Neuro-ophthalmic evaluation and management of pituitary disease

Neuro-ophthalmic evaluation is a crucial component of the diagnostic and prognostic assessment of pituitary disease and compressive chiasmopathy, and can inform the timing of vision-restoring tumour resection surgery. The most common disease affecting the pituitary with neuro-ophthalmic implications are pituitary adenomas. Neuro-ophthalmic manifestations include decreased vision, abnormal colour vision and impaired visual field or diplopia. The recognition of these syndromes is critical to achieve early diagnosis and treatment and to improve prognosis. The pattern of vision loss in chiasmal compression is determined by the anatomical relationship between the pituitary lesion and optic chiasm, and potential visual field defects include bitemporal deficits, junctional scotomas, monocular cecocentral defects, and incongruous homonymous hemianopias. Rarer neuro-ophthalmic manifestations of pituitary disease include ophthalmoplegia, nystagmus, and obstructive hydrocephalus. There is growing evidence that demonstrates the strong diagnostic utility of optical coherence tomography (OCT) parameters in detecting the presence of compressive chiasmopathy, as well as the prognostic ability to predict the rate and degree of visual recovery following decompression surgery. Long-term neuro-ophthalmic monitoring is critical for detecting delayed vision loss following resection surgery, which may represent tumour recurrence or secondary complications.


INTRODUCTION
Tumours of the pituitary gland and parasellar region comprise up to 15% of all primary intracranial lesions [1], and can be associated with reversible visual dysfunction secondary to compression of the optic chiasm in 30-70% of cases [2,3].Although several types of lesions can lead to compressive chiasmopathy, benign pituitary adenomas are the most commonly identified cause in adults [4].The presentation of patients depends on the type of pituitary tumour.Functioning adenomas are more commonly diagnosed secondarily to symptoms that are associated with hormone excess, before mass effect from the tumour can cause chiasmal compression.Non-functioning pituitary adenomas generally have a greater tumour volume and more commonly present with visual impairment.Other significant compressive lesions that may cause chiasmal compression include parasellar meningiomas, craniopharyngiomas, chiasmal and third ventricular gliomas and vascular abnormalities; while astrocytomas may infiltrate the optic chiasm [2,4].
The neuro-ophthalmic management of patients with pituitary disease encompasses understanding the spectrum of clinical symptoms and signs associated with chiasmal compression.The pattern of vision loss in compressive chiasmopathy is dependent on the anatomical relationship between the lesion and optic chiasm.The chiasm contains the decussation of nasal retinal nerve fibres while the fibres from the temporal hemiretina (nasal visual field) remain ipsilateral to enter the optic tract.Therefore, visual information corresponding to a hemifield is encoded in the contralateral optic tract.For example, the fibres that subserve the right hemifield are located in the left optic tract.
It has been historically postulated that some fibres loop anteriorly 1-2 mm into the terminal portion of the opposite optic nerve before turning to enter the chiasm, known as Willbrand's knee.These primarily serve the superotemporal portion of the contralateral visual field from the inferonasal retinal of the contralateral eye.Therefore, damage to these fibres is the cause of junctional scotoma.It has been shown that Willebrand knee may be an artifact in monkeys, but not necessarily in humans.
The chiasm is located 10 mm above the sella turcica and is 12 to 18 mm in diameter.The anatomic position of the chiasm is described as prefixed, normal, or postfixed based on the relative position of the chiasm (anterior, above, or posterior) to the sella turcica.The most common position (80%) is when the chiasm overlies the diaphragma sellae (80%).Less commonly, the chiasm is prefixed, or overlying the tuberculum sellae (15%), and postfixed, located over the dorsum sellae (5%).[Fig.1] The chiasm itself is approximately 12-18 mm wide, 4 mm thick with a length of 8 mm (from the anterior to the posterior commissure).It is estimated that 53% of the fibres from the optic nerve decussate in the chiasm.I Neuro-ophthalmic features associated with chiasmal compression include decreased visual acuity, visual field defects, impaired colour perception and optic atrophy.Other symptoms include diplopia, impaired stereoscopic vision and photophobia.Visual field defects associated with chiasmal compression include bitemporal hemianopic defects, junctional scotomas, monocular cecocentral defects, bitemporal hemianopic scotomas and incongruous homonymous hemianopias [5][6][7].Efferent neuroophthalmic manifestations of pituitary and parasellar lesions, such as ophthalmoplegia and nystagmus, are less frequently observed and may be associated with cavernous sinus invasion [7,8].In rare cases, compression of the third ventricle can also lead to hydrocephalus [9].
In recent decades, there has been growing evidence of the powerful diagnostic and prognostic utility of spectral domain optical coherence tomography (OCT) parameters, including peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell complex (mGCC) measurements, in identifying the presence of chiasmal compression and predicting long term visual recovery following surgical resection [10][11][12][13].OCT is a rapid, non-contact, non-invasive ocular imaging technique based on infrared light which allows in-vivo assessment of eye tissue structure.Early diagnosis of pituitary and parasellar lesions is critical for facilitating sight-restoring decompression surgery, prior to the development of irreversible optic atrophy [2].The purpose of the current article is therefore to highlight pertinent points in the neuro-ophthalmic evaluation and management of pituitary disease.

