|Year : 2020 | Volume
| Issue : 7 | Page : 2--6
Endocrinology Essentials for Neurosurgeons
Mario Giordano, Rudolf Fahlbusch
Department of Neurosurgery, International Neuroscience Institute, Rudolf Pichlmayr Str. 4, Hannover 30625, Germany
Dr. Mario Giordano
International Neuroscience Institute- Hannover, Rudolf Pichlmayr Str. 4, Hannover 30625
The aim of the present paper is to provide essential knowledge of neuroendocrinology. This article is based on the daily experience and frequent confrontation with endocrinological problems interdisciplinary cooperation since the early time when determination of pituitary hormones became available.
|How to cite this article:|
Giordano M, Fahlbusch R. Endocrinology Essentials for Neurosurgeons.Neurol India 2020;68:2-6
|How to cite this URL:|
Giordano M, Fahlbusch R. Endocrinology Essentials for Neurosurgeons. Neurol India [serial online] 2020 [cited 2020 Jul 5 ];68:2-6
Available from: http://www.neurologyindia.com/text.asp?2020/68/7/2/287666
Neuroendocrinology knowledge is of pivotal importance in neurosurgery. In fact, nowadays the role of neurosurgeons should not be reduced to the performance of the surgery in the sellar and parasellar region, but also for diagnosis of pituitary disease and beyond this for determining the optional treatment plan, decide the ideal perioperative care and for long-term management.
One of the best examples of utility of endocrinological knowledge for neurosurgeons is Cushing disease (CD) and its total dependence on diagnosis and surgical outcome. In 80% of the cases, the syndrome is ACTH- dependent while other causes such as adrenal adenomas are less common. Thus, precise knowledge of the diagnostic tests is fundamental for differential diagnosis and indication for surgery. Moreover, the definition of “cure” is also purely based on endocrinological criteria: After the remission, the high recurrence rate requires the long-term follow-up of the patient with appropriate tests. This article is based on the daily experience and frequent confrontation with endocrinological problems interdisciplinary cooperation since the early time when the determination of pituitary hormones became available.
Neurosurgery pioneers, such as Harvey Cushing, have contributed enormously to the neuroendocrinology field at the beginning performing hypophysectomy in dogs to define endocrine deficits on a clinical basis. At the beginning of the pituitary tumor surgical era, the neurosurgeons were establishing the approaches to this region. The trans cranial route was introduced with the experiences of Sir Victor Horsley, Charles Frazer (and Walter E. Dandy) at the beginning of the last century. During the same period, the first transnasal approach was described by Hermann Schloffer with complete dislocation of the nose. This route was then perfected by Cushing in 1909 with the transsphenoidal approach that combined many methods such as sublabial incision, paraseptal dissection and use of nasal specula. It is interesting to point out that Cushing himself abandoned this route preferring the trans cranial approach, mainly for better visual outcome, followed by the neurosurgical community of that period. Of course, one of the greatest achievements was his autopsy-related definition of “Cushing's disease” in 1932. Thanks to one of his pupils, Norman Dott, this was reintroduced in the middle of the century. One of the game changers in pituitary surgery was the introduction of the surgical microscope in the sixties allowing to perform “selective adenomectomy” as stated by Jules Hardy in his publications about transsphenoidal approach. Although he was not able to document his vision by endocrinological data at that time.
Hardy's teacher Gerard Guiot was the first neurosurgeon who described surgical fails in acromegaly defined on still elevated growth hormone levels. In recent years, the pituitary surgery has improved tremendously benefiting from the introduction of endoscopy, that led to a second renaissance of the transsphenoidal technique. New technologies, such as neuronavigation and intraoperative MRI, have further improved resection rate and safety of the approaches.
Endocrinology and centralization of medical excellence
The German Society of Endocrinology (Deutsche Gesellschaft für Endokrinologie) defines itself with this sentence: “endocrinology deals with basic research, clinical, and other application fields of endocrine organs and functions, and furthermore with endocrine signal transducers, acting via endocrine, paracrine and autocrine mechanisms”. In this scenario, the neurosurgeon should deal with this complex system in order to improve his diagnostic and treatment skills. The concept of a centre of excellence regards the quality of care provided to a certain group of patients. These structures have been found to be useful especially for complex pathologies such as pituitary adenomas, where multidisciplinary teams composed of experts are involved for surgical and medical treatment. As stated by the “Pituitary Society” in a recent publication the goals should include early tumor diagnosis, planning of a treatment strategy, surgical and/or medical treatments to eliminate hormonal hypersecretion, prevention of tumor recurrence and caring for the acute and delayed complications.
