by Wesley P. Fairfield, M.D.
NEPTCC Newsletter MGH Neuroendocrine Center Bulletin Vol 5, Issue 1, Winter 1999
Introduction and Overall Concepts
"It is quite probable that the psychopathology of everyday life hinges largely upon the effects of a ductless gland discharge upon the nervous system" Harvey Cushing, 1913.
Patients with pituitary adenomas have a higher prevalence of cognitive dysfunction than found in the general population. The current literature has evaluated this association with case control studies and are subject to the many biases inherent to retrospective analyses. Although pituitary adenomas account for 10-15% of intracranial tumors, their relatively low prevalence makes systematic prospective evaluation difficult. In addition, clinical endpoints to evaluate cognitive functioning are often poorly standardized. It is entirely plausible that pituitary adenomas are linked to cognitive changes. The pituitary gland is situated in a region of the diencephalon known to be important for memory processing. Patients who have been diagnosed and treated for a pituitary adenoma may be exposed to several factors which contribute to changes in cognition including mass effect, hormone hypersecretion, hormone hyposecretion, radiation damage, surgical damage and psychiatric issues related to concomitant medical illness. Given a 9% prevalence of mood disorders in the general outpatient population, most of the neurocognitive changes observed in patients with small non-functioning pituitary adenomas without surgical or radiation therapy are likely to be coincidental. The prevalence of cognitive dysfunction in patients with pituitary tumors and the relative contribution of known variables will be discussed.
Pituitary tumors can present with raised intracranial pressure, pituitary dysfunction or visual field compromise. Other tumors commonly located in the region of the sella turcica include craniopharyngiomas and suprasellar meningiomas and can present with similar symptoms. Each of these tumors may produce alteration in mental status that precedes the aforementioned features. In one retrospective review of 49 patients with cranio-pharyngiomas, the initial presenting feature was mental status abnormalities in 19% of cases. Attribution of cognitive changes directly to mass effect is confounded by the association of large sellar tumors with hypopituitarism as well as surgical and radiation therapies employed to treat these tumors.
Some forms of pituitary tumors may result in psychiatric disturbance attributable to hormone hypersecretion by the pituitary adenoma in the absence of mass effect, hypopituitarism, surgical therapy or radiation therapy. Harvey Cushing in his original description reported emotional disturbance as a prominent feature of the syndrome bearing his name. Subsequently many series have documented a high rate of neuropsychological deficits with endogenous hypercortisolemia including cognitive changes, affective disorders, disordered vegetative functions and acute psychoses. In a series of 209 patients with Cushing’s, nearly 60% had significant psychiatric illness and while the severity did not correlate with degree of hypercortisolemia the depression was alleviated with adrenalectomy. In a study by Dorn et. al., 33 patients with active Cushing’s syndrome (29 with pituitary adenomas) were evaluated before as well as 3, 6 and 12 months after correction of their hypercortisolism. At baseline, 67% of patients had significant psychopathology which persisted in 24% of patients at least 12 months after cure despite recovery of the hypothalamic-pituitary-adrenal axis by conventional criteria. The authors speculate that long-term exposure to high levels of cortisol may cause persistent psychiatric abnormalities through dysregulation of hypothalamic CRH production, an area of active investigation. Psychiatric symptoms attributable to hypercortisolemia have also been reported in association with adrenal ACTH-independent hypercortisolemia as well as ectopic ACTH-dependent hypercortisolemia arguing against any psychiatric effect of the pituitary adenoma itself, independent of hypercortisolemia in Cushing’s disease. In addition, the neurocognitive and behavioral effects of exogenous glucocorticoids are well described. However, the depression observed with Cushing’s syndrome is often contrasted with the mood elevation observed with exogenously administered therapeutic steroids. These differences are presumed to be related to either the chronicity of hypercortisolemia or differing levels of biologically active steroids centrally and peripherally in the two different scenarios.
In several case reports, hyperprolactinemia has been reported in association with psychiatric disease independent of the use of psychotropic medications. It is not clear that an association exists and in many such reports, it is difficult to determine which effects may be due to estrogen deficiency or other gonadal steroid changes versus the effects of hyperprolactinemia alone.
The psychiatric accompaniments of acromegaly have not been studied systematically although mood lability, apathy and lack of initiative have been reported in association with this disorder. Determination of an independent psychiatric effect of having a somatotroph adenoma from the physical disfigurement and symptoms associated with acromegaly is likely to be difficult.
Hypopituitarism may result from impairment of normal pituitary function by a pituitary adenoma. Neuropsychiatric abnormalities have commonly been reported in association with hypopituitarism including depression, apathy, and memory impairment. In addition, cognitive changes are a well described feature of hypogonadism, hypothyroidism, and adrenal insufficiency. Some studies have reported neuropsychiatric abnormalities in patients with growth hormone deficiency which improve with growth hormone therapy. However in a study conducted at our center, Baum et. al. investigated the effects of growth hormone on cognitive function in 40 men treated for hypopituitarism (32 had pituitary adenomas), all with untreated growth hormone deficiency. Patients were randomized to receive either physiologic doses of growth hormone or placebo in a double-blinded fashion. Patients with growth hormone deficiency tested normally with respect to cognitive functioning and IQ though scored relatively lower on tests of memory and learning when compared with a standardized population. At baseline and after 18 months of therapy, there were no differences observed in cognitive function testing, psychometric testing and sense of well being assessments. Neuropsychiatric abnormalities are subtle (if present) in patients with adult-onset growth hormone deficiency and neuropsychiatric function does not appear to improve with growth hormone replacement therapy. Patients with cognitive defects attributable to hypogonadism, adrenal insufficiency and hypothyroidism typically respond to hormone replacement therapy as indicated. However, patients with long-standing hypopituitarism have been described with persistent apathy and loss of drive despite the institution of replacement therapy.