DIAGNOSIS
A comprehensive neuro-ophthalmic examination is required to detect early signs of compressive optic neuropathy before retrograde optic atrophy develops.This involves a careful history and examination encompassing visual acuity, colour vision testing, pupil responses, stereoscopic optic nerve assessment, visual field testing and ancillary tests such as optical coherence tomography.
Vision loss.Examination of the afferent visual system is required in patients suspected of chiasmal compression secondary to pituitary disease.This includes visual acuity, colour vision, pupils, visual fields and optic nerve assessment.Visual acuity may be normal even in the presence of a dense bitemporal hemianopia.When visual acuity loss or reduction is present it is typically slowly progressive or detected incidentally on routine ophthalmic screening [2,7,19].However, sudden visual decline can also occur with rapid expansion of the mass lesion and/or chiasmal infarction, such as in pituitary apoplexy [20,21].Subjective visual complaints in pituitary disease are frequently non-specific, and many patients may not perceive peripheral vision impairment [22].Commonly reported symptoms include difficulty performing fine motor tasks requiring stereopsis and binocular vision, as well as slowly dimming and blurry vision [2,22].The average duration of ophthalmic symptoms at the time of diagnosis ranges from 6 to 24 months [7,19].
Visual acuity can range from normal to no light perception in compressive chiasmopathy, and usually remain unaffected until associated field defects encroach centrally towards fixation [5,7,19,23].Colour vision deficits can be detected both in the presence or absence of reduced visual acuity [19,24].Patients can occasionally miss reading figures that fall in the temporal field, and temporal red desaturation may also be detected when tested across the vertical meridian [2].Patients with complete bitemporal visual field defect will not have a relative afferent pupillary defect (RAPD).However, a RAPD will be present if there is significant asymmetry in the visual field loss.
Pituitary lesions compressing the optic chiasm cause peripheral visual field defects more commonly than compromised central acuity [5,7,19,23], and therefore automated static perimetry is recommended routinely in the neuro-ophthalmic evaluation of affected patients.The pattern of visual field loss is dependent on a myriad of factors, including individual microanatomical variation in the decussation of nerve fibres, the anatomical relationship between the chiasm and skull base, as well as the type and location of the compressive lesion [2].Chiasmal contact and compression usually do not occur until pituitary adenomas expand 8 mm or more above the diaphragma sellae [6].Typical visual field deficits include bitemporal defects, junctional scotomas, monocular cecocentral defects, and incongruous homonymous hemianopias [2,[5][6][7] [Fig.2].
Bitemporal visual field defects respecting the vertical meridian are the most commonly detected pattern in 32-81% of patients with visual impairment [5,6,19].This pattern of field loss is associated with lesions affecting the central portion of the chiasm, which preferentially damage decussating fibres originating from the nasal hemiretina of both eyes [25].In most cases, central visual acuity remains preserved [5,7,19,23], although patients may miss letters on the chart in the temporal field of each eye.

