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Anti-aquaporin-4 Antibody Positive Optic Neuritis Following Scrub Typhus in an Elderly Female

Bae, Dae Woong, MD; An, Jae Young, MD, PhD

doi: 10.1097/NRL.0000000000000196
Case Report/Case Series

Introduction: Aquaporin-4 antibody (AQP4-Ab) is specific for neuromyelitis optica spectrum disorder (NMOSD) and so is helpful to distinguish NMOSD from other autoimmune diseases. Several viral infections may play a role in the onset of NMOSD.

Case Report: We describe a case of a previous healthy 82-year-old woman who presented with acute visual loss occurring 3 weeks after scrub typhus. Physical examination showed a relatively afferent pupillary defect in the right eye and ophthalmoscopy revealed edema of the right optic disc. Enhanced magnetic resonance imaging revealed enhancement of the right optic nerve. Serological testing showed AQP4-Ab. After methylprednisolone pulse therapy followed by oral tapering of prednisolone, visual dysfunction was improved. Subsequently she experienced no attacks for 5 years.

Conclusions: Optic neuritis (ON) associated with scrub typhus is extremely rare. Our case support that scrub typhus could trigger ON in a lifelong asymptomatic patient with AQP4-Ab and AQP4-Ab should be considered in a very old age patient with suspected postinfectious inflammatory ON.

Department of Neurology, St. Vincent Hospital, College of Medicine, The Catholic University of Korea, Gyeonggi-do, Korea

The authors declare no conflict of interest.

Reprints: Jae Young An, MD, PhD, Department of Neurology, St. Vincent’s Hospital, The Catholic University of Korea, 93-6, Ji-dong, Paldal-gu, Suwon, Gyeonggi-do, 442-723, Korea. E-mail:

Optic neuritis (ON) is an inflammatory optic neuropathy that is mostly idiopathic. However, it can be associated with variable causes. The important differential diagnoses are multiple sclerosis and neuromyelitis optica (NMO). Recently, after the discovery of a specific autoantibody [aquaporin-4 antibody (AQP4-Ab)] in the serum of NMO patients, a new term, neuromyelitis optica spectrum disorder (NMOSD), was proposed for a broad clinical spectrum of AQP4-Ab-mediated diseases.1 In up to 30% of NMO patients, an NMO attack is preceded by infection.2 There are no previous reports regarding scrub typhus preceding NMO, and the association of ON with scrub typhus is rare.3,4 Here, we describe a case of AQP4-Ab positive acute ON triggered by scrub typhus in a previously healthy 82-year-old woman.

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An 82-year-old woman was admitted to our hospital with a 14-day history of visual disturbance. One month before the onset of visual symptoms, she presented with fever, chill, and myalgia at another hospital. An eschar was present on the right upper arm. After diagnosis of scrub typhus, she was treated with doxycycline treatment for 7 days. The patient’s medical history was otherwise unremarkable. Fever, chill, and myalgia resolved. Two weeks later, she developed right periorbital pain combined with visual blurring, which rapidly progressed to complete visual loss. Ophthalmoscopy revealed edema of the right optic disc (Fig. 1A), and there was a relatively afferent papillary defect in the right eye. Gadolinium-enhanced, fat-suppressed, T1-weighted magnetic resonance imaging showed enhancement of the right optic nerve (Fig. 1B). Routine complete blood count, serum biochemistry profiles, and thyroid function test were normal. Autoimmune antibody screening tests for angiotensin-converting enzyme, antinuclear antibody, double-stranded DNA, anti-Ro, anti-La, and antineutrophil cytoplasmic antibody were negative, but an enzyme-linked immunosorbent assay (ELISA) and cell-based indirect immunofluorescence assay (CIIFA) kit (Euroimmun, Luebeck, Germany) for AQP4-Ab in the serum were positive. In ELISA, the optical density was twice cut-off and the titer of AQP4-Ab was 1:160 in CIIFA. An indirect fluorescent antibody test for Orientia tsutsugamushi was positive. Cerebrospinal fluid analysis (CSF) was unremarkable. Oligoclonal bands in the CSF were negative. Cultures for bacteria, fungi, and tuberculous bacillus and polymerase chain reaction for mycoplasma, varicella zoster virus, herpes simplex virus, cytomegalovirus, and Epstein-Barr virus in the CSF were negative. She was treated with intravenous methylprednisolone 1000 mg for 5 days, followed by a tapering course of oral prednisolone. Visual acuity gradually improved, and there were no residual visual defects 4 months after the onset of the visual disturbance. Although we fully explained the usefulness of immunosuppressant to prevent further relapse of NMO, she refused to take the medication because of the risk of adverse effect of drugs and the inconvenience of long-term medication. She did not want the follow-up test for AQP4-Ab or imaging studies. However, she has experienced no additional attacks in 5 years.



