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02_EDITORIAL MESSAGE 03_ADVANCES IN OPTICAL COHERENCE TOMOGRAPHY (OCT) TECHNOLOGY 06_THE NON-VISUAL EYE 08_NEW PERSPECTIVES IN THE IOP MANAGEMENT IN GLAUCOMA – AN ASIAN POPULATION EXPERIENCE 10_MULTI-DISCIPLINARY APPROACH TO ORBITAL DISEASE: NEURO-SURGEON AND ENT’S PERSPECTIVE 13_ONCOLOGIST PERSPECTIVE ON OCULAR AND ORBITAL DISEASES 16_ANSWERS TO PHOTOQUIZ 24 17 _PHOTOQUIZ 25

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02_EDITORIAL MESSAGE

03_ADVANCES IN OPTICAL COHERENCE TOMOGRAPHY (OCT) TECHNOLOGY

06_THE NON-VISUAL EYE

08_NEW PERSPECTIVES IN THE IOP MANAGEMENT IN GLAUCOMA – AN ASIAN POPULATION EXPERIENCE

10_MULTI-DISCIPLINARY APPROACH TO ORBITAL DISEASE: NEURO-SURGEON AND ENT’S PERSPECTIVE

13_ONCOLOGIST PERSPECTIVE ON OCULAR AND ORBITAL DISEASES

16_ANSWERS TO PHOTOQUIZ 24

17_PHOTOQUIZ 25

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EDITORIAL TEAM

Editor-in-Chief

Adjunct Associate Professor Lee Shu YenSenior Consultant, Retina Centre, SNEC

Dr Jean ChaiConsultant, Cornea and External Eye Disease Department, SNEC

Editorial Board

Dr Aliza JapSenior Consultant, CGH Eye Service

Dr Loo Jing LiangConsultant, Neuro-Ophthalmology Department, SNEC

Associate Professor Ian YeoDeputy Medical Director (Education)Senior Consultant, Retina Centre, SNEC

Ms Chia Hui YienSecretariat

by Dr Jean Chai

Happy New Year to all our readers! This year marks a very important year for SNEC. We are celebrating our 25th anniversary and the high point of our celebration was the SNEC 25th Anniversary International Meeting held here in May. We organized a series of courses, symposia, and lectures conducted by a distinguished panel of both international and local experts that will culminate years of experience and advances in various subspecialty fields. The meeting was a resounding success with more than 1,400 participants.

On another note, we are saddened to have seen the passing of our Founding Director, Professor Arthur Lim last year, whose contribution to the development of ophthalmology both locally and regionally cannot be underscored. He was passionate about education, mentoring numerous specialists both locally and overseas and envisioned SNEC to be an international centre of excellence in education, training and development. Indeed, this newsletter is just one of the ways that SNEC works towards this ideal and honors his intentions.

“If you operate on one man, you restore vision to one man; but if you teach your colleagues how to perform quality cataract surgery, they will solve the problem of cataract blindness in the world.” – Professor Arthur Lim.

02 CME NEWSLETTER ISSUE 25 AUGUST 2015

EDITOR’S NOTES

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Presented by A/Prof Seah Lay Leng and Dr Teoh Khim Hean on 20 February 2013 Written by Dr Deborah Tan

Key Points• Optical coherence tomography is a non-contact imaging modality that utilizes low coherence interferometry to measure distance indirectly, using near infrared light of wavelength 600-2000nm.

• The time-domain OCT was the introduced in 2003, and since then, the Fourier-domain OCT with 2 different configurations (the Spectral-domain and Swept-source) have been developed with faster acquisition speeds, higher resolution and imaging of deeper retinal layers.

• The OCT has increased our understanding of retinal diseases,our ability to diagnose and track disease progression as well as treatment response.

ADVANCES IN OPTICAL COHERENCE TOMOGRAPHY (OCT) TECHNOLOGY

Optical coherence tomography (OCT) is a non-invasive and non-contact investigative modality, and hence comfortable for the patient. It also provides high resolution images of high sensitivity, is reproducible and easy to use. It uses low coherence interferometry to measure indirect distances with reflected light. It uses a wavelength of 600-2000nm, which has a low absorption for tissue, water and pigment. The light beams recombine and an interference pattern is created.

The OCT was first demonstrated in 1991 and in 2003, the Stratus OCT (a time-domain OCT) became commercially available. It produces 400 A-scans per seconds, with 6 radial slices orientated 30 degrees apart. It is accurate to about 10 micron depth. Macular edema secondary to vein occlusion as well as choroidal neovascularization can be clearly demonstrated with the OCT. However, the limitation of the time-domain OCT is the speed at which the mirror can be moved by the machine. Hence, some drawbacks include alignment artefacts, poor registration, slow image acquisition speed with movement artefacts, poor definition of outer retinal boundaries, and missed pathologies as cuts are 30 degrees apart.

The Fourier-domain OCT was then introduced in 2006. It has an enhanced speed of acquisition and higher resolution. There are 2 configurations: the Spectral-domain (SDOCT) and Swept-source (SSOCT). The SDOCT produces 20000-52000 A-scans per second and has a resolution up to 5-7 microns. An ultra-high resolution of up to 3 micron is also available.

