A 16-year-old boy presented to a private clinic in Brazil, in September 2019. He came with his father as he was experiencing cognitive dysfunction and weakness in his lower limbs. He explained that his symptoms had started a year earlier, with frequent muscle spasms in his thighs and legs, particularly after physical exercise. The boy claimed that drinking sweetened beverages helped improve the symptoms. A few weeks after the symptoms began, he went to a local clinic, where the doctor diagnosed him with hypoglycemia based on blood tests. The boy had no previous medical or surgical history and denied addictions like smoking or alcohol consumption. He had a positive family history of hypertension and type 2 diabetes. However, the physician simply advised him to eat properly. He did not recommend any investigations.
Over the next few months, the muscle spasms and weakness in his lower limbs continued to worsen. He continued to consume sweet beverages to alleviate his symptoms. Around one year after the initial symptoms appeared, his condition deteriorated further. He started experiencing confusion, unusual behavior, and aggressiveness, mostly at night. His father would rush him to the emergency room for intravenous glucose infusions each time this occurred, which would bring him back to a normal state. As a result of the worsening symptoms, he had to give up his nursing studies at the university. To prevent hypoglycemic episodes, he had to wake up every two hours at night to eat something.
Therefore, his parents decided to consult a neurologist. The first neurologist diagnosed him with epilepsy based on clinical symptoms alone, without conducting any investigations. He prescribed him anticonvulsant medications, including carbamazepine and phenytoin, that resulted in an increase in liver enzymes but did not alleviate the confusion episodes. Consequently, they decided to get a second opinion from another neurologist.
The second neurologist performed a neurological examination and found that the boy had weakness in his lower limbs, specifically in the proximal muscles. He had difficulty standing upright and walking. However, there were no abnormalities in his cranial nerves or upper limbs. Further tests, including nerve conduction tests and needle electromyography, revealed evidence of chronic neurogenic changes in the muscles of his lower limbs. These findings indicated the presence of a recently developed axonal peripheral polyneuropathy, predominantly affecting his motor functions.
The neurologist referred the patient to an endocrinologist, who made a diagnosis of insulinoma based on normal serum insulin and C-peptide levels during a hypoglycemic episode. During the initial consultation with the endocrinologist, the patient had a normal mental status and a blood glucose level of 71 mg/dL. The physical examination revealed a pulse of 88 beats per minute, a blood pressure of 120/80 mmHg, a temperature of 36.5 °C, a weight of 90 kg, a height of 195 cm, and a body mass index of 23.7 kg/m². There was a decrease in muscle mass in the lower legs upon inspection. The rest of the clinical examination was unremarkable, and a chest X-ray showed no abnormalities.
Association with Insulinoma
When dealing with a pancreatic neuroendocrine tumour such as an insulinoma, it is important to rule out multiple endocrine neoplasia type 1 (MEN-1), a hereditary condition that increases the risk of developing multiple endocrine cell tumours. These tumours commonly affect the parathyroid gland, pancreatic islet cells, and pituitary gland. In cases where MEN-1 patients have a pituitary tumour, about 90% of them secrete prolactin. In this patient’s case, MEN-1 was ruled out because there was no family history of endocrine neoplasia and the prolactin levels were normal. Moreover, there was no evidence of hyperparathyroidism, and there was no history of peptic ulcer, suggesting the presence of a gastrinoma.
Apart from glucose, insulin, and C-peptide levels, the patient’s blood test results were normal. However, the patient had mild hyperbilirubinemia and primarily unconjugated bilirubin. This could be attributed to Gilbert’s Syndrome, an inherited condition characterized by reduced bilirubin glucuronidation in the liver. It results in unconjugated hyperbilirubinemia, which may cause recurrent episodes of jaundice.
He also had altered levels of adrenocorticotropic hormone (ACTH) and insulin-like growth factor-1 (IGF-1) during a severe hypoglycemic episode. These elevated levels were considered a normal defence mechanism since both ACTH and IGF-1 are counterregulatory hormones, and the blood sample was collected during a time of severe hypoglycemia. A subsequent blood sample taken after the insulinoma resection showed normal cortisol and IGF-1 levels.
Doctors conducted an abdominal MRI, which showed no abnormalities. This led to an endoscopic ultrasound, which revealed a peripancreatic nodule measuring 2.2 × 1.3 cm in the body-tail transition of the pancreas. A core biopsy confirmed the presence of a neuroendocrine pancreatic tumour.
Management: Surgery for Insulinoma
The patient was referred to a hepatobiliary surgeon. He performed a laparotomy, pancreatic nodulectomy, and resection of abdominal lymph nodes (two intercavoaortic and four splenic lymph nodes). The anatomopathological analysis revealed a well-differentiated neuroendocrine pancreatic tumour measuring 1.5 cm (grade 1) without invasion of blood vessels or nerves. The mitotic count was 02/10, and the lymph nodes showed no signs of malignancy. Immunohistochemistry confirmed the presence of a well-differentiated neuroendocrine neoplasm characterized by intermediate and monomorphic cells arranged in a solid, organoid, and extensively hyalinized pattern in the pancreatic tissue. Neuroendocrine differentiation was confirmed by positive expression of chromogranin A, synaptophysin, and insulin. The findings indicated a grade 2 neuroendocrine tumour (NET) according to the World Health Organization (WHO) classification.
Following the surgery, the patient did not experience hypoglycemic episodes or muscle spasms in the lower limbs. Thus, doctors discontinued all medications for insulinoma and neuropathy. He found regular weightlifting exercises at the gym helpful and continued them for about four months. Six months after the surgery, the patient’s ability to walk had improved, although there was still a slight weakness in the distal lower limbs, particularly on the left side.
On a follow-up visit after two years, the patient was living a normal life. He engaged in daily cycling, worked in construction, and pursued a nursing degree. However, he still reported reduced muscular strength in the lower limbs. His weight was 76 kg, resulting in a body mass index of 19.7 kg/m². Doctors conducted nerve conduction tests on both the upper and lower limbs. The muscle action potentials and motor conduction velocities were normal. However, the needle electromyography results remained unchanged, showing chronic neuropathy in the same lower limb muscles as before.
However, despite the absence of complaints or abnormalities in the upper limbs during the physical examination, nerve conduction tests of the upper limbs revealed reduced muscle action potentials and a slight prolongation of distal motor latencies in the ulnar nerves. Additionally, doctors observed mild chronic neurogenic changes in muscles innervated by the ulnar and median nerves.