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NMOSD cover a broad range of disorders that include limited forms of disease, such as recurrent isolated longitudinal extensive transverse myelitis, recurrent isolated ON, atypical cases that include brain lesions and autoimmune disorders.5 In particular, AQP4-Ab is useful in distinguishing NMOSD from other demyelinating disorders that affect the optic nerve or spinal cord. A previous report had revealed that parainfectious pathogensis, such as infection of varicella zoster virus, human immunodeficiency virus, cytomegalovirus, Dengue virus, Hepatitis A virus, Epstein-Barr virus, and influenza A, may play a central role in a subgroup of patients with NMO.6,7 The clinical course was usually monophasic, but complete recovery was only achieved in 25% of patients.6 A pathogenetic autoimmune cascade similar to that in acute disseminated encephalomyelitis may be activated in NMO following systemic infection.6

Scrub typhus is an acute febrile illness caused by O. tsutsugamushi and is transmitted by the bite of the larval form of trombiculid mites which are both the reservoir and the vectors of the disease.8 This disease is endemic in the “tsutsugamushi triangle” which extends from northern Japan and far-eastern Russia in the north, northern Australia in the south and Pakistan in the West.9 The disease is characterized by focal or disseminated vasculitis and perivasculitis which may involve the lungs, heart, liver, spleen, and central nervous system. The neurological manifestations of scrub typhus are not uncommon but are diverse. Meningoencephalitis is common but cerebellitis, cerebrovascular accident, cranial nerve palsies, plexopathy, Guillain-Barré syndrome, acute disseminated encephalomyelitis, transverse myelitis, neuroleptic malignant syndrome, and parkinsonism are rare manifestations reported in the literature.10 There are only 2 previously reported cases of ON caused by scrub typhus.3,4 These 2 cases were in children, and response to steroid treatment was excellent. The postulated mechanism of ON in these cases is a postinfectious inflammatory reaction due to occurrence of ON at a convalescent period of scrub typhus. However, the presence of AQP4-Ab was not determined in these cases.

Currently, diverse methods are available for detecting AQP4-Ab. ELISA have lower sensitivity (mean sensitivity, 64%) and occasionally yield false-positive results (0.5% to 1.3%), but cell-based assays are considered the most accurate techniques (mean sensitivity, 76 and 0.1% false-positive rate).1 Confirmatory testing is recommended, ideally using ≥1 different AQP4-Ab assay techniques.1 Given the results of both ELISA and CIIFA in our case, the possibility of false-positive of AQP4-Ab is considered to be extremely low.

We reported the first case of AQP4-Ab positive, monophasic ON in a previously lifelong asymptomatic female occurring after scrub typhus. Although scrub typhus may be simply a cause of postinfectious inflammatory ON and AQP4-Ab is a coincidental finding, the specificity of AQP4-Ab for NMOSD combined with the rareness of the association of ON with scrub typhus suggests that scrub typhus can trigger a clinical symptom of NMOSD. Thus, AQP4-Ab should be considered in the evaluation of postinfectious inflammatory ON, even in previously healthy patients of advanced age.

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neuromyelitis optica spectrum disorder; scrub typhus; anti-aquaporin-4 antibody

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