The SDOCT gives a good understanding of retinal pathology and vitreoretinal relationships. However, it is not able to give more details of the deeper structures like the choroid. SDOCT Enhanced depth imaging (EDI) produces multiple B-scans from the same retinal location and they are then averaged together. This increases signal-to-noise ratio,reduces ‘speckling’, increases continuity and enhances retinal and choroidal features. Hence, it enables imaging of the deeper layers. The choroid is shown to be thickest subfoveally and thins out nasally, witha negative correlation with thickness and age.

The SSOCT produces 100,000 to 236,000 A-scans per second with 12mm long scans. It has an increased wavelength of 1050nm and it uses laser instead of an optical light source, hence allowing deeper penetration and reduced scatter. It is also better in the presence of media opacities and also gives an improved visualization of the choroid. Hence, the benefits of the SSOCT includes a longer scan length, greater resolution, faster image acquisition, better visualization of the vitreous and vitreoretinal surface and the deeper layers (ie the choroid). It also enables follow-up analysis and ‘en face’ imaging (viewing of the different retinal layers).

The OCT has enabled improved understanding of disease, the natural history and visual prognosis. We have come to understand more about “new” disease entities such as myopic macular schisis where splitting of retinal layers is seen. Post-operative OCT can then be performed to demonstrate good anatomical outcomes. Other examples in which OCT is useful: central serous chorioretinopathy, OCT can detect Retinal Pigment Epithelium (RPE) irregularities that may correspond to the point of leakage. It also gives an idea about the visual prognosis, where a poorer prognosis is expected if there is IS-OS disruption, foveal thinning or a change in choroidal thickness. It also allows for follow-up response to treatment in CNV, showing intraretinal changes and subretinal fibrosis and choroidal thinning. In macula edema, FDOCT allows for enhanced visualization and better measurement of the central retinal thickness.

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Figure 1. Proposed mechanism of subretinal autofluorescence in CSCR.

ADVANCES IN OPTICAL COHERENCE TOMOGRAPHY (OCT) TECHNOLOGY

04 CME NEWSLETTER ISSUE 25

The OCT has improved understanding of disease, the natural history and visual prognosis. We have come to understand more about “new” disease entities such as myopic macular schisis where splitting of retinal layers is seen.

Post-operative OCT can then be performed to demonstrate good anatomical outcomes. Other examples in which OCT is useful: central serous chorioretinopathy, OCT can detect Retinal Pigment Epithelium (RPE) irregularities that may correspond to the point of leakage. It also gives an idea about the visual prognosis, where a poorer prognosis is expected if there is Photoreceptor Inner and Outer Segment Disruptions (IS-OS) disruption, foveal thinning or a change in choroidal thickness. It also allows for follow-up response to treatment in CNV, showing intraretinal changes and subretinal fibrosis and choroidal thinning. In macula edema, FDOCT allows for enhanced visualization and better measurement of the central retinal thickness.

Newer technologies such as the intraoperative SDOCT (Bioptigen, Spectralis & Optovue iVue) could also be helpful to ensure adequate removal of epiretinal membrane and relief of vitreomacular traction. The Doppler OCT evaluates blood flow and volume of retinal and choroidal vasculature, highlights vessels with flow, evaluate abnormal vessels in retina and choroid, better understating and evaluation of Age-related Macular Degeneration (AMD), Polypoidal Choroidal Vasculopathy (PCV) and Central Serous Chorioretinopathy (CSCR).

In summary, the OCT has increasingly become an essential tool in the management of vitreoretinal diseases as it has enhanced our understanding of disease processes, provides a more accurate diagnosis, guides treatment and has enabled us to track treatment response and prognosticate visual outcome. We await greater resolution scans as the SSOCT become more widely available and also possibly better surgical outcome with the intraoperative OCT.

Central Serous Chorioretinopathy (CSCR) Update

Key points1) Choroidal hyperpermeability underlies the pathogenesis of CSCR. Chronic elevation of the retina leads to atrophy of the photoreceptors and retinal pigment epithelium.

2) Management options in CSCR include expectant management, risk factor modification, laser photocoaugulation and photodynamic therapy (PDT). Various PDT protocols have been reported with reasonable short-term success.

3) Mineralocorticoid disturbances are currently being assessed as a potential therapeutic target.

Multi-modal imaging of CSCR includes structural studies which involve the use of Optical Coherence Tomography (OCT), either Spectral Domain-OCT with enhanced depth imaging, or Swept Source OCT and functional studies which include autofluorescence (AF). One of the newer technologies includes high-resolution imaging of resolved CSCR using adaptive optics scanning laser ophthalmoscopy, but it is currently used for research purposes.

