Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 47

Neurology of the pituitary SHANIKA SAMARASINGHE*, MARY ANN EMANUELE, AND ALALEH MAZHARI Division of Endocrinology and Metabolism, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

BACKGROUND The anterior pituitary hormones are essential for reproduction, growth, metabolic homeostasis, stress response, and adaptation to the external environment. Each pituitary hormone is secreted in a distinctive pulsatile manner reflecting its regulation by the central nervous system through a complex interaction between hypothalamic neuroendocrine pathways, feedback effects from peripheral target gland hormones, and intrapituitary mechanisms (Table 47.1).

PITUITARYADENOMAS: EPIDEMIOLOGY AND PATHOGENESIS Pituitary adenomas can be classified based on size ( 3.0 mg, therapy for lowering IGF-1; levels normalize in more

698 S. SAMARASINGHE ET AL. than 90% of patients (Chanson et al., 2009) with subsehyperglycemia in adults with endogenous Cushing’s quent improvement in symptoms. Continued adenoma syndrome and type 2 diabetes who have failed surgery. growth is possible and should be monitored by MRI, Adverse effects include moderate to severe hypokalebut this appears uncommon. An increase in tumor size mia, hypertension and clinical signs of adrenal insuffiwas noted in 3.2% of 684 patients for whom MRI data ciency (Castinetti et al., 2009). were available over a mean duration of 1.7 years (Trainer, 2009). Elevations in hepatic transaminases Radiotherapy have also been reported (Melmed, 2009). Finally, as somatotroph tumors also express D2 receptors, DA Radiotherapy is reserved for patients who have failed agonists do have a limited role in the treatment of acrosurgical and/or medical therapies or who are unable to megaly, especially in those that cosecrete prolactin. tolerate the risks of surgery due to medical comorbidites. High-dose bromocriptine (20–40 mg/day) normalizes This includes those with persistent or recurrent hormonal IGF-1 in 10% of patients (Colao et al., 1997). Cabergoline hypersecretion states. It is the rational step after failed appears to be more effective, with up to 40% of select transsphenoidal surgery in Cushing’s disease as medical patients responding (Abs et al., 1998). therapy is poor. Pituitary irradiation has also decreased the incidence of Nelson’s syndrome, the development CUSHING’S DISEASE of locally aggressive ACTH-producing tumors due to Surgery is also the primary treatment modality for Cushloss of feedback inhibition at the corticotrope in patients ing’s disease. Unfortunately, 10–30% of patients fail to who have undergone bilateral adrenalectomy. achieve remission after initial surgery and a similar perRadiation may be indicated after resection of a recurcentage may recur (Patil et al., 2009). Thus limited medrent or inadequately resected sellar mass. These tend to ical therapy, radiotherapy, and bilateral adrenalectomy display aggressive features such as cavernous sinus invaare also utilized in the management of Cushing’s disease. sion, compression of the carotid artery, erosion into the Pharmacologic treatments focus on diminishing adrenal clivus or sphenoid sinus. Postoperative radiotherapy is cortisol synthesis by enzymatic inhibition and include favored in those with craniopharyngioma. Radiotherapy agents such as ketoconazole, metyrapone, etomidate, has a high therapeutic index, delivering high-energy and mitotane. Side-effects are common. In addition, if ionizing radiation to arrest growth of tumor while minthe pharmacologic blockade is incomplete, the rise in imizing exposure to the normal surrounding tissue ACTH secretion overrides the blockade and hypercorti(Minniti et al., 2009). The aim is to prevent tumor prosolemia remains. Their primary role is to temporarily gression and normalize elevated hormone levels. It is control cortisol levels in patients awaiting the therapeutic successful in achieving tumor control in up to 95–97% effects of radiation. of patients at 10 years and 88–92% of patients at 20 Agents that specifically target the pituitary in Cushyears. Hormonal control is less successful with 60– ing’s disease include the DA agonist cabergoline and 80% of patients in remission dependant on tumor type the somatostatin analogue pasireotide. Chronic cabergoafter radiotherapy (Patil et al., 2009). Conventional line therapy has been associated with a clinically relevant radiotherapy requires several years to become maximal reduction in hypercortisolemia, although rare normalizaand may require continued medical therapy in the tion. Pasireotide has a high affinity for somatostatin interim. Hypopituitarism is the most common complicareceptor subtype 5 which can be present in corticotroph tion with up to 80% of patients demonstrating gonadoadenomas. Activation of this subtype inhibits corticotrotroph, somatotroph, thyrotroph, or corticotroph deficits pin secretion. In a recent study by Colao et al, pasireotide within 10 years after radiation (Anderson et al., 1999). decreased urinary free cortisol by a mean of 48% and Additional complications of conventional radiotherapy normalized it in 26% and 15% of patients receiving a include optic neuropathy (1.5% risk), brain necrosis 900 mcg or 600 mcg dose, respectively (Colao et al., (0.2%), secondary malignancies such as gliomas and 2012). However, hyperglycemia-related adverse events astrocytomas (2%), cerebrovascular disease, and possiwere common, occurring in 73% of patients (Colao ble cognitive impairment (Brada et al., 2004; Vance, et al., 2012). Another medical therapeutic option is 2005). The development of modern stereotactic technolmifepristone, which at high doses is a glucocorticoid ogies that can deliver high dose radiation more precisely receptor antagonist. It has been shown to be rapidly to the tumor can minimize complications and allow effective for certain symptoms of Cushing’s syndrome, for more rapid reduction in hormonal hypersecretion. such as cortisol-induced psychosis and hyperglycemia Stereotactic irradiation can be given as a single fraction (Castinetti et al., 2009). As such, mifepristone has radiosurgery (SRS) using either a cobalt unit (Gamma been recently approved in the United States to control knife) or linear accelerator (LINAC) or as lower

NEUROLOGY OF THE PITUITARY fractionated doses over several treatments using a linear accelerator or proton source (Castinetti et al., 2010). The precision achieved with stereotactic techniques allows for a reduction in safety margins around the tumor leading to sparing of normal brain from high radiation doses. Despite theoretical advantages, long-term outcomes and efficacy have yet to be defined.

FUTURE DIRECTIONS Improvement in hormonal assays and imaging techniques will allow for earlier diagnosis of pituitary problems even prior to symptom development. Further development of molecular tools will help determine the aggressiveness and genetic implications of pituitary adenomas. Continued advancements in surgical and radiation techniques as well as newer medical therapies will continue to evolve.

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Neurology of the pituitary.

The anterior pituitary hormones are essential for reproduction, growth, metabolic homeostasis, stress response, and adaptation to changes in the exter...
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