Nelson syndrome - Clinicals, Diagnosis, and Management

Endocrinology, Metabolism and Nutrition

Clinicals - History

Fact Explanation
Headache Stretching of the diaphragma sellae the bony compartment, which contains the pituitary causes headache and it's commonly seen. Headache
Stretching of the diaphragma sellae the bony compartment, which contains the pituitary causes headache and it's commonly seen.
Visual disturbance Common complaints are due to loss of peripheral vision (eg, bumping into walls), or visual loss in one eye. This is due to either compression or invasion of the optic nerve and it's pathway by the pituitary mass.The symptoms and signs vary depending on where the pathway of the optic nerve is compressed. Prechiasmatic compression results in symptoms affecting one eye, while chiasmatic lesions result in quadrantanopsia or bitemporal hemianopia. Homonymous hemianopia can result from post-chiasmatic lesions . Visual disturbance
Common complaints are due to loss of peripheral vision (eg, bumping into walls), or visual loss in one eye. This is due to either compression or invasion of the optic nerve and it's pathway by the pituitary mass.The symptoms and signs vary depending on where the pathway of the optic nerve is compressed. Prechiasmatic compression results in symptoms affecting one eye, while chiasmatic lesions result in quadrantanopsia or bitemporal hemianopia. Homonymous hemianopia can result from post-chiasmatic lesions .
poor growth in a child This is due to hypopituitarism which occurs either due to disruption of the hypothalamic-pituitary portal system or the normal pituitary tissue by the tumour. Growth hormone deficiency gives rise to poor growth. poor growth in a child
This is due to hypopituitarism which occurs either due to disruption of the hypothalamic-pituitary portal system or the normal pituitary tissue by the tumour. Growth hormone deficiency gives rise to poor growth.
Cold intolerance, constipation, slowing of mentation, dry skin and coarse hair, and change in the shape of the face This is due to hypothyroidism due to thyroid stimulating hormone deficiency in turn causing deficiency of thyroxin. Cold intolerance, constipation, slowing of mentation, dry skin and coarse hair, and change in the shape of the face
This is due to hypothyroidism due to thyroid stimulating hormone deficiency in turn causing deficiency of thyroxin.
Pubertal delay in girls Breast development (thelarche) is delayed in adolescent girls while a reduction in breast size or a softening of breasts are seen in post pubertal women. This is due to hypoestrogenism. Pubertal delay in girls
Breast development (thelarche) is delayed in adolescent girls while a reduction in breast size or a softening of breasts are seen in post pubertal women. This is due to hypoestrogenism.
Pubertal delay in boys Scrotal development and testicular enlargement is delayed in adolescent boys. Pubertal delay in boys
Scrotal development and testicular enlargement is delayed in adolescent boys.
Galactorrhoea May results from Hyperprolactinemia owing to the interruption of hypothalamic-pituitary portal axis. Galactorrhoea
May results from Hyperprolactinemia owing to the interruption of hypothalamic-pituitary portal axis.
Polyuria, Nocturia and polydipsia. This is due to diabetes insipidus due to inadequate secretion of ADH from posterior pitiutary. Presence of nocturia or diluted urine in the morning first void is also suggestive of diabetes insipidus. Polyuria, Nocturia and polydipsia.
This is due to diabetes insipidus due to inadequate secretion of ADH from posterior pitiutary. Presence of nocturia or diluted urine in the morning first void is also suggestive of diabetes insipidus.
Hyper pigmentation This is often noticed by the patient when there's increased pigmentation of the scars, gingivae, and palmer creases. This is due to increased Adrenocorticotrophin secretion by the pituitary due to loss of negative feed back from corticosteroids which are usually secreted from the adrenal glands. Hyper pigmentation
This is often noticed by the patient when there's increased pigmentation of the scars, gingivae, and palmer creases. This is due to increased Adrenocorticotrophin secretion by the pituitary due to loss of negative feed back from corticosteroids which are usually secreted from the adrenal glands.
Previous history of excessive weight gain with truncal obesity, easy bruising, stretch marks on the breasts, arms, abdomen, and thighs These features are suggestive of previous Cushing's syndrome due to adrenal adenoma. These features are due to excessive corticosteroid secretion. Previous history of excessive weight gain with truncal obesity, easy bruising, stretch marks on the breasts, arms, abdomen, and thighs
These features are suggestive of previous Cushing's syndrome due to adrenal adenoma. These features are due to excessive corticosteroid secretion.

