Review Hiccups

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Clinical Neurology and Neurosurgery 102 (2000) 1317

Case report

Persistent hiccup as presenting symptom in medulla oblongatacavernoma: a case report and review of the literature

Angelo Musumeci *, Luciano Cristofori, Albino Bricolo

Department of Neurosurgery, Uni6ersity Hospital, Piazzale Stefani 1, 37126 Verona, Italy

Received 22 March 1999; received in revised form 31 August 1999; accepted 31 August 1999

Abstract

A rare case of persistent intractable hiccup as presenting symptom of cavernous angioma in the medulla oblongata is reported.

Pathophysiologic hypotheses about the triggering mechanism of hiccup are discussed, with special reference to the causes affecting

the central nervous system. A review of the literature concerning medullary lesions presenting with persistent hiccup is also

reported. Finally we have included some brief considerations about cavernous angiomas and the patterns of their clinical

presentation, focusing on those located in the medulla oblongata. 2000 Elsevier Science B.V. All rights reserved.

Keywords: Brainstem lesions; Cavernous angioma; Hiccup; Pathophysiology

www.elsevier.com/locate/clineuro

1. Introduction

The etiology of persistent intractable hiccup is ob-

scure and several hypotheses have so far been proposed

regarding its pathophysiology. Hiccup is defined in-

tractable when it persists for 24 h, lasting in some cases

more than 25 years. Other terms as chronic [1,2],

persistent [3] and obstinate [4] were used to describe

such a long duration.

The afferent pathway of hiccup reflex arc comprises

the sensory branches of the phrenic and vagus nerves as

well as dorsal sympathetic fibers; its main efferent limbcausing spasm of the diaphragm is mediated by motor

fibers of the phrenic nerve [5]. Hiccup may be triggered

by central nervous system (CNS) lesions or by the

irritation of the phrenic and vagus nerves [5]. Recently,

more attention was focused on its central etiology, in

particular on those lesions located in the brainstem,

interfering with specific neuronal circuits in the dorso-

lateral aspect of the medulla oblongata [610].

2. Case report

A 46-year-old man complained of some episodes of

violent vomiting and nausea that remitted sponta-

neously. After a few days a persistent and intractable

hiccup occurred and led to severe insomnia and a seven

pounds weight loss. He was examined in another hospi-

tal with gastroscopy and thoracic abdominal CT-

scans. They were normal. CT-scan of the brain showed

a hyperdense lesion, not enhanced after contrast

medium infusion, in the medulla oblongata. Two

months after the onset of the symptoms the patient wasadmitted to our Department and neurological examina-

tion showed diplopia in upward gaze and persistent

hiccup refractory to chlorpromazine, metoclopramide

and cusaprid. MRI of the brain confirmed a well-cir-

cumscribed dorsal medullary lesion, hyperintense, with

an isointense nucleus in T1-weighted images, without

Gadolinium-enhancement, beneath the caudal floor of

the fourth ventricle (Fig. 1). A cavernous angioma was

suspected.

The patient was operated on by the senior author

(AB), in a semi-sitting position. Suboccipital median

craniectomy and C1-laminectomy were carried out. Thedura was opened in a Y-shaped fashion, the cerebellar

* Corresponding author. Tel.: +39-045-8072695; fax: +39-045-

916790.

E-mail address: [email protected] (A. Musumeci)

0303-8467/00/$ - see front matter 2000 Elsevier Science B.V. All rights reserved.

PII: S 0 3 0 3 - 8 4 6 7 ( 9 9 ) 0 0 0 5 8 - X


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A. Musumeci et al. /Clinical Neurology and Neurosurgery 102 (2000) 131714

tonsils were gently retracted laterally and the floor of

the fourth ventricle was exposed. A red mulberry-like

cavernous angioma was raised from the obex, at the

right side of calamus scriptorius, exophytic in the lower

third of the fourth ventricle (Fig. 2a). It was easily

reduced and radically removed including its gliotic-

haemosiderin wall (Fig. 2b), avoiding rough traction to

the brainstem. Bleeding was slight and there were no

abnormalities in respiration and blood pressure, al-

though severe bradycardia was observed transientlyduring the debulking of the mass. Interrupted suturing

was used for a watertight closure of the dura. The

muscles and skin flap were closed in the usual manner.

Hiccup resolved from the day after surgery and the

patient no longer complained of diplopia in the upward

gaze. At discharge neurologic examination was normal.

Pathology confirmed the lesion as a cavernous an-

gioma. After 1 year the patient was hiccup free.

3. Discussion

Hiccup or singultus is a repeated, myoclonic, syn-

chronous and involuntary contraction of the di-

aphragm. Inspiratory (external) intercostal muscle

contractions are followed (in 35 ms) by a sudden clo-

sure of the glottis, stopping the air exchange abruptly

and producing the typical hic [11,12].

Etiology of persistent hiccup is still unknown and

several folk [1315], pharmacological [1625], not in-

vasive [2628] and extremely invasive [2932] therapeu-

tic remedies were tried.

Generally the causes of hiccup could be divided into

peripheral and central. Peripheral is any factor out-

side the CNS that may produce afferent nerve impulses

which finally reach the phrenic motor fibers. Central

are all those causes which act directly upon the CNS to

stimulate the phrenic motor fibers [33].

Hiccup was considered a gastrointenstinal reflex [12]

whose center should be located in the spinal cord at the

cervical-thoracic level. However, a well-coordinated

contraction suggests the relay by a supraspinal polysy-

naptic center of coordination.