The main problem in the pathogenesis of CSCR is choroidal hyperpermeability which then puts stress on the retinal pigment epithelium (RPE). Figure 1 shows the proposed mechanism of subretinal autofluorescence in CSCR.The leak causes a circumscribed elevation of the macula. The elevated retina is no longer in contact with the retinal pigment epithelium and hence the shed photoreceptors are not phagocytized. The increasing accumulation of degenerated photoreceptors creates an increasing amount of reaction products that are autofluorescent. With chronic detachment, the photoreceptors eventually atrophy, leading to a decrease in the subretinal accumulation, with concurrent atrophy of the RPE.

AUGUST 2015

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ADVANCES IN OPTICAL COHERENCE TOMOGRAPHY (OCT) TECHNOLOGY

05 CME NEWSLETTER ISSUE 25

Choroidal hyperpermeability previously could only be demonstrated by ICG but now enhanced depth imaging OCT (EDIOCT) enables us to assess the choroid better. A thickened choroid in CSCR can be seen with the EDIOCT as well as the swept-source OCT(SSOCT).

The management of CSCR includes:

“Classic” CSCR resolves spontaneously within 3 to 4 months after onset. Recurrent CSCR makes up about 25-50% of acute cases. Chronic CSCR is usually associated with pathological changes and visual loss as it involves photoreceptor death, loss of Inner Segment-Outer Segment (IS-OS) line, outer retinal tubulations and RPE loss.

1) Observation and risk factors modification, 2) Discontinuation of steroids, 3) Laser photocoagulation, or4) Photodynamic therapy (PDT) with verteporfin.

In a prospective randomized trial by Peter Leaver and Christine Williams published in BJO in 1979 on “Argon laser photocoagulation in the treatment of CS(C)R”, they showed that argon laser hastened resolution of the serous detachment. However, no evidence was found to suggest that treatment influenced the final visual outcome in eyes with initial VA of 6/12 or better.

Standard PDT with verteporfin was found to be effective and safe in chronic CSCR treatment with a significant improvement in the long term, both anatomic and visual, without inducing additional retinal atrophy or systemic adverse effects (Rufino et al). Single treatment with half-dose PDT was also found to give improved and stable vision (Chan WM Ophthalmology 2008).The success of half-dose PDT in eyes with chronic CSCR also depended on the distribution of fluid in the neuro-epithelium. Half-dose PDT might not be effective or the recurrence rate might be high in eyes with posterior retinal cystoid degeneration (Am J Ophth 2012). High-fluence PDT was also found to be as effective as conventional PDT, whilst minimizing the deleterious effect on choriocapilaries perfusion and retinal thickness (Joo YS et al, Retina 2011).

Recent studies have also found that mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy (Min Zhao et al, J Clin Invest 2012). Current human studies involving the use of spironolactone are ongoing.

In summary, CSCR affects the choroidal vasculature, the RPE and neurosensory retina. Multi-modal imaging allows structural assessment by OCT down to photoreceptor level and functional assessment by autofluorescence imaging. PDT is effective in treating CSCR and reduces choroidal hyperpermeability and thickness. Variations appear to have favorable results but long term results are limited. Mineralocorticoid disturbances are currently being assessed as a potential therapeutic target.

AUGUST 2015

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Presented by Dr Dan Milea on 18 September 2013Written by Dr Gillian Teh

THE NON-VISUAL EYE

The relationship between light, the eye and the human brain is a complex one. Nature adapts to different light conditions and so do humans. The circadian rhythm is 24 hours and can be externally entrained by temperature and light, as seen in Michael Siffre’s cave study (1962) where, despite living in complete darkness and without a clock, he unintentionally kept to regular cycles of sleeping and waking within 24hours. This provided evidence for a human internal clock, the suprachiasmatic nucleus (SCN), which governs our circadian rhythm. Subjective time is also compressed in darkness, as Siffre emerged from his cave experiment after two months, while thinking that only one month had passed. Our mood is also impacted by light and darkness, as seen in seasonal affective disorder (SAD), and is remedied by light therapy.

Can the brain “see” without light perception in the eye? Yes, by way of the pineal gland, which secretes melatonin. But in humans, the pineal gland has no role in photoreception, as the eye is the only location in the body which senses non-visual light. In Clyde Killer’s experiments using mice with no photoreceptors(1923), a normal pupillary reaction was still measured. This is because normal retinal ganglion cells (RGCs) also consist of melanopsin expressing RGCs, which are intrinsically photosensitive and will still have normal pupil reaction and hence result in normal circadian rhythms. These cells comprise of 1% or less of the total retinal ganglion cells and consist of giant sized soma with long dendrites forming a bilayered photoreceptive dendritic net in the inner plexiform layer. These cells function as non-visual light detectors and are sensitive to blue light at a wavelength of 480nm. Their axons project into the brain to the SCN in the hypothalamus, which then project to pineal gland, and then to the mesencephalon which governs the pupillary reaction.