Clinicals - Examination

Fact Explanation
Reduced height and poor growth Pituitary lesions can give rise to growth hormone deficiency and reduction in the height and growth velocity. Previous Cushing's syndrome may have caused weight gain but it's important to measure the weight as well. Reduced height and poor growth
Pituitary lesions can give rise to growth hormone deficiency and reduction in the height and growth velocity. Previous Cushing's syndrome may have caused weight gain but it's important to measure the weight as well.
Bradycardia or Tachycardia If there's hypothyroidism due to Thyroxine deficiency, bradycardia occurs but in acute adrenal insufficiency, a reflex tachycardia may be present. Bradycardia or Tachycardia
If there's hypothyroidism due to Thyroxine deficiency, bradycardia occurs but in acute adrenal insufficiency, a reflex tachycardia may be present.
Hypertension or postural hypotension Hypertension can occur due to two reasons either due to hypercortisolism of Previous Cushing's syndrome or as a pitfall in the management where there's excessive mineralocorticoid replacement. Hypotension is also present in some. Especially a postural drop is noted in patients with acute adrenal crisis or again as a pitfall in the management where there's inadequacy in the mineralocortcoid replacement. Hypertension or postural hypotension
Hypertension can occur due to two reasons either due to hypercortisolism of Previous Cushing's syndrome or as a pitfall in the management where there's excessive mineralocorticoid replacement. Hypotension is also present in some. Especially a postural drop is noted in patients with acute adrenal crisis or again as a pitfall in the management where there's inadequacy in the mineralocortcoid replacement.
Hyperpigmentation of the skin This is due to increased adrenocorticotrophin (ACTH) by the pitiutary due to loss of negative feed back from adrenal corticosterids. Patients usually appear hyperpigmented in linea nigra, scars, gingivae, palmer creases, scrotum and areolae. Hyperpigmentation of the skin
This is due to increased adrenocorticotrophin (ACTH) by the pitiutary due to loss of negative feed back from adrenal corticosterids. Patients usually appear hyperpigmented in linea nigra, scars, gingivae, palmer creases, scrotum and areolae.
Assessment of the pubertal stage Excessive adrenal androgens in patients with previous Cushing syndrome can cause premature pubarche. In post pubertal females, secondary hypoestrogenism results in softening and reduction in the size of breasts where as breast development is delayed in adolescent girls. In males, loss of body hair, small soft testes, increased upper–to–lower segment ratio are some features seen. Assessment of the pubertal stage
Excessive adrenal androgens in patients with previous Cushing syndrome can cause premature pubarche. In post pubertal females, secondary hypoestrogenism results in softening and reduction in the size of breasts where as breast development is delayed in adolescent girls. In males, loss of body hair, small soft testes, increased upper–to–lower segment ratio are some features seen.
Visual disturbances- Decreased visual acuity, visual field defects, papilloedema or optic atrophy Visual acuity, visual field assessment by confrontation, and ophthalmological examination for papilledema or optic nerve atrophy should be done. Visual defects are due to invasion or compression of optic nerve and it's pathway by the tumour. Prechiasmatic compression affects one eye, while chiasmatic lesions result in quadrantanopsia or bitemporal hemianopia. Homonymous hemianopia can result from post-chiasmatic lesions Visual disturbances- Decreased visual acuity, visual field defects, papilloedema or optic atrophy
Visual acuity, visual field assessment by confrontation, and ophthalmological examination for papilledema or optic nerve atrophy should be done. Visual defects are due to invasion or compression of optic nerve and it's pathway by the tumour. Prechiasmatic compression affects one eye, while chiasmatic lesions result in quadrantanopsia or bitemporal hemianopia. Homonymous hemianopia can result from post-chiasmatic lesions
Reduced sensation of the forehead If there's tumor invasion of the ipsilateral cavernous sinus, first division of trigeminal nerve may be involved causing reduced sensation of the forehead Reduced sensation of the forehead
If there's tumor invasion of the ipsilateral cavernous sinus, first division of trigeminal nerve may be involved causing reduced sensation of the forehead
Ocular movement defects If the tumour invades the ipsilateral cavernous sinus, III, IV, VI cranial nerves may be involved causing extra-ocular muscle paralysis and movement defects
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Ocular movement defects
If the tumour invades the ipsilateral cavernous sinus, III, IV, VI cranial nerves may be involved causing extra-ocular muscle paralysis and movement defects
[3
Hyporeflexia and delayed relaxation This can be present in patients with hypothyroidism which resulted from reduced thyroxine secretion. Hyporeflexia and delayed relaxation
This can be present in patients with hypothyroidism which resulted from reduced thyroxine secretion.

