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Intractable hiccup caused by medulla oblongata lesions: A study of an autopsy patient with possible neuromyelitis optica

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Abstract

We report the first autopsy verification of medulla oblongata lesions involving bilateral nucleus tractus solitarius (NTS) as a cause of intractable hiccup in an autopsy patient. The female patient first developed pain and weakness in the lower limbs and urinary incontinence at age 48, and was given a diagnosis of myelitis. Intractable hiccup was accompanied by urinary retention on the third attack. She died of respiratory failure when the fifth attack occurred at age 51. Autopsy disclosed severe involvement of the medulla oblongata and entire spinal cord. Optic nerve lesions were also identified unexpectedly. Dual involvement of the optic nerve and spinal cord, necrotic spinal cord lesions involving not only myelin but also neurons and axon, and marked extension of the spinal cord lesions in both the longitudinal and transverse directions suggested the diagnosis of neuromyelitis optica rather than multiple sclerosis. Although animal experiments have shown that NTS is a critical structure in the hiccup reflex, we demonstrated for the first time the involvement of the NTS in an autopsy patient with intractable hiccup.

Introduction

Hiccup is a repetitive involuntary, spasmodic, and temporary contraction of the diaphragm accompanied by sudden closure of the glottis [1], which is mediated through the center located in the medulla oblongata [2]. In neuromyelitis optica (NMO), involvement of medulla oblongata has been reported [3], [4], [5], [6], [7], and clinical observations suggest a possible link with intractable hiccup. Recently, Misu et al. reported that intractable hiccup was found in eight of 47 cases of relapsing NMO but in none of 130 cases of multiple sclerosis (MS) [4].

There has been a long controversy as to whether NMO is a variant of MS or a distinct disease [8]. However, recent serological findings strongly suggest that NMO is a distinct disease that has characteristic clinical and pathological features [9]. The main target antigen is aquaporin 4 (AQP4) that is a water channel protein located in the astrocytic foot process. AQP4 is found on all surfaces of astrocytes, but occurs at the highest concentration in the perivascular and peripial end-feet, and ependymal-cell membranes. In the nervous system, AQP4 is predominantly expressed within optic nerves, spinal cord, and periventricular regions such as brainstem and hypothalamus, and this correlates with the predominant lesion sites in NMO [10]. Histopathologically, AQP4 immunoreactivity is undetectable at the lesions of NMO [6], [8], [11] in contrast to MS [8], [11], [12]. Here, we demonstrated the involvement of the nucleus tractus solitarius (NTS) in a patient with possible NMO who developed intractable hiccup.

Section snippets

Case report

A 48-year-old woman noticed pain around the left triceps muscle of the calf, weakness at the distal portion of the right leg and urinary incontinence within 3 weeks prior to admission to our hospital. Neurological examination disclosed distal weakness and hyperreflexia in the bilateral lower limbs with hypesthesia below the S2 dermatome. Hyperintensities at the cervical cord were noted on T2-weighted image. Cerebrospinal fluid (CSF) examination showed pleocytosis (cell count 237/mm3,

Neuropathological findings

Brain weight was 1280 g after fixation. Samples were fixed with 10% formalin and embedded in paraffin. Ten-μm-thick sections were prepared from the bilateral optic nerves, cerebrum, midbrain, pons, medulla oblongata, cerebellum, and spinal cord (C6, C7, C8, Th3, Th6, Th10, L3, L5, and S1). These sections were stained with hematoxylin–eosin (H&E) and Klüver–Barrera (KB). For immunohistochemistry, we prepared four-μm-thick sections, and used anti-CD68 (KP1, mouse, monoclonal Dako, 1:100),

Discussion

Clinical features of this patient are characterized by recurrent myelitis, later complicated by bulbar dysfunctions, manifesting as intractable hiccup, respiratory failure, and dysphagia. Clinically, our case did not fulfill the diagnostic criteria of NMO [13] because there were no visual manifestations throughout the clinical course. Further, serum antibodies to AQP4 could not be measured. Abnormalities of the optic nerves might have been detected if visual evoked potentials were examined. On

Acknowledgements

The authors thank Yo Shoda and Kyoko Suzuki for the excellent photographic assistance.

This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology (14570957) and a research grant from the Zikei Institute of Psychiatry.

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