Insulinomas arising from beta cells of pancreas secrete excessive insulin that causes hypoglycemia. They represent 1–2% of all pancreatic neoplasms either evenly distributed in the pancreas or show a slight predominance in the head and tail regions. (2–4)–4) About 90% of insulinomas have been reported to be benign, 90% are solitary, > 90% occur at intrapancreatic sites, and 90% are < 2 cm in diameter. (4–7) The remaining 10% of patients report with malignant insulinoma. Symptoms of insulinoma often lead to misdiagnosis, as was initially perceived as psychosomatic syndrome in our patient. Whipple's triad criterion was fulfilled in our patient which comprised of autonomic (palpitations, sweating and tremulousness) and neuroglycopenic (agitation, disorientation, and alterations in vision and behavior) symptoms of hypoglycemia, plasma glucose concentration < 55 mg/dL (3.0 mmol/L), and resolution of the symptoms after administration of glucose. (8) CT abdomen further helped in localization of pancreatic tumour, pointing towards insulinoma in our patient. The sensitivity of contrast CT and MRI, two traditional non-invasive techniques used to locate insulinoma, ranges between 33–64% and 40–90% respectively. (9) Invasive modalities, such as endoscopic ultrasonography and arterial stimulation venous sampling, are more accurate and superior to non-invasive techniques for pre-operative localization. (10)
The patient underwent enucleation of tumour, an organ-preserving surgical resection which is the treatment of choice for insulinoma. Other choices include laparoscopic approach, whose short and long-term comparable results have been reported as compared to mechanical enucleation of insulinoma. (8) Whipple procedure was not opted considering relatively better prognosis of enucleation and young age of the patient.
Insulinoma is rarely reported to occur associated with any unrelated medical condition in some case reports spanning over the last decades. These rare associations include ACTH-independent macronodular hyperplasia AIMAH, Polycystic ovarian syndrome (PCOS) and hyperandrogenism, tuberous sclerosis, adrenocorticotropin deficiency and hypergonadotropic hypogonadism, type II non-insulin dependent DM (NIDDM), fatty replacement of unknown etiology in the pancreas, neurofibromatosis and gastrinoma. (11–18) Gray Matter Heterotopia (GMH), as found concordant with insulinoma in our patient, is not documented in medical literature as an association of insulinoma so far. This case report is first of its kind.
Gray matter heterotopia GMH are malformations of cortical development due to arrested neuroblast migration. (19) They may be discovered as neurons present at abnormal sites in brain during evaluation of epilepsy, or as incidental findings. They are divided into pathological classification as nodular and laminar forms (20), and into broad clinical classification: 1) sub-ependymal 2) subcortical, and 3) band heterotopias, all of which have distinct clinico-radiologic syndromes and genetics. (21) The severity of presentation is related to the location, pattern and extent of heterotopia which determines management plan and predicts prognosis. (22) Sub-ependymal heterotopia (SEH), also called periventricular nodular heterotopia PNH as reported in our patient, is the most common clinical subtype. They can arise due to mutations at gene filamin 1 FLN1 at chromosome Xq28. (23) Most symptomatic patients with SEH come to clinical attention because of epilepsy during second decade of life, as reported in our patient, with partial complex and absence seizures more common than drop attacks. Seizures can arise from both within heterotopia or from other dysplastic sites, as shown on surface EEG as generalized or multifocal abnormalities. But EEG was reported unremarkable in our patient. Other clinical manifestation of SEH ranges from asymptomatic nodules to extensive clusters of heterotopia lining the lateral ventricles causing intellectual disabilities and/or neuropsychiatric symptoms including aggression, impulsivity and depression which were not reported in our patient. (24, 25) MRI, the main investigation of choice, helped in diagnosis of SEH. It showed sub-ependymal nodules characteristically appearing as round to ovoid, iso-intense to mature gray matter, and protruding slightly into the ventricular cavity resulting in an irregular ventricular outline. Rest of brain structures including other ventricles, cisterns and fissures were clear with no evidence of hematoma, edema or midline shift. No CSF extended into abnormal growths from lateral ventricle. These findings conform to the diagnosis of epilepsy since his childhood. On neurology consult, patient was prescribed anti-epileptic medications and responded well. Hence, alternate options to treat seizures which don’t respond to anti-epileptics, including focal therapeutic electrode implants, surgical resection of the lesions and magnetic resonance guided laser ablation, were not explored in our patient.
This is a first of its kind case suggesting that if a patient presents with hypoglycemic symptoms and a pancreatic mass, it is important to consider brain imaging to rule out a rare association of insulinoma i.e. sub-ependymal heterotopia, a subtype of gray matter heterotopia.