Fig. 1 Anatomical position of optic chasm relative to the sella turcica. A
The position of the chiasm is directly above the pituitary gland in the majority of people.A 'prefixed' is when the chiasm lies over the tuberculum sella while a 'postfixed' chiasm is when it lies over the dorsum sella.
The bitemporal hemianopia may initially be limited to the superior quadrants in infrachiasmal lesions, such as pituitary adenomas, tuberculum sellae and medial sphenoidal ridge meningiomas, before progressing to the inferotemporal then inferonasal quadrants [7,19].Conversely, visual field loss associated with suprachiasmal lesions tends to begin in the inferotemporal quadrants [26].Other causes of bitemporal visual field loss include enlarged physiological blind spots, posterior staphyloma, and refractive scotomata, although visual field defects secondary to these ocular causes do not necessarily respect the vertical meridian.
Junctional scotomas occur in 4-39% of patients with preoperative visual impairment [5,6,27].The field deficit occurs when an anteriorly located lesion compresses the medial aspect of the junction between the optic nerve and chiasm, thereby affecting nerve fibres from the ipsilateral optic nerve, as well as the Willebrand knee fibres originating from the inferonasal retina of the contralateral eye [28].The resulting visual field defect therefore comprises an ipsilateral central scotoma and a contralateral superotemporal defect [28].These cases highlight the importance of routine visual field assessment of the fellow eye in patients complaining of gradual monocular visual loss, as the contralateral superotemporal defect can be subtle and may not necessarily be reported subjectively.
Homonymous hemianopia and monocular defects are less commonly observed in pituitary disease [2,29].Homonymous hemianopic visual field deficits associated with pituitary lesions are typically incongruous, and occur when the chiasm is prefixed, or if the compressive tumour predominantly affects the lateral chiasm or optic tracts [5,29].Occasionally, a small lesion may only affect decussating fibres from the ipsilateral eye, and the resulting visual field deficit may be a monocular temporal hemianopia or paracentral scotoma [2,5,28].Compression of the posterior portion of the optic nerve may also occur in isolation, which causes a monocular central or cecocentral defect [2,5].
Compressive lesions may not necessarily exert the same effect on fibres originating from each eye, and asymmetrical visual field defects associated with a relative afferent pupillary defect are observed in 15-77% of patients prior to tumour resection [2,7].
Post-fixational blindness is a visual phenomenon that can occur in patients with complete bitemporal hemianopia [30].During convergence, the two blind temporal hemifields overlap in the region posterior to the point of fixation [2,30].This results in disturbances of depth perception, and difficulty in performing fine motor tasks that rely on stereopsis and binocular vision [30].
Optic atrophy.Optic atrophy can be present or absent in chiasmal syndromes, and represents retrograde degeneration of the retinal ganglion cells and axons secondary to chronic compressive damage.In compressive chiasmopathy, decussating fibres originating from the nasal hemiretina from both eyes are preferentially affected, while temporal retinal ganglion cell fibres are relatively spared [25].Within the retina, nasal macular fibres course directly to the temporal sector of the optic disc, while peripheral nasal fibres enter into the nasal disc sector [2].This results in the characteristic bow-tie or band atrophy appearance visible on ophthalmoscopy, whereby pallor extends horizontally as a band across the nasal and temporal sectors of the optic disc [31] [Fig.3].
This pattern has also been corroborated in OCT studies.Compression of the optic chiasm caused by pituitary adenomas may induce RNFL thinning, which reflects retrograde axonal degeneration.The classic pattern caused in cases of bitemporal  hemianopias is thinner nasal and temporal sectors, although diffiuse RNFL thinning also occurs [Fig.4].Furthermore, there is binasal mGCC atrophy in chiasmal compression, as well as preferential nasal and temporal sectoral pRNFL thinning [24,32] [Fig.5].
In recent years, the powerful diagnostic utility of OCT parameters has become well established, and routine mGCC and pRNFL assessment are therefore recommended in the neuroophthalmic evaluation of patients with suspected chiasmal compression [10][11][12][13].Strong correlations between both OCT parameters and the severity of pre-operative visual field deficits have been consistently reported [24,32].However, visual field defects typically occur earlier than OCT changes, while more recent studies have suggested that mGCC dropout might precede the onset of pRNFL thinning [33].Moreover, OCT-A studies have also demonstrated reduced peripapillary and superficial macular vessel densities in patients with chiasmal compression [34].
Pre-operative OCT pRNFL and mGCC are strong prognostic markers for predicting both the degree and rate of visual recovery following surgical resection of pituitary and parasellar lesions [10][11][12][13] Thinner pre-operative pRNFL measurements of less than 85 μm are associated with poorer long-term visual field and acuity recovery [35].Patients with pre-operative pRNFL above the fifth percentile of age-matched normative values experience most of their visual field recovery within the first 6 weeks following surgical resection, while those with pRNFL below the fifth percentile demonstrate slower improvement during the first 6 months [11].Several multivariate risk prediction models incorporating age, pre-operative visual function and OCT measurements, and/or MRI compression grading have also been developed, and exhibit moderate-to-high prognostic performance in predicting long-term visual recovery [10,12].
