapy may not always be required. Of numerous autoantibodies currently recognized as biomarkers of AGID, the ganglionic acetylcholine receptor autoantibody is the only proven pathophysiologic effector. Certain neuronal nuclear and cytoplasmic autoantibodies are highly predictive of an underlying malignancy. [Copyright &y& Elsevier]

OBJECTIVE: To define the diagnostic characteristics and predictors of treatment response in patients with suspected autoimmuno dementia. PATIENTS AND METHODS: Between January 1, 2002, and January 1, 2009, 72 consecutive patients received immunotherapy for suspected autoimmune dementia. Their baseline clinical, radiologic, and serologic characteristics were reviewed and compared between patients who were responsive to immunotherapy and those who were not. Patients were classified as responders if the treating physician had reported improvement after immunotherapy (documented in 80% by the Kokmen Short Test of Mental Status, neuropsychoiogical testing, or both). RESULTS: initial immunotherapeutic regimens included methylprednisoione in 56 patients (78%), prednlsone in 12 patients (17%), dexamethasone in 2 patients (3%), intravenous immune giobuiin in 1 patient (1%), and plasma exchange in I patient (1%). Forty-six patients (64%) improved, most in the first week of treatment. Thirty-five percent of these immunotherapy responders were initiality diagnosed as having a neurodegenerative or prion disorder. Pretreatment and posttreatment neuropsychological score comparisons revealed improvement in almost au cognitive domains, most notabiy learning and memory. Radiologic or eiectroencephaiographic improvements were reported in 22 (56%) of 39 patients. immunotherapy responsiveness was predicted by a subacute onset (P<.001), fluctuating course (P<.001), tremor (P=.007), shorter delay to treatment (P=.005), seropositivity for a cation channel compiex autoantibody (P=.01; neuronal voitage-gated potassium channel more than calcium channei or neuronal acetyichoilne receptor), and elevated cerebrospinal fluid protein (>100 mg/dL) or pleocytosis (P=.02). Of 26 immunotherapy-responsive patients followed up for more than 1 year, 20 (77%) relapsed after discontinuing immunotherapy. CONCLUSION: identification of clinical and seroiogic ciues to an autoimmune dementia allows early initiation of immunotherapy, and maintenance it needed, thus favoring an optimal outcome. [ABSTRACT FROM AUTHOR]

Collapsin response-mediator protein 5 (CRMP5) immunoglobulin G (IgG) has been associated with paraneoplastic optic neuritis, vitritis, retinitis, or a combination thereof, but few reports of these findings exist in the literature. We reviewed the neuro-ophthalmic findings and visual outcomes in a large series of CRMP5 IgG–positive patients to characterize further its clinical phenotype and response to treatment. Retrospective case series. Seventy-six patients with CRMP5 autoimmunity examined at the Mayo Clinic, Rochester, Minnesota. Single academic medical center chart review of all CRMP5 IgG–positive (serum titer, >1:240) patients seen between 2001 and 2017. Neuro-ophthalmic manifestations and outcomes of CRMP5 autoimmunity, coexisting neural autoantibody presence and paraneoplastic associations, and the impact of immunosuppressant therapy. Twenty-nine of 76 patients (38%) demonstrated neuro-ophthalmic manifestations. Of the 29 patients with neuro-ophthalmic findings, the median age was 67 years (range, 33–88 years) and 20 (69%) were women. Cancer was diagnosed in 62% of the patients (small-cell carcinoma in 83%). Neuro-ophthalmic symptoms occurred before the diagnosis of cancer in 72%. Seventeen of 29 patients (59%) showed ocular (i.e., anterior visual pathway or intraocular) manifestations; presenting median visual acuity was 20/50 (range, 20/20–counting fingers) and the final median visual acuity was 20/40 (range, 20/20–hand movements). Fourteen of 17 patients (82%) demonstrated optic neuropathy, with 12 of these patients also showing retinitis or uveitis. Three of 17 patients (18%) showed retinitis or uveitis without optic neuropathy. All 12 patients with optic neuropathy and a documented fundus examination at visual symptom onset demonstrated optic disc edema. No patients showed optic nerve enhancement on magnetic resonance imaging. Twelve of 29 patients (41%) demonstrated ocular motility dysfunction consisting of central nystagmus and diplopia. Among those receiving immunosuppressive therapy, visual function improved in 50%. In our cohort of 29 CRMP5 IgG–positive patients with neuro-ophthalmic manifestations, optic neuropathy presented with optic disc edema, often associated with uveitis, retinitis, or both. The combination of retinitis, vitritis, and optic disc edema without optic nerve enhancement should prompt serologic testing for CRMP5 IgG to expedite vision-sparing immunosuppressant therapy and a targeted search for a systemic cancer. [ABSTRACT FROM AUTHOR]

