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Home , Chiasmal syndrome, Foster Kennedy syndrome, Pituitary adenoma, Pituitary disease

CHAPTER 31 Tumors of the Pituitary

John W. Gittinger, Jr.

ANATOMY OF THE PITUITARY COMPLEX PITUITARY PITUITARY METASTASES TO THE AND PITUITARY General Considerations GLAND Types of Pituitary Adenomas MIMICS OF PITUITARY ADENOMAS Ophthalmic Manifestations of Pituitary Tumors PITUITARY ABSCESS Treatment of Pituitary Adenomas Visual Prognosis in Patients with Pituitary Adenomas

Tumors of the are so important from a histopathologic features of pituitary tumors, the clinical pre- neuro-ophthalmologic standpoint that they are considered in sentations of patients with pituitary tumors, the various a separate chapter. In this chapter, we discuss the normal modes of treatment of pituitary tumors, and the prognosis of the pituitary endocrine unit, the endocrine and in patients with various types of pituitary tumors.

ANATOMY OF THE PITUITARY COMPLEX The hypophysis cerebri or pituitary gland lies at the weighs about 0.6 g, and may double in size during pregnancy base of the brain below the nestled in a (1). The larger anterior lobe or glandular portion is the ade- ‘‘Turkish saddle’’ (sella turcica) of bone that is part of nohypophysis; the posterior lobe or neural portion is the the body of the sphenoid. Lying above the pituitary is a neurohypophysis. The of the neurohypophysis are sheet of dura, the , that connects the and . Those of the adenohypophysis are clinoid attachments of the tentorium cerebelli. This is discussed below. The adenohypophysis is derived from an perforated by a hole that allows the infundibular stem or evagination of stomodeal ectoderm called Rathke’s pouch, stalk of the neural portion of the gland to connect to the remnants of which are thought to give rise to craniopharyngi- (Fig. 31.1). omas. Adenohypophyseal cells give rise to pituitary adeno- .mm, mas and the much rarer pituitary 6 ן 9 ן The gland itself normally measures 12

PITUITARY ADENOMAS GENERAL CONSIDERATIONS especially the , and the ocular motor The characteristic pituitary tumor is the . Uncom- in the (Fig. 31.2 mon in children (2), its incidence increases with age and may TYPES OF PITUITARY ADENOMAS approach 30% in an older population (3). Pituitary adenomas constitute 6–12% of all symptomatic intracranial tumors Pituitary adenomas are arbitrarily grouped by size into (4,5). Most are sporadic, but pituitary adenomas are a com- microadenomas (less than 10 mm in greatest diameter) and ponent of multiple endocrine neoplasia type 1, a familial macroadenomas. They are also classified according to their endocrine cancer syndrome characterized by primary hyper- secretory function, although a single tumor may secrete more parathyroidism, endocrine enteropancreatic tumors, and ad- than one . Many tumors that secrete hor- renocortical and thymic/bronchial neuroendocrine tumors mones—, (somatotrophin), adre- (6). As a grows and extends beyond the nocorticotropic hormone (ACTH or corticotrophin), and thy- sella turcica, it may then impinge upon the visual pathways, roid-stimulating hormone (TSH)—present clinically as 1531 1532 CLINICAL NEURO-OPHTHALMOLOGY

Figure 31.1. The location of the pituitary gland. A, Schematic drawing showing the relationship of the pituitary gland to the intracranial (ON) and chiasm (C). The heavily stippled portion of the gland is the adenohypophysis; the lightly stippled portion is the neurohypophysis. The arrows point to the diaphragma sellae. B, A postmortem specimen cut midsagittally through the pituitary gland, showing its relationships. (From Renn WH, Rhoton AL Jr. Microsurgical anatomy of the sellar region. J Neurosurg 1975;43Ϻ288–298.)