Diplopia.Binocular diplopia occurs in 2-10% of patients with pituitary disease, and can develop from two main mechanisms [7,27].Lateral invasion of the lesion into the cavernous sinus can cause direct compression of the ocular motor cranial nerves III, IV, and VI, leading to ophthalmoplegia [30].The resulting paretic binocular diplopia may have vertical, horizontal, or torsional components, depending on the combination of ocular motor  Fig. 2 Visual Field Defects Associated With Chiasmal Compression.A Bitemporal hemianopia: most common lesion produced by chiasmal compression.B Early bitemporal loss in the superior quadrant suggestive of compression of the fibres in the inferior chiasm.C Right Incomplete incongruous hemianopia: pre-fixed chiasm or a tumour that impact on the optic tract.D Left Junctional Scotoma or 'anterior chiasmal syndrome': a lesion located at the medial aspect of the junction between the chiasm and the left optic nerve will affect the left optic nerve fibres and the fibres that cross in the anterior chiasm to the contralateral side producing a left central scotoma and a right temporal hemianopic defect.E Unilateral hemianopia: a small lesion damaging only the crossing fibres of the right eye at the anterior chiasm can produce a monocular temporal hemianopic defect.cranial nerves affected [2,30].Moreover, ptosis and mydriasis might also be observed with cranial nerve III involvement.Trigeminal sensory neuropathy can occur when the ophthalmic and/or maxillary branches of cranial nerve V are affected within the cavernous sinus [2,30].A post-ganglionic Horner's syndrome might be detected with damage of the oculosympathetic fibres, typically in combination with cranial nerve VI involvement [30].
Hemifield slide phenomenon is an uncommon cause of binocular diplopia in pituitary disease, and occurs in the presence of intact ocular motility [30].In patients with bitemporal hemianopia, there is a significant reduction in overlap between the temporal hemifield of one eye from the nasal hemifield of the contralateral eye, which disrupts the ability of the brain to maintain fusion and/or control any underlying latent heterophoria [2,30].The resulting comitant esodeviation, exodevation, or hyperdeviation can lead to the perception of overlapping or divergent images [2].
Nystagmus.Seesaw torsional nystagmus is an unusual type of involuntary ocular movement, which can be associated with chiasmal compression or rostral midbrain lesions [8].The pendular oscillations are comprised of cycles of elevation and intorsion in one eye, with synchronous depression and extorsion in the contralateral eye [2,8].Although the pathophysiology is not fully understood, it has been hypothesized that the loss of crossed visual input from decussating fibres at the optic chiasm can contribute to the disruption of visual-vestibular interactions [8].In some patients, seesaw nystagmus can induce symptoms of oscillopsia [8].
Other neuro-ophthalmic presentations.In rare cases, posterosuperior expansion of pituitary or parasellar lesions can result in compression of the third ventricle with resultant hydrocephalus from obstruction of cerebrospinal fluid flow [36].Associated signs can include papilloedema, superior gaze palsy, convergence retraction nystagmus, and pupillary light-near dissociation [30,36].Hydrocephalus and papilloedema are more frequently associated with suprachiasmal than intrasellar lesions [30].
Isolated cases of compressive chiasmopathy presenting with photophobia, phosphenes, increased glare, and visual hallucinations have also been reported in the literature, although the underlying mechanisms are not fully understood [14][15][16].
Systemic symptoms.Headache is present in 33-72% of patients with pituitary lesions, and often localizes to the brow and periorbital region [37].The symptom can arise from traction and displacement of pain-sensitive structures including the dura mater, blood vessels, and cranial nerves within the cavernous sinus [37].Symptoms of endocrine dysfunction can be associated with both excessive secretion or deficiency of pituitary hormones, and are summarized in Table 3 [17,38].During pregnancy, tumour enlargement occurs in up to 30% of patients with preexisting macroprolactinomas, which can exacerbate chiasmal compression and visual symptoms that may spontaneously improve following delivery [39].
Pituitary apoplexy is an acute, life-threatening syndrome caused by infarction or haemorrhage of a pituitary tumour [17].The condition occurs in 1.6-2.1% of patients with pre-existing pituitary tumours, and secondary haemorrhage and oedema cause rapid compression of the surrounding structures, including the optic chiasm and cavernous sinus [40,41].The event is usually heralded by severe headache, nausea, altered consciousness, as well as sudden deterioration in visual field defects and ophthalmoplegia [17,40].Extravasation of blood into the subarachnoid space can precipitate vasospasm and secondary stroke [42].Acute endocrine dysfunction may also be associated with life-threatening complications, including adrenal crisis [43].

