Hypoglycemia causes refractory epilepsy?

*It is only for medical professionals' reference.
Is pituitary tumor without obvious mass effect the cause of epilepsy? Epilepsy is a common disease in neurology, but seizures may also be related to endocrine diseases.

In the following case published by Kumawat BL and others in the BMJ sub-journal [1], the cause of refractory epilepsy in young women is far from simple as imagined! Pituitary tumor is the culprit causing repeated seizures? The protagonist of the story is a 29-year-old woman with no history of physical fitness, menstruation, and pregnancy.
She has seen repeated general tonic-clonic seizures (grand seizures) over the past two years and has taken 2 anti-epileptic drugs in sufficient quantities.
not effectively.

The patient's neurological examination was normal, the interictal EEG examination showed epileptiform discharges, and the brain CT scan showed no abnormalities.

Further examination of the brain MRI showed that the pituitary gland had a microadenoma with a size of 6×6×4 mm, which was enhanced after the injection of contrast agent, without any other evidence of brain damage.

Brain MRI: Pituitary microadenoma[1] In addition to the significant increase in prolactin to 4423 U/mL (127–637 U/mL), the patient’s pituitary hormones (LH, TSH, FSH, ACTH) and estrogen levels No abnormalities were seen.

Although the patient has a functional pituitary tumor, which may cause seizures, the pituitary tumor in this patient is a microadenoma (the possibility of benign prolactinoma is high), and imaging examination does not show obvious mass effect or signs of metastasis, consider It is probably not related to seizures.

So, who is the culprit that causes patients to have repeated seizures? Is hypoglycemia the initiator of repeated seizures? During the patient's repeated seizures, the doctor found that the patient had hypoglycemia, and his seizures improved with the intravenous infusion of glucose.

The patient began to investigate the cause of recurrent hypoglycemia.
The latter indicated that fasting insulin and C-peptide levels increased to 36.
11 uU/ml (2.
6–24 uU/ml) and 8.
6 ng/mL (1.
1–5 ng/mL), respectively.
, In line with hyperinsulinemic hypoglycemia.

A CT examination of the abdomen showed a round soft tissue mass of about 17×10 mm in the head of the pancreas.
The homogeneous enhancement in the arterial phase (rich in blood vessels), the venous phase and the delayed phase of the contrast agent quickly faded.

Abdominal CT examination of the arterial phase: high-density pancreatic head mass [1] In addition, from the CT scan, the doctor also accidentally found that the patient had bilateral kidney stones, right ureteral stones with hydroureter.

Abdominal CT examination: bilateral kidney stones [1] Combined with the patient's repeated hypoglycemia and the above-mentioned imaging signs, the doctor considered the patient to have pancreatic neuroendocrine neoplasm (pancreatic neuroendocrine neoplasm).

About 3% of primary pancreatic tumors are pancreatic neuroendocrine tumors (can be divided into functional and non-functional tumors), and 75%-85% are non-functional pancreatic neuroendocrine tumors [2].

Functional pancreatic neuroendocrine tumors mainly include insulinoma and gastrinoma, and other types include glucagonoma, growth hormone tumor and so on.

The pancreas is the most important site of insulinoma, which is derived from pancreatic β cells.

Insulinoma is more common in young adults.
Whipple's triad is the most important clinical symptom, namely hypoglycemia (palpitations, dizziness, headache, tremor, sweating, increased hunger, mental behavior changes on an empty stomach, before meals or after exercise) , Blood glucose <2.
8 mmol/L at the onset, and symptoms of hypoglycemia relieved after taking glucose.

Hypoglycemia caused by insulinoma can also manifest as transient or repeated seizures.

Prolonged episodes of hypoglycemia can cause permanent damage to the central nervous system.

Therefore, in view of the fact that the patient's hypoglycemia occurred during repeated seizures, and the seizures improved after glucose supplementation.

Therefore, hypoglycemia caused by insulinoma is likely to be the initiator of repeated seizures.

It can be further confirmed that the patient’s recurrent seizures are not closely related to pituitary microadenoma.

In addition to hypoglycemia, what other clues are there that are densely covered by suspicions? So far, the evidence chain of "insulinoma-hypoglycemia-seizures" is almost an ironclad fact.