Investigations - Diagnosis

Fact Explanation
Serum Adrenocorticotropin (ACTH) level In Nelson syndrome the level of ACTH is very high and other derivatives of the precursor peptide, proopiomelanocortin (POMC). Serum Adrenocorticotropin (ACTH) level
In Nelson syndrome the level of ACTH is very high and other derivatives of the precursor peptide, proopiomelanocortin (POMC).
Thyroid function test Free thyroxine (T4) levels can be below the lower limit of the reference range even though clinical hypothyroidism may not be apparent.Thyroid-stimulating hormone (TSH) levels can either be low, normal, or slightly elevated. Thyroid function test
Free thyroxine (T4) levels can be below the lower limit of the reference range even though clinical hypothyroidism may not be apparent.Thyroid-stimulating hormone (TSH) levels can either be low, normal, or slightly elevated.
Serum Prolactin level Dopaminergic inhibition due to invasion of the pituitary stalk or hypothalamic-pituitary portal system results in hyperprolactinemia. Patients with pituitary macroadenomas tend to have very high Prolactin levels. Serum Prolactin level
Dopaminergic inhibition due to invasion of the pituitary stalk or hypothalamic-pituitary portal system results in hyperprolactinemia. Patients with pituitary macroadenomas tend to have very high Prolactin levels.
Serum Growth hormone level Since there's inadequate secretion of growth hormone by the anterior pituitary, the serum level may be low Serum Growth hormone level
Since there's inadequate secretion of growth hormone by the anterior pituitary, the serum level may be low
Serum Gonadotropin level Hyperprolactinemia causes hypogonadotropic hypogonadism therefore gonadotrophin levels are low. Serum Gonadotropin level
Hyperprolactinemia causes hypogonadotropic hypogonadism therefore gonadotrophin levels are low.
Urine osmolality or specific gravity test If the tumor has destroyed the posterior part of the pituitary gland, central diabetes insipidus occurs. In normal people, the urine osmolality or specific gravity should be greater than 600-700 mOsm/kg or 1.010 respectively in an early morning urine specimen. But in these patients urine is dilute. Urine osmolality or specific gravity test
If the tumor has destroyed the posterior part of the pituitary gland, central diabetes insipidus occurs. In normal people, the urine osmolality or specific gravity should be greater than 600-700 mOsm/kg or 1.010 respectively in an early morning urine specimen. But in these patients urine is dilute.
MRI scan of the pituitary and parasellar region This can demonstrate the tumor if it's large and shows compression or invasion of surrounding structures as well therefore helps in the management. MRI scan of the pituitary and parasellar region
This can demonstrate the tumor if it's large and shows compression or invasion of surrounding structures as well therefore helps in the management.
Visual field assessment by perimetry To assess the visual field as visual field defects are common due to compression or invasion of the optic nerve and it's pathway. Visual field assessment by perimetry
To assess the visual field as visual field defects are common due to compression or invasion of the optic nerve and it's pathway.
Biopsy of the tumour Tumors are immunostain positive for ACTH and tumors have cytological features as in any malignancy such as increased cellular proliferation, with mitoses and cellular and nuclear pleomorphism. Biopsy of the tumour
Tumors are immunostain positive for ACTH and tumors have cytological features as in any malignancy such as increased cellular proliferation, with mitoses and cellular and nuclear pleomorphism.

