Reversal of a Neurologic Paraneoplastic Syndrome with Octreotide (Sandostatin) in a Patient with Glucagonoma ALEX HOLMES, M.B.B.s., CHRISTINE KILPATRICK, M.D., JOSEPH PROIETTO, M.B.B.s., Ph.D., MICHAELD. GREEN, M.B.B.s., Victoria, Australia

A 69-year-old woman with classic glucagon- oma syndrome had associated progressive neuro- logic disease manifest as dementia, ataxia, optic atrophy, and lower limb weakness. Visual evoked responses (VERs) were absent biiteral- ly. After an attempt at resection was unsuccess- fuJ therapy was started with somatostatin ana- logue (Sandostatin, SMS 201495). Over the ensuing 3 months, there was a decrease in the plasma glucagon level, resolution of the rash, weight gain, reversal of the dementia, and an improvement in coordination and limb weakness. Subsequent VERa revealed bilateral delayed responses.

From the Departments of Medical Oncology (AH, MDG), Neurology (CK), and Endocrinology (JP), The Royal Melbourne Hospital, and the Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.

Requests for reprints should be addressed to Michael D. Green, M.B.B.S., Department of Medical Oncology, c/o Post Office, The Royal Melbourne Hospital, Victoria 3050, Australia.

Manuscript submitted June 15, 1990, and accepted in revised form November 19. 1990.

CASE REPORT History

A previously healthy 69-year-old woman was di- agnosed as having diabetes mellitus in 1979. This was well controlled with diet alone until 1987, when therapy with gliblenclamide was started. At that time, angular stomatitis was noted. In the ensuing months, the patient developed a migratory ulcerat- ing rash on the lower limbs in addition to gradual weight loss, visual deterioration, slowed mentation, gait disturbance, and urinary incontinence. In Jan- uary 1988, a computed tomographic (CT) scan of the abdomen revealed a 5-cm pancreatic mass with a single lesion in the left hepatic lobe. This was believed to be due to a pancreatic cancer with me- tastasis. Her diabetes progressively worsened over this time, and insulin therapy was started in May 1988. Over the next 12 months, there was persistent diarrhea and fecal incontinence, progressive de- mentia, ataxia, and leg weakness that rendered the patient bedridden, and extensive progression of the rash, especially around the perineum. In April 1989, a calf vein thrombosis was diagnosed and treated with anticoagulant.

In August 1989, the patient was hospitalized for re-evaluation. Examination revealed extensive ne- crolytic migratory erythema (NME) with onycholy- sis and stomatitis. Neurologic examination revealed a global decrease in cognitive function, with partic- ular involvement of short-term memory and ab- stract thinking and an abnormally labile affect. There was gross truncal and limb ataxia, and lower limb examination revealed flaccid profound weak- ness in all muscle groups with hyperreflexia and bilateral extensor plantar responses. The patient had great difficulty in writing, as evidenced by her signature (Figure l), and was unable to read any form of printed matter. Visual acuity was reduced bilaterally to 6/60, and funduscopy revealed bila- teral optic atrophy.

Laboratory Studies Laboratory examination of blood samples re-

vealed the following values: serum glucagon 4,400 pg/mL (normal: 20 to 150 pg/mL), albumin 28 g/L, alkaline phosphatase 101 IU/L (normal: less than 90 III/L), and y-glutamyltransferase 121 IU/L (nor-

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1989 ( 3 months of treatment )

Figure 1. Sample of patient’s signa- tures over a 3-year period.

