저혈당성 뇌병증을 동반한 인슐린 종 1례

울산대학교병원 내과1, 외과2, 병리과3, 신경과4

김경훈1, 김은숙1, 박찬성1, 고명관1, 변성수1, 홍정민1, 이무열1, 남궁일성1, 김영일1, 나양원2, 최혜정3, 권지현4

교신저자: 김은숙, 울산광역시 방어진 순환도로 877번지 울산대학교병원 내분비내과, E-mail: es10@unitel.co.kr

INTRODUCTION

Insulinoma is the most common functioning

pancreatic neuroendocrine tumor, occurring in

about one person per million per year[1]. The

leading symptoms in establishing the diagnosis of

insulinoma are included in the Whipple’s triad:

symptoms of neuroglycopenia, documented

hypoglycemia (plasma glucose levels < 50 mg/dL),

and rapid symptom relief following glucose

administration, often within 5-10 minutes[2].

Symptoms can be classified as either adrenergic,

i.e. resulting from a catecholaminergic response

such as anxiety, tremor, nausea, sweating, and

palpitations, or neuroglycopenic, such as headache,

lethargy, amnesia, seizures and, in more severe

cases, confusion or coma[3]. The mean length of

symptoms is approximately three years due to the

non-specific nature of neuroglycopenic symptoms.

Transient hypoglycemic events are common,

especially in diabetic patients, and are usually not

life-threatening or associated with persistent

neurological deficits or organ damage[4]. However,

severe persistent hypoglycemia or recurrent mild

hypoglycemia may cause long-lasting coma,

seizures, and neurologic deficits[5,6]. This

syndrome has been cal led hypoglycemic

encephalopathy, but is not well defined in the

literature and the pathophysiology is poorly

understood[7]. Here, we report a case of insulinoma

that went undiagnosed for 11 years and induced

mild cognitive impairment with suspicious frontal

lobe dysfunction, as confirmed by a Korean-Mini

Mental State Examination (K-MMSE).

CASE REPORT

A 47-year-old male with recurrent abnormal

behavior and loss of consciousness was referred to

our clinic. Ten years prior to presentation, the

patient had presented to the Emergency

Department with loss of consciousness caused by

Original Articles & Case Reports

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http://dx.doi.org/10.4093/jkd.2013.14.2.98

Abstract

A 47-year-old male with recurrent abnormal behavior for ten years was referred to our clinic. He was diagnosed with insulinoma and cognitive dysfunction. Persistent hypoglycemia leads to a high risk of cognitive dysfunction in diabetic patients. However, cognitive dysfunction associated with insulinoma is rare. In this case study, cognitive dysfunction was confirmed by neurological testing. (J Korean Diabetes 2013;14:98-101) Keywords: Insulinoma, Hypoglycemia, Encephalopathy

A Case of Insulinoma with Hypoglycemic Encephalopathy

Kyung Hoon Kim1, Eun Sook Kim1, Chan Sung Park1, Myung Kwan Ko1, Sung Su Byun1, Jung Min Hong1,Mu Yeol Lee1, Il Sung Nam-Goong1, Young Il Kim1, Yang Won Na2, Hye Jung Choi3, Ji Hyun Kwon4 Department of Internal Medicine1, General Surgery2, Pathology3, Neurology4, Ulsan University Hospital, College of Medicine University of Ulsan, Ulsan, Korea

hypoglycemia (serum glucose 25 mg/dL). However,

at that time, he refused further evaluation. He

continued to experience similar symptoms almost

daily for the next ten years, including dizziness,

headache, slurred speech, and abnormal behavior

(murmuring, drooling, and agitation) without

consciousness. Symptoms usually occurred during

sleep at night in addition to being aggravated by

hunger and exercise, and were relieved by glucose

intake. On admission, his body temperature and

vital signs were normal. He appeared well and was

not in acute distress, but reported slow speech and

an impaired sense of direction.

