Case Report

Long-standing Hiccup in a Patient with Sarcoidosis

Tetsuri KONDO, Toshimori TANIGAKI, Hideo SUZUKI, Seiji TAMAYA, Yasuyo Ohta and Hajime YAMABAYASHI

The patient was a 67-year-old male. A diagnosis of sarcoidosis was made both by transbronchial lung biopsy and by scalene node biopsy. The findings of his chest roentgenogram were categorized as the group II. There were no symptoms during follow-up period of one year at the out-patient clinic with no medication. The chest X-ray findings of the patient wereslowly progressive. Intractable hiccup developed one year after his first visit to the hospital. With administration of prednisolone, serum angiotensin converting enzyme level decreased promptly, and the incidence of the hiccup attack decreased. As the dose of prednisolone was tapered, the hiccup recurred. All the drugs used for hiccup including quinidine sulfate and methochropramide was not effective. A thoracic CT revealed slight enlargement of mediastinal lymph nodes. A brain CT and a brain MRI demonstrated no abnormalities. Acetazolamide, which induces acidosis in brain extra-cellular fluid, worsened the symptoms. As prednisolone was given again, infiltrates on the chest roentgenogram began to resolve and the incidence of hiccup decreased. We conclude that the long-standing hiccup observed in this patient may be brought by the lesion in central nervous system due to sarcoidosis.

Key Words: Brain stem, Acetazolamide, Prednisolone, Angiotensin converting enzyme, Neurosarcoidosis

Hiccup is a clonic contraction of diaphragm, and 1) demonstrated numerous small nodules of up to is usually a benign and transient disorder. However, 8 mmin diameter scattered in the both lungs. The hiccup is rarely associated with sarcoidosis (1). Since nodules distributed more densely in the upper lung hiccup is occasionally associated with tumor or fields and some of them were confluent. No hilar thrombosis in the brain stem (2), it may arise from lymphadenopathies were seen. The hematocrit was granulomatous brain stem lesion as well. We pre- 39.8 percent. A white blood cell count was sent a case of sarcoidosis with long-standing hiccup. 6800/cumm with the normal hemograms. The The time course and the responses to several drugs calcium level was 4.5 mg per liter. The laboratory suggested that the hiccup may etiologicalry be related data were GOT 22 IU/1, GPT 13 IU/1, creatinine to sarcoidosis in this patient. 1.7 mg/dl, and ESR 25 mm/hr. Serum angiotensin converting enzyme(ACE) was 33 IU/1 (normal value CASE REPORT 8.3-21.4). Pulmonary function tests revealed FVC In April, 1982, a 67-year-old male was referred 2.50 1 (88.79/o of the normal predicted value), to the hospital because of abnormal infiltration on FEV1>02.25 1 and DLCO 14 ml/min/mmHg. The the chest X-ray film. A physical examination re- lung tissues obtained by transbronchial lung biopsy vealed crepitant rales over the left lateral thorax, and (TBLB) showed granulomatous infiltration with a a small lymphnode of 8 mm in diameter at the left few multinucleated giant cells with negative tuber- supraclavicular region. A chest roentgenogram (Fig. culous bacilli. The supraclavicular lymphnode was

From The Department of Medicine, School of Medicine, Tokai University, Isehara. Received for publication July ll, 1988 eprint request to: Tetsuri Kondo, MD, Department of Medicine, School of Medicine,

R Tokai University, Isehara, Kanagawa 259-1 1, Japan

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4 s e c Fig. 2. Records during an attack. Air flow at mouth (top Fig. 1. Chest roentgenogram at first visit to the hospital trace), chest wall (middle) and abdominal wall movements was compatible with group II sarcoidosis. (bottom). Hiccup paroxysms are indicated by arrows. replaced by multifocal non-necrotizing granulo- All the oral medications including 1.6 mg matous inflammation including Langhans giant alprazolam a day, 600 mg quinidine sulfate a day, cells. The findings of both specimens were consistent 400 mg vaporate sodium a day, 300 mg phenytoin with sarcoidosis. The patient was followed without a day, 1.0 mg clonazepam a day, had no effects on medications at out-patient clinic. hiccup. Intravenous administration of 10 mg of One year later frequent attack of hiccup methochropramide (3) or 100 mg of phenytoin had developed, and persisted for four to five days con- alsono effects. Two days after 500 mg administra- tinuously. A physical examination revealed that tion of acetazolamide, hiccup developed and lasted breath sounds were audible at the inspiratory phase for 10 days. Hiccup ceased on the following day of hiccup. A high-pitch voice characteristic of hiccup after acetazolamide was discontinued by himself, washeard in most occasions. The intercostal muscles and did not appeared for subsequent 5 days. appeared not to be involved in hiccup. A neurologic A chest X-ray film taken in September 1987 examination and a radiograph of upper GI tracts showed advanced fibrotic changes. No abnormal were negative. He was followed at out-patient clinic findings were detected on the brain CT and brain ith no medication for one more year. magnetic resonance image (MRI). An electroencep-

w Achest roentgenogram taken in September 1984 halogram (EEG) was also within normal limits. A disclosed that his fibrocystic changes were thoracic CT revealed mild swelling of mediastinal aggravated. The serum ACE was 70 IU/1, and the lymphnode. The level of ACE was 28.9 IU/1 and ESR was 38 mm/hr. The FVC was 2.08 1, and ESR was 30 mm/hr. PSL administration of 30 mg FEV10 was 1.75 1. With oral administration of a day was started again from September 1987. As prednisolone (PSL) of 30 mg a day, the incidence the serum ACE decreased promptly to ll.4 IU/1, and intensity of hiccup decreased gradually. As the the incidence and intensity of hiccup decreased again dose of PSL reduced to 10 mg a day, the incidence as shown in Fig. 3. of hiccup increased again. Hiccups persisted approximately for 10 days and subsided for DISCUSSION following 10 days. Figure 2 shows the record of The fact that diaphragmatic contraction and air flow at the mouth, and of chest and abdominal vocal cord closure were concurrently observed in this wall movements during an attack. It shows that at patient indicates that the attack was real hiccup and each paroxysms of hiccup air flow stops abruptly, not diaphragmatic flutter (4). The diagnosis of and then the thoracic dimension reduces and abdo- sarcoidosis was also definite on the basis of the minal dimension increases, suggesting that the vocal clinical findings including the chest roentgenogram, cord is closed. tissues obtained by TBLB and lymphnode biopsy,

