Cox’s Conference: A case of persistent headache and visual field deficits

In today’s Cox’s Conference, Dr. Megan Kypreos presented a case of acromegaly to expert discussant, Dr. Jessica Abramowitz. In this post, we will summarize the case, discussion, and relevant clinical pearls. Clinical asides by either Dr. Abramowitz, our residents, and chief residents are paraphrased in bold.

Dr. Kypreos: The patient is a 36 year old man with a no significant past medical history who initially presented with progressive headaches. These headaches began 7 years prior to presentation. They were initially intermittent, located in his bilateral temporal regions with radiation to the occiput, associated with phonophobia and photophobia. The headaches typically began in the morning. The frequency of the headaches increased over the ensuing year such that they became constant. There was no associated nausea or vomiting but was notable for associated bitemporal vision loss.

In the evaluation of headache, imaging should only be reserved for red-flags that may suggest space-occupying lesions, vascular abnormalities, bleeding, infection, or systemic problems (e.g., vasculitis or metabolic disturbances). These include: 

  • Focal neurologic signs, seizures, papilledema
  • Progression of symptoms, change in quality of headache, acceleration of frequency
  • Constitutional findings (e.g., weight loss, fever, night sweats, anorexia)
  • Immunocompromise (e.g., HIV, immunosuppressive medications, transplant patients)
  • New onset >40 years of age
  • altered mentation
  • meningismus 
  • worsening with Valsalva maneuvers or awakening from sleep
  • thunderclap headache or post-traumatic headache

If imaging is chosen, MRI is the imaging modality of choice outside of the acute setting when acute bleed must be ruled out. MRI is more sensitive than CT for the detection of structural or vascular lesions.

In this patient, there are at least two alarm findings: visual field deficits and progression of symptoms that provide indication for imaging.

Dr. Kypreos: The patient denied fevers, chills, weight loss, trauma, focal weakness, numbness. He did note low energy and lack of morning erections. He denied polyuria, nocturia, history of fractures, skin or hair changes, cold or heat intolerance.

In the context of daily progressive headaches and bilateral temporal visual deficits, pituitary adenomas and sellar masses feature prominently on our differential diagnosis. Among pituitary adenomas, the differential diagnosis can be divided into functional/secretory tumors and non-secretory tumors.

The secretory adenomas include: prolactinomas, growth hormone-secreting tumors (leading to acromegaly in adults and pituitary gigantism in children), ACTH-secreting tumors (Cushing disease), TSH-secreting tumors, and gonadotroph-secreting tumors (usually do cause clinically significant effects from their secretory products). While rare, these tumors can occasionally hypersecrete more than one trophic hormone. 

Independent of the effects of the hormones they may or may not secrete, pituitary tumors can result in symptoms related to their mass effect. These include bitemporal hemianopsia due to impingement on the optic chiasm, hormonal hyposecretion. Importantly, if there is involvement of the hypothalamus or pituitary stalk (either from an extensive pituitary mass or from a separate CNS mass that invaded into the sella), central diabetes insipidus must be considered. 

When a pituitary mass is considered, one must elicit a history that appropriately rules in or rules out the various endocrinopathies that are associated with hormonal hyper- and hyposecretion as well as mass effect. These include:

  • For hyperprolactinemia
    • Men: erectile dysfunction, galactorrhea, changes in libido
    • Women: amenorrhea or change in menses (quite sensitive to abnormal prolactin secretion), galactorrhea, infertility
  • For gonadotroph deficiency
    • Men: loss of morning erections, testicular atrophy, loss of libido
    • Women: breast atrophy, loss of libido
    • Children: delayed or lack of puberty
  • For acromegaly
    • children: gigantism
    • adults
      • frontal bossing
      • prognathism
      • changes in hat size, shoe size, ring size
      • coarse facial features (reference old pictures)
      • prognathism
      • hirsuitism
      • diabetes mellitus and its clinical sequela
      • carpal tunnel
  • For growth hormone deficiency
    • Children: failure to thrive/growth retardation
    • reduced muscle mass
    • decreased strength and energy
    • obesity
  • For Cushing disease
    • central obesity
    • purple striae
    • easy bruising
    • proximal muscle weakness
    • mood disturbances
    • weight gain
  • For corticotrophin deficiency
    • fatigue
    • nausea/vomiting
    • orthostatic hypotension/hypotension
  • For TSH-secreting tumors
    • tremor
    • anxiety
    • palpitations
    • heat intolerance
    • weight loss
    • fevers
    • diarrhea
  • For thyrotropin deficiency
    • weight gain
    • malaise
    • constipation
    • cold intolerance
    • coarse skin and hair
    • depression
  • For diabetes insipidus
    • polyuria
    • nocturia
    • dilute/clear urine
    • polydipsia

Of these symptoms, the patient may have evidence of hypogonadism in light of his lack of morning erections and fatigue. This may suggest hyperprolactinoma or gonadotroph deficiency. 