These intrinsically photosensitive retinal ganglion cells (ipRGCs) are rather like melanopsin positive photoreceptors. Several types of ipRGCs have been identified, and are characterized anatomically and functionally. Blue light, which stimulates these melanopsin-expressing RGCs, drives a gradual and sustained modulation in pupil size whereas cone photoreceptor activation drives a more rapid pupil response. Some other non-visual functions of ipRGCs consist of Circadian rhythm photoentrainment, suppression of nocturnal melatonin, increasing the heart rate and affecting electroencephalography (EEG) waves. Constriction of the pupil to blue light is slower and more sluggish as compared to a coloured light stimulus. Hence, changes in chromatic pupil reflex can thus indicate outer photoreceptor dysfunction versus ganglion cell dysfunction. This finding is currently being investigated and is the basis of ongoing research at the Singapore National Eye Centre.

Interestingly, patients who are blind can still have migraine triggered by light. This indicates that the melanopsin expressing ipRGCs are still involved in triggering photophobia. These patients “sense” light, which triggers their migraines, without sight. This finding may be a source of future work in the management of migraines.

Perhaps even more interesting still, is the interplay between blindness and depression (Berson, 2007). Patients who have no photoreceptor function do not get depression whereas patients with no ganglion cell function, such as in glaucoma or other optic neuropathies, may have mood problems. This is also the basis of some applications of light therapy in the treatment of SAD during winter in Nordic countries.

06 CME NEWSLETTER ISSUE 25

Key Points• Melanopsin expressing retinal ganglion cells (RGC) comprise 1% or less of total retinal ganglion cell population, and are intrinsically photosensitive.

• They are stimulated by blue light, and can drive a gradual and sustained change in pupil size.

• Other functions include Circadian rhythm photoentrainment, suppression of nocturnal melatonin, increasing the heart rate and affecting electroencephalography (EEG) waves.

• There are a plethora of potential applications and more research is awaited in this area.

AUGUST 2015

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THE NON-VISUAL EYE

07 CME NEWSLETTER ISSUE 25

Vanderwalle et al found that subjects who underwent cognitive tests in blue light had better performance. This finding must be balanced with the fact that melanopsin-expressing RGCs are stimulated by blue light, which then downregulates melatonin secretion and results in poor sleep. This then poses the question of whether yellow-tinted intraocular lenses (implanted after cataract removal to protect the retina from supposed harmful effects of blue light) may affect the patient’s quality of sleep (Landers 2009).

Given these findings, some new potential applications include melanopsin blockers to aid jet lag or migraine; blue light blocking filters to prevent downregulation of melatonin (useful for people working late at night on computers) to aid sleep and help mood; and last but not least, light therapy for mood disorders other than SAD.

In conclusion, ipRGCs mediate multiple non-imaging functions – a finding which poses a plethora of potential applications. This includes the use of the pupil response as a powerful biosensor and may lay the groundwork for future work detecting photoreceptor function via pupil response. RGCs play a role in the detection of light, and this has exciting future implications in the field of artificial vision.

AUGUST 2015

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Presented by Micheal S. Kook, M.D., University of Ulsan, Asan Medical Centre,Seoul, Korea on 2 October 2013Written by Dr Lim Hou Boon

NEW PERSPECTIVES IN THE IOP MANAGEMENT IN GLAUCOMA – AN ASIAN POPULATION EXPERIENCE

08 CME NEWSLETTER ISSUE 25

Intraocular pressure (IOP) should not be taken as just being an absolute number, but a measurement that should be taken in the context of its interaction with other physiological parameters, which can ocular or systemic. For example, it has been reported that optic nerve head blood flow decreases more in patients with lower systemic mean arterial pressure as compared to individuals with normal arterial pressures.

In patients with NTG, the IOP increase at night when in a supine position is higher than that in normal people. At the same time, there is physiological drop in arterial blood pressure when patients are asleep. Through the combination of these physiological effects, an accentuated drop in optic nerve head blood perfusion has been documented, suggesting a possible pathophysiology of this disease.

Intraocular pressure has also been found to be related to the integrity of the lamina cribosa. Normal tension glaucoma patients with the same severity of visual field loss has been reported to have thinner lamina cribosas when compared with comparative primary open angle glaucoma patients. This suggests that NTG patients could have had thinner lamina cribosas to start with, thus predisposing them to developing the disease.

Cerebrospinal fluid (CSF) pressure has previously been reported to be associated with age. With increasing age, CSF pressure diminishes. At the same time, it has also been reported that patients with primary open angle glaucoma have lower CSF pressures when compared with normal individuals, and that lower CSF pressures is related larger cup-disc ratios. These findings suggest that IOP alone may not account for the development or progression of the disease.

As another example, NTG patients have been found to have a lower mean body mass index (BMI) when compared with POAG patients, while a higher BMI has been reported to be protective for glaucoma in women. Furthermore, it is known that CSF pressure increases with increasing BMI. The multitude of factors in play thus reflects the interactive nature of the disease with multiple physiological parameters, and not just IOP alone.

In conclusion, IOP should be managed in the context of the surrounding parameters that it is in constant interaction with. As IOP is dynamic and is affected by physiological changes, it should be assessed by both using short-term measurements, as well as monitoring individual 24 to 48-hour IOP patterns. Individualised treatment for IOP modulation, based on continuous IOP monitoring, can then potentially be realised through the selection of optimal dose and timing of medical agents in the future.

