Panhypopituitarism

A 65-year-old woman presented with fatigue, anorexia, and persistent nausea and vomiting for seven days. She had a history of hypertension and hypercholesterolemia, but had otherwise been in her usual state of health. Examination revealed a blood pressure of 150/110mmHg supine and 145/ 80mmHg erect. The skin and mucous membranes were dry without hyperpigmentation. The neurological exam including visual fields and acuity testing were normal. The patient had a serum sodium of 114 mM and urine sodium of 105 mM. Other serum chemistries including potassium, chloride, bicarbonate, urea nitrogen, creatinine, and glucose were normal. Serum AM cortisol was 4.0 mcg/dL (normal 4.018.0) and rose to 20.9 mcg/dL (normal> 11.0) after adrenocorticotropin (ACTH) administration. The patient's plasma ACTH level was 5pg/ml (normal 9-52). Thyroid function tests revealed a total T4 of 4.3 mcg/dL (normal 4.0-11.0), resin T3 uptake of 24% (normal 25-36) and thyroid stimulating hormone (TSH) level of 0.72mU/L (normal 0.38-6.13) Prolactin and growth hormone levels were 33ng/ml (normal 2-20) and

The patient was rehydrated to euvolemia with intravenous normal saline. However, her serum sodium continued to decline despite fluid restriction. (Figure 1) Three days after admission, the patient was hypotensive with a systolic pressure of 65mmHg and a serum sodium of 106mM. She was resuscitated with hypertonic saline and started on intravenous hydrocortisone. A head CT with contrast revealed a 3cm. enhancing mass eroding into the clinoid processes and the sellar floor. (Figure 2A) Magnetic resonance imaging (MRI) revealed a single lobed aneurysm filling the sella turcica and obliterating the sphenoid sinus. (Figure 2B) No mass effect was seen on the optic chiasm. Magnetic resonance angiography (MRA) demonstrated slow flow in the aneurysm arising from the posterior cavernous portion of the left internal carotid artery (ICA). (Figure 2C) The patient had the aneurysm embolized by the placement of 17 Guliemi Detachable Coils through an endovascular catheter. Subsequent angiography revealed greater than 90% occlusion of the aneurysm and a patent left ICA. The patient has been maintained for several months on prednisone without any endrocrine or neurologic complaints. Her serum sodium has normalized.

DISCUSSION

The Presentation: Endocrine/Neurologic Deficits

Parasellar intracranial aneurysms as a cause of endocrinopathy and neurological deficit are a well-described but infrequent phenomenon. Since Bramwell's 1887 description,1 numerous cases have been reported.2,3,4,5 Cushing, for example, noted that an intracranial aneurysm "by its compression effect can cause outspoken hypopituitarism."

By far, visual change is the most frequently encountered symptom. In White and Ballantine's review of 35 patients, 80% presented with visual changes - of which 33% were bitemporal hemianopsia. Anterior pituitary deficiency was clinically noted in a third of the patients. A more recent review by Fernandez8 demonstrated a female preponderance (2.7:1) as well as a pituitary-gonadal axis involvement in 67.5%, pituitary-adrenal in 48.6%, pituitary-thyroid in 40.5%. This differential involvement is comparable to those described in other types of hypopituitarism.

Our case is unique in that the patient presented with evidence of hypopituitarism without any visual change or other neurological signs related to mass effect or hemorrhage. Review of the literature shows that most patients do have subtle signs of neurological involvement.9 Nukta10 described a 69 year-old man who presented with non-specific symptoms of weakness, weight loss, nausea and vomiting. The patient had no evidence of visual defects, but did have a broad-based gait and a positive Babinski sign. Work-up revealed a global pituitary deficiency secondary to an aneurysm of the anterior communicating artery. Similarly, Cartlidge's11 50 year-old female patient was somnolent with a positive Babinski sign and brisk deep tendon reflexes, though without visual changes. Perhaps the closest approximation to our patient is that presented by Michils,12 who described a 73 year-old woman who presented with severe hyponatremia and seizures without focal neurologic findings. Past medical history, however, did reveal transient diploplia secondary to palsy in the right extraocular muscles.

Pathophysiology: The Mechanism of Pituitary Dysfunction

Various pathophysiologic mechanisms have been proposed to explain hypopituitarism. In 1956, Gallagher13 described a 54 year-old patient who presented with panhypopituitarism and cited pituitary atrophy from compression as a factor. Van't Hoff14 proposed ischemia in the hypothalmic nuclei as a competing theory.

