,Journal o! the ,%'urological ,5'cle/J,c,. !i~: : I~191 i :-:i 144 :~ ~ ~ 1991 Elsevier Science Publishers B'~ ~o22-:-,li!X~)i$:i~:!: JNS 03549 Intractable hiccup induced by brainstem lesion Saleh M. AI Deeb ~, H. Sharif 2, K. A1 Moutaery I and N. Biary 1 JDept. of Clinical Neuroscience, 2Dept. of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh l 1159 (Kingdom of Saudi Arabia) (Received 23 January, 1991) (Accepted 25 January, 1991) K e y words: Hiccup; Intractable hiccup; Brainstem infarction; Brainstem tuberculoma; Saudi Arabia Summary Four patients with brainstem lesions presented with intractable hiccup and mild to moderate neurological signs. Two of the patients had been initially diagnosed as having a psychogenic cause for their hiccup. Magnetic resonance imaging (MRI) demonstrated brainstem infarction in one case, tuberculoma at the junction of the medulla oblongata and the cervical spinal cord in two, and a vermian tuberculoma compressing the brainstem in one. The brainstem infarct and one of the medullary tuberculoma were not detected on high resolution enhanced computed tomography. The 3 patients with CNS tuberculoma were free of hiccup 1-5 months after antituberculous chemotherapy. It is proposed that hiccup is not an abnormal reflex, but a myoclonus generated by repetitive activity of the "inspiratory solitary nucleus" due to release of higher nervous system inhibitory/-regulatory control. The neuroanatomical network and the mechanisms underlying the formation of intractable hiccup are outlined. The value of MRI in the initial diagnosis and follow-up of patients with intractable hiccup due to brainstem lesions is emphasised. Introduction TABLE 1 REPORTED CNS LESIONS CAUSING INTRACTABLE HICCUP Intractable hiccup continues to fascinate as well as confuse physicians and patients alike. H i c c u p is defined as an a b r u p t involuntary contraction o f the d i a p h r a g m and intercostal muscles with sudden closure of the glottis 35 msec after onset ( N e w s o m Davis 1970). The term "intractable" is given to those hiccups with a duration ranging from 24 h to m o r e than 25 years. Other terms that have been used to describe hiccups with long duration include " c h r o n i c " ( K o z i k and O w s i a n o w s k a 1971; M c F a r l i n g and Susac 1979), "persistent" (Jansen et al. 1990), and " o b s t i n a t e " (Bellingham Smith 1938). The incidence o f intractable hiccup is rare as can be j u d g e d from the fact that only 220 cases were r e p o r t e d from a large institution over a 30 year period ( S o u a d j i a n and Cain 1968). Publications on the subject are relatively scanty and deal mostly with m o d e s o f therapy. Charles M a y o ' s r e m a r k that the a m o u n t o f knowledge on any subject such as this can be considered as being in inverse p r o p o r t i o n to Correspondence to: Dr. Saleh M. AI. Deeb, Consultant and Head of Neurology, Dept. of Clinical Neuroscience, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Kingdom of Saudi Arabia. Lesion Authors Intracranial neoplasm Gigot (1952); Bellingham Smith (1938) McFarling et al. (1979); Jacobsen et al. (1981); Stotka et al. ( 1962); Birkhead and Friedman (1987) Noble (1934); Jansen et al. (1990) Bellingham Smith ( 1938); Noble (1934) Rosenow (1926); Currier etal. (1961) Noble ( 1934); Bellingham Smith (1938); Rosenow (1927) Brain (1923); Economo (1920) Bellingham Smith (1938); Noble (1934) Lipps et al. (1990) Dimitri ( 1921) Stotka et al. (1962) Kozik and Owsianowska (1976) Newsom Davis (1970) Laing et al. (1981) Multiple sclerosis Abscess Hemorrhage Brainstem infarction Encephalitis Encephalitic lethargia Meningitis Cervicomedullary ependymoma Syringobulbia Brainstem tumor Tumor of the medulla oblongata CVA AVM of posterior fossa 145 the number of different treatments suggested and tried, is still valid today. Perhaps one is justified in saying that there is no disease which has had more forms of treatment and fewer results from treatment than has persistent hiccup (Mayo 1932). Most articles do not clarify the pathophysiology, but assume peripheral gastrointestinal reflexes to underlie the phenomenon, or pass it over in silence. The great majority of cases reported in the literature have been diagnosed as being of peripheral origin with intra-abdominal