Dr. Kypreos: The patient’s past medical history did not include any prior known brain masses, radiation, or neurosurgical procedures. There was no history of hyperparathyroidism, medullary thyroid cancer, pituitary adenomas, pancreatic neuroendocrine tumors, or pheochromocytomas in the family. He was not on any medications or supplements. He had no allergies.

In patients with suspected pituitary tumors, it is important to screen for for familial syndromes, particularly MEN1, which is characterized by hyperparathyrodism due to parathyroid hyperplasia, pancreatic neuroendocrine tumors (e.g., gastrinoma and insulinoma), and pituitary adenomas. 

The patient’s physical exam was notable for normal vitals. He was tall and in mild discomfort from a headache. His eye exam was unremarkable. His oropharynx was clear and without evidence of mucosal neuromas or rash. His head was atraumatic but notable for frontal bossing and wide-spaced teeth. His neck exam was without thyromegaly, adenopathy or masses. His heart, lung, and abdominal exam did not disclose any abnormalities. There was no evidence of central adiposity, striae, or suprascapular adiposity. Neurologic examination was notable for bitemporal hemianopsia (later confirmed on formal visual field testing). There was no muscle weakness, edema, or rash.

The patient’s physical examination discloses features suggestive of acromegaly secondary to a pituitary adenoma. As noted earlier, it is important to seek out physical exam findings that can suggest hyper- or hyposecretion of trophic hormones. To diagnose acromegaly, an IGF-1 level is the initial test. Unlike growth hormone, its levels remain relatively stable over the course of 24-hours. If IGF-1 levels are elevated (adjusted for age and gender), oral glucose tolerance test is performed (typically 75 grams of glucose). In this test, a baseline growth hormone is measured followed by the glucose load. The growth hormone level and serum glucose (to confirm induced hyperglycemia) is measured 2 hours later. A growth hormone level that cannot be suppressed to less than 2 mcg/L strongly suggests acromegaly. 

Dr. Kypreos: The patient’s initial labs demonstrated normal serum chemistries and complete blood count. IGF-1 levels were 465 ng/mL (reference range 54-310 ng/mL) with a Z-score of 3. Oral glucose tolerance testing failed to suppress his growth hormone levels. Total testosterone levels were 24 ng/dL (reference range 249-839 ng.dL). FSH was 2.6 mIU/mL. Serum prolactin level was mildly elevated at 29 ng/mL. TSH, free T4, AM cortisol, ACTH, and serum calcium levels were normal. MRI of the brain was obtained; it demonstrated a large sellar mass mearusring 40 x 28 x48 mm with suprasellar extension into the optic chiasm.

The patient’s elevated IGF-1 level and positive oral glucose tolerance test strongly suggests a diagnosis of acromegaly. The patient also has an inappropriately normal FSH level in the setting of low total testosterone, consistent with hypogonadotrophic hypogonadism secondary to mass effect. Moreover, the patient has mild hyperprolactinemia likely due to stalk compression (which causes disruption of tonic inhibition by dopamine from the hypothalamus via the pituitary stalk). 

This patient certainly meets criteria for surgical resection of his pituitary tumor. The treatment of prolactinomas should initially be dopamine agonists (cabergoline or bromocriptine). Surgery should be considered if prolactin levels fail to lower or size does not decrease with dopamine agonists. For other secretory (except for gonadtroph) pituitary tumors, surgery is recommended. Patients with gonadotroph-secreting or nonfunctional tumors should undergo surgical resection if there are neurologic sequela. Patients who are asymptomatic can be considered for observation or surgery depending on risk-benefit discussion with the surgeon; hyposecretion should carefully elicited and treated if found. 

Post-operative management of the patient should include early colon cancer screening (increased colon cancer risk in patients with acromegaly), baseline echocardiography due to cardiomyopathy, and repeat IGF-1 levels to monitor for residual disease. If IFG-1 levels remain elevated, the patient should be imaged for evidence of resectable residual disease. If no resectable disease is available, medical therapy, including somatostatin analogues and GH-receptor antagonists (pegvisomant), is trialed. Failing medical therapy, stereotactic radiation can be considered.

Dr. Kypreos: The patient underwent transsphenoidal resection of his pituitary mass, began testosterone replacement therapy, and was empirically started on thyroid hormone replacement and maintenance hydrocortisone until his hypothalamic-pituitary axis was confirmed to be intact post-operatively (these were normal on repeat dexamethasone suppression test and thyroid function testing, and the patient was weaned off). Pathology demonstrated a sparsely granulated growth hormone cell adenoma; notably, sparsely granulated growth hormone cell adenomas are less likely to respond to somatostatin analogues relative to densely granulated growth hormone cell adenomas. The patient’s IGF-1 levels remained elevated. He was subsequently started on octreotide and continues to be followed in clinic.

Final diagnosis: acromegaly