Intractable hiccups, nausea, and vomiting, an unnerving cause of vision loss
Shanmugam Mahesh Kumar, Vaishali Venkatraman, Akkayasamy Kowsalya, Jayasri Narayanamoorthy, Marappan Jayasudha
Department of Neuro-Ophthalmology, Aravind Eye Hospital, Madurai, Tamil Nadu, India
Date of Submission 07-Mar-2021
Date of Decision 15-Aug-2021
Date of Acceptance 30-Aug-2021
Date of Web Publication 02-Nov-2022
Vaishali Venkatraman
Plot No. 105, Third East Cross Street, Annanagar, Madurai - 625 020, Tamil Nadu
DOI: 10.4103/ojo.ojo_65_21
Acute optic neuritis (ON) is caused by variety of complex disorders that can be differentiated with the help of history, radiology, and serology. Identification of nonneurological symptoms that occur before the demyelinating event aids in timely diagnosis and prevention of further neurological attacks. We describe a case of unilateral ON with a history of intractable hiccups, nausea, and vomiting, wherein the possibility of area postrema syndrome (APS) was overlooked until the development of visual symptoms. APS recently identified as a hallmark of neuromyelitis optica spectrum disorder is a rare neurologic cause of gastrointestinal symptoms. This atypical presentation of APS results from autoantibodies directed against the aquaporin-4 rich sites, such as area postrema. This case brings to light the importance of eliciting history of intractable hiccups, nausea, and vomiting in a patient with ON. Despite being a commonly encountered symptom, it may rarely raise a suspicion for neuromyelitis optica.
Keywords: Area postrema syndrome, demyelination, intractable hiccups, neuromyelitis optica spectrum disorder, optic neuritis
Kumar SM, Venkatraman V, Kowsalya A, Narayanamoorthy J, Jayasudha M. Intractable hiccups, nausea, and vomiting, an unnerving cause of vision loss. Oman J Ophthalmol 2022;15:366-9
Kumar SM, Venkatraman V, Kowsalya A, Narayanamoorthy J, Jayasudha M. Intractable hiccups, nausea, and vomiting, an unnerving cause of vision loss. Oman J Ophthalmol [serial online] 2022 [cited 2023 Jan 27];15:366-9. Available from: https://www.ojoonline.org/text.asp?2022/15/3/366/360421
Neuromyelitis optica spectrum disorder (NMOSD) comprises inflammatory disorders of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and spinal cord. We present this case with unilateral optic neuritis (ON), preceded by an episode of intractable hiccups, nausea, and vomiting, who was later diagnosed to have area postrema syndrome (APS). This case report emphasizes the importance of correlating prior systemic history with vision loss, uniqueness of neuroimaging in NMOSD, and need for caution in the management of the same.
A 36-year-old male presented to our hospital with complaints of sudden loss of vision in the right eye (RE) for 2 days. He was referred for visual symptoms while being treated at a gastroenterology center for intractable hiccups, nausea, and vomiting. Extensive blood work up, upper gastrointestinal endoscopy, and ultrasonography abdomen were normal. Having ruled out the local and metabolic causes for gastrointestinal symptoms, he was diagnosed to have gastroesophageal reflux disease and treated for the same. After 2 weeks of treatment, he continued to have intractable hiccups, nausea, and vomiting and further developed sudden onset defective vision in the RE, necessitating ophthalmology referral.
On examination, his best-corrected visual acuity (BCVA) in RE was hand movements and left eye (LE) was 6/6. Anterior segment revealed Grade 3 relative afferent pupillary defect in RE. Extraocular movement and posterior segment examination were normal in both eyes. Color vision and visual fields could not be assessed in RE due to poor BCVA whereas both the tests were normal in LE. He was afebrile and neurological examination was unremarkable. The only significant medical history was the recent episode of intractable hiccups, nausea, and vomiting that lasted for 2 weeks. A clinical diagnosis of ON was made and investigated further. Complete blood count, C-reactive protein, renal and liver function tests, electrolytes (Na, K, Cl), serum analysis for antinuclear antibodies were found to be within normal limits. The erythrocyte sedimentation rate at the end of 1st hour was 55 mm. Contrast-enhanced magnetic resonance image of the brain, T2/fluid-attenuated inversion recovery demonstrated hyperintense lesion over intraorbital part of right side optic nerve [Figure 1], optic chiasm, optic tract [Figure 2] and [Figure 3], lateral geniculate body was noted. Bright signals in the brainstem, around the fourth ventricular outflow tract inclusive of area postrema, indicated the possibility of a demyelinating process, most probably NMOSD. To confirm the diagnosis, serum immunoassay for aquaporin-4 (AQP-4) immunoglobulin G (IgG) test was done which was positive in 1:10 dilution. Considering the clinical course, radiology, and serology, a diagnosis of NMOSD was made. The symptoms of intractable hiccups, nausea, and vomiting before the onset of ocular symptoms were suggestive of APS, a known manifestation of NMOSD.
Figure 1: Magnetic resonance image of the brain and orbit. Axial T2-weighted image showing hyperintensity involving intraorbital part of right optic nerve
Figure 2: Magnetic resonance image of the brain and orbit. Axial T2-weighted image showing hyperintensity involving optic chiasm and optic tract
Figure 3: Magnetic resonance image of the brain and orbit. FLAIR – Axial view showing hyperintensity involving bilateral intracranial part of optic nerve and optic chiasm
The patient was then treated with intravenous methylprednisolone (IVMP) 1 g once a day, for 5 consecutive days. In addition, two doses of injection Rituximab (RTX) 500 mg were given as intravenous infusion once a day in 2-week interval, along with oral azathioprine (AZA) 50 mg once a day, to reduce residual disability postrecovery. After 2 weeks, intractable hiccups, nausea, and vomiting subsided with no further recurrence and the patient's visual acuity in RE improved from hand movements to 4/60 following treatment. Maintenance dose of oral steroids was given for 5 weeks, starting from 50 mg for 7 days, tapered by 10 mg every week. Oral AZA 50 mg once a day was continued to reduce relapses in the future. After 1 month, BCVA in RE had further improved to 6/60 with the onset of mild disc pallor and LE was normal with BCVA of 6/6. During his last follow-up, 1 year since diagnosis, BCVA, and the ocular examination remained the same.