Verbalis, however, wrote the most detailed and recent analysis in 1982.15 Three disease processes were hypothesized: functional pituitary adenomas, nonfunctional pituitary adenomas, and nonpituitary mass lesions. Nonfunctional pituitary adenomas and nonpituitary masses have a common pathway-mass effect. The mass effect leads to damage via compression or ischemia.

By impinging on the hypothalamus or pituitary stalk, a parasellar mass can cause secondary hormone hypersecretion or hormone deficiencies due to interruption of releasing factors arriving at the anterior pituitary. Hypersecretion is often manifest as hyperprolactinemia. In either case, compression can leave viable pituitary tissue such that reversal of the pituitary dysfunction maybe achieved after appropriate therapy. Indeed, complete recovery is well-documented in the literature.16,17,18,19 For example, Kahn's 42 year-old female patient with left temporal hemianopsia and galactorrhea returned to her usual health after surgery. Thorough endocrine evaluations, including dynamic testing with releasing factor stimulation, are therefore crucial to document viability prior to treatment. Some findings suggestive of reversality are: hyperprolactinemia, positive but blunted responses to releasing factors, and short duration of symptoms. Reassessment 6-8 weeks post-operatively is recommended before instituting indefinite hormone replacement therapy. Lastly, mass effect may take the form of ischemia and necrosis of pituitary tissue. This phenomenon is typified by a primary hormone deficiency and non-response to dynamic testing with releasing factors.

Pathophysiology: The Mechanism of Hyponatremia

Although classically described, symptomatic hyponatremia as an initial indicator of hypopituitarism is unusual. The resulting hyponatremia is corrected by administration of glucocorticoids, but not mineralocorticoids.20 This is explained by the fact that aldosterone secretion is relatively independent of pituitary control via ACTH. At first glance, it seems as if hyponatremia is caused by excess retention of water through an inappropriate ADH effect, rather than a salt-wasting syndrome as in a mineralocorticoid defect.21 This construct, however, is flawed as evidenced by the serum sodium trend in our patient. Sodium values declined despite fluid restriction. Sodium imbalance in the setting of hypopituitarism is corrected by the administration of saline.20 ADH plays a supporting role at best in a mixed sodium wasting/water retention picture.

How then does hyponatremia occur? Decreased activity level of renin leading to increase in urinary sodium plays a key role. Hyporeninism responsive to cortisol administration has been reported in patients with hyponatremia secondary to hypopituitarism.22 An indirect regulatory or permissive effect of cortisol on plasma renin activity has been postulated. This hypothesis is supported by the fact that patients with Cushing's syndrome display increased plasma renin activity.

Diagnosis: The Association Between Aneurysms and Adenomas

Historically, confusion between pituitary tumors and aneurysms has been common. Raymond in 1978 estimated that between 1.4-5% of aneurysms simulated pituitary tumors.23 Numerous reports describe an aneurysm initially diagnosed as a pituitary tumor and only later properly identified by carotid angiography, or at the time of autopsy in some unfortunate cases.24,25,26,27

In addition to the similarities in plain film, CT and clinical presentations there are other factors that contribute to the confusion. There is a well-documented association between intracranial aneurysms and pituitary adenomas, such that the chances of the two simultaneously existing is far greater than that explained by coincidence.28,29,30 Pia studied the occurrence of brain tumors in general with aneurysms and speculated local circulatory changes as one mechanism in which tumors facilitate aneurysmal dilatation.31 Anticipating possible coexistence is prudent for a neurosurgeon, as evidenced by Tsuchida's misfortune of rupturing an anterior communicating artery aneurysm during transsphenoidal removal of a pituitary adenoma.32 Wakai estimated the frequency of association between an intracranial aneurysm and pituitary adenoma to be 7.4%,33 while Jakubowski, in his review of 150 pituitary tumors, approximated the incidence to be 6.7%.34

Confirming the Diagnosis: Imaging

In the pre-CT era, calcification in the posterior fossa on lateral plain film with enlargement of superior orbital fissures was used as suggestive evidence of intracranial aneurysms. The enlarged fissure was estimated to occur in 75% of patients with aneurysms but only in 5% of pituitary tumors.