The Optic Neuritis Treatment Trial, a landmark study completed in 1991, stratified the risk of multiple sclerosis in patients with optic neuritis. Since that time, unique biomarkers for optic neuritis have been found. The antibody against aquaporin-4 (AQP4)-immunoglobulin G (IgG) discovered in 2004 was found to be both the pathologic cause and a reliable biomarker for neuromyelitis optica spectrum disorders. This finding enabled an expanded definition of the phenotype of neuromyelitis optica spectrum disorder and improved treatment of the disease. Subsequently, myelin oligodendrocyte glycoprotein (MOG) IgG was recognized to be a marker for MOG-IgG-associated disorder, a central demyelinating disease characterized by recurrent optic neuritis, prominent disk edema, and perineural optic nerve enhancement on magnetic resonance imaging. Most multiple sclerosis disease-modifying agents are ineffective for AQP4-IgG-positive neuromyelitis optica spectrum disorder and MOG-IgG-associated disorder. Because there are crucial differences in treatment and prognosis between multiple sclerosis, AQP4-IgG-positive neuromyelitis optica spectrum disorder, and MOG-IgG-associated disorder, ophthalmologists should be aware of these new biomarkers of optic neuritis and incorporate their testing in all patients with atypical optic neuritis. [ABSTRACT FROM AUTHOR]

Abstract Recognition of autoimmunity as a cause of encephalopathy has increased. Recent studies have validated the use of Antibody-Prevalence-in-Epilepsy (APE) and Responsive-to-immunotherapy-in-Epilepsy (RITE) scores in the evaluation and management of autoimmune-epilepsy. We aim to assess the utility of these models for patients with cognitive dysfunction. Among the evaluated patients, 17% had antibodies universally associated with autoimmune-encephalopathy. NMDA-R-IgG and LGI1-IgG were the most common antibody specificities. Antibody-Prevalence-in-Epilepsy-and-Encephalopathy (APE2) score ≥ 4 was 99% sensitive and 93% specific for neural-specific-antibodies. Responsive-to-immunotherapy-in-Epilepsy-and-Encephalopathy (RITE2) score ≥ 7 had 96% sensitivity and 86% specificity for favorable initial immunotherapy response. Application of these models may optimize autoantibody evaluations and immunotherapeutic trials. Graphical abstract Unlabelled Image Highlights • Neural-specific antibodies associated with autoimmune-encephalopathy were detected in 17% of the patients evaluated. • NMDA-R IgG and LGI-1 IgG were the most common neural antibody specificities detected. • APE2 score ≥4 was 99% sensitive and 93% specific for neural-specific-antibodies. • RITE2 score ≥7 had 96% sensitivity and 86% specificity for favorable response to initial immunotherapy. • RITE2 score < 7 was associated with refractoriness to initial immunotherapy even among patients with neural-specific autoantibodies. [ABSTRACT FROM AUTHOR]

Purpose To determine the aquaporin-4 and myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) serostatus and visual outcomes in patients with recurrent optic neuritis (rON) initially seeking treatment. Design Cross-sectional cohort study. Participants The study identified patients by searching the Mayo Clinic computerized central diagnostic index (January 2000–March 2017). The 246 eligible patients fulfilled the following criteria: (1) initially seeking treatment for at least 2 consecutive episodes of optic neuritis (ON) and (2) serum available for testing. Methods Serum was tested for aquaporin-4 IgG and MOG IgG1 using an in-house validated flow cytometric assay using live HEK293 cells transfected with M1 aquaporin-4 or full-length MOG. Main Outcomes Measures Aquaporin-4 IgG and MOG IgG1 serostatus, clinical characteristics, and visual outcomes. Results Among 246 patients with rON at presentation, glial autoantibodies were detected in 32% (aquaporin-4 IgG, 19%; MOG IgG1, 13%); 186 patients had rON only and 60 patients had rON with subsequent additional inflammatory demyelinating attacks (rON-plus group). The rON-only cohort comprised the following: double seronegative (idiopathic), 110 patients (59%); MOG IgG1 positive, 27 patients (15%; 4 with chronic relapsing inflammatory optic neuropathy); multiple sclerosis (MS), 25 patients (13%); and aquaporin-4 IgG positive, 24 patients (13%). The rON-plus cohort comprised the following: aquaporin-4 IgG positive, 23 patients (38%); MS, 22 patients (37%); double seronegative, 11 patients (18%); and MOG IgG1 positive, 4 patients (7%). The annualized relapse rate for the rON-only group was 1.2 for MOG IgG1−positive patients, 0.7 for double-seronegative patients, 0.6 for aquaporin-4 IgG−positive patients, and 0.4 for MS patients (P = 0.005). The median visual acuity (VA) of patients with the worst rON-only attack at nadir were hand movements in aquaporin-4 IgG−positive patients, between counting fingers and hand movements in MOG IgG1−positive patients, 20/800 in idiopathic patients, and 20/100 in MS patients (P = 0.02). The median VA at last follow-up for affected eyes of the rON-only cohort were counting fingers for aquaporin-4 IgG−positive patients, 20/40 for idiopathic patients, 20/25 for MS patients and MOG IgG1−positive patients (P = 0.006). At 5 years after ON onset, 59% of aquaporin-4 IgG−positive patients, 22% of idiopathic patients, 12% of MOG IgG1−positive patients, and 8% of MS patients were estimated to have severe visual loss. Conclusions Glial autoantibodies (MOG IgG1 or aquaporin-4 IgG) are found in one third of all patients with rON. Aquaporin-4 IgG seropositivity predicts a worse visual outcome than MOG IgG1 seropositivity, double seronegativity, or MS diagnosis. Myelin oligodendrocyte glycoprotein IgG1 is associated with a greater relapse rate but better visual outcomes. [ABSTRACT FROM AUTHOR]