NMOSD comprises a broadening clinical spectrum that needs to be distinguished from that of multiple sclerosis (MS). Understanding the pathophysiology and serology and radiological features can aid in differentiating from other diverse neurological diseases including inflammatory, infectious, malignant, vascular, and hereditary etiologies that may resemble the phenotypes of NMOSD [Table 1].[1] The pathological features of NMO include perivascular deposition of immunoglobulin and activated complement, loss of astrocytic AQP-4, inflammatory infiltration with granulocyte and macrophage accumulation, and demyelination with axon loss.[2] AQP-4 antibody levels can predict long-term prognosis as well as therapeutic response in patients with NMOSD.[3]
Table 1: Differential diagnosis of neuromyelitis optica spectrum disorder
Area postrema has a less restrictive blood–brain barrier, thereby acting as a portal for entry of circulating IgG into the CNS.[4] Nausea and vomiting have been documented in some patients at the peak of their NMO-IgG titer.[5] NMO lesions in area postrema are distinct from other CNS lesions, in being inflammatory, nondestructive, and nondemyelinating which explains the intractable but reversible nature of nausea or vomiting.[5]
Intractable nausea and vomiting are nonspecific symptoms that are not commonly appreciated as a possible initial manifestation of a serious neurological disorder. Indeed, Apiwattanakul et al. reported intractable vomiting as the initial symptom in 12% of the seropositive AQP-4 patients, similar to our patient whose primary symptom was gastrointestinal and not neurological.[4] Apiwattanakul et al. found a median interval of 11 weeks (range: 1–156 weeks) between intractable vomiting and neurological symptoms, in contrast to the 2-week interval seen in our patient.[4]
Posterior involvement of the optic nerve, including chiasm and simultaneous bilateral disease, seen predominantly in NMOSD, can aid in differentiation from MS.[6] Our patient had an extensive involvement of anterior visual pathway till optic chiasm and area postrema, 2 weeks following the onset of gastrointestinal symptoms.
Acute episode is treated with IVMP to suppress inflammation, minimize CNS damage, and do not provide neuroprotection.[7] AZA, mycophenolate mofetil, and RTX are all effective in reducing relapse and improving the clinical symptoms of patients with NMOSD. RTX is probably more effective and is probably the best choice at present.[8] In our patient, IVMP was used to curb the acute episode followed by use RTX and AZA to prevent relapse. Early initiation of treatment for APS could have prevented subsequent neurological damage in the form of ON.
In patients with ON, a detailed medical history is essential. Intractable hiccups, nausea, and vomiting in a severe neurological disorder like NMO can lead to an erroneous diagnosis as they closely mimic common gastrointestinal disease. APS may present in isolation without overt neurological deficits, and hence, ophthalmologists must have high index of suspicion for early diagnosis and swift initiation of treatment. Examination should focus not only on the primary symptoms but also on disease indicators that could suggest alternative diagnoses or concomitant autoimmune disorders. Understanding the unique pathogenesis and characteristic radiological lesions helps us in tailoring our approach regarding investigation, management, and prognosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Kim SM, Kim SJ, Lee HJ, Kuroda H, Palace J, Fujihara K. Differential diagnosis of neuromyelitis optica spectrum disorders. Ther Adv Neurol Disord 2017;10:265-89.
Levin MH, Bennett JL, Verkman AS. Optic neuritis in neuromyelitis optica. Prog Retin Eye Res 2013;36:159-71.
Kim SM, Waters P, Woodhall M, Kim JY, Kim JE, Yang JW, et al. Utility of aquaporin-4 antibody assay in patients with neuromyelitis optica spectrum disorders. Mult Scler 2013;19:1060-7.
Apiwattanakul M, Popescu BF, Matiello M, Weinshenker BG, Lucchinetti CF, Lennon VA, et al. Intractable vomiting as the initial presentation of neuromyelitis optica. Ann Neurol 2010;68:757-61.
Takahashi T, Miyazawa I, Misu T, Takano R, Nakashima I, Fujihara K, et al. Intractable hiccup and nausea in neuromyelitis optica with anti-aquaporin-4 antibody: A herald of acute exacerbations. J Neurol Neurosurg Psychiatry 2008;79:1075-8.
Khanna S, Sharma A, Huecker J, Gordon M, Naismith RT, Van Stavern GP. Magnetic resonance imaging of optic neuritis in patients with neuromyelitis optica versus multiple sclerosis. J Neuroophthalmol 2012;32:216-20.
Compston DA, Milligan NM, Hughes PJ, Gibbs J, McBroom V, Morgan BP, et al. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 2. Laboratory results. J Neurol Neurosurg Psychiatry 1987;50:517-22.
Yang Y, Wang CJ, Wang BJ, Zeng ZL, Guo SG. Comparison of efficacy and tolerability of azathioprine, mycophenolate mofetil, and lower dosages of rituximab among patients with neuromyelitis optica spectrum disorder. J Neurol Sci 2018;385:192-7.
Kumar SM
Venkatraman V
Kowsalya A
Narayanamoorthy J
Jayasudha M
Area postrema syndrome
demyelination
intractable hiccups
optic neuritis