Neuromyelitis optica spectrum disorder (NMOSD) is a rare, inflammatory disorder of the central nervous system that results from immune-mediated demyelination and axonal damage, predominantly of the optic nerves and spinal cord neurons. Studies estimate that the prevalence of NMOSD can be up to 10 people per 100,000.1 Originally thought to be a variant of multiple sclerosis, NMOSD is a distinct entity based on the disease-specific serum NMO-immunoglobulin G that binds selectively to aquaporin-4 (AQP4). NMOSD is frequently associated with a number of systemic autoimmune disorders, such as hypothyroidism, pernicious anemia, ulcerative colitis, myasthenia gravis.2 Although typically NMOSD presents with attacks of optic neuritis with transverse myelitis, it has been found that 1.8% of seropositive cases of NMOSD have reported bradycardia during their attack.3 Knowledge of the mechanism and cardiovascular associations with NMOSD could decrease delays in diagnosis and prompt initiation of therapy. Here, we present a patient whose initial presentation with bradycardia preceded the diagnosis of NMOSD.
A 65-year-old female presented to the emergency department with two to three weeks of progressive generalized weakness, requiring assistance to ambulate by her husband. Two months prior, she experienced recurrent falls and was admitted to an outside hospital with bradycardia. She was diagnosed with sick sinus syndrome and underwent permanent pacemaker placement. Prior to that admission, the patient was teaching workout classes and engaged in moderate intensity exercise multiple times per week. After discharge, the patient reported increasing bilateral upper and lower extremity weakness, tremors, and difficulty ambulating. She had no personal or family history of autoimmune diseases and her only home medication was metoprolol tartrate. On initial physical exam, cranial nerves II-XII were grossly intact. She had hypertonia with clonus of the lower extremities bilaterally, left arm fasciculations, and a resting tremor. Muscle strength was 3/5 in the upper extremities and 4/5 in the lower extremities. Grip strength was 1/5 in the right hand, and 5/5 in the left hand. Reflexes were 1+ at the brachioradialis, triceps, biceps, patellar, and Achilles’ tendons. There was positive Babinski bilaterally, severe dysmetria with finger to nose bilaterally, and intact sensation throughout.
Her neurological condition quickly deteriorated, with onset of spastic progressing to flaccid quadriplegia, absence of reflexes, left eye blurry vision and pain with movement, and autonomic dysregulation with hypothermia, urinary retention, and bowel incontinence. Initial non-contrast CT of the head was within normal limits, with CT of the cervical spine revealing multilevel foraminal spondylosis and canal stenosis. Due to the clinical findings out of proportion to the CT results, MRI of the brain, orbits, and cervical spine were conducted, revealing scattered periventricular and subcortical white matter T2 hyperintensities, enhancing plaques adjacent to the lateral ventricles suggestive of demyelination, left optic neuritis, and increased T2 signal noted throughout the cord. Serum studies included ESR 38, CRP 0.86, blood cultures negative, HIV nonreactive, hepatitis panel negative, ANA screen negative. Cerebrospinal fluid was studied, with the following results: meningitis panel negative, lymphocytes 95, protein 174, glucose 73, IgG 16.3, VDRL non-reactive, negative MBP, and faint oligoclonal bands. Anti-aquaporin 4 (anti-AQP4) antibodies were positive, consistent with diagnosis of acquired NMOSD.
The patient was started on alternating doses of intravenous methylprednisolone and plasma exchange for ten days, without improvement in symptoms, followed by one dose of rituximab. She has follow-up with Neuroimmunology as an outpatient for continued rituximab therapy.
Our patient initially presented with abrupt onset of symptoms attributed to bradycardia and had no personal or family history of autoimmune diseases. The pathogenesis of NMOSD-associated bradycardia is believed to be due to anti-AQP4 antibodies disrupting astrocyte glutamate buffering in the nucleus tractus solitarius, leading to predominantly bradycardic v. excitatory effects on caudovagal neurons. It is important to consider autoimmune neurological diseases, such as NMOSD, in patients with progressive neurological signs and symptoms despite appropriate treatment for autonomic/cardiovascular dysfunction. Initial treatment is intravenous methylprednisolone, with plasma exchange as a rescue treatment in unresponsive patients.4 Long-term immunotherapy is indicated for prevention of attacks, to be started as soon as diagnosis is established. Eculizumab, inebilizumab, and satralizumab are approved, but data for optimal regimen and duration remains to be determined. There exists data that shows rituximab has evidence of efficacy in preventing relapse at one and six years compared to other immunotherapies; it was chosen for our patient for this reason as well as physician preference and experience compared to other options.5
- Papp V, Magyari M, Aktas O, et al. Worldwide incidence and prevalence of neuromyelitis optica: A systematic review. Neurology. 2021 Jan 12;96(2):59-77. doi: 10.1212/WNL.0000000000011153. Epub 2020 Dec 11.
- Iyer A, Elsone L, Appleton R, et al. A review of the current literature and a guide to the early diagnosis of autoimmune disorders associated with neuromyelitis optica. Autoimmunity. 2014 May;47(3):154-61. doi: 10.3109/08916934.2014.883501. Epub 2014 Feb 10.
- Majed M, Lucchinetti C, Benarroch E, et al. Autoimmune AQP4 channelopathy and bradycardia: Expanding the NMOSD spectrum (P5.306). [online] Neurology. https://n.neurology.org/content/86/16_Supplement/P5.306. First published April 4, 2016. Accessed July 15, 2021.
Clinical Practice, Hospital-based Medicine, Medical Education, Medical Ethics, Research, SGIM
Dr. Brown (firstname.lastname@example.org) is a first-year Internal Medicine resident at the University of South Florida Morsani College of Medicine. Dr. Giangreco (email@example.com) is an associate professor of medicine at Tampa General Hospital and University of South Florida Morsani College of Medicine. Dr. Gupta (firstname.lastname@example.org) is an associate professor of medicine at Tampa General Hospital and University of South Florida Morsani College of Medicine.
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