Insulinoma as a cause of seizure-like activity and spontaneous hypoglycaemia

Background

Paul Langerhans originally described pancreatic islet cells in 1869 while still a medical student. Frederick Banting and Charles Best found insulin from a solution extract from a dog’s pancreas 53 years later, in 1922. William J Mayo, who undertook the first insulinoma operation in 1927, discovered the link between hyperinsulinaemia and a functional pancreatic islet cell tumour. Unfortunately, the growth was cancerous and could not be removed. Roscoe Graham, however, conducted the first surgical cure of an islet cell tumour 2 years later.1

Ten per cent of the patients with insulinoma have multiple endocrine neoplasia type 1 (MEN-1). The parathyroid, anterior pituitary and pancreas all develop tumours in MEN-1, an autosomal dominant condition. Parathyroid tumours are the initial presentation in more than 85% of patients, resulting in primary hyperparathyroidism.2 So it is imperative to screen all patients with insulinoma for MEN-1 by a simple calcium measurement and basal pituitary profile. It takes 1.5 years on average to get an appropriate diagnosis of insulinoma.3 A variety of variables might cause a diagnosis to be delayed. Insulinoma, for example, can cause a variety of neurogenic and neuroglycopenic symptoms. These symptoms are very similar to neuropsychiatric symptoms, which in most individuals include unconsciousness, disorientation, seizures, personality changes and odd conduct. Furthermore, more than half of patients with these symptoms are misdiagnosed with neuropsychiatric illnesses like epilepsy at first.3 4 Management of insulinoma is limited to case studies due to its rarity and hence a lack of randomised control data exists, emphasising the importance of case reports.

Neuroglycopenic symptoms can have an unequivocal presentation, which at times can lead to the diagnosis of seizure-like activity for the unsuspected physician. Our patient had recurrent symptoms, which were unexplained by brain imaging and baseline blood biochemistry. By the time of her arrival in the emergency department, she was found to be symptom free and was labelled to have first seizure-like activity. Blood glucose measurement on this first presentation was 9.4 mmol/L. No haemoglobin A1c (HbA1c) measurement was taken on her initial presentation. On her subsequent visits to the emergency department with presentation of altered sensorium, she was found to be hypoglycaemic with a blood glucose level of 1.9 mmol/L, raising suspicion for an insulinoma. This case highlighted the pivotal importance of the basics of history taking and checking blood glucose levels in any patient with altered sensorium.

Case presentation

A woman in her 60s presented to our centre with transient episodes of confusion and diplopia. This first happened a few months ago resulting in her crashing her car. She reported a subsequent episode of confusion where she was found to be driving on the wrong side of the road. A few days after her second episode, she had a further episode of blurred vision, confusion and ataxia as witnessed by her sister, lasting 30 min. She had amnesia of the events and lived alone, making an accurate collateral history of these events difficult to obtain. When she came to the hospital, her full blood count, biochemistry and blood glucose levels were normal. Additionally, she underwent neuroimaging with CT and MRI of her brain, which did not show any abnormality. She also had an echocardiogram and telemetry, which did not reveal any abnormal findings. She was referred to a neurologist with regard to further workup and management of her suspected recurrent seizures. She was commenced on levetiracetam 250 mg two times per day and discharged home with advice to stop driving.

A few years prior, she was investigated with similar symptoms; however, investigations at that time did not reveal any abnormal pathology. These investigations were carried out in a different hospital but we had no access to their medical records. She denied having any sugar cravings and did not have any weight gain. She had no significant medical history and was not on any regular medications. She had no personal or family history of diabetes mellitus. There was no evidence of any surreptitious use of insulin or sulfonylureas mentioned in the collateral history and did not have ease of access to them either. There was also no suspicion of MEN-1 in the family history, and she had no features of a parathyroid or pituitary disorder. She only drank alcohol occasionally and was also a non-smoker. Her mother died secondary to hepatocellular carcinoma and her father due to a myocardial infarction.

She was readmitted in October with another episode of confusion and abnormal movement of her limbs, which was witnessed by her niece. While having tea, she was found to be fatigued and suddenly did not know how to use the remote control. Later in the night, she was noted to be confused with involuntary movement of her limbs. The whole episode lasted for approximately 1 hour and she was unable to recognise her niece during the event. When the paramedics arrived, she was found to be hypoglycaemic with capillary blood sugars of 1.9 mmol/L, which did not always correlate with venous levels. She was provided with cake and glucagon by the paramedics. She did not have any urinary incontinence or tongue biting.

On a detailed history at this presentation, the patient reported that she had multiple episodes of confusion in the last few days, with poor recollection of the sequence of events. At one time, she had a fall between the bed and the window while doing the laundry, which led to the bruising of her shoulder and front of her chest along with a small haematoma on the left side of the head. She had amnesia of the event but only recollected that she found herself on the floor. The next day, she was at her sister’s house and noticed seeing double that lasted for an hour. She reported two additional similar episodes over the days preceding this admission. She could not identify any triggers to these episodes and never had any headaches.

Prior to this presentation, she was seen by a neurologist who increased her dose of levetiracetam to 500 mg two times per day based on the suspected diagnosis of complex partial seizures with a plan to perform an electroencephalography.

