ALERTS, NOTICES, AND CASE

642

infusing 0.5 to 1.0 grams per kg of mannitol (10% or 20%) resulted in "significant" improvement in 5 (42%) and "dramatic" improvement in 3 (25%) of 12 patients with ciguatera fish poisoning.25 There have been no controlled studies of any of these agents in ciguatera poisoning, and appropriate caution should be used in employing these therapies. Public health officials should be notified as soon as a case of ciguatera poisoning is suspected, as an epidemic may rapidly unfold. Ciguatera poisoning is not specifically a reportable disease, but it is a food-borne illness. In California, physicians are required to report immediately by telephone when two or more cases or suspected cases of food-borne illness from separate households are suspected to have the same source of illness (title 17, California Code of Regulations, sections 2500, 2504, 2574). Acknowledgements Tim McCarthy, PharmD, San Francisco Bay Area Regional Poison Control Center, assisted with the prompt diagnosis of the outbreak; Fran Taylor, MD, and Mr Ben Gale, San Francisco Department of Public Health, assisted with notifying the county and providing clinical consultation; Tim Berger, MD, Department of Dermatology, San Francisco General Hospital Medical Center, provided clinical assistance and manuscript review; and Ben Werner, MD, and Mr Warren Crawford, Infectious Diseases Branch, California State Department of Health Services, assisted with notifying the state and providing clinical consultation. REFERENCES 1. Ciguatera fish poisoning. Calif Morbid October 28, 1977 2. Lange WR, Lipkin KM, Yang GC: Can ciguatera be a sexually transmitted disease? J Toxicol Clin Toxicol 1989; 27:193-197

3. Hughes JM, Merson MH: Current concepts, fish and shellfish poisoning. N

EngI J Med 1976; 295:1117-1120

4. Calvert GM, Hryhorczuk DO, Leikin JB: Treatment of ciguatera fish poisoning with amitriptyline and nifedipine. J Toxicol Clin Toxicol 1987; 25:423-428 5. Lipkin KM: Ciguatera poisoning presenting as a psychiatric disorder. Arch Gen Psychiatry 1989; 46:384-385 6. Davis RT,Villar LA: Symptomatic improvement with amitriptyline in ciguatera fish poisoning (Letter). N EngI J Med 1986; 315:65 7. Bogart JN, Perrotta DM: Ciguatera intoxication from Texas Gulf Coast fish (Letter). Tex Med 1989; 85:15 8. Vogt RL, Liang AP: Leads from the MMWR: Ciguatera fish poisoning-Vermont. JAMA 1986; 255:2727 9. Helfrich RM, Henning KG, Dunlop E, Martin SE, Rosenberger EA, Montgomery County Health Dept: Ciguatera fish poisoning-Maryland. MMWR 1980; 29:610611 10. Ho AMH, Fraser IM, Todd ECD: Ciguatera poisoning: A report of three cases. Ann Emerg Med 1986; 15:1225-1228 11. Morris PD, Campbell DS, Freeman JI: Ciguatera fish poisoning: An outbreak associated with fish caught from North Carolina coastal waters. South Med J 1990; 83:379-382 12. Lange WR: Ciguatera toxicity. Am Fam Physician 1987; 35:177-182 13. Legrand AM, Galonnier M, Bagnis R: Studies on the mode of action of ciguateric toxins. Toxicon 1982; 20:311-315 14. Bagnis R, Chanteau S, Chungue E, Hurtel JM, Yasumoto T, Inoue A: Origins of ciguatera food poisoning: A new dinoflagellate, Giambierdiscus toxicus Adachi and Fukuyo, definitively involved as a causal agent. Toxicon 1980; 18:199-208 15. Dembert ML, Strosahl KF, Bumgarner RL: Diseases from fish and shellfish ingestion. Am Fam Physician 1981; 24:103-108 16. Auerbach PS: Ciguatera toxin poisoning. West J Med 1985; 142:380-381 17. Bidard JN, Vijverberg HP, Frelin C, et al: Ciguatoxin is a novel type of Na+ channel toxin. J Biol Chem 1984; 259:8353-8357 18. Bagnis R, Kuberski T, Laugier S: Clinical observations on 3,009 cases of ciguatera (fish poisoning) in the South Pacific. Am J Trop Med Hyg 1979; 28:10671073 19. Sime JK: A theoretical discourse on the pharmacology of toxic marine ingestions. Ann Emerg Med 1987; 16:1006-1015 20. Sakamoto Y, Lockey R, Krzanowski JJ Jr: Shellfish and fish poisoning related to the toxic dinoflagellates. South Med J 1987; 80:866-872 21. Morris JG: Ciguatera fish poisoning (Letter). JAMA 1980; 244:273-274 22. Bowman PP: Amitriptyline and ciguatera (Letter). Med J Aust 1984; 140:802 23. Lange WR, Kreider SD, Hattwick M, Hobbs J: Potential benefit of tocainide in the treatment of ciguatera: Report of three cases. Am J Med 1988; 84:1087-1088 24. Palofax NA, Jain LG, Pinano AZ, Gulick TM, Williams RK, Schatz IJ: Successful treatment of ciguatera fish poisoning with intravenous mannitol. JAMA 1988; 259:2740-2742 25. Peam JH, Lewis RJ, Ruff T, et al: Ciguatera and mannitol: Experience with a new treatment regimen. Med J Aust 1989; 151:77-80