Investigations - Management

Fact Explanation
Growth monitoring Growth parameters are need to be monitored especially giving attention to height as these patients are likely to be stunted due to growth hormone deficiency, as well as due to hypothyroidism. Growth velocity can be measured when serial height, weight values are present. This also helps in adjusting the growth hormone therapy in the management. Growth monitoring
Growth parameters are need to be monitored especially giving attention to height as these patients are likely to be stunted due to growth hormone deficiency, as well as due to hypothyroidism. Growth velocity can be measured when serial height, weight values are present. This also helps in adjusting the growth hormone therapy in the management.
Blood pressure monitoring These patients are put on mineralocorticoids and glucorcoticoids as a part of the management. Both of these hormones when excessive cause water retention contributing to high blood pressure. Also adrenal rest tissue in the testis can get stimulated with Nelson syndrome and cause recurrence of Cushing's syndrome. Therefore monitoring of blood pressure in the follow up is necessary Blood pressure monitoring
These patients are put on mineralocorticoids and glucorcoticoids as a part of the management. Both of these hormones when excessive cause water retention contributing to high blood pressure. Also adrenal rest tissue in the testis can get stimulated with Nelson syndrome and cause recurrence of Cushing's syndrome. Therefore monitoring of blood pressure in the follow up is necessary
Overnight growth hormone sampling As these patients are having growth hormone deficiency, this test is done to monitor their growth hormone level. Overnight growth hormone sampling
As these patients are having growth hormone deficiency, this test is done to monitor their growth hormone level.
Thyroid function tests This should be measured at least every 6 months as they are likely to be hypothyroid and hypopituitarism can also occur as a complication. Thyroid function tests
This should be measured at least every 6 months as they are likely to be hypothyroid and hypopituitarism can also occur as a complication.
Serum sodium Children on treatment with Desmopressin need to have regular sodium measurements as this drug may interfere with serum sodium level. Serum sodium
Children on treatment with Desmopressin need to have regular sodium measurements as this drug may interfere with serum sodium level.
Perimetry Residual tumour tissue may give rise to visual symptoms in the follow up, therefore, if the patient complains of any visual disturbances, these tests need to be done. Perimetry
Residual tumour tissue may give rise to visual symptoms in the follow up, therefore, if the patient complains of any visual disturbances, these tests need to be done.
Serum ACTH This is done to detect hypopituitarism which can occur as a complication of Nelson syndrome. Low ACTH level is seen in Hypopitiuitarism. Serum ACTH
This is done to detect hypopituitarism which can occur as a complication of Nelson syndrome. Low ACTH level is seen in Hypopitiuitarism.
Seminal fluid analysis There could be adrenal rest tissue in the testis, which have migrated during embryogenesis. This can be stimulated in Nelson's syndrome and known to cause painful testicular enlargement and sometimes even oligozoospermia. Therefore seminal fluid analysis in a male is important if symptoms are present. Seminal fluid analysis
There could be adrenal rest tissue in the testis, which have migrated during embryogenesis. This can be stimulated in Nelson's syndrome and known to cause painful testicular enlargement and sometimes even oligozoospermia. Therefore seminal fluid analysis in a male is important if symptoms are present.
Full blood count To exclude anemia prior to surgery Full blood count
To exclude anemia prior to surgery
Coagulation studies To exclude any coagulopathy prior to surgery Coagulation studies
To exclude any coagulopathy prior to surgery
Renal function tests- Serum Creatinine, Blood urea nitrogen To exclude any renal dysfunction and assess the fitness for anesthesia Renal function tests- Serum Creatinine, Blood urea nitrogen
To exclude any renal dysfunction and assess the fitness for anesthesia
Electrocardiogram These patients are likely to have suffered from Cushing's syndrome therefore ECG abnormalities such as high voltage QRS complexes and inverted T waves, Left ventricular hypertrophy and asymmetric septal hypertrophy are observed frequently in patients with Cushing’s syndrome. Electrocardiogram
These patients are likely to have suffered from Cushing's syndrome therefore ECG abnormalities such as high voltage QRS complexes and inverted T waves, Left ventricular hypertrophy and asymmetric septal hypertrophy are observed frequently in patients with Cushing’s syndrome.
Fasting blood sugar In Cushing's syndrome, glucose intolerance or frank diabetes occurs in 60% of patients and is related to reduced insulin secretion and non‐insulin‐mediated glucose disposal in the presence of elevated insulin concentrations. Fasting blood sugar
In Cushing's syndrome, glucose intolerance or frank diabetes occurs in 60% of patients and is related to reduced insulin secretion and non‐insulin‐mediated glucose disposal in the presence of elevated insulin concentrations.
Serum cholesterol These patients are likely to have suffered from Cushing's syndrome and they usually have abnormal lipid levels. In addition to that untreated hypothyroidism can also give rise to high cholesterol levels. Serum cholesterol
These patients are likely to have suffered from Cushing's syndrome and they usually have abnormal lipid levels. In addition to that untreated hypothyroidism can also give rise to high cholesterol levels.
Insulinlike growth factor–1 (IGF-1) and insulinlike growth factor–binding protein-3 (IGF-BP3) level This is used as a screening method for growth hormone deficiency in children older than 3 years. Insulinlike growth factor–1 (IGF-1) and insulinlike growth factor–binding protein-3 (IGF-BP3) level
This is used as a screening method for growth hormone deficiency in children older than 3 years.