Figure 31.2. Coronal section through the pituitary gland, showing its relationship to the , internal carotid arteries, , and cavernous sinuses. The open white arrows on the right side of photograph indicate the boundaries of the cavernous sinus. The open white arrows on the left side of photograph outline the boundaries of cranial nerves. 3, oculomotor nerve; 4, trochlear nerve; VI, ophthalmic division of the trigeminal nerve; VII, maxillary division of the trigeminal nerve; 6, ; V.N., vidian nerve. (Courtesy of Dr. William F. Hoyt.) TUMORS OF THE PITUITARY GLAND 1533 endocrinopathies. As a result, secreting tumors are often di- enous hypercortisolism, the differential of which remains a agnosed while still microadenomas. clinical challenge (16). Nonsecreting tumors are usually recognized when they Cushing’s disease, a disorder much more common in have grown large enough to produce visual symptoms or women than men, refers to excess secretion of ACTH by a , thus tending to present as macroadenomas. By the pituitary adenoma that results in secondary adrenal hyperpla- mid-1990s, these nonfunctional tumors represented about sia and hypercortisolism. The majority of persons not taking 10% of clinically diagnosed pituitary adenomas (7). The with Cushing’s syndrome have Cushing’s widespread use of imaging has led to the discovery of silent disease, but significant minorities have adrenocortical or microadenomas, termed ‘‘incidentalomas’’ (8), measuring other tumors, especially small cell carcinoma of the lung, as small as 2–3 mm and present in 10–20% of the general that secrete ACTH (17). population (9). The prevalence of microadenomas at When adenomas were difficult to detect prior to modern may be as high as 30%. The imaging procedure of choice neuroimaging, many patients underwent bilateral adrenalec- in the detection of parasellar tumors, including pituitary ade- tomies for their Cushing’s disease. Freed from the restraint nomas, is high-field magnetic resonance (MR) imaging per- of hypercortisolism on corticotropin secretion and tumor formed both with and without gadolinium (10). growth, such patients often develop progressive cutaneous melanosis (Nelson’s syndrome) (18). In about 30% of per- Prolactin-Secreting Adenomas sons with Nelson’s syndrome, a large aggressive pituitary tumor is eventually recognized (7). is normal following pregnancy. When women who have not recently been pregnant develop galac- Somatotroph (Growth Hormone-Secreting) Adenomas torrhea, its is most often caused by a prolactin-secreting ade- noma. Such tumors account for about 40% of all pituitary Growth hormone-secreting tumors cause and tumors (11). Galactorrhea, in this setting, is frequently asso- giantism. Most such tumors are pituitary adenomas, but ec- ciated with (Forbes-Albright syndrome). Be- topic acromegaly from growth hormone-secreting carcinoid cause the are usually small, there are no visual or pancreatic islet cell tumors also stimulates pituitary hyper- symptoms or signs. plasia that mimics an adenoma on imaging studies (19,20). Normal prolactin levels are below 25 ng/mL in The differential diagnosis is made even more difficult be- women and below 20 ng/mL in men. Levels increase 10- cause both neuroendocrine tumors and pituitary adenomas fold in pregnancy. Adenomas that do not secrete prolactin are features of multiple endocrine neoplasia type 1 (21). and other parasellar processes may compress the pituitary Because the characteristic coarsening of facial features stalk, decreasing the normal dopaminergic inhibition and and other bodily changes—enlargement of the hands and increasing prolactin secretion. In this instance, the serum feet (the literal meaning of ‘‘acromegaly’’), , der- prolactin level is only moderately elevated. Other, nonneo- mopathy, and hypertrophic arthropathy—are gradual, they plastic causes of moderately elevated prolactin levels include may not be noticed until far advanced. Review of old photo- pregnancy, medications that affect metabolism graphs may reveal evolution of acromegaly over a decade (e.g., phenothiazines, metoclopramide, risperidone, vera- or more (Fig. 31.3). Proximal myopathy and carpal tunnel pamil), renal failure, and primary (12). Pro- syndromes are sometimes the first clinical manifestations lactinomas are generally associated with prolactin levels (22), and , not necessarily related to tumor growth, above 200 ng/mL and, in some cases, exceed 10,000 ng/mL. are common. Diabetes is observed in persons with acromeg- Pregnancy may result in enlargement of a prolactin-secret- aly because of growth hormone’s effects on insulin recep- ing adenoma, but the risk of visual loss during pregnancy tors, as are and premature vascular disease. from a microadenoma is low (13). In contrast to pregnant As it is harder to recognize the dysmorphic changes asso- women with known macroadenomas, where formal visual ciated with excessive growth hormone than galactorrhea or fields should probably be obtained at least once a trimester, the stigmata of Cushing’s syndrome, somatotroph adenomas women with microadenomas do not require routine field test- are less often detected as microadenomas. The frequency of ing during pregnancy (14). suprasellar extension and defects in somatotroph Men with prolactinomas become impotent and infertile. adenomas is therefore intermediate between prolactin- and They may be obese with gynecomastia but do not usually corticotropin-secreting tumors and nonsecreting adenomas have galactorrhea. Because the clinical picture is less spe- (23). cific than in women, men with prolactinomas tend to have larger tumors at presentation. Thyrotroph (TSH-Secreting) Adenomas

Corticotroph (ACTH-Secreting) Adenomas Fewer than 3% of pituitary adenomas secrete thyrotropin (24). They usually present with as the result Cushing’s syndrome refers to the effects of excessive glu- of ‘‘TSH toxicosis’’ or with visual loss. Thyrotroph adeno- cocorticoids on the body (15). Hypercortisolism from any mas tend to be large and invade surrounding structures (25). cause, including taking corticosteroids such as prednisone, In the NIH series of 25 thyrotroph adenomas, about one third dexamethasone, or methylprednisolone, produces Cushing’s of patients (36%) had visual field defects (26). In contrast syndrome. Endocrinologists are more concerned with endog- to Graves’ disease, affected individuals are not at risk for 1534 CLINICAL NEURO-OPHTHALMOLOGY

Acidophilic adenomas were likely to secrete growth hor- mone, while basophilic adenomas were likely to secrete ACTH. The advent of more sophisticated diagnostic tech- niques has made this classification of historic interest only, but the term ‘‘chromophobe’’ still appears occasionally in the literature to denote a nonfunctioning adenoma.

OPHTHALMIC MANIFESTATIONS OF PITUITARY TUMORS While improved endocrine and neuroimaging techniques have reduced the proportion of pituitary adenoma patients with primarily neuro-ophthalmic presentations, visual loss and ophthalmoplegia remain important manifestations of pi- tuitary adenomas and other sellar and parasellar tumors. The classic dictum that an unexplained decrease in acuity should prompt testing of the visual field to look for a bitemporal pattern of field loss remains valid. Instances of delay in the diagnosis of pituitary and other chiasmal tumors when this rule is violated abound (28–31).