Investigations

The patient’s full blood count, renal profile, liver function test and C reactive peptide were within normal limits. She underwent a 72-hour fast with a view to repeating insulin and C peptide measurements coupled with hypoglycaemia. After 12 hours, she developed symptomatic hypoglycaemia with a venous glucose level of 1.7 mmol/L. Serum insulin and C peptide levels taken at the same time were 23.65 mIU/L (164.2 pmol/L) and 4.44 µg/L, which were inappropriately elevated in the presence of severe hypoglycaemia. We needed to move away from normal ranges when assessing hyperinsulinaemia and instead should consider what was appropriate in the setting of hypoglycaemia. Beta-hydroxybutyrate and acetoacetate were 0.05 mmol/L (normal range <0.4 mmol/L) and 0.034 mmol/L (normal range <0.3 mmol/L). Suppressed ketones demonstrated that there was insulin secretion, which was inappropriate in the setting of hypoglycaemia. When a patient had hypoglycaemia but was not in ketosis, this was abnormal and pointed to either hyperinsulinism or an inherited flaw in the way fat was used for energy. Calculations of the insulin–glucose ratios were done using concentrations that were expressed in pmol/L and mmol/L, respectively, with a normal range of 32.2 (pmol/L)/(mmol/L) or less.5 For our patient, amended insulin–glucose ratio came out to be 164.2 pmol/L.

Her other blood tests were as follows: follicle-stimulating hormone 42.2 IU/L (normal range post-menopausal 25.8–134.8 mIU/L, luteinising hormone 12.7 IU/L (normal range post-menopausal 7.7–58.5 mIU/L), oestradiol 134 pmol/L (normal range post-menopausal 91–533 mIU/L), testosterone 0.48 nmol/L (normal range 0.22–2.9 nmol/L), intact parathyroid hormone 45.5 pg/mL (normal range 15–65 pg/mL), adrenocorticotropic hormone levels at 08:00 hrs 3.5 pmol/L (normal range 1.1–13.2 pmol/L), HbA1c 27 mmol/mol (normal range 20–42 mmol/mol) and thyroid-stimulating hormone 0.939 mIU/L (normal range 0.27–4.2 mIU/L).

She also underwent short Synacthen test that reported cortisol levels of 164 nmol/L (0 min), 533 nmol/L (30 min) and 695 nmol/L (60 min), which were within normal reference range. This was performed prior to confirmation of hyperinsulinaemia. Anti-insulin antibody and anti-insulin receptor antibody were negative. Her chromogranin A was 81 ng/mL (normal range <108 ng/mL) and ammonia was 32 µmol/L (normal range 0–65 µmol/L). Her IGF1 somatomedin C was also normal at 65 µg/L (normal range 57–173 µg/L).

Following confirmation of inappropriate hyperinsulinaemia, she underwent a CT of the pancreas triple phase, which did not reveal any focal abnormality (figure 1). She subsequently underwent MRI of the pancreas with contrast, which revealed a subtle hyperintense 16 mm lesion in the uncinate process of the pancreas, and a probable diagnosis of insulinoma was made (figure 2). Her endoscopic ultrasound report showed a 2 cm hypoechoic, homogeneous and fairly well-defined mass in uncinate process, which was 2 mm from main pancreatic duct (figure 3).

Histopathology revealed a well-differentiated neuroendocrine tumour (NET). Tumour cells were positive for chromogranin, synaptophysin, CD56 and insulin. It was negative for gastrin and somatostatin receptors 2A.

Differential diagnosis

There was no suspicion of any surreptitious insulin use in this patient. Her C peptide levels were elevated, which would otherwise be suppressed in case of exogenous insulin administration. There was no family history of diabetes mellitus/MEN-1. Her parathyroid and calcium levels came back normal along with normal pituitary biochemistry, making MEN-1 unlikely. Her Synacthen test was normal, which ruled out adrenal insufficiency as a cause of her spontaneous hypoglycaemia, although it would not explain a hyperinsulinaemia state.

Chromogranin A levels were also not raised so there was no indication of any other type of NET. A final diagnosis of spontaneous hypoglycaemia secondary to insulinoma was made.

Treatment

Due to the fact that our patient was getting frequent hypoglycaemic episodes, she was commenced on complex carbohydrate diet by the dietitian. She was also advised to increase the frequency of her meals so that her hypoglycaemic episodes can be curtailed.

Additionally, she was commenced on diazoxide at a dose of 50 mg three times a day while awaiting discussion for surgical management of her insulinoma. This was subsequently uptitrated to 150 mg three times a day due to recurrent hypoglycaemic episodes. She developed intolerable side effects on higher dose of diazoxide including nausea, reduced appetite and fluid retention.

She was discussed with the national neuroendocrine multidisciplinary meeting, which advised medical management with a trial of prednisolone 20 mg while awaiting surgery, which significantly improved her blood sugar levels. Other treatments include somatostatin analogues like octreotide, although only 30%–50% responded to this and some might even get worse after its usage.6

She underwent a pancreaticoduodenectomy (Whipple’s procedure) with no significant postoperative complications. She has remained symptom free and has had no hypoglycaemic events since her surgery.

Outcome and follow-up

After resection of her insulinoma, she had no recurrence of spontaneous hypoglycaemic events and remained symptom free. She has a follow-up appointment with hepatobiliary surgery team in 6 months’ time.