Key Points• It is increasingly becoming understood that intraocular pressure (IOP) is not the only determinant or factor in the pathophysiology and progression of normal tension glaucoma (NTG). - Other physiological parameters such as arterial pressure, optic nerve head blood flow, integrity of the lamina cribosa, cerebrospinal fluid pressure, body mass index can influence IOP.

• IOP is dynamic and should be managed in the context of its related physiological parameters.

• Short-term or continuous IOP monitoring can help in the individualization of treatment for NTG.

AUGUST 2015

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NEW PERSPECTIVES IN THE IOP MANAGEMENT IN GLAUCOMA – AN ASIAN POPULATION EXPERIENCE

09 CME NEWSLETTER ISSUE 25

Updates On Normal Tension Glaucoma Management

Key points1) Locally, half of newly diagnosed glaucoma patients have normal intraocular pressures.

2) Management of normal tension glaucoma (NTG) can be challenging.

3) There is considerable variability in disease progression among NTG patients, and risk factor profiles and formulas to predict progression have been developed.

4) Risk factors for NTG include female gender, a history of migraine, previous episodes of significant blood loss and the use of anti-hypertensive medication.

5) In patients in whom treatment is indicated, IOP reduction of 30% should be targeted.

In Singapore, 49% of newly diagnosed glaucoma patients have intraocular pressures of less than 21mmHg. In another study conducted in Guangzhou, China, it was reported that about 50% of primary open angle glaucoma patients have normal intraocular pressures. These findings suggest that NTG forms a large proportion of glaucoma patients.

In order to plan the management of NTG, it is important to understand the natural course of the disease. To demonstrate the variability in the rate of disease progression, Professor Kook presented 3 of his NTG patients as case studies. Amongst them, one patient had no disease progression over 15 years; another had significant disease progression over 20 years, while the last patient’s NTG progressed quickly, demonstrating significant visual field losses of -4.0dB a year.

It has been reported that 5% of NTG patients progressed rapidly, while 45% progressed slowly. In addition, 50% of patients with NTG did not seem to experience any disease progression at all. Overall, the mean rate of visual loss amongst all patients was -0.22dB a year. It is important to note, however, that the likelihood and rate of disease progression as reported in the study may have been affected by the duration and frequency of follow-up assessments.

Known risk factors to the development and progression of NTG include female gender, a history of migraine, previous episodes of significant blood loss and the use of anti-hypertensive medication. Risk factor profiles and formulas to predict disease progression in NTG have been developed based on these. However, many other risks factors remain possibly unidentified, and it remains to be seen if current risk calculators are actually accurate and useful.

Treatment of NTG can be challenging. In elderly patients who demonstrate no or a slow rate of progression, no treatment is indicated. In patients where treatment is assessed to be indicated, an IOP reduction of 30% should be targeted. However, experience has shown this to be difficult to achieve. And even in patients that achieve this, up to 50% of them may still experience disease progression.

Surgical management may be feasible in cases where the benefits are assessed to outweigh the risks. In a Japanese study, it was however reported that glaucoma surgery on average reduced the rate of disease progression but does not arrest it completely.

AUGUST 2015

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Presented by A/Prof Ang Beng Ti andDr Ng Yuk Hui on 5 February 2014 Written by Dr Yong Kailing

MULTI-DISCIPLINARY APPROACH TO ORBITAL DISEASE: NEURO-SURGEON AND ENT’S PERSPECTIVE

10 CME NEWSLETTER ISSUE 25

Neurosurgical approach to Orbital Disease

There are 2 main ways to access the orbit: an anterior orbital approach by ophthalmologists, or an extraorbital approach, either via the superior / superolateral orbit by neurosurgeons (transcranial), or via inferior / inferiomedial orbit through nasal cavity by ENT surgeons.

The skull anatomy pertinent to orbital lesions includes the following: 1) the brow prominence of the skull represents the landmark of anterior cranial fossa floor, 2) the zygomatic arch marks the floor of the middle cranial fossa, 3) the inferior orbital fissure, which leads the orbit to the infratemporal fossa (hence has no intracranial communication), and 4) the superior orbital fissure, which has intracranial communication.

The neurosurgeons are involved in orbital surgeries in mainly 2 settings: 1) if the lesion has overt intracranial extension, or 2) the presence of a superior orbital lesion which erodes the bone with involvement of the dura, necessitating excision of the dura with CSF fistula repair.

Craniotomy for orbital lesions can be uni-frontal, fronto-temporal or bi-frontal. During incision reflection of the scalp for exposure, we must remember the layers of scalp in the respective regions: the temporalis fascia has deep and superficial layers, and within this plane runs fat and the temporal branch of facial nerve. During dissection, the fat must be reflected superficially to prevent facial nerve injury.

For reconstruction, there are many materials available: Medpore implant is the preferred choice for the neurosurgeons. Titanium implant for calvarium is reported to have a high rate of bone erosion.

