● a rare condition that follows 10–30% of total bilateral adrenalectomies (TBA) performed for Cushing’s disease.
● classic triad: hyperpigmentation (skin &mucus membranes), abnormal ↑ ACTH, and progression of pituitary tumor (the last criteria is now controversial)
● treatment options: surgery (transsphenoidal or transcranial), XRT, medication.
Usually occurs 1–4 years after TBA (range: 2 mos-24 years) 1). Theoretical explanation (unproven) 2): following TBA, hypercortisolism resolves, and CRH levels increase back to normal from the (reduced) suppressed state; corticotroph adenomas in patients with NS have an increased & prolonged response to CRH resulting in increased growth. Also, corticotrophs in NS and CD show reduced inhibition by glucocorticoids. It is controversial if some cases may be related to insufficient glucocorticoid replacement after TBA 3).
1. hyperpigmentation (due to melanin stimulating hormone (MSH) cross reactivity of ACTH and actual increased levels of MSH due to increased proopiomelanocortin production). Often the earliest sign that Nelson’s syndrome is developing. Look for linea nigra (midline pigmentation from pubis to umbilicus) and hyperpigmentation of scars, gingivae, and areolae. DDx of hyperpigmentation includes: primary adrenal insufficiency (high levels of ACTH), ectopic ACTH secretion, hemochromatosis (more bronze color), jaundice (yellowish)
2. tumor growth →increased mass effect or invasion: the most serious consequence. These corticotroph tumors are among the most aggressive of pituitary tumors 4). May produce any of the problems associated with macroadenomas (optic nerve compression, cavernous sinus invasion, pituitary insufficiency, H/A, bony invasion…) as well as necrosis with precipitous intracranial hypertension 5); see pituitary apoplexy.
3. malignant transformation of the corticotroph tumor (very rare).
4. hypertrophy of adrenal tissue rests: may be located in the testes → painful testicular enlargement and oligospermia. Rarely the rests can secrete enough cortisol to normalize cortisol levels or even cause a recurrence of Cushing’s disease despite the adrenalectomy.
a) ACTH > 200 ng/L (usually thousands of ng/L)(normal:usually < 54 ng/L)
b) exaggerated ACTH response to CRH (not required for diagnosis)
c) other pituitary hormones may be affected as with any macroadenoma causing mass effect and endocrine screening should be done
2. Formal visual field testing: should be done in patients with suprasellar extension or in those being considered for surgery (as a baseline for comparison)
Management options including resection and medical therapy are traditional approaches. Ionizing radiation in the form of Gamma Knife radiosurgery (GKRS) is also being utilized to treat Nelson's syndrome. In a study Cordeiro et al., sought to better define the therapeutic role of stereotactic radiosurgery (SRS) in Nelson's syndrome.
Study patients with Nelson's syndrome were treated with single-fraction GKRS (median margin dose of 25 Gy) at 6 different centers as part of an International Radiosurgery Research Foundation (IRRF) investigation. Data including neurological function, endocrine response, and radiological tumor response were collected and sent to the study-coordinating center for review. Fifty-one patients with median endocrine and radiological follow-ups of 91 and 80.5 months from GKRS, respectively, were analyzed for endocrine remission, tumor control, and neurological outcome. Statistical methods were used to identify prognostic factors for these endpoints.
At last follow-up, radiological tumor control was achieved in 92.15% of patients. Endocrine remission off medical management and reduction in pre-SRS ACTH level were achieved in 29.4% and 62.7% of patients, respectively. Improved remission rates were associated with a shorter time interval between resection and GKRS (p = 0.039). Hypopituitarism was seen in 21.6% and new visual deficits were demonstrated in 15.7% of patients.
GKRS affords a high rate of pituitary adenoma control and improvement in ACTH level for the majority of Nelson's syndrome patients. Hypopituitarism is the most common adverse effect from GKRS in Nelson's syndrome patients and warrants longitudinal follow-up for detection and endocrine replacement 6).