or intrathoracic cause. Central causes have been referred to the spine in thoracic lesions, but only few reports have referred to cerebral or brainstem lesions (Table 1). Many cases of centrally generated hiccup were, and still are, misdiagnosed as idiopathic or psychogenic, or are even interpreted as hysterical (Souadjian and Cain 1968). We report on 4 cases with intractable hiccup caused by brainstem lesions, all of whom were initially misdiagnosed as being due to either gastrointestinal or psychological causes. The neuroanatomical network and the mechanisms underlying the formation of intractable hiccup are outlined. The value of a thorough neurological examination in such Fig. 1a. Fig. lb. Fig. 1. A 55-year-old man presenting with intractable hiccup and generalised weakness. (A)Midsagittal MRI (spin echo (SE), repetition time (TR) = 500 msec, echo time (TEl - 3(I msec) done after i.v. administration of Gd-DTPA shows rim enhancement of a nodule measuring 2 cm in diameter and located at the junction of the medulla oblongata and tile cervical spinal cord (arrowheads). The central area within the nodule probably represents necrosis. Similar nodules were seen in the right parietal lobe of the left cerebellum. The features are characteristic of multiple tuberculomas. (B) Midsagittal MR image done 5 months alter (A) while the patient is on antituberculous therapy. (Same pulse sequencc as (A) and also done after i.v. contrast.) Therc is a definite decrease in the size of the tuberculoma (arrowheads). (C)Midsagittal MR image done 12 months after (A) while the patient is still on antitubcrculous therapy. (Same pulse sequence as (A) and also done alter i.v. contrast,) The tuberculoma has completely disappeared. The patient was free of hiccup and his generalised weakness had dramatically improved. 146 Fig. 2. A 45-year-old m a n presenting with intractable hiccup, confusion and dizziness. (A) CT axial image shows punctate calcifications in the vermis (arrows) and bilateral areas of decreased attenuation in cerebellar hemispheres. (B) CT axial image at the same level as (A) shows marked enhancement of the vermian lesion. (C) Midsagittal MR image (SE, TR = 500 msec, TE = 30 msee) shows a space occupying lesion in the inferior aspect of the vermis and cerebellar tonsils (arrowheads). The mass is causing complete obstruction of the foramina of Luschka and Magendie with resultant dilatation of the ventricular system. The lesion is mostly isointense with brain tissue except for linear and focal areas of low signal intensity presumably representing the calcifications noted on CT. (D) Midsagittal MR image (SE, TR = 1800, TE = 50 msec) shows diffuse hyperintensity in the cerebetlar mass noted in (C). MR contrast agents were not available. The appearances on CT and M R imaging are compatible with a glioma or a tuberculoma. The patient improved dramatically on antituberculous chemotherapy and was free of hiccup. 147 p a t i e n t s is e m p h a s i s e d a n d t h e n e e d for m o r e a d v a n c e d Case histories p r o c e d u r e s s u c h as M R I for e v a l u a t i n g t h e b r a i n s t e m is All p a t i e n t s w e r e d i a g n o s e d a n d t r e a t e d at the A r m e d stressed. F o r c e s H o s p i t a l in R i y a d h , S a u d i A r a b i a . Case I A 55-year-old male was doing well until 2 months prior to admission when he started to have hiccups that severely distressed him. He was seen by many physicians and was given a variety of medications. Soon, he developed gingival hemorrhaging. Drug-induced thrombocytopcnia was diagnosed and he was given prednisolone and platelets. Nitrazepam and amitriptyline, prescribed for the hiccup, had no effect. The thrombocytopenia improved with prednisolone and he was discharged in spite of the intractable hiccup which was interpreted as being due to depression and anxiety. Two months later the patients developed generalised weakness, Fig. 3a. Fig. 3b. Fig. 3. A 24-year-old man presenting with difficuhy o n swallowing and intractable hiccup. (A) MRI axial image (TR = 500, TE 30) at the level of the brainstem shows a rounded nodule in the medulla on the right side (arrowheads). The nodule is isointense with brain tissue and shows a central area of low signal probably representing necrosis. Note the proximity