REPORTS

Sarcoidosis of the Breast, Central Nervous System, and Exocrine Glands in a Patient With Sicca Symptoms KENNETH H. FYE, MD RIPLEY H. HUNTER, MD San Francisco, California

SARCOIDOSIS IS A SYSTEMIC inflammatory disease of unknown etiology characterized by noncaseating epithelioid cell granulomata. The lungs and reticuloendothelial system are typically involved, and virtually any organ system, including the salivary glands, may be affected. Clinical involvement of the I

breast, however, is exceedingly rare.2 syndrome is an autoimmune disorder characterized by keratoconjunctivitis sicca, xerostomia, and clinical or laboratory evidence of systemic autoimmunity.3 The disorder is pathogenetically defined by mononuclear cell infiltration into exocrine glands, and the diagnosis can be confirmed by minor salivary gland biopsy. Sarcoidosis can also affect exocrine glands and cause sicca symptoms.4 In such patients, minor salivary gland biopsy will show typical noncaseating granulomata that will distinguish sarcoidosis from Sj6gren's syndrome. Herein we report the case of a woman who presented with sicca symptoms and lymphadenopathy consistent with Sjogren's syndrome and with a hard left breast mass suggestive of breast cancer. Minor salivary gland and breast biopsies revealed only noncaseating granulomata diagnostic of

Sjogren's

sarcoidosis.

Report of a Case

The patient, a 70-year-old white woman, was seen in November 1989 because of a firm left axillary lymph node enlarged to about 4cm in diameter. A thorough breast examination revealed no abnormalities. A complete blood count, liver function test values, a chest x-ray film, mammography, and computed tomography (CT) of the chest and mediastinum were all normal. Fine-needle aspirate of the node revealed lymphocytes, histiocytes, and a rare "immunoblastic" cell. The patient refused open biopsy. By April of 1990, she had begun to have neck and jaw pain, xerostomia, and xerophthalmia with significant bilateral submandibular gland enlargement. A needle biopsy of one of the submandibular glands revealed lymphocytic infiltration of benign salivary gland tissue. Treatment with fast-acting nonsteroidal anti-inflammatory agents resulted in symptomatic improvement. In July, acute diplopia and vertigo developed. On physical examination, the patient had a left lateral rectus muscle palsy, sublingual and labial salivary gland hypertrophy, persistent

submandibular gland enlargement, left axillary lymphadenopathy, and a hard mass 3 cm in diameter in the lower inner

(Fye KH, Hunter RH: Sarcoidosis of the breast, central nervous system, and exocrine glands in a patient with sicca symptoms. West J Med 1991 Dec; 155:642-644)

From the Division of Rheumatology, Department of Medicine, University of Califomia, San Francisco, School of Medicine. Reprint requests to Kenneth H. Fye, MD, 900 S Eliseo Dr, Greenbrae, CA 94904.

