First Case of Association between Autoimmune Autonomic Ganglionopathy (AAG) and Myeloproliferative Neoplasms (MPNs)

Introduction Autoimmune autonomic ganglionopathy (AAG) is a rare disease that presents with different autonomic symptoms and positive autoantibodies against the ganglionic acetylcholine receptor (gAChR) in 50 % of the cases. Eighty percent of seropositive patient has extra-autonomic manifestations. Extra-autonomic manifestations include sensory disturbance, central nervous system involvement, endocrine disorders autoimmune diseases, and cancers. It has been reported with various malignancies, such as small lung cancer, thymoma, ovarian tumors and others. Method We report a case from MD Anderson cancer center (MDACC) and to our knowledge it is first case in literature of a patient Autoimmune autonomic ganglionopathy associated with primary myelofibrosis Result A 55-year-old African American male diagnosed with JAK2 V617F positive primary myelofibrosis in 2005 and placed on observation until September 2012 when he was referred to MDACC for further management. He was started on protocol with Ruxolitinib + lenalidomide and did well initially, but during the course of treatment, he started to experience leg weakness. Initially in the left leg and then the right leg. lenalidomide was placed on hold and in April 2015, ruxolitinib was held as well. On examination he has left leg weakness in addition to weak hand grip on the same side. On Further evaluation, he was diagnosed with inclusion body myositis after muscle biopsy He was then lost to follow up and followed with outside hematologist In February 2020, he developed cytopenias and was referred back to MDACC for management. He was seen and we performed a bone marrow shortly thereafter. He continued to have PMF, molecular, cytogenetics could not be performed on bone marrow due to dry tap. Patient started on "investigational agent. In early 2021 patient started to have orthostatic hypotension and syncope. Serum paraneoplastic antibody panel revealed acetylcholine Receptor Gang Neuronal Ab.The above finding along with his automimic symptoms consists with diagnosis of autoimmune autonomic ganglionopathy. Conclusion Autoimmune autonomic ganglionopathy (AAG) with extra-autonomic manifestations is a very rare and not well known. It is reported before to be associated with solid malignancy, we describe here first association with hematological malignancy which is primary myelofibrosis. We aim to add this to literature, and to increase the knowledge and awareness of both hematologists and neurologists about this association and possible other hematological malignancies may be reported in the future Disclosures Verstovsek: Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Genentech: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Ital Pharma: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

Orthostatism, Constipation, and Early Satiety

A 65-year-old woman with a history of Graves disease, status post radioactive iodine therapy, and a biopsy-proven benign calcified breast nodule sought care for evaluation of multiple symptoms. She had constipation for 8 years, with prior fecal urgency, and intermittent diarrhea for the previous year. She was diagnosed with irritable bowel syndrome. Her weight remained stable until 1 1/2 years earlier, and she had lost 6.8 kg. For the previous 3 years, the patient had experienced multiple urinary symptoms including hesitancy, urgency, incontinence, and retention. She was diagnosed with a cystocele, the correction of which did not help. She had noted difficulty focusing her eyes when moving from a dark to a well-lit environment, or vice versa. She also reported orthostatic light-headedness for 1½years, which worsened on exposure to a hot environment. Neurologic examination showed abnormally dilated pupils with prominently sluggish constriction in response to light. Autonomic reflex screening indicated patchy postganglionic sympathetic sudomotor, marked cardiovagal, and cardiovascular adrenergic failure, with neurogenic orthostatic hypotension. Thermoregulatory sweat testing showed 82% anhidrosis. A nuclear medicine gastric-emptying study indicated delayed gastric emptying and colonic hypomotility. Serum testing was markedly positive for ganglionic (alpha 3) acetylcholine receptor autoantibodies. The patient was diagnosed with autoimmune autonomic ganglionopathy. The patient received intravenous immunoglobulin. She returned and reported 80% improvement in all symptoms, and neurologic examination showed normal pupillary response to light. Autonomic reflex screening indicated improvement of her adrenergic function, and thermoregulatory sweat testing showed an impressive improvement of her sudomotor function. Her postganglionic sympathetic sudomotor and cardiovagal function remained impaired. Gastric emptying remained mildly delayed. She was maintained on intravenous immunoglobulin, which was later tapered after azathioprine was started. Autoimmune autonomic ganglionopathy usually presents subacutely, much like other autoimmune neurologic diseases. Typical features of this disorder are the impaired pupillary reaction to light and prominent sicca symptoms, indicating prominent cranial parasympathetic (cholinergic) impairment. Also consistent with this diagnosis are the prominent gastrointestinal tract symptoms. Prominent cholinergic failure helps distinguish autoimmune autonomic ganglionopathy from peripheral autonomic neuropathy or neurodegenerative disorders such as pure autonomic failure.