mal: less than 50 IU/L). Generalized hypoaminoaci- demia was present. Fasting serum insulin and C- peptide levels were 120 mU/L (normal: less than 15 mu/L) and 2.6 nmol/L (normal: 0.2 to 0.69 nmol/L), respectively. Serum bilirubin, serum electrolytes, gastrin, parathyroid hormone, calcitonin, vasoac- tive intestinal peptide, amylase, cholesterol, calci- um, creatine kinase, hemoglobin, platelet and dif- ferential white cell counts, clotting profile, Bi2, and folate were all normal. Results of serologic testing for Treponema pallidurn, human immunodeficien- cy virus, and human T-cell leukemia virus type I were negative. The cerebrospinal fluid was acellular with a normal protein concentration and no oligo- clonal bands. A CT scan of the abdomen showed a spherical 5-cm mass in the body of the pancreas, with proximal and distal pancreatic duct calcifica- tion and splenic vein dilation. A magnetic reso- nance imaging (MRI) scan of the abdomen demon- strated two superficial 2-cm liver metastases. A CT scan of the brain revealed mild cortical and cerebel- lar atrophy and ventricular dilation. An MRI scan of the brain detected multiple white-matter lesions of up to 1.5 cm in size on Tz-weighted images, espe- cially in the periventricular regions. In addition, significant brainstem atrophy was found. Results of a total myelogram were normal. Visual evoked re- sponses (VERs) to pattern reversal stimulus using checks were absent. Histopathologic examination of a skin biopsy of the rash was consistent with NME.

Progress and Management A laparotomy was performed in September 1989.

The tumor was found to be adherent to superior mesenteric vasculature, and debulking was exclud- ed because of high tissue vascularity. An excision biopsy of the hepatic lesions was performed. Micro- scopic examination of biopsy specimens demon- strated solid sheets of cuboidal cells with uniform nuclei and sparse amphophilic cytoplasm strongly staining for glucagon. The development of NME

within and adjacent to the laparotomy scar was not- ed 48 hours after surgery. Somatostatin analogue (SMS 201-995) in a dose of 50 pg subcutaneously twice daily was started 7 days after laparotomy.

Over the next 3 months, all of the patient’s symp- toms markedly improved. At follow-up in Decem- ber 1989, the rash, angular stomatitis, and diarrhea had resolved, and the patient had gained 10 kg. She was reading and walking with the assistance of a walker; in addition, her handwriting had dramati- cally improved (Figure 1). Neurologic examination revealed normal visual acuity and fields but persis- tent optic atrophy. Lower limb power was im- proved, although there was residual pyramidal weakness with flaccidity, hyperreflexia, and exten- sor plantar responses. Mental status examination revealed normal cognitive function and affect. The plasma glucagon level was 167 pg/L. MRI scan of the brain showed persistence of the white-matter lesions. An abdominal CT scan found no change in tumor size. VERs demonstrated latencies to PI00 of 128 and 115 ms and amplitudes of 4 PV and 3.5 PV in the left and right eyes, respectively, indicating improvement in optic nerve conduction.

COMMENTS The glucagonoma syndrome has been well de-

scribed. Its most common features are NME, angu- lar stomatitis, onycholysis, mild diabetes, diarrhea, monochromic monocytic anemia, hypoaminoacide- mia, and recurrent venous thrombosis associated with a tumor of the (Y islet cells of the pancreas. Hypocholesterolemia, gastrointestinal disturbance, and neuropsychiatric symptoms have also been re- ported [1,2].

Khandekar et al [2] described a patient with clas- sic features of glucagonoma with a syndrome of pro- gressive dementia, optic atrophy, ataxia, nystag- mus, generalized hyperreflexia, and lower limb weakness and spasticity. Results of a CT scan of the head were normal, and glucagon was found in the cerebrospinal fluid. The patient was treated with

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streptozotocin and &fluorouracil, resulting in a marked improvement in symptoms and signs as well as a return of normal cognitive function. The similarity between that case and the one now re- ported strongly supports the existence of a specific neurologic paraneoplastic syndrome associated with glucagonomas. Furthermore, isolated central scotoma has been described as an early phenome- non in the glucagonoma syndrome [2,3]. This has been thought to be due to retrobulbar neuritis [3], and may represent an alternative manifestation of the same pathologic process.