Radiology and laboratory investigations
Dedicated magnetic resonance imaging (MRI) protocols, with and without gadolinium contrast, are the neuroradiological study of choice for the characterisation of intrasellar and parasellar lesions [44].A number of studies have reported that increased tumour size on MRI is predictive of poorer visual recovery following surgical resection [10,19,45,46].High-resolution computed tomography (CT) with fine cuts between 1.5 and 3.0 mm can be considered in patients with contraindications to MRI [44].
Laboratory investigations to screen for hypopituitarism and hormonal hypersecretion are usually warranted, and should be requested in consultation with an endocrinologist [17,47].The clinical practice guidelines of the Endocrine Society (United States) recommend complete biochemical screening in both patients with and without symptoms of endocrine dysfunction, and are summarised in Table 4 [47].

MANAGEMENT Medical and surgical treatment
The treatment of pituitary tumours requires a multi-disciplinary approach, with medical management typically being guided by an endocrinologist, and surgical debulking performed by a neurosurgeon or otorhinolaryngologist [17].Management decisions are dependent upon tumour size, secretory function, and associated visual impairment, and the goals of treatment include control of tumour growth, restoration of endocrine function, and preservation and/or recovery of visual function [17,38,48].Although some hormone-secreting pituitary adenomas are amenable to medical treatment, most tumours with demonstrable compressive chiasmopathy and visual loss require surgical resection [17,38,48].
Medical treatment options can be trialled initially in prolactinomas, somatotroph and thyrotroph adenomas [49][50][51].Dopamine agonists, including bromocriptine and cabergoline, have been demonstrated to reduce prolactinoma size and reverse hyperprolactinaemia [49].In patients with macroprolactinomas, dopamine agonist therapy has been demonstrated to induce tumour shrinkage in 50-90% of cases, and normalisation of serum prolactin levels in 60-95% of cases [52].Previous imaging studies have also reported that the greatest reduction in tumour size and serum prolactin levels occurs during the first 3-6 months of  treatment, and the lack of significant improvement within this period is a strong predictor of pharmacological resistance to dopamine agonist therapy [53].Octreotide, a somatostatin analogue, can shrink both somatotroph and thyrotroph adenomas and normalise endocrine imbalances [50,51].Earlier studies have shown that octreotide monotherapy can achieve biochemical control in 20-35% of patients with somatotroph adenomas, although therapeutic success can be further enhanced to 52% when combined with cabergoline treatment [54].
Pituitary tumour resection can be performed using transsphenoidal, trans-frontal, or trans-pterional approaches [17,38,48].Surgical debulking is usually indicated in cases with confirmed compressive chiasmopathy and vision loss, cavernous sinus involvement, and pituitary apoplexy, as well as patients that are unable to tolerate or demonstrate no response to medical therapy [17,38,48].In addition, prolactinomas with significant cystic features accounting for more than 80% of tumour volume on MRI T2 sequences are unlikely to respond sufficiently to medical therapy alone, and are therefore directly treated by surgical resection [17,38,48,55].Previous studies have demonstrated that visual field improvement occurs in 79-95% of patients following pituitary adenoma resection, and visual acuity improvement occurs in 45-86% of cases [2,56].An earlier meta-analysis of 17,509 patients showed that 5-year post-operative recurrence rates ranged from 4% in somatotroph adenomas, 11% in corticotroph adenomas, 12% in non-functioning pituitary adenomas, and 18% in prolactinomas [57].Radiation therapy is usually administered for smaller tumours distant from the optic chiasm, or as adjunctive treatment in patients with incompletely resected tumours or post-operative recurrence [58].