Visual Field Testing Strategies Just testing the visual field may be more important than the method used, but the strategy should incorporate compar- ison of the nasal and temporal hemifields within 20–30 de- grees from fixation (32). Threshold static testing appears well suited to this task but may not be more sensitive than Goldmann kinetic perimetry in experienced hands (33,34). In a personal series collected before 1985, Frise´n found superotemporal defects to a single, small Goldmann isopter that were not detected by the static perimetry then available (33). Adding additional isopters did not improve sensitivity. The variations in examiner skill levels in the performance of Goldmann perimetry and the availability of increasingly accurate and less time-consuming testing protocols, how- ever, mean that automated threshold static perimetry is re- Figure 31.3. The gradual development of acromegaly in a woman with placing Goldmann perimetry as the standard (35–37). Auto- a somatotroph adenoma at age 19 (A), at age 32 (B), and at age 45 (C). mated threshold static perimetry has the further advantage Note increasing coarseness of facial features, broadening of nasal bones that serial fields should be more precisely comparable, al- and mandible, and thickening of neck. Also note large hands. lowing better assessment of progression or improvement.

The Chiasm -related ophthalmopathy as they do not have the un- derlying immunologic abnormalities. The optic chiasm or chiasm is a plate of neural tissue formed by the semidecussation of the optic nerves. When Endocrine-Inactive Adenomas viewed from above or below, the chiasm is usually thought to resemble an X (the Greek letter chi, from which it derives Pituitary adenomas that do not secrete any hormones are its name). Frise´n (38) preferred to describe the chiasm as a minority, although some secreting tumors do not produce ‘‘a symmetrically deformed letter H.’’ The chiasm lies about recognizable endocrinologic manifestations and thus behave 1 cm above the sella turcica and thus is not affected by clinically as though they were nonsecreting. Endocrine-inac- pituitary adenomas until they extend well above the pituitary tive tumors include null cell tumors, oncocytomas, and go- fossa, by which time they are macroadenomas of considera- nadotropin-secreting, glycopeptide-secreting, and silent cor- ble size that have almost always eroded bone. ticotropin-secreting tumors (27). Bitemporal field loss in the presence of a normal-sized Classically, tumors with agranular cytoplasm on conven- sella turcica thus indicates a tumor other than a pituitary tional light microscopy were designated chromophobe ade- adenoma, with a few exceptions (39). Early in the last cen- nomas to distinguish them from chromophiles. The latter tury Cushing (40,41) recognized that a ‘‘chiasmal syn- had cells with cytoplasmic granules that stained brightly with drome’’ of bitemporal hemianopia, optic atrophy, and nor- acid fuchsin (acidophilic) or with aniline blue (basophilic). mal sella on plain films was typical of TUMORS OF THE PITUITARY GLAND 1535 arising from the tuberculum sellae but occurred rarely with myelination as a guide to immune modulation therapy, this pituitary adenomas. A normal sella on plain skull films is should seldom be an issue. also a feature of , optic , aneu- Sudden monocular visual loss may be the presentation of rysms, and chordomas. The issue is effectively moot as plain (49,50). When such patients are evaluated skull films are now seldom critical or even obtained. An emergently, careful testing of the visual field of the fellow exception may be in the urgent evaluation of possible pitui- eye may not be performed. Monocular visual field defects tary apoplexy (discussion following), where computed to- were detected in 9% of the 1,000 patients with adenomas in mography (CT) sometimes gives false-negative results, and the Mayo Clinic series published in 1973 (51) and in 38.7% a plain skull film can provide an important clue to the correct of 307 cases of acromegaly evaluated in a Paris referral cen- diagnosis. ter between 1951 and 1996 (23). In both series, a supertem- The chiasmal bar consists of decussating that origi- poral quadrantanopsia was the most common monocular de- nate in the ganglion cells of the nasal to the fovea and fect. pass through the optic nerves. These carry information from In Hershenfeld and Sharpe’s series of 24 patients with the temporal visual fields of both eyes. Even taking into monocular temporal hemianopias, 15 had pituitary adeno- account the blind spot, the temporal fields have a larger area mas (52). Caution should be exercised in attributing a mono- than the nasal. A greater number of cular temporal hemianopia to chiasmal dysfunction, as this axons project contralaterally through the chiasm, approxi- is a common pattern of functional (psychogenic) visual loss mately 53% (42), than remain ipsilateral, except in albinism, (53). A functional etiology should be considered likely when where the proportion of decussating fibers is considerably there is no relative afferent pupillary defect or optic atrophy greater (43). Once decussation has occurred, the optic tracts and may usually be confirmed by the persistence of the hemi- are formed, carrying the axons serving the entire contralat- anopia on binocular testing (54). eral hemifields to the lateral geniculate bodies in the thala- mus, thereby fulfilling for the the requirement that all sensory information is processed in the contralateral Junctional Defects cerebral hemisphere. One pattern of field loss whose localizing value is still a matter of discussion is a central in one eye associ- Chiasmal Field Defects ated with temporal field loss in the other, a combination Pituitary adenomas usually compress the chiasm from thought to point to the junction between the optic nerve and below. The visual field defect most often produced is supe- the chiasm on the side of the scotoma. In his classic mono- rior, bitemporal, and greater nearer fixation. While the mac- graph An Introduction to Clinical Perimetry, Traquair called ula represents only a small area on the retina, axons arising attention to the hemianopic quality of the scotoma and used from macular ganglion cells occupy large portions of the the phrase ‘‘junction scotomata’’ (his quotes) (55). An iso- optic nerves, chiasm, and optic tracts (44–46). One conse- lated, monocular temporal hemianopic paracentral scotoma quence is that compression of either the optic nerve or chi- is thus sometimes referred to as a junctional scotoma and asm tends to reduce acuity and to depress the central field. may be the presentation of a pituitary adenoma (56). The Loss of stereopsis may be an early sign of chiasmal compres- hemianopic temporal arcuate scotoma described by Trobe sion and bitemporal scotomatous field loss (47). has the same significance (57). For the most part, efforts to use specific patterns of visual Traquair also attributed to Wilbrand and Saenger the ob- field loss for precise localization are futile. The anatomy is servation that ‘‘involvement of the knee of crossed fibers better delineated by high-resolution MR imaging, and in any from the opposite nerve may be the source of a temporal event, large tumors impinging upon the chiasm distort the defect in the opposite field’’ (55). Horton has provided evi- tissues to a degree that belies such attempts (Fig. 31.4). dence that Wilbrand’s knee fibers were an artifact of mono- Frise´n (33) divided chiasmal visual field defects into me- cular enucleation (58). In a patient with pituitary adenoma dial and lateral syndromes. Medial chiasmal syndromes have described by Karanjia and Jacobson with a central scotoma predominately bitemporal field defects, and lateral chiasmal in one eye and a temporal field defect in the fellow eye syndromes have temporal field defects on the side of the localizing to the prechiasmatic optic nerve, Horton pointed tumor and another type of field defect in the fellow eye. out that careful review of their imaging actually reveals ante- Acuity in medial chiasmal syndromes is reduced in both rior chiasmal compression (59,60). In another recently re- eyes, often asymmetrically. In lateral chiasmal syndromes, ported instance of what could be interpreted as a junctional the acuity may be reduced only in the eye with the temporal defect, imaging demonstrated a large mass extending out of field defect. the sella and compressing the chiasm (61). Independent of the actual existence of knee fibers, the Monocular Visual Field Defects value of a central scotoma in one eye associated with a tem- The occasional patient with sudden visual loss in one eye poral field defect in the fellow eye should direct attention as the result of a pituitary adenoma once ran the risk of to the posterior optic nerve where it joins the chiasm. This being misdiagnosed with retrobulbar (48). As pattern is less often encountered with pituitary adenomas virtually everyone with the putative diagnosis of optic neuri- than with other pathologies, such as , aneurysm tis now undergoes MR imaging to look for evidence of de- (62), and inflammation (63,64). 1536 CLINICAL NEURO-OPHTHALMOLOGY