THE WESTERN JOURNAL OF MEDICINE

THE

WESTERN

JOURNAL

OF

MEDICINE

DECEMBER 1991

o *

DECEMBER

o *

1991

155

155

o *

quadrant of the left breast. There was no hepatosplenomegaly. A complete blood count and the results of an electrolyte panel, glucose, renal and thyroid function tests, quantitative immunoglobulin assay (IgG, IgM, and IgA), and urinalysis were normal. The erythrocyte sedimentation rate (Westergren) was 19 mm per hour. Liver function test values were normal except for a lactate dehydrogenase of 227 units per liter (normal 90 to 225) and an aspartate aminotransferase (formerly SGOT) of 63 units per liter (normal 0 to 35). The serum calcium level was 2.42 mmol per liter (9.7 mg per dl) and the phosphorus level 1.32 mmol per liter (4.1 mg per dl). The serum angiotensin-converting enzyme level was 1,050 nmol liter-' second`' (63 IU/ml; normal < 670 nmol liter-l second-'). A latex fixation test was negative for rheumatoid factor, but the antinuclear antibody assay was positive to a titer of 1:320 (speckled). An x-ray film and CT of the chest were again normal, as was CT of the abdomen. A CT scan of the head with contrast revealed an area of possible enhancement in the suprasellar region. Biopsy of the minor salivary glands showed epithelioid noncaseating granulomata, and stains and cultures were negative for acid-fast bacilli and fungi. A diagnosis of sarcoidosis was established, but we could not rule out a concurrent and unrelated breast cancer. Therefore, an excisional biopsy of the breast lesion was done. Careful histologic examination revealed only epithelioid noncaseating granulomata and numerous multinucleated giant cells diagnostic of sarcoidosis (Figure 1). There were no signs of malignancy. A regimen of 40 mg of prednisone per day was started, with plans to taper the dose when clinically warranted. Within a month, the left lateral rectus palsy and vertigo had disappeared and the lymph node and salivary gland enlargement had resolved. Four months later, the patient was asymptomatic on a maintenance dose of 5 mg of prednisone per day. Discussion Even though x-ray films and CT scans of the chest were repeatedly normal, our patient clearly had sarcoidosis. First, she had a modest elevation in angiotensin-converting enzyme levels. Although these levels may be elevated in a host of chronic inflammatory disorders, in the proper clinical circumstances, they are strongly suggestive of sarcoidosis.5 P

P44

-

_.I: r

.~'

.~.

.91

Figure 1.-Histologic examination of a breast biopsy specimen shows a noncaseating granuloma with multinucleated giant cells typical of sarcoidosis thematoxylin and eosin stain; original magnification x 160).

6 6

643

Second, histologic examination of minor salivary gland and breast biopsy specimens showed multiple epithelioid noncaseating granulomata typical of sarcoidosis. Mycobacterial and fungal infections were excluded by the use of appropriate staining and culture techniques. The presence of antinuclear antibody was not incompatible with a diagnosis of sarcoidosis, as antinuclear antibodies have been observed in sarcoid patients.6 The association of sarcoidosis with sicca symptoms is well known. Drosos and co-workers described the cases of five patients with xerophthalmia and xerostomia, documented by a positive rose bengal or Schirmer's test and decreased salivary flow, in whom the diagnosis of sarcoidosis was made by minor salivary gland biopsy (3 patients) or transbronchial lung biopsy (2 patients).' The presence of granulomata in minor salivary gland tissue allows clinicians to distinguish sarcoidosis from Sjogren's syndrome because noncaseating granulomata are found in the minor salivary glands of patients with sarcoidosis even when sicca symptoms are not present, but they are not seen in patients with known Sjogren's syndrome.7 Giotaki and associates found no noncaseating granulomata in the biopsy specimens of minor salivary glands of 28 patients with Sjogren's syndrome, all of whom showed typical lymphocytic infiltration, fibrosis, or both.8 In patients with sarcoidosis, the finding of noncaseating granulomata in minor salivary glands is often associated with an increased uptake of radioactive gallium into salivary glands, with hilar adenopathy, or with the presence of sicca symptoms.7 We did not do a gallium scan because the diagnosis of sarcoidosis was made on the basis of a minor salivary gland biopsy done during the evaluation of what we thought was Sjogren's syndrome. Although our patient had dramatic peripheral lymphadenopathy, hilar adenopathy was not observed even with serial x-ray films and CT scans of the chest. Our patient did, however, have sicca symptoms. Because cranial nerve palsies are characteristic of neurosarcoidosis,9 we think our patient's lateral rectus muscle palsy was a manifestation of her sarcoidosis. Computed tomography has almost eliminated the need for myelography, air-contrast studies, or angiography in the evaluation of neurosarcoidosis,'0 but magnetic resonance imaging may be even better than CT for assessing intracranial lesions." Because in our patient CT scans were abnormal and a diagnosis of sarcoidosis had already been made on minor salivary gland biopsy, magnetic resonance imaging was not felt to be necessary. The area of contrast enhancement noted in the suprasellar region of our patient is consistent with previous observations that intracranial sarcoid granulomas do enhance with the administration of a contrast medium. 12 The resolution of the lateral rectus muscle palsy was expected because neurosarcoidosis frequently responds to corticosteroid therapy. " Breast involvement is exceedingly unusual in sarcoidosis. In 1978 Rigden reported the development of sarcoidosis of the breast in a 29-year-old woman five years after the onset of pulmonary sarcoidosis.2 In 1984 Raju and McShine reported the case of a 60-year-old woman who presented with a breast mass suggestive of cancer that proved on excisional biopsy to be sarcoidosis. ' Two years later Banik and colleagues reported the case of a 28-year-old woman in whom the diagnosis of sarcoidosis was made serendipitously when sarcoid granulomata were found in the mammary lobules adjacent to a fibroadenoma that had been resected. ' It is known that