Neuro-ophthalmic surveillance
Long-term neuro-ophthalmic surveillance for pituitary and parasellar lesions is desirable for detecting delayed visual loss, which may be the first sign of tumour recurrence [59][60][61].Visual acuity and colour vision testing, and automated static perimetry should ideally be performed within 2-3 months of surgical resection or radiotherapy [2,59].Long-term neuro-ophthalmic monitoring thereafter should ideally occur routinely at 3-12 monthly intervals, or sooner should subjective complaints of visual change be reported by the patient [2,59].Periodic neuroimaging studies are also warranted, although the timing might be dependent on the outcome of surgical debulking or radiotherapy response, and should be determined in consultation with the neurosurgeon and neuroradiologist [59].
Delayed vision loss following primary treatment can occur due to a variety of reasons [59,[62][63][64].Chiasmal compression secondary to tumour recurrence or the expansion of fat packed within the sella turcica intra-operatively, and delayed radionecrosis may be detected on serial perimetry assessment [59,62,63].Traction of the chiasm due to adhesions, or descent and herniation in secondary empty sella syndrome can also lead to post-operative vision loss [59,64].MRI neuroimaging is required to differentiate between the possible causes of delayed vision loss and inform ongoing treatment decisions [59,[62][63][64].

CONCLUSIONS
In conclusion, neuro-ophthalmic testing forms an integral part of the diagnostic and prognostic evaluation of pituitary disease and  chiasmal compression, and helps to guide treatment decisions surrounding the timing of potentially sight-preserving tumour resection surgery.The pattern of vision loss can be variable in compressive chiasmopathy and is dependent on the anatomical relationship between the lesion and optic chiasm, with potential visual field defects including bitemporal deficits, junctional scotomas, monocular cecocentral defects, and incongruous homonymous hemianopias.Less common neuro-ophthalmic presentations of pituitary lesions include ophthalmoplegia, nystagmus, and obstructive hydrocephalus.Recent studies have highlighted the strong diagnostic ability of OCT pRNFL and mGCC parameters in detecting the presence of chiasmal compression, as well as the powerful prognostic performance in predicting the rate and extent of visual recovery following tumour resection.Long-term neuro-ophthalmic surveillance is desirable for detecting delayed post-operative vision loss that can be secondary to tumour recurrence, chiasmal descent or adhesions, sellar fat expansion, radionecrosis.Table 3. Clinical presentation of endocrine dysfunction in pituitary disease [17,38].

Fig. 3
Fig. 3 Optic nerve band atrophy.a Optical coherence tomography (OCT) scan of a left optic nerve in a patient who had band atrophy from chiasmal compression.Note the preferential loss of retinal nerve fibre layer nasally and temporally.b Optic nerve photo of the same patient.

Fig. 4
Fig. 4 Patient with normal appearing optic nerves and OCT RNFL thickness.However, visual field test demonstrates a bitemporal hemianopia and ganglion cell layer thickness shows corresponding binasal loss.

Fig. 5
Fig. 5 Patient with bitemporal defect.The pre-operative OCT demonstrates a RNFL thickness of 82um on the right and 89 um on the left.OCT RNFL has been shown to predict visual field recovery.Post-operative visual field shows improvement of the bitemporal visual field defect.

Table 2 .
[18]dence of pituitary adenoma in the United States by age group[18].