All routine laboratory parameters were within

normal ranges except for a low blood glucose level

(53 mg/dL) and elevated levels of serum insulin

(75.5 μU/mL), pro insulin (637.9 pmol/L), and

c-peptide (8.17 ng/mL). We investigated for the

possibility of accompanying multiple endocrine

neoplasia type I. Basal pituitary hormone levels

were within normal ranges (growth hormone 0.08

ng/mL, thyroid stimulating hormone 4.32 uU/mL,

luteinizing hormone 6.12 mlU/mL, follicle

stimulating hormone 5.78 mlU/mL, prolactin 21.45

ng/mL) except for an e levated leve l of

adrenocorticotropic hormone (61.40 pg/mL). There

were no features of multiple endocrine neoplasia

type I in an overnight dexamethasone suppression

test, or on a sellar magnetic resonance image or

parathyroid scan. A pancreas computed

tomography scan and transhepatic portal venous

sampling were performed to localize the

insulinoma. The computed tomography scan

showed an enhanced 8-mm nodule in the superior

aspect of the pancreatic body (Fig. 1A).

Transhepatic portal venous sampling showed an

elevated serum insulin level of 662.7 μU/mL in the

body of pancreas (Fig. 1B).

Surgical resection of the insulinoma at the body

of the pancreas was performed. The mass was

2-cm in diameter, well-demarcated, and solid,

with a pale yellowish color. Microscopic study

demonstrated a solid, trabecular, and gyriform

growth pattern. The tumor cells had small and

relatively uniform nuclei with granular cytoplasm.

Hyalinized stroma with calcification was evident

(Fig. 2).

Three days after the operation, the patient’s

serum insulin and c-peptide levels returned to

normal (serum insulin 8.4 μU/mL, serum c-peptide

1.80 ng/mL). However, his slow speech and the

impaired sense of direction did not return to

normal. To examine the cognitive dysfunction, a

neuropsychological battery of tests (K-MMSE,

Attention, Language fluency, Controlled Oral Word

Association Test, and Seoul Verbal Learning Test)

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The Journal of Korean Diabetes

저혈당성 뇌병증을 동반한 인슐린 종 1례

Fig. 1. (A) Pancreas computed tomography scan showing an enhanced 8-mm nodule in the superior aspect of the pancreas body. (B) Transhepatic portal venous sampling revealed an elevated serum insulin level (662.7 μU/mL) in the body of the pancreas.

was performed. Total percentile score on the

K-MMSE was 0.02, implicating cognitive

impairment, and spontaneous speech was non-

fluent. The Seoul Verbal Learning Test (SVLT)

revealed verbal memory dysfunction (immediate

recall total percentile score of 10.38). Controlled

Oral Word Association Test (COWAT) revealed

frontal lobe dysfunction (phonemic total percentile

score of 3.51). Considering the age and academic

ability of the patient, generalized cognitive

dysfunction and frontal lobe dysfunction were

diagnosed. The patient was discharged without any

su rg i c a l c omp l i c a t i ons and f o l l ow-up

neuropsychological tests were performed after five

months. At that time, cognitive impairment was

normalized (total percentile score on the K-MMSE

of 36.32). Spontaneous speech was fluent, and both

verbal memory and frontal lobe dysfunction had

improved relative to the immediate post-surgery

time point (immediate recall total percentile score

of 31.92, phonemic total percentile score of 18.94).

DISCUSSION

Neuroglycopenic manifestations are common in

patients with insulinoma, but are frequently

misdiagnosed because of their unusual

manifestations. Failure to recognize the presence of

an insulinoma may result in permanent

neurological damage, or even death[8]. The brain

regions most vulnerable to hypoglycemia are cornu

ammonis area 1, subiculum, dentate gyrus of the

hippocampus, and the outer layers of the cortex.

All of these regions are important for learning and

memory[9]. Patients who recover from severe

hypoglycemia may be left with cognitive

dysfunction, particularly short-term memory[10].

The pathophysio logy of hypoglycemic

encephalopathy is poorly understood. However, it is

known that hypoglycemic neuronal injury is

precipitated almost entirely by sustained glutamate

receptor activation (excitotoxicity), which is

mediated by Poly ADP-ribose polymerase-1

(PARP-1)[11,12]. The only treatment for

hypoglycemic brain damage is blood glucose

repletion and, currently, there are no useful

interventions to prevent the neuronal death that

develops after correction of hypoglycemia.