Figure 31.4. Compression of the anterior visual system by pituitary adenomas. A, Basal view of a pituitary adenoma that has compressed the anterior visual system. The tumor is adjacent to the ventral surface of the brain but does not compress it. The dura beneath the tumor has been removed intact with this specimen and has been peeled away (D) to reveal the tumor. B, Basal view of the intracranial portions of the optic nerves, chiasm, and optic tracts after removal of the tumor seen in A. Both optic nerves have been flattened by the tumor, as has the optic chiasm. The left side of the chiasm has been reduced to a thin, diaphanous membrane (arrow). C, A pituitary adenoma is seen from below in a 65-year-old man who was blind in his left eye and had a temporal hemianopia in his right eye. The tumor is compressing the optic chiasm and the left . The tumor does not involve either of the optic nerves or the right optic tract. The patient’s visual disturbance was thought to be caused by the combined effects of optic chiasmal compression that produced a bitemporal field defect and compression of the left optic tract that produced a right homonymous hemianopia. The right eye thus had an isolated temporal hemianopia, while the left eye had loss of the temporal field from involvement of the chiasm and loss of the nasal field from involvement of the right optic tract. D, Basal view of the optic chiasm of a 71-year-old woman with a large pituitary adenoma. The tumor has been removed to show marked elevation and thinning of the optic chiasm (OC) and tuber cinereum (TC). The optic tracts are deformed and compressed (arrowheads). With further growth, the tumor would have penetrated the floor of the third ventricle. The optic nerves do not appear to have been affected by the tumor. TUMORS OF THE PITUITARY GLAND 1537

Ophthalmoplegia of a pituitary adenoma as the result of hemorrhage or infarc- tion, an entity known as pituitary apoplexy (Fig. 31.5). Pitui- Third, fourth, and sixth nerve palsies individually and in tary apoplexy may also present with visual loss alone or combination are less common than optic nerve involvement in association with Horner’s syndrome (67). Precipitating in pituitary adenomas but still constitute an important clini- factors include head trauma, treatment with radiation or bro- cal manifestation. As an isolated motor neuropathy, third mocriptine, estrogen administration or pregnancy (68), angi- nerve involvement is most frequent (65) and may be painful ography (69), anticoagulation (70), cardiac or other recent (66). surgery (71), dialysis (72), dynamic pituitary function or Pituitary Apoplexy stimulation tests (73), and transient changes in (ICP) from coughing or sneezing (74) or spinal Headache, ophthalmoplegia with or without visual loss, anesthesia (75). The majority, however, have no identifiable and alteration in consciousness suggest sudden enlargement precipitant (70,76).