Advances in technology have also enabled the neurosurgeons to perform neuronavigation pre-operatively or intra-operatively, which is especially useful for bony lesions. Intra-operative Magnetic Resonance Imaging also can be performed now in Singapore General Hospital. Other new advances include stereotactic radiosurgery, which is the administration of a focused volume of radiation to lesion. In Singapore General Hospital, NOVALIS® radiosurgery is utilised, and this allows precise and accurate treatment to prevent injury to adjacent critical structures.

Key Points• Extraorbital approaches to the orbit include trancranial or transnasal approaches which are undertaken by the neurosurgeons and ENT surgeons respectively.

• Advances in technology have enabled neuronavigation pre-operatively and intra-operatively, intra-operative magnetic resonance imaging and stereotactic radiosurgery.

• An endoscopic approach to the orbit has advantages of being minimally invasive while affording better visualisation, but has its technical challenges.

AUGUST 2015

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MULTI-DISCIPLINARY APPROACH TO ORBITAL DISEASE: NEURO-SURGEON AND ENT’S PERSPECTIVE

ENT approach to Orbital Disease

Advantages of an endoscopic approach to the orbit include: 1) Better visualisation, 2) Minimally invasive approach, 3) Less or no visible scarring. New advances in powered ENT instruments give controlled resection of bony structures, which is especially useful for medially located lesions. However, the disadvantages of an endoscopic approach include: 1) Loss of binocular visualisation, 2) Loss of bimanual manipulation as it is essentially a single-handed technique, 3) Technically challenging especially when there is profuse bleeding.

The anatomy of the sinuses must be well understood as part of sinus surgery. The sphenoid sinus is the most posterior sinus with the optic nerve and carotids indenting it. It is a useful landmark in endoscopic surgery for identifying the optic nerve and gives access to the pituitary. It can be reached via transnasal or transethmoidal approaches.

The maxillary sinuses are paired sinuses. It lies directly below the orbit and can be accessed via the Caldwell-Luc procedure or middle meatal antrostomy. It gives access to orbital floor, and is limited anteriorly by the nasolacrimal duct.

The ethmoid sinuses are divided into anterior and posterior sinuses. It is the most commonly affected sinus in orbital complications of sinusitis. They need to be completely cleared before entering the orbit via lamina papyracea. Caution needs to be taken as the anterior and posterior ethmoidal arteries traverse the sinuses.

The frontal sinuses are the most anterior pair of sinuses. In orbital decompression, it is advisable to leave 1-1.5cm of lamina below the frontal ostia to prevent frontal sinusitis.

Endoscopic orbital decompression in the surgical management of thyroid eye disease addresses the medial wall and medial part of orbital floor. It is also good for accessing the posterior part of orbit and orbital apex. Medial wall decompression alone is reported to give only 1.7-2mm of decompression, medial with inferior wall decompression gives 3.4 – 5mm while three wall decompression gives a reduction of 6.4mm. Hence a combined approach is recommended. Complications of endoscopic orbital decompression include diplopia and sinusitis.

Endoscopic approach to orbital lesions first entails complete ethmoidectomy, then removal of lamina paprycea. The medial rectus should be identified and retracted to prevent injury.

Endoscopic optic nerve decompression has also been reported, mainly in traumatic cases. Results are not encouraging as decompression cannot reverse the initial insult to the optic nerve. A trial of steroid is recommended first, and surgical decompression only attempted if bony fragments impinge on the optic nerve.

Case Presentations 1

A 73 year-old lady with active severe thyroid eye disease with compressive optic neuropathy was deteriorating despite 3 courses of intravenous methylprednisolone. She underwent a combined medial wall, medial floor and lateral orbital decompression surgery by ophthalmologist and ENT surgeons. Post operatively, her optic neuropathy and extraocular movements improved.

Pre and Post-operative appearance of the patient

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MULTI-DISCIPLINARY APPROACH TO ORBITAL DISEASE: NEURO-SURGEON AND ENT’S PERSPECTIVE

Case Presentations 2

A 50 year old lady with a left superior orbital mass with bony erosion and possible dural invasion underwent a combined left lacrimal gland tumor resection, orbital rim excision and reconstruction by the oculoplastics surgeon and neurosurgeon. Post operatively her ptosis and hypoglobus improved. Histology showed the tumor to be an high grade carcinoma.

CT scan showing lacrimal mass eroding into the roof of orbit and possible dural invasion

Intraoperative photos of tumor excision, reconstruction and the tumor removed was 4.5cm in size.

Pre and post-operative photos of patient showing improvement of ptosis, hypoglobus and upper lid deformity.

AUGUST 2015

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Presented by Dr Richard Quek on 21 May 2014 Written by Dr Woo Jyh Haur

ONCOLOGIST PERSPECTIVE ON OCULAR AND ORBITAL DISEASES

13 CME NEWSLETTER ISSUE 25

Key Points• The most common primary intraocular cancers are melanomas and lymphomas.

• The diagnosis of primary vitreoretinal lymphoma requires a high index of suspicion, and is closely associated with central nervous system lymphoma.

• Primary uveal lymphoma is typically indolent marginal zone B-cell lymphoma with no central nervous system association.