The gold standard for diagnosis continues to be angiography, but less invasive techniques are playing an increasingly large role. Aneurysms on CT appear as hyperdense lesions that enhance with contrast. Numerous reports exist, however, wherein contrast enhanced CT scans failed to identify giant aneurysms.35,36,37

MRI has become a first-line diagnostic tool, because it helps to characterize location, size, residual lumen size and flow. It does not require contrast administration as in angiographic studies.8 On precontrast T1 weighted images, aneurysms have a similar density as cerebrospinal fluid. On "spin" echo imaging, it shows up as a distinctive iflow voidi with a black appearance. This occurs because rapidly flowing areas have no signal. Partially or totally thrombosed aneurysms therefore can have areas of high intensity. Finally, MR/CT angiography has added to the armamentarium of the modern neuroradiologist. It further helps in assessing the vessel of origin, contiguity of the aneurysm with adjacent vessels, lumen size, and additional aneurysms.38,39

Management Principles

Direct surgical clipping or endovascular coiling is the preferred treatment of intracranial aneurysms.40 Both techniques eliminate the aneurysm from normal circulation and prevent further dilatation or hemorrhage.

In weighing the risks and benefits of treating a patient with an unruptured aneurysm, accompanying symptoms, size and accessibility to direct surgical clipping must be considered. Though the natural history of asymptomatic, unruptured, untreated aneurysms is not well known, bleed rates have been estimated at 3-4% per year.41 There is widespread agreement that larger size accelerates this rate further.42 Surgical management should therefore be offered to patients with giant aneurysms regardless of symptoms especially if direct clipping is possible.19 In fact, in his editorial comment, Ojemann recommended surgical treatment for all aneurysms greater than 7mm in size.43

Surgery is also recommended for symptomatic aneurysms because symptoms are thought to be a marker of rapid enlargement. Improvement in neurological function is immediately recognizable. Potentially avoiding the long-term effects of hypopituitarism on life expectancy is another advantage. In retrospective analysis of 172 patients between 1967-94 with partial or complete hypopituitarism (excluding Cushing's and acromegaly), Bates found an increase in all cause mortality compared to an age and sex-matched control population.44 The ratio of observed to expected deaths was 1.73, while that restricted to females was even higher at 2.29.

CONCLUSION

We report a case of a giant ICA aneurysm which presented as profound hyponatremia. Hyponatremia was likely caused by insufficient ACTH levels resulting from pituitary insufficiency, which lead to a state of hyporeninism. The unique aspect of this case is that the patient had no neurological complaints related to mass effect or hemorrhage. The absence of typical neurologic symptoms should therefore not dissuade the clinician from considering intracranial aneurysms as a cause of pituitary dysfunction. Given the grave mortality ruptured aneurysms and the morbidity of persistent endocrine deficits, thorough evaluation (including dynamic hormone testing, MRI and angiography) and treatment is recommended.

REFERENCES

1. Bramwell B. Edinb MedJ 1887;32:911-22.

2. Wallace S, Jaffe ME. Radiol 1967;88:90-3.

3. Uozumi T, Shima T, Moris. No Shinkei Geka 1979;7:25-31.

4. Shantaram VV, Clift GV. JAMA 1974; 229:1473.

5. Dussault J, Plamomndon C, Volpe R. Can Med Assoc J 1969:101:51-6.

6. Cushing H. The Pituitary Body and its Disorders: Clinical States Produced by Disorders of the Hypophysis Cerebri. Philadelphia. JB Lippincott, 1912.