Management - Supportive

Fact Explanation
Parental and patient education This is important especially regarding the etiology, nature, course and prognosis of the disease, available treatment options and the importance of follow up. Patient should be reassured especially regarding pubertal delay and counseling maybe needed. Parental and patient education
This is important especially regarding the etiology, nature, course and prognosis of the disease, available treatment options and the importance of follow up. Patient should be reassured especially regarding pubertal delay and counseling maybe needed.
Regular follow up Proper periodical follow up is needed to assess the enzyme deficiencies and the adequacy of replacement. Regular follow up
Proper periodical follow up is needed to assess the enzyme deficiencies and the adequacy of replacement.

Management - Specific

Fact Explanation
Medical management with cabergoline This is a dopamine receptor agonist which causes decline and normalization of adrenocorticotropin (ACTH) levels and also resolution of the pituitary macroadenoma or microadenoma Medical management with cabergoline
This is a dopamine receptor agonist which causes decline and normalization of adrenocorticotropin (ACTH) levels and also resolution of the pituitary macroadenoma or microadenoma
Medical management with octreotide or other analogue of somatostatin Helpful to control ACTH levels, although only useful until definitive treatment is undertaken as it does not cause much of tumor shrinkage. Because it also suppresses other hormones, including insulin, it may result in carbohydrate intolerance too. Medical management with octreotide or other analogue of somatostatin
Helpful to control ACTH levels, although only useful until definitive treatment is undertaken as it does not cause much of tumor shrinkage. Because it also suppresses other hormones, including insulin, it may result in carbohydrate intolerance too.
Medical management with cyproheptadine cyproheptadine with and without bromocriptine is shown to cause significant reduction in plasma ACTH and prolactin concentration Medical management with cyproheptadine
cyproheptadine with and without bromocriptine is shown to cause significant reduction in plasma ACTH and prolactin concentration
Medical management with sodium valproate. This has also shown to reduce plasma ACTH level. Medical management with sodium valproate.
This has also shown to reduce plasma ACTH level.
Radiotherapy Important in patients with Nelson syndrome. But has a high risk of adverse effects. Recently stereotactic radiosurgery, called gamma knife surgery (GKS), has been performed in secretory pituitary tumors including Nelson syndrome tumors and became successful Radiotherapy
Important in patients with Nelson syndrome. But has a high risk of adverse effects. Recently stereotactic radiosurgery, called gamma knife surgery (GKS), has been performed in secretory pituitary tumors including Nelson syndrome tumors and became successful
Surgical management Treatment of choice for large tumors producing acute compression of the optic nerve, optic pathway and other surrounding vital structures. Transsphenoidal surgery is optimal because it has the lowest risk of hypothalamic injury. Surgical management
Treatment of choice for large tumors producing acute compression of the optic nerve, optic pathway and other surrounding vital structures. Transsphenoidal surgery is optimal because it has the lowest risk of hypothalamic injury.
Management with Temozolomide This is a type of chemotherapy used to treat primary brain tumors called glioblastoma can also be used. Management with Temozolomide
This is a type of chemotherapy used to treat primary brain tumors called glioblastoma can also be used.
Steroid replacement As these patients have undergone bilateral adrenalectomy, they need to have adrenal steroid with glucocorticoids and mineralocorticoids Inadequate mineralocorticoid replacement results in increased glucocorticoid requirement that can cause re-appearance of Cushing's syndrome. Steroid replacement
As these patients have undergone bilateral adrenalectomy, they need to have adrenal steroid with glucocorticoids and mineralocorticoids Inadequate mineralocorticoid replacement results in increased glucocorticoid requirement that can cause re-appearance of Cushing's syndrome.

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