Lesions involving the pituitary gland
The main causes of pituitary involvement in neurosurgical pathologies are sellar region lesions that can be primary, metastatic, inflammatory or traumatic. In the personal experience of the authors, the most common tumors are represented by adenomas, craniopharyngiomas, meningiomas and miscellaneous cystic lesions such as Rathke's cleft cyst or Empty sella syndrome that in some cases can require hormone replacement. More rare lesions are metastases and optico-hypothalamic gliomas.
Traumatic brain injury may also lead to dysfunction of the hypothalamic-pituitary axis (31/100000 cases) with an indirect mechanism triggered by increased intracranial pressure or direct compression on the pituitary gland/stalk. It should be considered that delayed hormonal deficits in children after moderate brain injury are not detectable before one year.
Pituitary adenomas are the most common type of pituitary disorder and account for 15% of all intracranial masses. In many cases, they remain undiagnosed (25% of frequency in autopsy series) or, on the other hand, diagnosed as incidental finding (incidentaloma). They are commonly classified depending on the capability of hormones production. In order of frequency, we can distinguish the following: Non-functioning, prolactinomas, GH-omas, ACTH-producing, and rarely TSH-omas, with the first two entities being the most common. The hormonal secretion can be shared with the most common combination being PRL/GH producing adenomas. Symptoms can vary enormously depending on the type and size of the tumor: Syndromes of hormone hypersecretion or deficiency and/or neurologic manifestations from mass effect (usually in non-functioning lesions) such as visual deficit and signs of intracranial hypertension.
Endocrinology starts with blood collection. There is always time to sample blood and perform hormonal test before surgery.
In case of clinical suspect and/or finding of a sellar space occupying lesion, it is fundamental to evaluate the pituitary function for the diagnosis of hypo- or hypersecretion. The timing should be in the morning (8 a.m.) in a fasting condition.
The basal hormonal serum evaluation includes testing of:
Corticotropic axis: An 8 a.m. serum cortisol level may suffice for diagnostic purposes. If levels at this time are below 80 to 110 nmol/L, then adrenal insufficiency should be suspected. In many cases, further provocative functional testing is needed. Serum cortisol should be tested on the first postoperative day: It is important to verify that patient did not receive dexamethasone during surgery in order not to have false-positive resultsThyrotropic axis: Basal thyroid-stimulating hormone (TSH) and free thyroxin (fT4) levelsGonadotropic axis: Secondary hypogonadism can be detected with inappropriately low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), with a simultaneously low testosterone level. In women, low gonadotropin levels in the face of low estradiol levels indicate secondary hypogonadismSomatotropic axis: Growth hormone deficit (GH) is usually not clinically manifest in adults and it should be can be confirmed by measurement of hormone levels. However, GH secretion is pulsatile and single evaluation are insufficient. Insulin-like growth factor 1 (IGF-1) evaluation is also necessary but its level can be normal in cases of GH deficiency: For these reasons, functional tests are necessary. It important to consider the age dependency of IGF-1 and its long hang time: It should be tested at least two months after surgeryProlactin (PRL): It is important to sample also blood at -15 minutes time to avoid increased values caused by stress. Elevation of prolactin levels greater than 200 ng/ml in the absence of pregnancy, is often diagnostic for prolactinoma., The presence of a pituitary lesion with abnormal prolactin levels below 200 μg/L, can be suspicious of a prolactinoma with mild hormone secretion. A moderate elevation of PRL (2-3 times the normal value) can be caused by a non-functioning lesion of the sella that lead to compression of the pituitary stalk resulting in loss of inhibition of prolactin release, the so called 'stalk effect'., Together with the basal hormones serum level, functional tests are fundamental to detect pituitary gland pathologiesThe insulin-hypoglycaemia test (IHT) is pivotal for functional testing of the hypothalamic-pituitary adrenocortical axis. The principle of this test is that normal response to hypoglycaemia is release of ACTH and growth hormone (GH), which counteracts low blood sugars. Patients deficient in GH and ACTH show no hormonal response to hypoglycaemia. It is performed with intravenous insulin at a dose of 0.15 IU/kg body weight with cortisol serum level measured immediately before administration and at 30 minutes interval for two hours. The absolute cortisol peak is the important value for diagnosis with a level of 500 nmol/L as the threshold value., This test is also used for studying GH secretion: A peak lower than 3 μg/L is very strong evidence for GH deficiency. Alternatively, the GHRH (growth-hormone- releasing hormone)-arginine test can be used to determinate deficit of GH productionThe ACTH test is used to rule out secondary adrenal insufficiency. ACTH is given intravenously, and the serum cortisol level is measured at time 0 (or even 15 min before administration) and after 30 min interval. In secondary adrenal insufficiency, the Synacthen-induced rise in cortisol should be lower because of partial atrophy of the adrenal gland, providing indirect evidence of an intact HPA axis. Long-term follow-up studies have shown that the ACTH is highly predictive for the exclusion of secondary adrenocortical insufficiencyOral glucose tolerance test (OGTT): In healthy individuals, GH serum levels is suppressed by oral glucose administration but in acromegaly this mechanism fails. The criteria for GH suppression after oral glucose have evolved with the availability of more sensitive techniques. In patients with elevated or borderline serum IGF-1 levels, the diagnosis of acromegaly can be confirmed by a lack of suppression of GH to <1 μg/L following documented hyperglycaemiaThe serum should be correctly stored at 4°C for up to 28 h or -25°C for a longer time in order to avoid degradation.