In this prospective evaluation of serum and CSF samples, all but two CSF GFAPα-IgG positive patients had autoimmune meningoencephalomyelitis while serum GFAPα-IgG positivity alone was less specific. Phenotypes were diverse among patients that were serum positive only. Adult and pediatric clinical presentations were similar. Most patients were immunotherapy responsive. Co-existing NMDA-R-IgG and cancer were associated with lack of response to first-line immunotherapy. Among patients with follow-up information, 18% had relapses. This study demonstrates CSF GFAPα-IgG is a specific autoimmune meningoencephalomyelitis biomarker, with favorable corticosteroid response. Lack of response should prompt evaluation for co-existing NMDA-R-IgG or malignancy. [ABSTRACT FROM AUTHOR]

Anti-N-methyl-d-aspartate receptor antibody has been associated with a severe stereotypic form of subacute encephalitis, often found in women with ovarian teratoma. Reported here is the diagnosis of anti-N-methyl-d-aspartate receptor encephalitis in a 5-year-old girl who presented with subacute encephalopathy and movement disorder without evidence of malignancy. Early diagnosis and treatment with immune globulin and steroids resulted in near-complete recovery. [Copyright &y& Elsevier]

Background: Antibodies have been implicated in the pathogenicity of multiple sclerosis by findings of immunoglobulins in patients' CSF and often IgG and complement in lesions, and by a 2012 report that nearly half of patients' serum samples contain IgG specific for a glial potassium-channel, KIR4.1. We aimed to establish the frequency of KIR4.1-binding IgG in serum and CSF of patients with multiple sclerosis, and whether KIR4.1 immunoreactivity is retained or lost in demyelinating lesions. Methods: Using ELISA with a KIR4.1 peptide, we tested archival serum from 229 population-based and 57 clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, and CSF from 25 patients with multiple sclerosis and 22 disease controls. We tested all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1, using cell-based immunofluorescence and immunoprecipitation (solubilised recombinant human KIR4.1). We assessed KIR4.1 immunoreactivity in archival brain samples from 15 patients with histopathologically confirmed multiple sclerosis (22 plaques [eight early active, eight inactive, and six remyelinated], 13 periplaque regions and eight normal-appearing white-matter and grey-matter regions) and from three controls with non-neurological diseases. Findings: Three of 286 serum samples from patients with multiple sclerosis and two of 208 serum samples from controls showed KIR4.1 reactivity on ELISA; none of the CSF samples from patients or controls showed KIR4.1 reactivity. IgG in none of the 50 serum samples from clinic-based patients immunoprecipitated KIR4.1, but a commercial KIR4.1-specific control IgG did. By immunofluorescence, one of 50 serum samples from patients with multiple sclerosis yielded faint plasmalemmal staining on both KIR4.1-expressing and non-expressing cells; 16 bound faintly to intracellular components. In all cases, IgG binding was quenched by absorption with liver powder or lysates from non-transfected cells. Binding by the KIR4.1-specific control IgG was quenched only by lysates containing KIR4.1. IgG in none of the 25 CSF samples from patients with multiple sclerosis bound to KIR4.1-transfected cells. Glial KIR4.1 immunoreactivity was increased relative to expression in healthy control brain in all active demyelinating lesions, remyelinated lesions, and periplaque white matter regions. Interpretation: We did not detect KIR4.1-specific IgG in serum or CSF from patients with multiple sclerosis or KIR4.1 loss from glia in multiple sclerosis lesions. Serological testing for KIR4.1-specific IgG is unlikely to aid diagnosis of multiple sclerosis. The target antigen of multiple sclerosis remains elusive. Funding: The National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic Robert and Arlene Kogod Center on Aging. [ABSTRACT FROM AUTHOR]