7. White JC. Ballantine HT, Jr.J Neurosurg 1961;18:34-50.

8. Fernandex-Real JM, Fernandex-Castaner M, Billabona C, et al. Clin Investigation 1994; 72:302-6.

9. Ooi TC, Russell NA. Can]Neurol Sci 1986;13:70-1.

10. Nukta EM, Taylor HC. Can Med Assoc J 1987;137:413-5.

11. Cartlidge NE, Shaw DA. J Neurosurg 1972;36:640-3.

12. Michils A, Baleriaux D, Mockel J. Postgrad Med J 1991;67:285-8.

13. Gallagher PG, Dorsey JF, Stefanini M, Lonney JM. Neurol 1956;6:829-37.

14. Van't Hoff W, Hornabrook RW, Marks V. Brit Med J 1961;2:1190-4.

15. Verbalis JG, Nelson PB, Robinson AG. Neurosurg 1982;10:604-11.

16. Giustina A; Scalvini T, Cerudelli B, et al. Minerva Endocrinol 1989;14:255-8.

17. Kahn SR, Leblanc R, Sadikot AF, Fantus IG. Can J Neurol Sci 1997;24:64-6.

18. Kita Y, Kawato M, Nakabayashi H, et al. Nippon Naika Gakkai Zasshi 1986;75:1756-63.

19. Heroes RC, Nelson PB, Ojemann RG, et al. Neurosurg 1983;12:153-63.

20. Bethune JE, Nelson DH. NEJM 1965;272:771-6.

21. Davis BB, Bloom ME, Field JB, Mintz DH. Metabolism 1969;18:821-32.

22. Major P, Kuchel O, Boucher R, et al. J Clin Endocrinol Metab 1978;46:15-9.

23. Raymond LA, Tew J. J Neurol Neurosurg Psychiatry 1978;41:83-7.

24. Arlot S, Lalau JD, Galibert P, Quichaud J. Rev Med Interne 1985;6:505-9.

25. Barotini F, Ammannati F, Gagliardi R, et al. Ital J Neurol Sci 1994;15:369-72.

26. Chien WY, Want PW, Huang HS, Huang MJ. Chang Keng I Hsueh Tsa Chih 1989;12:161-6.

27. Kayath MJ, Lengyel AM, Nogueira, et al. J Endocrinol Invest 1991; 11:975-9.

28. Gokalp HZ, Avman N, Ozkal E,Gokben B. Acta Neurochirurgica 1980;53:267-73.

29. Wada M, Takahashi K, Hasegawa T, et al. Neuro Surg 1982;10:215-20.

30. Plangger CA, Twerdy K, Mohsenipour I, Grunert V. Nervenarzi 1987;58:279-86.

31. Pia HW, Obrador S, Martin JG. Acta Neurochir 1972;27:189204.

32. Tsuchida T; Tanaka R, Yokoyama M, Sato H. Surg Neuro 1983;20:67-70.

33. Wakai S, Fukushima T, Furihata T, Sano K. Surg Neurol 1979;12:503-7.

34. Jakubowski J, Kendall B. J Neurol Neurosurg Psychiatry 1978;41:972-9.

35. MacPherson P, Anderson DE. Neuroradiol 1981;21:177. 36. Lumenta CB, Lins E, Bock WJ. Neurochirurgia (Stuttg) 1984;27:117-9.

37. Mindel JS, Sachdev VP, Kline LB, Sivak MA. Surg Neurol 1983;19:163-7.

38. Fitzpatrick M, Tartaglino LM, Hollander MD, et al. Radiol Clinics NAmer 1999;37:101-21.

39. Demaerel P, Marchal G, Casteels I, et al. Neuroradiol 1990;32:322-4.

40. Chang SD, Steinberg GK. Vasc Med 1998;3:315-26.

41. Jane JA, Winn HR, Richardson AE. Clin Nerosurg 1974;24:176-84.

42. Hamburger C, Schonberger J, Lange M. Neurosurg Rev 1992;15:97-103.

43. Bates AS, Van't Hoff W, Jones PJ, Clayton RN. J Clin Endocrinol Metab 1996;81:1169-72.

Susanna I. Lee, MD, PhD, Shyoko Honiden, MD, Elaine B. Fain, MD, Dominick Tammaro, MD, Fred J. Schiffman, MD

Susanna I. Lee, MD, PhD, is Instructor in Radiology, Harvard Medical School and Assistant Radiologist, Massachusetts General Hospital.

Shyoko Honiden, MD, is is a medical resident, Mt. Sinai Hospital, New York City.

Elaine B. Fain, MD, is in private practice.

Dominick Tammaro, MD, is Assistant Professor ofMedicine, Brown Medical School.

Fred J. Schiffman, MD, is Professor of Medicine, Brown Medical School.

CORRESPONDENCE:

Fred J. Schiffman, M.D. The Miriam Hospital 164 Summit Avenue Providence, RI 02906 phone: (401) 793-4035 fax: (401) 793-4022

e-mail: fred_schiffman@brown.edu

Copyright Rhode Island Medical Society Feb 2003
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