Hassler [34] thought that hiccup could be the subcor-

tical equivalent of myoclonus possibly generated at the

level of the ponto-medullary so-called myoclonic trian-

gle of GuillanMollaret: inferior olive, dentate nucleus,

red nucleus. Other authors [35 38] developed, for

palatal myoclonus, the concept of denervation super-

sensitivity caused by a disfunction of the inferior oli-

vary complex, nucleus ambiguous and adjacent

postero-lateral reticular formation of medulla oblon-

gata due to medullary lesions. Al Deeb et al. [6] and Dela Fuente-Fernandez [8] proposed a similar genesis for

the hiccup.

Few reports exist in the literature regarding persistent

intractable hiccup due to lesions located in the medulla

oblongata [1,6,7,9,10,3943]. Fisher et al. [40], in 1961,

and other authors [6,7] more recently, reported dorsal

and lateral medullary infarctions presenting with persis-

tent hiccup. Kumral and Acarer [42] described an un-

usual case of primary medullary haemorrhage with

intractable hiccup. Vascular anomalies with neurovas-

Fig. 1. Preoperative MRI. T1-weighted images on the sagittal (left) and axial (right) planes showing a well-circumscribed bleeding lesion in the

dorsal aspect of the medulla oblongata, beneath the caudal floor of the fourth ventricle.


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A. Musumeci et al. /Clinical Neurology and Neurosurgery 102 (2000) 1317 15

Fig. 2. (a) Intraoperative photograph. Medullary cavernous angioma

dorsally exophytic from the obex in the fourth ventricle. (b) Intraop-

erative photograph. The floor of the fourth ventricle after total

removal of cavernous angioma.

tractable hiccup elicited by brainstem tumours:

low-grade gliomas [39,43], ependymoma [1], choroid

plexus papillomas of the fourth ventricle [7,9] and

tuberculomas [6] were reported. In all cases the lesions

developed slowly and were located near the dorso-lat-

eral aspect of the medulla oblongata. Among them, in

four cases [1,6,39,43] an involvement or extension to

the region of the obex was documented.

We report a rare case of persistent intractable hiccup

as the presenting symptom of a cavernous angioma

located near the obex of the medulla oblongata, dor-

sally exophytic in the fourth ventricle.

Houtteville (personal communication, 1998) showed

a similar clinical onset for a cavernous angioma associ-

ated with a venous angioma at the ponto-medullary

junction. Porter et al. [44], in their recent review of 100

brainstem cavernous malformations, reported hiccup as

the presenting symptom in three cases, but they did not

provide the exact location in the brainstem of the

cavernomas nor a pathophysiological explanation of

hiccup.

Moreover, cavernous angiomas were associated with

other movement disorders. Akbostanci et al. [45] de-

scribed a case of hemidystonia, reviewing 11 previous

cases of other movement disorders. Five cavernous

angiomas were located in the brainstem, one of which

was beneath the floor of the fourth ventricle: this case

was associated with oculopalatal myoclonus and syn-

chronous movements of the face, jaw, tongue and the

diaphragm.

Cavernous angioma is a hamartomatous berry-like

collection of vascular spaces lined by thin walls devoid

of smooth muscle [4648]. No brain tissue intervenes

between these vascular channels. Surrounding neural

tissue is often gliotic and haemosiderin-stained, and

may contain small low-flow feeding arteries and drain-

ing veins [45,46,49]. Cavernous angiomas are properly

vascular malformations but in the brainstem they were

considered vascular tumours [50] because they represent

real mass-lesions [5055]. Most frequently clinical pre-

sentations of intracranial cavernomas are seizures, focal

neurological deficits, and haemorrhages [51 56]. Re-

garding brainstem cavernous angiomas, long-tract signsor cranial nerves deficits are due to mass effect in such

densely eloquent area [53,55,57 59]. The symptoms

described for medullary cavernous angiomas, are

headache, diplopia, truncal ataxia, paresis of facial

nerve, weakness of arms and/or legs, dysphagia, numb-

ness of the face or body, dizziness, nausea and vomiting

[50,5457,5961] but hiccup has rarely been reported.

According to previous pathophysiologic consider-

ations, we believe that the slow growth of the cavernous

angioma, in the dorso-lateral aspect of the medulla

oblongata, in our case caused the irritation of the

cular contacts determining persistent hiccups were ad-

vocated [9,10,41]. Most reports describe persistent in-


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A. Musumeci et al. /Clinical Neurology and Neurosurgery 102 (2000) 131716

centrally mediated pathways for hiccup which remained

primarily for such a long time prior to the development

of localizing neurological signs. Experimental studies of

electrical stimulation in medulla oblongata of cats

[62,63] showed that the sites where the hiccup-like

responses are generated are located in the medullary

reticular formation lateral to the nucleus ambiguous, at

the rostrocaudal level between 1 and 2.5 mm rostral to

the obex. Moreover it was demonstrated that the nu-

cleus raphe magnus have GABA-containing cells and itcould be the source of the GABAergic inhibitory inputs

to the hiccups reflex arc. Thus we hypothesize that the

cavernoma in our case was most likely to interfere with

the neuronal connections between the nucleus raphe

magnus and those hiccup-evoking sites near the obex,

which could discharge when released from the higher

inhibitory control.

4. Conclusion

This case illustrates a very unusual presentation of

brainstem lesions and makes this etiology one of the

important considerations in the differential diagnosis of

persistent intractable hiccup. When neurological exami-

nation is normal, the diagnosis is easily missed. The

patient undergoes a large series of radiological exami-

nations of the gastrointestinal tract and is treated use-

lessly with a lot of palliative drugs or extremely invasive

remedies, like ablative procedures of the phrenic nerve.

However, when persistent intractable hiccup occurs

with or without a slow neurological worsening, a brain-stem lesion should be suspected. MR-imaging is

mandatory. Diagnosis of benign brainstem tumour

brings seriously surgery into the available treatments.

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