Autoimmunity targeting voltage-gated potassium channel complexes have not been systematically documented in children. Identified in the Neuroimmunology Laboratory records of Mayo Clinic were 12 seropositive children, 7 among 252 Mayo Clinic pediatric patients tested on a service basis for serologic evidence of neurologic autoimmunity (June 2008-April 2010), 4 during the assay’s preimplementation validation (before June 2008) and 1 non-Mayo patient with available clinical information. Neurologic manifestations were subacute and multifocal. Three had global developmental regression, 6 movement disorders, 4 dysarthria, 3 seizures, 1 Satoyoshi syndrome, 1 painful red feet, 2 insomnia, 2 gastrointestinal dysmotility, and 2 small fiber neuropathy. Neoplasia was found in 1 child. Treating physicians recorded improvement in all 7 children who received immunotherapy. Neurologic symptom relapse occurred in 3 of 6 children after ceasing immunotherapy. These findings highlight a diverse clinical spectrum of neuronal potassium channel complex autoimmunity in children, and they illustrate benefit from early initiated immunotherapy, with a tendency to relapse when therapy ceases. Diagnosis is generally delayed in the process of eliminating neurodegenerative causes. Currently 2.7% of pediatric sera evaluated for neurologic autoimmunity are positive for neuronal potassium channel complex-reactive immunoglobulin G. The frequency and full spectrum of neurologic accompaniments remains to be determined. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the prevalence and pathogenetic mechanisms of postural orthostatic tachycardia syndrome (POTS).Patients and Methods: We reviewed the medical records of patients with POTS seen at the Mayo Clinic in Rochester, Minn, from January 1, 1993, through December 31, 2003. All patients were required to have had a full autonomic reflex screen. The results of the following additional tests were evaluated: thermoregulatory sweat test, plasma catecholamine measurement, serum ganglionic (a3) acetylcholine receptor antibody detection, and 24-hour urinary sodium measurement.Results: We identified 152 patients (86.8% female; mean +/- SD age, 30.2+/-10.3 years) with a mean duration of symptoms of 4.1 years. The mean orthostatic heart rate increment was 44 beats/min. Half the patients had sudomotor abnormalities (apparent on both the quantitative sudomotor axon reflex test and thermoregulatory sweat test), and 34.9% had significant adrenergic impairment, indicating that at least half of the patients had a neuropathic pattern of POTS. In 13.8% of patients, onset was subacute, and ganglionic acetylcholine receptor antibody was detected in 14.6%, suggesting an autoimmune origin in at least 1 in 7 patients. Hyperadrenergic status was documented in 29.0% of patients (standing plasma norepinephrine level 2600 pg/mL), and at least 28.9% were presumably hypovolemic (24-hour urinary sodium level <100 mEq/24h). The lack of correlation between urinary sodium and standing norepinephrine levels suggests that mechanisms other than hypovolemia accounted for the hyperadrenergic state.Conclusion: Our findings suggest a neuropathic basis for at least half the cases of POTS and that a substantial percentage of cases may be autoimmune. Hyperadrenergic and hypovolemic correlates are likely compensatory or exacerbating. [ABSTRACT FROM AUTHOR]

• Objective: To analyze clinical presentation of and paraclinical test abnormalities in patients with paraneoplastic limbic encephalitis (PLE). • Patients and Methods: We retrospectively reviewed 24 patients seen at the Mayo Clinic in Rochester, Minn, between 1985 and 2002 in whom PLE was suspected. Patients were identified on the basis of clinical history and presence of cancer. Data were reviewed from magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, electroencephalography (EEG), and paraneoplastic serologic studies. • Results: Common manifestations were cognitive dysfunction (92%), seizures (58%), and psychiatric symptoms (50%); 13 patients had small cell lung carcinoma; 11 had other malignancies. Paraneoplastic neuronal autoantibodies were found in 14 (64%) of 22 patients tested. Electroencephalography showed focal or generalized slowing and/ or epileptiform activity, maximal in the temporal regions, in all 22 patients tested. Magnetic resonance imaging revealed increased T2 signal involving one or both temporal lobes in 15 (83%) of 18 patients. Cerebrospinal fluid test results were abnormal in 18 (78%) of 23 patients tested. Clinical or radiographic evidence of extralimbic involvement was documented in 12 (55%) of 22 patients. No abnormality on EEG, MRI, or CSF analysis correlated with a specific cancer type or with a specific paraneoplastic autoantibody. • Conclusions: In patients with suspected PLE, EEG is invaluable for confirming cerebral dysfunction. Magnetic resonance imaging can show unequivocal involvement of temporolimbic structures and helps exclude other diagnoses. When EEG and cranial MRI are both normal, PLE is unlikely. Comprehensive testing for paraneoplastic neuronal nuclear, cytoplasmic, and ion channel autoantibodies is an important part of the evaluation, but negative results do not rule out PLE. [ABSTRACT FROM AUTHOR]