Figure 31.5. Pituitary apoplexy. A 77-year-old woman experienced acute loss of vision in both eyes associated with severe headaches. She became increasing confused and lethargic. She was admitted to a local hospital, where she became somnolent and then comatose. She died 24 hours after admission. A, Midsagittal section through the brain shows a huge, hemorrhagic pituitary adenoma that displaces the third ventricle posteriorly, the rostrum of the corpus callosum and the anterior cerebral artery upward, and a portion of the orbital portion of the anteriorly. B, Coronal section through the same brain shows that the tumor extends anteriorly between both frontal lobes, displacing the olfactory nerves laterally. The poles of both temporal lobes have been removed to show the relationship of the tumor to the internal carotid arteries. Both arteries are pushed laterally and anteriorly by the tumor, which also displaces and compresses both optic nerves. The tumor has completely destroyed the optic chiasm. The oculomotor nerves partially encircle the posteroinferior aspect of the tumor but are not compressed by it. (From Lindenberg R, Walsh FB, Sacks JG. Neuropathology of Vision: An Atlas. Philadelphia, Lea & Febiger, 1973.) 1538 CLINICAL NEURO-OPHTHALMOLOGY

Fulminant pituitary apoplexy is a medical emergency, but agnosed as subarachnoid hemorrhage or meninigitis (77). its recognition may be delayed by the accompanying mental To further complicate the matter, pituitary apoplexy actually status changes and intercurrent medical issues. In some cases produces subarachnoid hemorrhage in the absence of aneu- the headache precedes the development of ophthalmoplegia rysm (78), and aneurysm and adenoma may coexist in the by several days. Pituitary apoplexy is often initially misdi- same patient (79). To evaluate a sudden, severe headache,

Figure 31.6. Foster Kennedy syndrome cause by a giant invasive pituitary adenoma. The patient was a 51-year-old woman with progressive loss of vision in the left eye for many years and recent visual loss in the right eye. Visual acuity was 20/20 OD and light perception OS. A, Right is swollen. B, Left optic disc is pale. C, Noncontrast T1-weighted magnetic resonance image reveals a huge pituitary adenoma causing marked compression of the left cerebral hemisphere. (From Ku¨che M, Seyer H. Foster Kennedy syndrome caused by extensive pituitary adenoma. Neuroophthalmology 1992;12Ϻ77–83.) TUMORS OF THE PITUITARY GLAND 1539

CT is usually performed without contrast, looking for sub- arachnoid hemorrhage. This may or may not lead to immedi- ate recognition of the adenoma (80). CT, although usually more readily available than MR imaging, is not as sensitive as MR imaging in the diagnosis of pituitary apoplexy (81–84). Conservative management of pituitary apoplexy is war- ranted if the patient is alert and has only ophthalmoplegia (85). Immediate replacement and other endo- crinologic support may be required, and surgical decompres- sion, usually by a transsphenoidal route, is indicated when there is visual loss or persistent or progressive cognitive dysfunction (86,87). Not all hemorrhagic infarctions of pituitary adenomas pro- duce dramatic . Occasionally, pituitary apoplexy may even be therapeutic, producing resolution of acromegaly, Cushing’s disease, or a nonfunctioning tumor (88). An empty sella may be a residuum of a previous apo- plectic event (89). For completeness, mention must be made of another defi- nition of pituitary apoplexy: infarction of normal pituitary gland. This characteristically develops postpartum in women with massive uterine hemorrhage that causes hypotension. The resulting primary , known as Sheehan’s syndrome, may also be accompanied by an empty sella.

Hallucinations, , and Other Visual Manifestations of Pituitary Adenomas Figure 31.7. The hemifield slide phenomenon that occurs in patients with Virtually any sign or symptom that can be produced by a complete bitemporal hemianopia or large dense bitemporal hemianopic damage to the anterior visual pathways and adjacent struc- . Diagram shows that in patients with full visual field (top), there tures may be encountered in patients with pituitary adeno- is overlapping of the nasal field of one and most of the temporal field of mas. These include formed and unformed hallucinations the opposite eye. This permits stable binocular fusion, even in patients (90,91), transient monocular blindness (92), and mental sta- with an , , or hyperphoria. When there is bitemporal tus changes (93–95). hemianopia, there no longer is any overlapping of the corresponding por- Papilledema is unusual with pituitary adenomas (96) as tions of the central visual field of the two eyes. The intact, noncorrespond- the axonal loss caused by direct compression results in optic ing, nasal hemifields from the two eyes simply are adjacent to each other atrophy before the tumor is of sufficient size to increase (middle). This may result in decompensation of a preexisting phoria (bot- tom). If the patient develops an , the remaining hemifields will ICP. If tumor growth is asymmetric, the Foster-Kennedy drift apart horizontally and the patient will not see certain letters in long syndrome may ensue (Fig. 31.6) (97,98). Bilateral disc words or certain words in a sentence. If the patient develops an , swelling from malignant hypertension associated with Cush- the remaining nasal hemifields will overlap slightly, resulting in superimpo- ing’s disease mimics true papilledema (99). The growth hor- sition of images. Finally, if the patient develops a , the nasal mone-secreting pituitary adenoma confined to the sella that hemifields will separate vertically, thus causing vertical separation of let- increases ICP (100) is presumably producing physiologic ters, words, or other images seen by the patient. changes similar to those in children administered recombi- nant human growth hormone for short stature and Turner syndrome who develop pseudotumor cerebri. with altitudinal defects as the result of optic nerve disease (102).