There are different therapeutic options for patients harbouring a sellar tumor, in particular pituitary adenomas: Wait-and-see, medical treatment, surgery and radiotherapy. Of course, a combination of these modality can be applied. Obviously, the strategy depends on the type of hormonal secretion and the mass effect of the tumor.
The medical treatment includes:
Hormonal replacement (hydrocortisone, L-Thyroxine, oestrogen/testosterone)Antiproliferative drugs.
In cases affected by prolactinoma, it is important to know the knowledge of their natural history. In fact, published studies demonstrated lack of increase in tumor size in the vast majority of patients with microprolactinomas (<10 mm maximal diameter)., This fact suggest that most small prolactin-secreting adenomas remain in the stage of a microadenoma. Therefore, in certain situations observation may be adequate. Thus, a patient with a microprolactinoma, with only a mild elevated of prolactin, normal pituitary functions and no desire of pregnancy can be observed. In the other cases, a treatment is required. The medical therapy is usually the treatment of choice except in countries where the high costs of continuous treatment cannot be covered by insurance companies. Lactotrophs are inhibited by dopaminergic effect from the hypothalamus, thus dopamine agonists inhibit prolactin secretion. Bromocriptine, cabergoline and quinagolide are the most commonly used drugs for the medical treatment of prolactinomas with a high response rate. Large series of treated patients demonstrated normalization of the PRL levels in 70-100%, tumor shrinkage in 80-90% and restoration of ovulatory menstrual periods in 60-100%.,, The drawbacks of the medical treatment are side effects (orthostatic hypotension, nausea) and the lack of tumoricidal effect in many cases. In such patients, the treatment should be continued life-long to avoid elevation of PRL levels and growth of the tumor. Surgery should be reserved for cases who are not-responders/intolerant to the medical therapy, rapidly progressive loss of vision (pituitary apoplexy) and if the patients do not want a life-long drug treatment. In our personal series, the normalization rate after transsphenoidal surgery was influenced by preoperative PRL level, tumor size and extension. Radiotherapy is rarely required and only reserved for invasive tumors that do not respond to medical or surgical treatment. Basal prolactin level below 25 μg/L is considered as the biochemical remission according to the literature. This value correlates with interruption of galactorrhea and normal menstrual periods. It should be stated that residual mild hyperprolactinemia without increase at follow-up and no residual tumor on imaging, may result from the 'stalk effect' and does not always necessarily have pathological significance. It should be stated that patients can become pregnant also with mildly elevated PRL value.
GH producing adenomas are a category of lesion with evident clinical manifestations causing acromegaly and gigantism. Growth hormone has an anabolic and diabetogenic effect with important and sometimes devastating effects for the patients: Soft tissue swelling, enlargement of the extremities, macroglossia, hyperhidrosis and metabolic disturbances. Patients may develop life-threating conditions such as cardiac and respiratory dysfunction with shortened life expectancy.,, The treatment of choice is surgical via transphenoidal approach because of the limited efficacy of the pharmacological therapy. In our personal series, the best remission rate was achieved in microadenomas with GH serum level <10 μg/L. Medical treatment is reserved for patients with severe surgical risk factors: It includes somatostatin analogues of first (octreotide and lanreotide) and second (pasireotide) generation that have a negative effect on GH production and somatotroph proliferation. Pegvisomant, a GH receptor antagonist, reduces the production of IGF-1 primarily responsible for the symptoms of acromegaly. The remission criteria are GH serum level <2.5 μg/L and GH <1 μg/L during OGTT test.
Rare TSH-producing adenomas have surgery as a treatment of choice and may respond to octreotide that can be used before surgery for normalization of thyroid hormones and postoperatively if there is persistent elevated TSH eventually in combination with radiotherapy.
Cushing disease needs to be analysed separately from other pituitary pathologies. As stated above, the differential diagnosis of CD and the indication for surgery is based on dynamic endocrinological tests. The inhomogeneous definition of remission of hypercortisolism and its still not fully understood pathophysiology could be the reason of the not always satisfying results in the literature: The observed remission rates were between 42-100% and recurrence between 3-63.2%. The clinical symptoms of CD can be very clear or almost absent. Therefore, the dynamic endocrive function test is of great importance.
