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Q1: Explain the ocular findings, and give the differential diagnosis
Figure 4 (see p 732) shows decreased abduction of the left eye consistent with a left abducens nerve lesion. The clinical finding of a left relative afferent pupillary defect denotes a deficit of the afferent visual pathway, anywhere from the retina to the optic tract. However a lesion causing optic nerve atrophy can be due to a primary retinal problem, optic nerve tumour, or asymmetric lesion of the optic chiasm. Usually a lesion of the chiasm or posterior to it (tracts to the lateral geniculate nucleus) will affect the optic discs bilaterally. Here the retina appeared normal on fundoscopic examination, hence the lesion must be of the optic nerve, or an asymmetric lesion of the chiasm. This is confirmed as the Humphrey's field analysis deficit affects only the left eye.
The Humphrey's field analysis reveals a unilateral defect affecting the left eye, but sparing the inferior temporal quadrant, at the time of initial presentation. Subsequent analysis performed after treatment, revealed that this lesion was localised to the superior half of the visual field. This would suggest that the lesion affects the inferior fibres of the optic nerve. As the pituitary gland is anatomically beneath the optic chiasm, this finding would be consistent with a pituitary tumour. Pituitary macroadenomas most commonly cause a bitemporal hemianopia, which in 8% progress to complete loss of vision in one eye. Nine per cent have a single eye defect, most commonly superior temporal. Bitemporal scotomas or monocular losses such as central scotomas may also occur. Through invasion of the cavernous sinus, ocular palsies may occur. The oculomotor nerve is most commonly affected.1 2
The differential diagnoses that must be considered in a patient who presents with an optic nerve lesion include trauma, tumour, multiple sclerosis, a vascular event such as a central retinal artery occlusion, a hypertensive vasculopathy, or temporal arteritis. However in this patient who experienced a gradual onset of his symptoms, which were found to be unilateral on examination, the most likely differential diagnosis is a tumour. A pituitary macroadenoma, applying pressure from below, would account for the optic nerve findings. The abducens neve findings, however, may be due to raised intracranial pressure due to an expanding mass within the cranium, or due to direct pressure of the tumour on the abducens nerve as it passes through the cavernous sinus. In this case, the computed tomogram revealed asymmetric involvement of the chiasm and involvement of the left cavernous sinus by the mass.
Q2: What further investigations would you perform?
Based on the moon facies and centripetal obesity visible in fig 1 (see p 732), and a history of recent weight gain, easy bruising and hypertension, a diagnosis of Cushing's syndrome should be suspected. With the associated ocular manifestations primary pituitary pathology is the most likely cause, namely Cushing's disease.
The screening test of choice for Cushing's syndrome is a 24 hour urinary free cortisol, or a 0800 plasma cortisol after 1 mg of dexamethasone at midnight. If raised, a low dose, 0.5 mg dexamethasone suppression test six hourly for two days is performed. If cortisol is not suppressed, the diagnosis of Cushing's syndrome is made. Localisation is further achieved by a high dose dexamethasone suppression test, plasma adrenocorticotrophic hormone concentration and radiology, in the form of coronal and axial MRI scan sections through the pituitary fossa.
Q3: What does his MRI scan reveal (see fig 3, page 733)?
The MRI scan shows a large pituitary mass, which extends anteriorly towards the left optic canal. The mass is encasing the siphon of the left internal carotid artery and appears to involve the left cavernous sinus.
With regards to pituitary dependent Cushing's disease, up to half of those who have a microadenoma may have no perceivable abnormality on MRI. In this patient, however, a large macroadenoma with extrasellar extension was detected, which is seen in about 10% of pituitary dependent Cushing's disease.
Q4: Outline initial management, and, should this fail, what alternative treatment options exist?
For a pituitary macroadenoma, the treatment of choice is trans-sphenoidal or frontal resection. This corrects hormonal overproduction within 24 hours in about 70% of patients with Cushing's disease.3 However in pituitary macroadenomas, success rates are much lower with regards to surgical intervention alone. Recurrence of visual field defects occurs in 85% over 10 years, but this figure drops to 15% if radiotherapy is combined with surgery. In patients with recurrence of the tumour, further radiotherapy and surgery may be useful to control the tumour bulk, and medical therapies may be used in an attempt to control endocrine manifestations.
The most commonly used medical therapeutic agent is ketaconazole, which acts by inhibiting steroidogenesis, but may cause abnormalities of liver function tests. If this fails, other options include metyrapone and aminoglutethimide. Metyrapone was found to control hypercortisolaemia and clinical features in up to 83% of 24 patients after pituitary irradiation.4 However all the aforementioned medications have a temporary suppressive action and lack a permanent ablative action on the adrenal gland. Mitotane (O,p′DDD) is an exception,5 as it may be curative in Cushing's disease if used for six months to two years at doses of 2 g per day. The usual concerns with side effects which arise when 12 g per day is used in the treatment of adrenal carcinoma do not appear to be of concern at such low doses. Another therapeutic modality is octreotide, however this maybe of use only when a patient's cortisol level is adequately suppressed; such that an upregulation of somatostatin receptors in the pituitary tumour occurs. Thus, when octreotide is introduced, there are more receptors to bind with and hence a shrinkage of tumour bulk can be achieved. Bilateral adrenalectomy is another therapeutic option, however the possibility of a patient developing Nelson's syndrome (an increase in pituitary tumour bulk due to a loss of the cortisol negative feedback system) is a major concern.
Our patient initially underwent a transfrontal resection. Despite two further surgical resections and two courses of radiotherapy, the tumour continued to grow and the patient experienced a recurrence and progression of his clinical symptoms. Unfortunately the ketaconazole had to be stopped because of an increase in his hepatic enzymes after starting treatment. Subsequently he was started on mitotane, with normalisation of plasma and urinary cortisol levels. In our patient, whose eye symptoms are particularly symptomatic and continuing to progress, octreotide is also being considered as adjuvant treatment with mitotane, for its potential benefit in decreasing tumour bulk.