ALERTS, NOTICES, AND CASE REPORTS

644

sarcoidlike stromal reactions with granuloma formation may be seen in patients with breast cancer,'5 and there may be an increased incidence of breast cancer in patients with a history of sarcoidosis. I6 Therefore, we took special care to be certain there was no evidence of malignancy in the breast biopsy specimen from our patient. The only abnormalities encountered on careful histologic examination of the biopsy specimen were epithelioid noncaseating granulomata diagnostic of sarcoidosis. To our knowledge, this is only the fourth case of sarcoidosis of the breast to have been reported in the English-language literature since 1978. REFERENCES 1. Mitchell DN, Scadding JG, Heard BE, Hinson KFW: Sarcoidosis: Histopathological definition and clinical diagnosis. J Clin Pathol 1977; 30:395-408 2. Ridgen B: Sarcoid lesion in breast after probable sarcoidosis in the lung. Br Med J 1978; 2:1533-1534 3. Strand V, Talal N: Advances in the diagnosis and concept of Sjogren's syndrome. Bull Rheum Dis 1980; 20:1042-1052 4. Drosos AA, Constantopoulos SH, Psychos D, Stefanou D, Moutsopoulos HM: The forgotten cause of sicca complex: Sarcoidosis. J Rheumatol 1989; 16:1548-1551 5. Romer FK: Angiotensin-converting enzyme activity in sarcoidosis and other disorders. Sarcoidosis 1985; 2:25-34 6. Soto-Aguilar MC, Boulware DW: Sarcoidosis presenting as antinuclear antibody positive glomerulonephritis. Ann Rheum Dis 1988; 47:337-339 7. Harvey J, Catoggio L, Gallagher PJ, Maddison PJ: Salivary gland biopsy in sarcoidosis. Sarcoidosis 1989; 6:47-50 8. Giotaki H, Constantopoulos SH, Papadimitriou CS, Moutsopoulos HM: Labial minor salivary gland biopsy: A highly discriminatory diagnostic method between sarcoidosis and Sjogren's syndrome. Respiration 1986; 50:102-107 9. Cahill DW, Salcman M: Neurosarcoidosis: A review of the rarer manifestations. Surg Neurol 1981; 15:204-21 1 10. Kendall BE, Tatler GL: Radiological findings in neurosarcoidosis. Br J Radiol 1978; 51:81-92 11. Cooper SD, Brady MB, Williams JP, Pilgreen KL, Harp DL, Weissman JR: Neurosarcoidosis: Evaluation using computed tomography and magnetic resonance imaging. J Comput Assist Tomogr 1988; 12:96-99 12. Kumpe DA, Rao CV, Garcia JH, Heck AF: Intracranial sarcoidosis. J Comput Assist Tomogr 1979; 3:324-330 13. Raju GC, McShine LAH: Sarcoid lesion in the breast presenting as carcinoma. Trop Geogr Med 1984; 36:297-298 14. Banik S, Bishop PW, Ormerod LP, O'Brien TEB: Sarcoidosis of the breast. J Clin Pathol 1986; 39:446-448 15. Bassler R, Birke F: Histopathology of tumour associated sarcoid-like stromal reaction in breast cancer. Virch Arch [A] 1988; 412:231-239 16. Brincker H: Solid tumors preceding or following sarcoidosis. Med Pediatr Oncol 1987; 15:82-88