Morning basal cortisol level higher than 2 μg/dl after administering 2 mg dexamethasone (suppression test) 12 hours before may indicate to the diagnosis of Cushing's syndrome. The pituitary origin may be diagnosed by suppression of the cortisol level to 50% of the original value after administration of 8–32 mg dexamethasone., Obviously, the function of the anterior pituitary lobe must be evaluated with a complete basal hormones screening (PRL, TSH, ACTH, FT3, FT4, LH, FSH, estradiol/testosterone) and a Cortisol stimulation test using ACTH injection (measurement of basal Cortisol, at 30 and 60 minutes after the injection).
Regarding the imaging studies, Magnetic resonance imaging (MRI) with thin slice sequences is fundamental to identify the microadenoma. Conventional T1-weighted has a reported sensitivity of 50 to 60%., Another useful modality is dynamic MRI and contrast enhanced volume-interpolated, breath-hold examination (CE-VIBE) can be used. These have demonstrated a higher sensitivity than standard T1 sequences, but also a higher false-positive rate in some studies.
If the diagnosis is still not confirmed, an inferior petrosal sinus sampling could be performed to measure and ACTH and local cortisol plasma levels in order to exclude an adrenal origin of the hypercortisolism or ectopic or paraneoplastic ACTH production. However, this test is used very rarely and its value to identify tumor lateralization is controversial.
Concerning the treatment of CS it has to be mentioned that preoperative therapy to improve the patients' clinical status prior to surgery is necessary only in cases with very severe metabolic changes using ketoconazole. Postoperatively, an early basal cortisol level is determined 24 hours after surgery (avoiding intraoperative administration of dexamethason and replacement is started if the cortisol levels are low. One week and about three months postoperatively dynamic endocrine function tests are repeated to confirm remission of the disease as well as to detect possible new endocrine deficits. The patient is defined as in “endocrinological remission” if the basal cortisol level following 2 mg DEXA is inferior then 2 μg/dl.
Perioperative management of electrolytes and fluid disorders
Antidiuretic hormone (ADH) is synthesized in hypothalamus and transported along axons in the neurohypophysis, where it is released to target specific V2 receptors located in the basal portion of tubule cells allowing water reabsorption. After pituitary surgery, fluid and electrolyte disorders can occur mainly due to alteration of this mechanism. Central diabetes insipidus (CDI), is characterized by the excretion of large volumes of dilute urine (polyuria) due to vasopressin (ADH) deficiency and polydipsia. Its diagnostic criteria are: Urine excess >2.5 ml/kg/h for two hours, urine osmolality <200 mosm/kg and plasma osmolality >300 mosm/kg.
It is very important to distinguish a transient postoperative CDI from a permanent condition. Transient CDI is a very common in the published literature and in the personal series with ranging from 20-40% of the cases,,, but permanent CDI is infrequent (2-4% of the cases in the personal series). After a transient polyuria, a phase of oliguria may occur, eventually followed by polyuria again with a so-called bi- or triphasic pattern. This oliguria was attributed to the release of vasopressin as a result of slow degeneration of magnocellular neurones. In our experience, the classical triphasic pattern was only seen in 1.1% of patients. More frequent were the biphasic or only hyponatriemia. Polyuria and hypo/hypernatriemia may become life-treating, for this reason, their management should be well known by neurosurgeon that observe the patient in the early postoperative phase.
Transient polyuria is very frequent (one third of the cases) on the first postoperative day after surgery. Treatment with desmopressin should be careful used in order not to cause a condition of hyponatriemia. The prevalence decreases to 6% on the 7th postoperative day. The use of desmopressin is usually temporary (one to three times in total) and usually it is not started before the second postoperative day. Permanent diabetes insipidus is in our experience rare with circa 1% of the patients under treatment after three months and 0.3% after one year.
Prevalence of hyponatriemia has its peak from 3rd to 7th postoperative day. It may become symptomatic in a small percentage of patients with headaches, nausea and vomiting. Treatment consists of water restriction or oral sodium supplement. In severe cases not responding at such treatment hypertonic saline infusion with 10% NaCl can be performed.
Brain tumors and endocrinology: Side effects of treatment
The neurosurgeon should consider in the everyday practice that adjuvant treatment of brain tumors, even not related with sellar region, can have side effects that include endocrine disturbances. These examples show how the knowledge of the pituitary function and its tests is important for every neurosurgeon.
Chemotherapy with Vincristine may lead to the syndrome of inappropriate antidiuretic hormone secretion (SIADH): It can have a neurotoxic effect on the hypothalamic pituitary axis influencing ADH secretionRadiotherapy for midline tumors can lead, especially in children, to radiation-induced pituitary hormone dysfunction such as GH deficiency, TSH deficiency, ACTH deficiency and hypogonadismLong-time treatment of brain edema with dexamethasone can lead to Cushing's syndrome, adrenal suppression, osteoporosis and immunosuppression.
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Conflicts of interest
There are no conflicts of interest.
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