Diplopia Without Ophthalmoplegia Seesaw While the vast majority of patients with pituitary adeno- Loss of sensory input may be important in some cases of mas who complain of have ophthalmoplegia, some seesaw nystagmus, a rare ocular oscillation where the eyes have normal ocular motility. This phenomenon, known as appear to be riding on a seesaw across the nose. One eye nonparetic diplopia or hemifield slide (101), occurs when elevates and intorts while the other eye is synchronously the degree of temporal visual field loss lessens the stabilizing depressing and extorting, then the cycle reverses (Fig. 31.8). effect of overlap with the contralateral eye’s nasal field (Fig. Parasellar tumors, including pituitary adenomas, are accom- 31.7). This is probably the same mechanism that decreases panied by seesaw nystagmus on rare occasions, and one pos- stereopsis (47). Nonparetic diplopia has also been described tulated mechanism is compression of the diencephalon in 1540 CLINICAL NEURO-OPHTHALMOLOGY

trol of tumor growth. Therapeutic options include medica- tion, surgery, and radiotherapy.

Medical Treatment of Pituitary Adenomas The primary treatment for all prolactinomas not acutely enlarging is a , in current practice either bromocriptine or (113). Bromocriptine is prefer- able when pregnancy is anticipated, as there are now over 20 years of experience with this drug without evidence of significant adverse effects on the mother or fetus. If the pro- lactin level does not return to normal with one drug, the other is substituted. Dopamine agonists also shrink tumors, producing visual improvement. These patients should be monitored with visual fields and undergo repeat MR imaging 3–6 months after initiation of therapy. Because of the likeli- hood of regrowth when the dopamine agonist is discontin- ued, patients with macroadenomas must remain on medica- tion indefinitely, although the required dosage may decrease. Medical treatment of acromegaly is less successful. Oc- Figure 31.8. Seesaw nystagmus. The eyes appear to ride a seesaw with treotide, a analog, is generally more effective its fulcrum at the base of the nose. (From Post KD, Jackson IMD, Reichlin than bromocriptine, but some patients respond only to bro- S. The Pituitary Adenoma. New York, Plenum, 1980.) mocriptine. will usually halve the tumor size and decrease hormone secretion but is generally used as adjunc- tive therapy either before or after surgery. The availability the region of the interstitial nucleus of Cajal. Usually these of a long-acting form, allowing monthly injections rather are large tumors with accompanying bitemporal field de- than every 8 hours, has simplified administration (114). An- fects. other somatostatin analog, (also available in a The occurrence of seesaw nystagmus in patients who have long-acting formulation), has effect on fewer tumors. A only either brain stem infarctions or visual loss demonstrates growth hormone receptor agonist, , may be even that either sensory or motor abnormalities alone are adequate better in correcting the metabolic abnormalities caused by causes (103,104). Seesaw nystagmus is also encountered in growth hormone secretion, but it does not control tumor children born without a chiasm (105). growth or normalize growth hormone levels because it does not act on the pituitary (115,116). Octreotide is also used in the treatment of thyrotropin- secreting tumors when surgery is refused, when surgery does Intolerance to light is a symptom of many disorders, from not result in a cure and radiation is refused, or when surgery ocular surface disease to . Photophobia is a common and radiation fail to control hyperthyroidism (26). Thyro- feature of trigeminal neuralgia (106) and may be prominent troph tumors respond to octreotide because they have so- in patients with chiasmal compression (107). A relationship matostatin receptors (117). to the painless central dazzle thought to result from thalamic Corticotroph adenomas are initially approached surgi- injury has been postulated (108). Fisher, in his original de- cally. If levels do not return to normal, adjunctive scription of central photophobia, also referred to as central medical therapy is used until another treatment modality (re- glare or dazzle, observed that it was usually accompanied peat surgery, radiotherapy, or bilateral adrenalectomy) takes by hemianopia and suggested that it was the result of damage effect (118). Ketoconazole inhibits cortisol synthesis but has in the occipital region (109). Subsequently, because of clini- significant hepatic and gastrointestinal side effects. Other cal similarities with thalamic pain syndrome and imaging adrenal enzyme inhibitors—metyrapone, aminoglutethi- that pointed to simultaneous thalamic and occipital involve- mide, and mitotane—are sometimes substituted when keto- ment, thalamic injury was implicated (110). conazole is ineffective or poorly tolerated. A case of monocular central dazzle with isolated bilateral The successful medical treatment of other types of pitui- ischemic lesions in the thalamus lends support to this hy- tary tumors is sporadic. Some nonfunctioning tumors do pothesis (111). The mechanism of the photophobia associ- shrink with administration of dopamine agonists or somato- ated with chiasmal compression remains uncertain (112). statin analogs, but these are not first-line therapies. Surgical Treatment of Pituitary Adenomas TREATMENT OF PITUITARY ADENOMAS is usually the treatment of choice The goals of treatment of pituitary adenomas are recovery when acute decompression of the visual pathways is re- or preservation of vision, reversal of any hypersecretory syn- quired, as in pituitary apoplexy. Most prolactinomas are drome with restoration of normal pituitary function, and con- managed medically and do not require