A Flow Cytometric Assay to Detect Functional Ganglionic Acetylcholine Receptor Antibodies by Immunomodulation in Autoimmune Autonomic Ganglionopathy

Autoimmune Autonomic Ganglionopathy (AAG) is an uncommon immune-mediated neurological disease that results in failure of autonomic function and is associated with autoantibodies directed against the ganglionic acetylcholine receptor (gnACHR). The antibodies are routinely detected by immunoprecipitation assays, such as radioimmunoassays (RIA), although these assays do not detect all patients with AAG and may yield false positive results. Autoantibodies against the gnACHR exert pathology by receptor modulation. Flow cytometric analysis is able to determine if this has occurred, in contrast to the assays in current use that rely on immunoprecipitation. Here, we describe the first high-throughput, non-radioactive flow cytometric assay to determine autoantibody mediated gnACHR immunomodulation. Previously identified gnACHR antibody seronegative and seropositive sera samples (RIA confirmed) were blinded and obtained from the Oxford Neuroimmunology group along with samples collected locally from patients with or without AAG. All samples were assessed for the ability to cause gnACHR immunomodulation utilizing the prototypical gnACHR expressing cell line, IMR-32. Decision limits were calculated from healthy controls, and Receiver Operating Characteristic (ROC) curves were constructed after unblinding all samples. One hundred and ninety serum samples were analyzed; all 182 expected negative samples (from healthy controls, autonomic disorders not thought to be AAG, other neurological disorders without autonomic dysfunction and patients with Systemic Lupus Erythematosus) were negative for immunomodulation (<18%), as were the RIA negative AAG and unconfirmed AAG samples. All RIA positive samples displayed significant immunomodulation. There were no false positive or negative samples. There was perfect qualitative concordance as compared to RIA, with an Area Under ROC of 1. Detection of Immunomodulation by flow cytometry for the identification of gnACHR autoantibodies offers excellent concordance with the gnACHR antibody RIA, and overcomes many of the shortcomings of immunoprecipitation assays by directly measuring the pathological effects of these autoantibodies at the cellular level. Further work is needed to determine the correlation between the degree of immunomodulation and disease severity.

Association between neurosarcoidosis with autonomic dysfunction and anti-ganglionic acetylcholine receptor antibodies

Objective To determine whether autonomic dysfunction in neurosarcoidosis is associated with anti-ganglionic acetylcholine receptor (gAChR) antibodies, which are detected in autoimmune autonomic ganglionopathy. Methods We retrospectively extracted cases of sarcoidosis from 1787 serum samples of 1,381 patients between 2012 and 2018. Anti-gAChR antibodies against the α3 and β4 subunit were measured by luciferase immunoprecipitation to confirm the clinical features of each case. We summarized literature reviews of neurosarcoidosis with severe dysautonomia to identify relevant clinical features and outcomes. Results We extracted three new cases of neurosarcoidosis with severe dysautonomia, among which two were positive for anti-gAChR antibodies: Case 1 was positive for antibodies against the β4 subunit, and Case 2 was positive for antibodies against both the α3 and β4 subunits. We reviewed the cases of 15 patients with neurosarcoidosis and severe dysautonomia, including the three cases presented herein. Orthostatic hypotension and orthostatic intolerance were the most common symptoms. Among the various types of neuropathy, small fiber neuropathy (SFN) was the most prevalent, with seven of nine cases exhibiting definite SFN. Six of eight cases had impaired postganglionic fibers, of which the present three cases revealed abnormality of 123I-MIBG myocardial scintigraphy. Of the 11 cases, 10 were responsive to immunotherapy, except one seropositive case (Case 2). Conclusions The presence of gAChR antibodies may constitute one of the mechanisms by which dysautonomia arises in neurosarcoidosis.