The therapeutic options for glucagonoma are sur- gical resection [4], chemotherapy [4,5], somatosta- tin analogue [6,7], interferon [8], and tumor emboli- zation [8,9]. As in the case presented, some reports have described resolution of the rash in response to somatostatin analogue [7,10], although this is not invariably associated with a decrease in plasma glu- cagon [ll]. Other investigators have described no response [12]. A reduction in tumor size is usually not noted, although occasional reports have sug- gested otherwise [13].

The importance of this case is in the suggestion that a circulating factor is associated with the devel- opment of the neurologic syndrome. This is unlikely to be glucagon, given the rarity of the syndrome even in patients with very high glucagon levels. The resolution of symptoms with somatostatin ana- logue, without a change in tumor size, suggests that the analogue is either inhibiting the production or blocking the action of this factor.

This is the second case reported of a well-defined neurologic paraneoplastic syndrome associated with glucagonoma and the first report of its success- ful treatment with somatostatin analogue. The pathologic nature of this syndrome is unclear, al- though it has some features consistent with para-

neoplastic encephalomyelitis. The case further sug- gests that, as an underlying process, a circulating factor exists that may have an important pathogen- ic role in this and other paraneoplastic neurologic syndromes.

ACKNOWLEDGMENT We would like to acknowledge Professor Brian Tress and Miss Lucy Negro for her secretarial assistance.

REFERENCES 1. Stacpoole PW. The glucagonoma syndrome: clinical features, diagnosis and treatment. Endocr Rev 1981; 3: 347-61. 2. Khandekar JD, Oyer D, Miller H. Vick NA. Neurological involvement in gluca- gonoma syndrome. Cancer 1979; 441 2014-6. 3. Lambrecht ER. van der LoosTUM. van der Eerden AHAM. Retrobulbar neuri- tis as the first sign of the glucagonoma syndrome. Int Opthalmoll987; 11: 13-5. 4. Prim FtA, Badrinath K. Banerji M, Sparagana M, Dorsch TR. Lawrence AM. Operative and chemotherapeutic management of malignant glucagon produc- ing tumours. Surgery 1981; 713-9. 5. Kvols LK, Buck M. Chemotherapy of metastatic carcinoid and islet cell tu- mors. Am J Med 1987; 82: 77-83. 6. Elsborg L, Glenthoj A. Effect of somatostatin in necrolytic migratory erythema of glucagonoma. Acta Med Stand 1985; 218: 245-9. 7. Altimari AF, Bhoopalam N, D’Dorsio T. Lange CL, Sandberg L, Prinz RA. Use of a somatostatin analogue (SMS 201-995) in the glucagonoma syndrome. Sur- gery 1986; 100: 989-96. 8. Sheehan-Dare RA, Simmons AU, Cotterill JA. Janke PG. Hepatic tumours with hyperglucagonemia. Response to treatment with human lymphoblastoid inter- feron. Cancer 1988; 62: 912-O. 8. Allinson PH. Therapeutic embolization. Br J Hosp Med 1979; 20: 707-15. 10. Boden G, Ryan IG, Eisenschmid BL. Shelmet JJ, Owen OE. Treatment of inoperable glucagonoma with long acting somatostatin analogue SMS 201-995. N Engl J Med 1986; 314: 1686-9. 11. Santangelo WC, Unger RH, Orci L. eta/. Somatostatin analog-induced remis- sion of necrolytic migratory erythema without changes in plasma glucagon concentration. Pancreas 1986; 1: 464-9. 12. Wood SM. Kraenzlin ME, Adrian TE, Bloom SR. Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue: symptomatic and peptide responses. Gut 1985; 26: 438-44. 13. Kvols LK, Buck M, Moertal CG, et al. Treatment of metastatic islet cell carcinoma with somatostatin analogue (SMS 201-995). Ann Intern Med 1987; 107: 162-8.

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