surgery. Somato- TUMORS OF THE PITUITARY GLAND 1541 troph, corticotroph, and thyrotropin adenomas are usually the empty sella is primary or secondary to prior subclinical approached surgically as primary therapy, as are other sellar events. tumors that are of sufficient size to threaten vision or when An unusual variant of what might be considered a true the diagnosis is in doubt. Asymptomatic small tumors are ‘‘empty sella’’ is pneumocephalus, intracranial air. Progres- generally left alone. sive, postoperative visual loss may be the result of a suprasel- The outcome of transsphenoidal adenomectomy is good, lar pneumatocele compressing the chiasm (139). Pneumo- with low morbidity and mortality, especially in experienced cephalus is also encountered after sinus surgery other than hands (119,120). In the United States the overall mortality transsphenoidal adenomectomy and is easily visualized on has fallen below 1% (121). The chance for cure of a somato- plain films, CT, and MR imaging (140). troph microadenoma by transsphenoidal surgery is estimated Spontaneous pneumocephalus, indicating a connection at 80% (122). between the nasal sinuses and intracranial space as the result of bony erosion by tumor, may also be the presentation of Radiotherapy of Pituitary Adenomas a pituitary adenoma (141). Adenomas that grow into the sinuses also may present with bloody saliva or nasal dis- Larger tumors are difficult to resect completely, and some charge (142). smaller tumors are not identified and removed at the time of surgery. Considered a second-line therapy, the use of ra- diation depends upon the tumor type, the patient’s age, and VISUAL PROGNOSIS IN PATIENTS WITH the necessity to retain pituitary function. Adjunctive radia- PITUITARY ADENOMAS tion is generally used when surgery fails to cure corticotroph or thyrotroph tumors (123). Gamma-knife stereotactic radio- The prognosis for return of visual function in patients surgery is an alternative to conventional external beam radia- whose tumors have caused loss of visual acuity, visual field, tion (124–126). or both depends on the duration of symptoms, severity of Hypopituitarism is the most frequent complication of ra- visual loss, presence or absence of optic atrophy, age of the diotherapy, presumably as a result of damage to the hypo- patient, and size of the tumor (143–150). The pattern of thalamus (127). Radionecrosis of the visual pathways is rare, recovery of visual function after decompression of the ante- but its effects may be devastating. From a literature search, rior visual pathways suggests at least three phases of im- van den Bergh et al. calculated an incidence of 1.36% in provement. The early fast phase (surgery to 1 week) of im- patients who had somatotroph adenomas treated with exter- provement may lead to normalization of visual fields in some nal beam photon radiation therapy (128). This is comparable individuals. The early slow phase (1–4 months) is the period to the 1.9% risk (4/215) of radionecrosis after stereotactic of most notable improvement. A late phase (6 months to 3 radiosurgery in a Mayo Clinic series that included meningio- years) of mild improvement does not appear significant over- mas, pituitary adenomas, and craniopharyngiomas (129). all but may be marked in some individuals. Each of these Remarkably, three out of these four Mayo Clinic patients phases may have one or more mechanisms underlying the had corticotroph adenomas where visual loss developed or observed improvement (150). progressed 18 to 61 months after treatment. Other cranial Significant improvement in visual function occurs within neuropathies may follow radiosurgery, including any of the 24 hours after surgery in most patients (148,150–152). Rare ocular motor nerves (130,131). patients show no change in vision for several weeks and Postirradiation —, meningioma, and then experience a rapid improvement in vision that is proba- sarcomas—are rare enough that it is difficult to determine bly caused by delayed collapse of the tumor capsule (153). which are chance occurrences (132,133). In a recent case In long-term studies, 75–95% of patients show improvement report from the National Hospital, Queen Square, a radia- in either visual acuity, visual fields, or both after either trans- tion-induced, low-grade fibrosarcoma’s evolution into a cranial or transsphenoidal surgery (148–150,154,155). Fur- more malignant osteosarcoma was heralded by a third nerve ther improvement in vision, particularly in visual field, may palsy 14 years after treatment of a null cell adenoma (134). occur several months and occasionally several years after surgery. Patients who are placed on bromocriptine experi- Secondary Empty Sella ence improvement in visual function within 24–72 hours Treatment of pituitary adenomas may lead to a radiolog- after starting the drug (156–158); however, in patients who ically empty sella. Herniation of the chiasm into this arach- undergo radiation therapy, visual improvement usually does noid diverticulum is the most commonly identified cause of not begin for several months. late visual loss not the result of tumor recurrence (23). Var- The recurrence rate for patients with nonsecreting tumors ious surgical techniques have been devised to relieve traction causing visual loss depends to a great extent on the initial on the chiasm to reverse the visual loss (135), and similar size and extent of the tumor and on the mode of therapy. benefits may result from reduction in medical treatment to When transcranial surgery alone is used to treat these tumors, allow the tumor to re-expand (136,137). The relationship of there is a recurrence rate of 7–35%; however, when surgery primary empty sella, which is thought to result from a defect is combined with radiotherapy, the 5-year recurrence rate is