of the lesion to the 9th nerve (whitc arrowhead). MR contrast was not available. (B)Midsagittal MR image ( T R - 2000, "IE 50) shows diffuse high signal intensity from the lesion noted in (A) (arrows). Similar lesions were seen in the brain parenchyma. (C)Coronal MR image (TR 2000, TE = 180) shows difl\lse increased signal t'rom the nodule noted in (A) and (B) (arrowheads). Gradual regression of the size of the nodules was noted on follow-up examinations while thc patient was on antituberculous tberap). The hiccup and difficulty ~ith swallowing have completely subsided 148 malaise, weight loss, vomiting and anorexia, as well as increase in frequency of the intractable hiccups which led to a second hospital admission. Examination revealed a left-sided hemiparesis, as well as pulmonary miliary tuberculosis, treated with INH/rifampicin/ethambutol/pyrazinamide. CT of the brain revealed no focal lesion. CSF was unremarkable, culture produced no growth. MRI showed 3 nodules each measuring about 1 cm in diameter, and located in the right posterior parietal, left cerebellar hemisphere, and in the lower end of the medulla oblongata. After intravenous contrast rim enhancement was noted, the central area presumably representing necrosis (Fig. IA). The diagnosis of multiple cerebral tuberculoma was made. Anti-TB medication was continued. The patient was seen again 1 year later, being free of hiccup and of neurological deficit. Follow-up MRI revealed gradual resolution of the medullary tubereuloma and the other lesions (see Fig. 1B and C). The hiccup was considered to be produced by brainstem tuberculoma. Case 2 This 65-year-old diabetic male was admitted to the hospital with a CVA manifesting with central facial palsy and lett-sided hemiparesis, dysarthria, dysphagia, and persistent hiccup. CT showed generalised cerebral and cerebellar atrophy with areas of decreased density in the pons and cerebellum indicative of multiple infarction. Sagittal MR imaging showed an additional small infarct in the medulla oblongata. After 2 weeks, the neurological symptoms started to improve; the recurrent hiccup remained unchanged. Clonazepam was given and the hiccup decreased in frequency and intensity after 2 months. Four months later the hiccup had disappeared. Case 3 A 45-year-old male was admitted with a state of" confusion, tizver, dizziness, horizontal nystagmus, vertigo, and hiccup. The patient was admitted with the diagnosis of meningitis or meningoencephalitis. Hiccups had been present for 7 years prior to admission; their cause was diagnosed as a small hiatus hernia with reflux esophagitis and he had been treated with a variety of medications to no effect, He had also been referred to the department of psychiatry where he was diagnosed as being psychologically unstable. Neurological examination was unremarkablc and CSF was normal. Unenhanced CT showed heavy calcifications in the region of the vermis, with marked enhancement noted after i.v. contrast (Fig. 2A). MRI demonstrated a space occupying lesion in the inferior part of the vermis compressing on the pons and the medulla oblongata (Fig. 2B). The differential diagnosis included either a glioma or tuberculoma. The patient refused further investigations as well as surgical intervention, and he was discharged oll antituberculous medication. Recently seen at the neurosurgical out-patient department 1.5 years after discharge, he claimed to have become free of hiccup and other complaints but refused to have CT or MR imaging. Case 4 A 24-year-old male presenting with difficulty in swallowing and intractable hiccup for the last 3 weeks. Physical examination revealed painful lymphadenopathy in the neck with no other abnormality. No definite neurological deficit was noted and the chest X-ray was normal. Acid-fast bacilli were isolated from the lymph node biopsy, which also showed multiple caseating granulomas. The CT brain scan showed multiple small discrete nodules distributed throughout the brain parenchyma, £ \ X IX C1 C2 C4 Fig. 4. Schematic drawing showing the neuroanatomical network involved in activating hiccups. (A) Nucleus tractus solitarius (dorsal group: inspiration). (B) Nucleus ambiguous (ventral group: inspiration and expiration). Responsible for eliciting the Hering-Breuer reflex. (C)Nucleus parabrachialus (pneumotaxie centre: terminating inspiration). (D) Hypothetical apneustic centre (cancels the activity ofpneumotaxic centre). IX: hypoglossal nerve; X: vagus nerve; C1, C2, C4: upper cervical nerves. Intercostal nerves: arrowheads. 