====== Nelson's syndrome ======

{{ ::nelson_s_syndrome.jpg?200|}}

Nelson's [[syndrome]] is a rare and challenging [[neuroendocrine]] disorder, and it is associated with elevated [[Adrenocorticotropic hormone ]] ([[ACTH]]) level, skin hyperpigmentation, and [[pituitary neuroendocrine tumor]] growth. 

Nelson's syndrome (NS) is a long-term complication of bilateral adrenalectomy in patients with [[Cushing's disease]]. 

===== Key concepts =====

● 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)
((Banasiak MJ, Malek AR. Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management.Neurosurg Focus.2007;23)).
Theoretical explanation (unproven)
((Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, et al. Corticotroph tumor progression after adrenalectomy in Cushing's Disease: a reappraisal of Nelson's syndrome. J Clin Endocrinol Metab. 2007; 49:381–386)):
following TBA, [[hypercortisolism]] resolves, and CRH levels increase back to normal from the (reduced) suppressed state; [[corticotroph adenoma]]s 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
((Banasiak MJ, Malek AR. Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management.Neurosurg Focus.2007;23)).

===== Clinical features =====

1. hyperpigmentation (due to melanin stimulating hormone (MSH) cross-reactivity of ACTH and actually 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 the 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
((Bertagna X, Raux-Demay M-C, Guilhaume B, et al., Melmed S. In: Cushing's Disease. The Pituitary. 2nd ed. Malden, MA: Blackwell Scientific; 2002:496–560)).
May produce any of the problems associated with [[macroadenoma]]s ([[optic nerve]] compression, [[cavernous sinus]] invasion, pituitary insufficiency, H/A, bony invasion...) as well as [[necrosis]] with precipitous [[intracranial hypertension]]
((Kasperlik-Zaluska AA, Bonicki W, Jeske W, Janik J, et al. Nelson's syndrome - 46 years later: clinical experience with 37 patients. Zentralbl Neurochir. 2006; 67:14–20)); 
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]].

===== Diagnosis =====

1. Laboratories

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)


===== Treatment =====

[[Nelson's syndrome treatment]].

===== Case reports =====
[[Nelson's syndrome]] is considered a severe side effect that can occur after total bilateral [[adrenalectomy]] in patients with [[Cushing's disease]]. It usually presents with clinical manifestations of an enlarging [[pituitary tumor]] including visual and cranial nerve alterations, and if not treated, can cause death through local brain compression or invasion. The first therapeutic option is [[surgery]] but in extreme cases of inaccessible or resistant [[aggressive]] [[pituitary tumor]]s; the off-label use of [[chemotherapy]] with [[capecitabine]] and [[temozolomide]] can be considered. However, the use of this treatment is controversial due to adverse events, lack of complete response, and inability to predict results. Mirallas et al. present the case of a 48-year-old man diagnosed with Nelson's syndrome with prolonged partial [[response]] and significant clinical benefit to treatment with capecitabine and temozolomide
((Mirallas O, Filippi-Arriaga F, Hernandez Hernandez I, Aubanell A, Chaachou A,
Garcia-Alvarez A, Hernando J, Martínez-Saez E, Biagetti B, Capdevila J.
Aggressive Pituitary Macroadenoma Treated With Capecitabine and Temozolomide
Chemotherapy Combination in a Patient With Nelson's Syndrome: A Case Report.
Front Endocrinol (Lausanne). 2021 Nov 11;12:731631. doi:
10.3389/fendo.2021.731631. PMID: 34858324; PMCID: PMC8632214.)).


===== References =====