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I n c i d e n c e o f h i c c u p s / d a y A C E 3 fl ? 0 of his hiccup. Exacerbation of hiccup by administra- 5 1 P S L 3 0 tion of acetazolamide strongly suggests that the 3 - S O - - 7 W attack is of a central origin, because this drug in- 蝣^ 5 0 - ' / "u r . - - x - - ~ v ｫ r 4 0 2 0 o duces acidosis of extracellular fluid in the brain. Sar- ｫ 3 0 蝣g 2 0 K 10 coidosis involves the nervous system in approxi- S I O mately 5 percent of all the cases (7). The most com- 2 3 4 5 6 7 m o n t h 19 8 6 1 9 8 7 1 9 8 8 y e a r monfeatures of neurosarcoidosis are peripheral neuropathies of cranial nerves and diabetes inspidus Fig. 3. Clinical course of the case. - is incidence of hiccup (days developing hiccups per month). - serumACE (8). Sinokawa et al. (9) reveiwed ll cases of level. Note, incidence of hiccups changed in parallel with neurosarcoidosis without diabetes inspidus, and serum ACE level and was markedly decreased by oral found that none of them developed hiccup. prednisolone therapy. Souadjian and Cain (1) reviewed 220 cases of hiccup, nd found only one case of sarcoidosis. and high level of serum ACE. The observation that Our intensive brain survey with CT, MRI and the incidence and intensity of hiccup varied with the EEG did not identify any definite sarcoid lesion in activity of sarcoidosis, suggests that the hiccup we thebrain. The CT findings in neurosarcoidosis are observed was related to sarcoidosis. However, either space-occupying lesion (10) or diffuse contrast hiccup may arise from any disorders other than enhancement which suggests meningeal involvement sarcoidosis (1). Any disorders in gastro-intestinal (7). However, small lesions less than 5 mm in the tracts are not likely in this case because there were brain stem are difficult to detect with CT. Diffuse no symptoms and no radiologic findings of the contrasta enhancement in CT may sometimes be gastro-intestinal tracts. Multiple sclerosis can also overlooked in the early stage of the disease. be excluded by the MRI findings. There were no Therefore,despite our negative study, wesuspect the evidence of systemic metabolic disturbance. brain stem lesion in this patient as an origin of Although glucocorticoids has extensively been used hiccup as all the clinical data suggest it. Since, to relieve cerebral edema in patient with brain acetazolamide has effects to inhibit epileptic seizure, tumor, his long-standing history for four years sug- mechanism other than irritative lesion in the brain gests that the origin of hiccup is not a brain tumor. stem (ll) might also be taken into consideration. Furthermore, a high-dose steroid invokes hiccups by However, knowledges on the mechanism of hiccup its effect on synaptic transmission or by its neuro- are very limited so far. Since sarcoidosis in the excitatory properties (5). Stern et al. (6) postulated central nervous system has been reported to be very that a patient has neurosarcoidosis if (i) systemic resistant to steroid therapy (12), it was not surprising sarcoidosis is present and the neurologic illness can that the hiccup were not completely suppressed by be reasonably attributed to sarcoidosis while other prednisolone therapy. causes are excluded, or (ii) other systemic manifesta- tions of sarcoidosis can not be established but REFEREN CES pathologic examination at the site of neurologic in- 1) Souadjian JV, Cain JC: Intractable hiccup, etiological volvement is consistent with the diagnosis of sar- factors in 220 cases. Postgrad Med 43: 72, 1968. coidosis and no other cause for the illness can be 2) Newsom-Davis J: An experimental study of hiccup. Brain 93: 851, 1970. identified.From above consideration, we conclude 3) Williamson BWA, Macintyre IMC: Management of hat our patient had neurosarcoidosis. intractable hiccup. Brit Med J 20: 501, 1977. Since the mechanism of hiccup involves both the 4) Rigatto M, De Medeiros NP: Diaphragmatic flutter, diaphragm and the laryngeal nerves, the responsible report of a case and review of literature. AmJ Med 32: 103, 1962. lesiont developing hiccup in this patient should be located in any area higher than phrenic moto- 5) Baethge BA, Lidsky MD: Intractable hiccups associated with high-dose intravenous methylprednisolone therapy. neurons. Thus, stimulation to the phrenic nerve Ann Int Med 104: 58, 1986. along its course, for instance, by the enlarged 6) Stern BJ, Krumhorz A: Neurosarcoidosis, presentation mediastinal lymph nodes, is not likely to be a cause and management, Ann NY Acad Sci 465: 722, 1986.

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Matsui Y: Cranial neuropathies in sarcoidosis. Shinkei l able hiccups as a manifestation of multiple sclerosis. Naika 3: 419, 1975. Neurol 29: 797, 1979. Shinokawa M, Mitsuma T, Onishi Y, et al: A case of Ikeda K, Nakajima A, Fujita H, et al: A case with sarcoidosis involving the central nervous system. Kokyu central nervous system sarcoidosis. Jap J Thoracic Dis 4: 344, 1985. 25: 1005, 1987.

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