Pretreatment using glutamate receptor antagonists

has been investigated in an attempt to reduce

hypoglycemic neuronal death, but these agents are

neurotoxic themselves and less effective when

administered after hypoglycemia has occurred[13].

According to Suh et al. [14], PARP-1 activation has

a pivotal role in the development of hypoglycemic

neuronal death and these authors provide proof of

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Original Articles & Case Reports

Fig. 2. Microscopically, the tumor showed a solid, trabecular, and gyriform growth pattern. The tumor cells had small and relatively uniform nuclei with a granular cytoplasm. Hyalinized stroma with calcification are seen (H&E, x200).

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principle that PARP-1 inhibition can rescue

neurons that would otherwise die after severe

hypoglycemia. However, these treatments are not

yet available, so the early diagnosis of insulinoma

is crucial in patients with atypical neuroglycopenic

presentation.

According to Daggett et al. [8], the most common

neuropsychiatric manifestations of insulinoma are

confusion, coma, and convulsions; less common

symptoms are blurred vision, paresthesiae,

diplopia, paralysis including hemiplegia,

monoplegia, and paraplegia. Therefore, blood

glucose levels should always be checked in patients

with neurologic deficits. When neurologic

symptoms are recurrent and associated with

hypoglycemia in non-diabetic patients, serum

insulin levels must be checked to rule out

insulinoma. Normally, when blood glucose levels

decrease, insulin production is reduced. In β-cell

adenomas, the production of insulin is elevated

despite decreased blood glucose levels. In our study,

the patient suffered from atypical neurologic

symptoms for ten years. When he visited the

Emergency Department ten years prior, insulinoma

was suspected; however, he refused further

evaluation and was discharged. Untreated

insulinoma leads to cognitive dysfunction.

According to Tam et al. [15], hypoglycemia is

associated with a higher risk of adverse motor and

cognitive outcomes at 12 months of age in infants

with neonatal encephalopathy. A previous study

also highlights the impact of hypoglycemia on

cognitive function in diabetic subjects who

developed the condition in childhood[10]. However,

insulinoma accompanying cognitive dysfunction is

rare. There have been many studies focusing on

neuroglycopenic symptoms of insulinoma; however,

as far as we aware, this is the first case document-

ing cognitive dysfunction and frontal lobe

dysfunction caused by insulinoma.

References

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1995. West J Med 1998;169:98-104.02.S Coelho C, Druce MR, Grossman AB. Diagnosis of

insulinoma in a patient with hypoglycemia without obvious hyperinsulinemia. Nat Rev Endocrinol 2009;5:628-31.

03.S Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zografos GN. Pancreatic insulinoma: current issues and trends. Hepatobiliary Pancreat Dis Int 2010;9:234-41.

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10.S Langan SJ, Deary IJ, Hepburn DA, Frier BM. Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-treated diabetes mellitus. Diabetologia 1991;34:337-44.

11.S Auer R, Kalimo H, Olsson Y, Wieloch T. The dentate gyrus in hypoglycemia: pathology impl icat ing exci totoxin-mediated neuronal necrosis . Acta Neuropathol 1985;67:279-88.

12.S Cosi C, Suzuki H, Milani D, Facci L, Menegazzi M, Vantini G, Kanai Y, Skaper SD. Poly(ADP-ribose) polymerase: early involvement in glutamate-induced neurotoxicity in cultured cerebellar granule cells. J Neurosci Res 1994;39:38-46.

13.S Nellgard B, Wieloch T. Cerebral protection by AMPA- and NMDA-receptor antagonists administered after severe insulin-induced hypoglycemia. Exp Brain Res 1992;92:259-66.

14.S Suh SW, Aoyama K, Chen Y, Garnier P, Matsumori Y, Gum E, Liu J, Swanson RA. Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia. J Neurosci 2003;23:10681-90.

15.S Tam EW, Haeusslein LA, Bonifacio SL, Glass HC, Rogers E E , J e re m y RJ , B a r ko v i c h A J , Fe r r i e ro D M . Hypoglycemia is associated with increased risk for brain injury and adverse neurodevelopmental outcome in neonates at risk for encephalopathy. J Pediatr 2012;161:88-93.

The Journal of Korean Diabetes

저혈당성 뇌병증을 동반한 인슐린 종 1례