in the diaphragma sella, to visual loss is less clear (138), lowered to 7–13% (159). The recurrence rate of patients and it is difficult in some instances to determine whether who undergo transsphenoidal resection of their nonsecreting 1542 CLINICAL NEURO-OPHTHALMOLOGY pituitary tumors followed by radiotherapy is not clear but is the scarring produced traction on the optic chiasm that, in probably less than 10%. In a series of 50 patients treated in turn, compromised its vascular supply and caused the visual this fashion, we observed no recurrences over an average field defect. It was therefore decided simply to observe the period of 15 years. We examined, however, a patient who patient, and she maintained stable vision over a period of developed recurrent loss of vision about 1 year after treat- about 5 years. ment and was found to have a cyst in the suprasellar region. Patients whose vision recovers incompletely or not at all Another patient suddenly developed a recurrent bitemporal after therapy may develop a recurrence of their tumor that hemianopia with preservation of visual acuity about 2 years is not detectable during a neuro-ophthalmologic examination after successful transsphenoidal removal of a nonsecreting because the recurrent tumor initially compresses an already pituitary adenoma followed by radiotherapy. In this patient, damaged anterior visual pathway. For this reason, patients MR imaging demonstrated no evidence of tumor recurrence, should be followed not only with neuro-ophthalmologic ex- but the optic chiasm was pulled downward, apparently by aminations but also with endocrinologic and neuroimaging postoperative or postradiation scarring. It was thought that studies after treatment for a pituitary adenoma. PITUITARY CARCINOMA As with some other histologically benign tumors, pituitary A pituitary carcinoma is defined not by the histopatho- adenomas may be locally invasive. Microscopic dural inva- logic features of malignancy but by its potential for distant sion confers a poorer prognosis for life, probably because it , either hematogenously or through the cerebro- indicates the tumor was larger when detected (160). Macro- spinal fluid. Such malignant pituitary tumors often have de- adenomas, with the exception of gonadotroph adenomas, ceptively benign routine and require specialized have a greater than 50% incidence of gross invasion (161). for characterization (165,166). Me- True malignancies, pituitary carcinomas, constitute only tastases characteristically appear years after the adenoma 0.1–0.2% of pituitary tumors. By 1996 only 64 cases had was initially recognized (167). Patients with metastases live been reported in the English language literature (162), most an average of 1 year, although there are a few instances of of which were endocrinologically functional (163). In a se- prolonged survival (164,168). ries of five patients with silent corticotroph carcinomas, all had visual symptoms at presentation (164). METASTASES TO THE SELLA TURCICA AND PITUITARY GLAND Diplopia or visual loss with bitemporal field defects may with a pituitary adenoma alone preoperatively) accompanied also represent metastatic disease to the sellar region by a rapidly progressing painful ophthalmoplegia. Surgical (169,170). Not surprisingly, lung and breast are the most decompression and radiation may have palliative value, im- common primary sites, but many pathologies are encoun- proving both pain and vision (172). Some tumors, such as tered. Occasionally, the metastasis is to a preexisting pitui- prostatic adenocarcinoma, may respond to chemotherapy tary adenoma (171). A clinical picture that suggests meta- with visual improvement (173). static disease is (unlikely to be present MIMICS OF PITUITARY ADENOMAS Primary lymphoma of the central nervous system may PITUITARY ABSCESS present as or hypopituitarism and appear Abscesses in the sella do not necessarily present with signs as a sellar and suprasellar mass on neuroimaging (174). The and symptoms of infection (189); most are discovered when differential diagnosis of sellar masses also includes cranio- pharyngioma, meningioma, germinoma and other germ cell the surgeon encounters a pus-filled cyst. The material aspi- tumors (175), schwannoma (176), infundibular glioma and rated may be sterile, but bacterial genera identified include (177), cysts (dermoid, epidermoid, Rathke’s Staphylococcus, Streptococcus, Neisseria, Corynebacteria, cleft, arachnoid [178,179], cysticercus [180]), sarcoidosis, diphtheroids, and even Brucella (190). As noted, fungal and histiocytosis (181), xanthogranuloma (182,183), infections parasitic abscesses also occur. Sphenoid mucoceles contain- (fungi [184], parasites, syphilis, and tuberculosis [185,186]), ing bacteria may extend into the sella and mimic pituitary and aneurysm (187). The differential diagnosis can usually adenoma and other parasellar processes (191). Late-develop- be narrowed by MR imaging, but sophisticated pathology ing sphenoid mucoceles are a complication of transsphenoi- may be required for definitive diagnosis. dal surgery and must be included in the differential diagnosis In addition to the tumors listed above, there are case of visual loss and ophthalmoplegia presenting years after reports of chondrosarcoma, chordoma, gangliocytoma, surgical treatment of adenoma (192). esthesioneuroblastoma, hemangiopericytoma, cavernous hemangioma, melanoma, and considered in- HYPOPHYSITIS distinguishable neuroradiologically from pituitary adenomas Chiasmal compression presenting during or just after (188). pregnancy may signal an autoimmune process known as TUMORS OF THE PITUITARY GLAND 1543 lymphocytic hypophysitis (193). Lymphocytic hypophysitis 20. Van den Bruel A, Fevery J, van Dorpe J, et al. 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