• While surgery is the mainstay of treatment for eyelid cancers, newer agents like Vismodegib have been used.

The incidence of primary eye cancer is approximately 0.9 per million in the population with 2730 new cases each year. The general oncological approach to suspected eye cancer involves history and physical examination, search for a primary lesion, radiological investigations, appropriate biopsy and exclusion of any potentially treatable infections. Secondary metastasis to the eye is by far more common than primary tumours. Staging and treatment of such lesions follow that of the primary cancer. As the disease tends to be advanced, palliation is the key goal, typically involving radiation and systemic therapy.

The two commonest primary intraocular cancers are melanoma and lymphomas. Primary vitreoretinal lymphoma is by far the most common, followed by uveal lymphoma.

Primary Vitreoretinal Lymphoma

The incidence of primary vitreoretinal lymphoma (PVRL) is 0.1 per 100,000 population in the US with 380 cases diagnosed annually. Locally, approximately 5 new patients are diagnosed with PVRL each year. It is an aggressive disease which remains in the primary location without distant metastasis. Histologically, the disease is typically diffuse large B-cell lymphoma and rarely, T-cell rich B-cell lymphoma or T-cell lymphoma. PVRL is also closely associated with primary central nervous system (CNS) lymphoma, with the peak incidence at 75-84 years of age. Fifteen to 25% of patients with primary CNS lymphoma (PCNSL) have ocular involvement, while 65-90% of ocular lymphoma have CNS involvement.

The presentation of PVRL tends to be insidious and a high index of suspicion is needed. Diagnosis is usually made by biopsy, looking specifically at morphology, immunohistochemistry, presence of monoclonality and interleukin levels. It is also important to exclude systemic and CNS disease.

The principal considerations in the treatment of PVRL include: poor intraocular penetration of systemic chemotherapy which necessitates local (intravitreal or radiation) treatment, the form of systemic therapy particularly in association with primary CNS lymphoma, treatment tolerance in elderly patients and renal function, as most agents that penetrate the CNS are cleared by the kidneys. The best modality of local treatment remains undefined – options include radiotherapy and intravitreal chemotherapy. As such, informed treatment decision needs to be taken. Intravitreal methotrexate and rituximab (a chimeric anti-CD20 monoclonal antibody) have been investigated in small studies. The typical systemic protocol involves chemotherapy in the first 10 weeks of treatment, followed by 5 weeks of radiotherapy. A more recent protocol aims to reduce the risk of CNS toxicity with the addition of rituximab, a higher dose of methotrexate and lower radiation doses for patients with complete response.

Uveal Lymphoma

Uveal lymphoma may be primary or secondary from disseminated disease. Primary uveal lymphoma is typically indolent marginal zone B-cell lymphoma with no association with PCNSL. Secondary uveal lymphoma is usually confined to the choroid. While diffuse large B-cell lymphoma is the most common, other types may include plasmacytoma, lymphoplasmacytic lymphoma and small lymphomcytic lymphoma.

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Orbital marginal zone B cell lymphoma has been found to be associated with Chlamydia psittaci and antibiotics (such as doxycycline and clarithromycin) have shown variable efficacy against the disease. Available reports have shown striking variability in this association across geographic regions and response to treatment with antibiotics. Otherwise, the disease is usually localized and can be treated with radiation.

Eyelid Cancers

Surgery is still the mainstay of treatment for eyelid cancers such as squamous cell, basal cell carcinoma (BCC) and melanoma. However, the role of Hedgehog pathway inhibitors, such as Vismodegib, has recently been studied in the medical therapy of basal cell carcinoma. The response rate of this agent in metastatic and locally invasive BCC have been reported at 30% and 43% respectively.

BRAF Mutant Melanoma: Change in Treatment Paradigm and Current Recommendation

Melanoma may be divided into a few anatomical subtypes: superficial spreading, nodular, melanoma lentigo maligna, acral, uveal and mucosa melanomas.

The staging of cutaneous melanoma involves histology (paying attention to the margins, depth, Breslow’s depth and Clark level), radiological investigation (in the form of CT/ MRI or PET scan) and sentinel lymph node biopsy (not routinely done in ocular melanomas). The American Joint Committee on Cancer (AJCC) staging system is often used.

Local therapy for melanoma

The role of local therapy in cutaneous melanoma has been evaluated. Biopsy based management prolongs the disease-free survival for all patients, in addition to the distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate thickness melanomas. The current practice in the local setting involves wide excision, sentinel lymph node biopsy and immediate lymphadenectomy if biopsy is positive.

The use of adjuvant radiotherapy after lymphadenectomy is controversial. Studies have shown that the lymph node field recurrence is reduced with the use of adjuvant radiotherapy compared to observation; however, there is no difference in the long term survival rate. Interferon alpha-2b has also been used as adjuvant chemotherapy, often administered for 1 year and not without side-effects such as hepatotoxicity, myelosuppression, constitutional and neurological toxic events. It has been showed to prolong relapse-free survival by 7 months and overall survival by 1 year.