The type of surgery used to remove pituitary tumors has evolved with advances in technology. The transfrontal route was the most widely used approach until the development of the intraoperative microscope resulting in faster and easier access to the pituitary via the transsphenoidal route when performed by an experienced neurosurgeon. Transsphenoidal surgery is considered less traumatic to the patient. Transfrontal surgery can still be used for very large tumors inaccessible via a transsphenoidal route and it is speculated that retraction of the frontal lobe may damage small perforating arteries of the internal carotid artery resulting in focal infarction and vasospasm. Any association observed in retrospective studies linking surgical therapy and neurocognitive changes will be confounded by selection bias as many larger tumors are more likely to be treated surgically, often receive adjunctive radiation therapy, and are associated with hypopituitarism.
Radiation was first used for the treatment of pituitary tumors in 1909 and remains one of the primary modalities of therapy for patients particularly with unresectable pituitary macroadenomas. The existence of long-term neuropsychological changes directly attributable to previous radiation therapy is debated in the literature. The incidence of side effects resulting from radiation therapy in the treatment of a pituitary adenoma is generally considered to be very low. However, hypopituitarism as a late sequelae in these patients is increasingly being recognized. Radiation necrosis is a well-documented complication of radiation therapy often resulting in severe impairment in cognition but is considered a rare side effect in patients receiving radiation therapy for pituitary adenomas.
Neurocognitive and Neuropsychologic Tests
Grattan-Smith et al described the spectrum of neuropsychological abnormalities in a series of patients with pituitary tumors. Although their primary interest was in patients treated with radiotherapy (38 patients), they extended the study to patients treated medically or surgically (27 patients) as well as a series of 21 inpatients with chronic disease used as controls. Specific tests evaluated patients by using eight neuropsychological tests in three domains: executive functioning, verbal memory, and visual memory. Both groups of pituitary tumor patients performed below clinically accepted norms on seven of eight tests, and performed well below the level of controls on tests of executive functioning, verbal and visual memory. Performance on the tests did not differ among pituitary patients treated with radiation versus other therapy. Although this study provides helpful descriptive data on neuropsychological abnormalities in these patients, the authors did not report the overall prevalence of specific deficits, and the study had several major limitations. The authors did not assess patients for depression, nor did they adjust for time interval since diagnosis and treatment. They were not able to adjust for other potentially confounding factors associated with poorer function including type of tumor, medication or recent treatment effects, and intercurrent illness. A final critical point is that since most patients had been treated before the study began, it was impossible to distinguish effects of the tumor from treatment effects.
A recent study by Peace et al examined 69 patients with pituitary tumors (23 each having undergone either transfrontal surgery, transsphenoidal surgery, or medical treatment), and 23 healthy controls . Some of the patients in both surgical groups received radiotherapy as well, and all surgeries were performed at least two years prior to the study. Attention, memory, and executive function were assessed using seven specific tests, in addition to a test for overall intelligence. The authors reported deficits in executive function and memory among patients with tumors, although patients treated medically had milder memory deficits. Patients treated with transfrontal surgery had the greatest degree of cognitive impairment, with 43.5% having three or more test scores below the 10th percentile. Among transsphenoidal patients, 30.4% scored below the 10th percentile on three or more tests, compared with 21.7% of medically treated patients, and 5% of controls. The authors do not report when surgery was performed and may overestimate the impact of surgical therapy given recent developments of new neurosurgical techniques resulting in less damage and less frequent use of anti-seizure medications which can also interfere with cognition. Radiotherapy treatment did not appear to affect test scores. Since treatment decisions are necessarily nonrandom, differences between treatment groups are subject to substantial selection bias and are not directly comparable. The strength of this study is that it highlights the high prevalence of cognitive abnormalities among patients with pituitary tumors, including those treated non-surgically.
In the largest study, Guinan described neuropsychological testing among 90 patients treated for pituitary adenoma of any etiology. Treatment groups included transfrontal surgery, transsphenoidal surgery with or without radiotherapy, radiotherapy only, and bromocriptine only. The investigators assessed general intellectual function, memory, executive function, language comprehension, and speed of mental processing. The authors of this study also found substantial memory deficits in all treatment groups compared with healthy controls. Anterograde memory was most substantially affected. Treatment group did not correlate with degree of impairment in general, although bromocriptine-treated patients had less impairment on one test of anterograde memory. Additional analyses showed no association between cognitive function and tumor type or time elapsed since treatment. This study was able to control for psychiatric disease and examine effects of interval since treatment. As with the reports from Grattan-Smith and Peace, the retrospective design limits evaluation of treatment effects, since selection bias is expected to strongly influence treatment choice and outcome. Nonetheless, these reports suggest that neuropsychological deficits, particularly memory impairment, are common among patients with pituitary tumors and persist long after treatment completion.
Patients with pituitary adenomas appear to be at risk for the development of neuropsychiatric abnormalities. Patients with Cushing’s disease appear to be particularly at risk for the development of psychiatric abnormalities. The available literature has not established an independent association between having a pituitary adenoma and cognitive changes when accounting for mass effect, hormone hypersecretion, hypopituitarism, surgical therapy and radiation therapy. Patients who report impaired memory or other neuropsychiatric symptoms should be evaluated with formal neuropsychiatric testing and referred appropriately based upon the results.
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