Isoniazid Overdose Successful Treatment With Pyridoxine and Hemodialysis JOSEPH M. CASH, MD Rapid City, South Dakota EDWARD T. ZAWADA, Jr, MD Sioux Falls, South Dakota

TUBERCULOSIS remains a major public health problem in the developing world. Native Americans, immigrants from the Third World, and immunocompromised patients are the groups in the United States at highest risk. Isoniazid, the hydrazide of isonicotinic acid, is the primary drug prescribed for the treatment of active tuberculosis and the prophylaxis of tuberculosis exposure. Mild, reversible hepatotoxicity is the most common adverse drug reaction associated with thera(Cash JM, Zawada ET Jr: Isoniazid overdose-Successful treatment with pyridoxine and hemodialysis. West J Med 1991 Dec; 155:644-646) From the Department of Internal Medicine, University of South Dakota School of Medicine, Rapid City (Dr Cash), and Sioux Falls (Dr Zawada), South Dakota. Reprint requests to Edward T. Zawada, Jr, MD, Department of Internal Medicine, University of South Dakota School of Medicine, 2501 W 22nd St, Sioux Falls, SD 57117-5046.

peutic dosages. Acute neurologic toxicity associated with overdose, however, may be fatal if not recognized and treated promptly. We present a recent case of isoniazid overdose successfully treated with pyridoxine hydrochloride and hemodialysis. Report of a Case The patient, a 16-year-old man, was placed on a regimen of isoniazid prophylaxis in November 1988 after the discovery of a 10-mm reaction to a purified-protein-derivative skin test. He had slashed his wrists twice before and had been treated for drug and alcohol abuse. His medical history was otherwise unremarkable. Eight months later, he ingested between 7,500 and 13,500 mg of isoniazid after a disagreement with his girlfriend. He collapsed 30 minutes later and was rushed to a local community hospital, being comatose on arrival. Three seizures were witnessed in the emergency department, whereupon 8.35 grams of pyridoxine and 8 mg of diazepam were infused. The patient regained consciousness and had no further seizures. He was transferred by air ambulance to Sioux Valley Hospital in Sioux Falls, South Dakota. On arrival, he was alert and fully oriented. Arterial blood gas determinations showed a pH of 7.42, a Pco2 of 29 mm of mercury, and a Po2 of 82 mm of mercury. Other laboratory values included a leukocyte count of20.1 x 109 per liter (20,100 per idl); hemoglobin 157 grams per liter (15.7 grams per dl); sodium 139, chloride 108, potassium 3.4, and carbon dioxide content 20 mmol per liter; glucose 5.0 mmol per liter (90 mg per dl); creatinine 80 itmol per liter (0.9 mg per dl); blood urea nitrogen 3.2 mmol per liter (9 mg per dl); aspartate aminotransferase (formerly SGOT) 36 units per liter; and alanine aminotransferase (formerly SGPT) 13 units per liter. Isoniazid levels, which were measured by the standard method of Scott and Wright,' are shown in Figure 1. Using a femoral vein catheter, hemodialysis was started shortly after admission for several reasons: A Toxline computer search indicated that this patient had ingested nearly double an amount that had previously resulted in death in some patients (80 to 150 mg per kg)2; the exact amount ingested was not known, and no charcoal or cathartic mixture had been given to prevent absorption; it was unclear if the initial isoniazid level, which was nearly five times the upper therapeutic level, was a peak or might continue to rise; and he had been symptomatic with the most severe toxic reactions to isoniazid-central nervous system toxicity. No further seizures were noted, and postdialysis isoniazid levels were negligible. He was transferred to a psychiatric facility the following day.

Discussion Epidemiology High rates of isoniazid overdose have been reported in Southeast Asian refugee women and Native Americans living on reservations. The government screens all refugees for tuberculosis and treats those with active disease and positive skin tests. The Indian Health Service aggressively identifies contacts of persons with active tuberculosis and provides appropriate treatment. In Olmsted County, Minnesota, the risk of isoniazid overdose in the Cambodian population is 14 cases per 111 person-years of isoniazid use.3 Nolan and co-workers estimate that 4.2% of Southeast Asian refugee women between the