However, the multiple urinary tract stones accidentally discovered by CT examination is still another mystery that is densely filled with suspicion.

Is there a possible connection between pituitary tumors, insulinomas and multiple urinary tract stones? After further examination, the patient's blood calcium, parathyroid hormone (PTH) increased, and blood phosphorus decreased, suggesting hyperparathyroidism.

Ultrasound of the neck further revealed that there is a clearly defined hypoechoic lesion in the right parathyroid gland below the right lobe of the thyroid, the size is 26×12 mm, and the peripheral blood vessels are abundant, suggesting a parathyroid adenoma.

X-ray examination of the hand showed bone resorption under the radial side of the middle phalanx, further suggesting bone changes caused by hyperparathyroidism.

Hand X-ray examination: subperiosteal bone resorption on the radial side of the middle phalanx [1] Can the case be concluded? It can be seen that the main manifestations of this patient are pituitary prolactinoma, insulinoma, and parathyroid adenoma, which is consistent with multiple endocrine neoplasia type 1 (MEN-1).

Multiple endocrine neoplasia refers to a clinical syndrome caused by the presence of ≥ 2 endocrine adenomas or hyperplasias in the same patient at the same time or successively.
It is mainly divided into MEN-1, MEN-2 and mixed types.

The third edition of the eight-year medical textbook MEN-1 is also known as Wermer syndrome, which is caused by an inactivating mutation of the tumor suppressor gene MEN-1 on the long arm of chromosome 11 (11q13).

From the occurrence of the first type of tumor to the second type of tumor, there is often an interval of 6 to 24 years [1].

The main components of MEN-1 include parathyroid adenoma or parathyroid hyperplasia (hyperparathyroidism), gastrointestinal pancreatic tumors (insulinoma) and pituitary tumors.
These tumors may be malignant tumors.

MEN-1 is usually inherited in an autosomal dominant manner (the risk of first-degree relatives is 50%), but 8%-14% of cases are sporadic cases [1].

Only 12% of MEN-1 cases can have three related tumors or lesions, and hyperparathyroidism is the most common (94.
5%) clinical manifestation of MEN-1.

Among pancreatic tumors in MEN-1 patients, 10%-30% are insulin-secreting islet β-cell tumors.

Insulinoma is rarely the first manifestation of MEN-1, and refractory epilepsy complicated by hypoglycemia is even rarer [1,3].

The diagnosis of MEN-1 should meet any of the following three criteria [4]: ​​The treatment principle of MEN1 is to target each tumor or lesion separately, and the specific treatment plan is usually similar to that of non-MEN1 patients with corresponding tumors.

However, because the tumors involved in MEN1 may be larger, more aggressive, and resistant to treatment, and malignant tumors may have multiple metastases at the same time, the therapeutic effect of MEN1 is often unsatisfactory, and the life expectancy of patients is shortened.

For this patient, the patient underwent pancreatic tumor resection (postoperative biopsy confirmed insulinoma) and bromocriptine treatment, and gradually stopped anti-epileptic drugs.

After 6 months of follow-up, the patient did not have seizures again.

Reference materials: [1]Kumawat BL,Sharma C,Shah MJ,Panchal M.
Multiple endocrine neoplasia type 1 presenting with refractory seizures.
BMJ Case Rep.
2017;2017:bcr2016218982.
Published 2017 Nov 1.
doi:10.
1136/bcr-2016 -218982[2]lou Wenhui,Wu Wenming.
Guidelines for the treatment of pancreatic neuroendocrine tumors (2014 edition)[J].
Chinese Journal of Digestive Surgery,2014(12):919-922.
[3]Marx S,Spiegel AM,Skarulis MC ,Doppman JL,Collins FS,Liotta LA.
Multiple endocrine neoplasia type 1:clinical and genetic topics.
Ann Intern Med.
1998;129(6):484-494.
doi:10.
7326/0003-4819-129-6-199809150- 00011[4]Thakker RV,Newey PJ,Walls GV,et al.
Clinical practice guidelines for multiple endocrine neoplasia type 1(MEN1).
J Clin Endocrinol Metab.
2012;97(9):2990-3011.
doi:10.
1210/jc .
2012-1230