149 noted only on post-enhanced examination. MRI revealed multiple nodules corresponding to the CT findings, seen best on T2-weighted images. A nodule was noted in the medulla oblongata at the anticipated location of the 9th-10th nerves (Fig. 3). A diagnosis of multiple cerebral tuberculomas was made, the brainstem lesion responsible for the hiccup. The patient was put on antituberculous treatment. Follow-up MRI was performed after 6 months and again after 1 year, and revealed a gradual decrease in thc size of the nodules. The patient had no more hiccup and was declared to be clinically normal. Discussion The patients presented above clearly demonstrate the value of MRI in elucidating a central cause of intractable hiccup. There is no doubt that in our cases intractable hiccup is to be attributed to the lesions in the brainstem with resolution of the lesions and disappearance of the hiccups after therapy in 3 patients. From the pertinent literature, only a few instances of intractable hiccup are available, part of which are allegedly due to encephalitis or CVA, and very few report brainstem lesions as a cause (see Table 1). The paucity of reports as compared with our personal series is to be explained by the lack of physicians' awareness of central nervous system causes of intractable hiccup as well as by the limited availability of MRI which is now firmly established as the method of first choice for evaluating the brainstem. The neuroanatomical network that activates the formation of hiccup is known in some detail and includes the following structures: (1) the inspiratory dorsal group of the nucleus tractus solitarius, (2)the ventral group of the nucleus ambiguus, relaying the Hering-Breuer reflex (inhibiting continued inspiration), both groups being under the control of (3)the pontine pneumotaxic centre (terminating inspiration) and, finally, (4)the hypothetical apneustic centre, which cancels the activity of the pneumotaxic centres. In addition, voluntary supranuclear control is mediated by (5) descending corticobulbar pathways ( Fig. 4). Normally, the inspirational signal from the solitary tract is not a short, instantaneous burst, but a ca. 2 sec lasting "'ramp" recruitment discharge, terminated by pneumotaxic centre activity (Guyton 1989). Clearly, in hiccup, this solitary ramp activity has changed into an abrupt, full discharge from the dorsal solitary group and is, in addition, followed by sudden discharge of the dorsal vagal motor nucleus closing the glottis, which is also clearly pathological inasmuch as the glottis normally remains open during inspiration. Accordingly, hiccup, and particularly intractable hiccup, must be regarded as an abnormal involuntary movement with the features of the myoclonic jerk, due to disruption of supranuclear as well as the ventral ambiguus regulatory comrol. Any lesion localised within the tel- encephalon, the pons or the ventral part of the medulla oblongata involving descending corticopontine or corticomedullary fibre systems, will release the dorsal group from control and facilitate the autonomous generation of myoclonic discharge of the solitary nucleus, active on its own and no longer being subject to regulatory feedback servo-control. Up to now, all relevant reports of brainstem lesions generating intractable hiccup are anecdotal. The patients presented above include cases of brainstem infarction and tuberculomas. To the best of the authors" knowledge, this is the first time that tuberculomas are identified as a causative factor of intractable hiccup. Neurological examination in these cases does not necessarily reveal marked deficit. Accordingly, if no satisfactory gastrointestinal or thoracic cause is found rendering a "'peripheral" explanation feasible, MR imaging is mandatory in this category of cases for ultimate evaluation of the brainstem. Acknowledgements The authors gratefulL~ acknowledge their indebtedness to Professor George Bruyn, Department of Neurology, Academisch Ziekenhuis Leiden, The Netherlands. 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