The optimal treatment for ocular melanoma remains unclear. For small lesions, debate continues between observation and treatment. Observation is an option for asymptomatic individuals with small tumours less than 10mm in diameter and 2mm in height. For symptomatic patients and those with larger tumours, active treatment is recommended with either radiation therapy or enucleation.

Treatment for metastatic melanoma

Chemotherapy with a single agent (Dacarbazine, DTIC) is standard of care for metastatic melanoma. Studies have compared combination therapy (Dartmouth regime: DTIC, cisplatin, carmustine, tamoxifen) with DTIC alone, with a response rate of 18% and 10% respectively. Other options include Temozolomide (which has similar response rates as DTIC and better brain penetration) and high dose interleukin IL-2.

Major achievements in the last decade

One of the key advancements in the field is molecular subclassification of melanomas. The somatic BRAF mutation is present in 66% of melanomas and 80% of these involve the V600E mutation. (Davies et al. Nature 2002) 80% of melanomas from non-chronic sun induced damage had BRAF and NRAS mutations. (Curtin el al. N Eng J Med 2005) The KIT mutation has also been reported in mucosal, acral melanomas and chronic sun damaged skin with rates of 39%, 36% and 28% respectively. Of note,

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in uveal melanomas, somatic GNAQ mutations and GNA11 mutations have been reported in 46% (Van Raamsdonk et al. Nature 2009) and 32% (Van Raamsdonk et al. N eng J Med 2010) of cases.

As such, therapy targeted at inhibition of BRAF V600E mutation in advanced melanoma, such as Vemurafenib, have been studied and showed improved response rate (48% compared to 5% seen in DTIC) and survival compared to conventional treatment. However, there are issues related to resistance in BRAF inhibition. Many mechanisms have been reported and are mainly MEK-dependent that does not require RAF signaling. Acquired resistance to Vemurafenib may also occur via mutually exclusive PDGFR-B upregulation and NRAS mutations. Tremetinib, an agent which inhibits MEK, has been shown to result in better progression-free and overall survival compared to conventional chemotherapy in V600E or V600K BRAF mutated melanoma. Combination therapy targeting both BRAF and MEK inhibition (Dabrafenib and Tremetinib) also showed to have better response rate and progression free survival than a single agent (Dabrafenib) alone. Of note, MEK inhibition may trigger off central serous retinopathy-like events in patients as it may alter the permeability of the outer blood retinal barrier by altering the tight junctions of the retinal pigmented epithelium. As such, patients on these agents need regular ophthalmological surveillance.

MEK inhibition in uveal melanoma has also been studied. Selumetinib, a MEK inhibitor, has been compared with temozolomide in a phase II study involving patients with advanced uveal melanoma. It has been shown that progression-free survival is improved with Selumetinib in both the overall and mutant only population.

Lastly, immune checkpoint inhibition is yet another exciting development in the field of melanoma management. This involves targeting the immune system and the main focus of research revolves around spontaneous regression of disease, tumour infiltrating lymphocytes and antigen specific cytotoxic T cells. Both the priming and effector phase of the immune response have been targeted with single agents such as ipilimumab, anti-PD-1 monoclonal antibody (lambrolizuamb) or in combination (ipilimumab and nivolumab) and the results have been promising with up to 53% response rate and shorter time to initial response with combination therapy. Unfortunately, most immune checkpoint inhibitor studies have always excluded mucosal and uveal melanomas, with only a retrospective study reporting a third of patients with metastatic uveal melanoma having either stable or responding disease at 6 months with ipilimumab treatment.

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Questions

Q1: What will this patient complain of? Name 4.

Q2: What eye signs would you expect to find in this patient? Name 3.

Q3: What is a possible treatment?

Answer :

This is a MRI brain sagittal cut showing a chiari malformation. This malformation is characterised by herniation of medulla, fourth ventricle and cerebellum through the foramen magnum as a result of a small posterior fossa.

In type I malformation as shown above, the cerebellar tonsil are displaced caudally into the foramen magnum. In type 2 malformation, both the 4th ventricle and inferior vermis extend below the foramen magnum and a lumbar meningomyelocoele is usually present .

1. Patient may complain of oscillopsia, diplopia, headache, neck pain or vertigo, worse on valsalva maneuver

2. Downbeat nystagmus, gaze evoked nystagmus, skew deviation, saccadic dysmetria

3. Suboccipital decompression

ANSWERS TO PHOTOQUIZ 24

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Please send your entries to: [email protected] or fax to: (65) 6226 3395 Attention: CME Newsletter Secretariat. Winners will each receive a 4GB thumbdrive and will be notified by post. The answers will be published in the next issue.

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Questions

Q1 a) What is the name of the test done in Picture A?

b) What are the possible differential diagnoses?

Q2 What is the sign shown in Picture B?

Q3 a) What is the name of the investigation shown in Picture C?

b) What does it show?

c) What is the diagnosis and what are the clinical signs associated with it?

d) What genetic association has been found?

Q4 a) What do you need to monitor for?

b) What are the treatment options?

A

PHOTOQUIZ 25

B

C

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