[CASE DISCUSSION GLAUCOMA] 1

I. Name Age & Sex Chief Complaint History Patients Information None 65 year old, African American Female Concerned about losing eyesight because sister has started losing her vision from glaucoma Denies any change in vision Type 2 Diabetes Mild intermittent Asthma Hypertension Metformin 1000 mg orally twice a day Albuterol two puffs every 6 hours (as needed for wheezing) Lisonopril 10 mg orally daily Ophthalmology report Patient has an IOP of 26 mmHg (As assessed by applanation tonometry) Gonioscopic examination reveals open anterior angles in both eyes Pachymetry reveals corneal thickness of 510 microns Ophthalmoscopy reveals cupping of optic discs in both eyes Visual field examination reveals a nerve fiber bundle defect consistent with glaucoma disc, choroid, and blood vessels. It is used to detect and evaluate symptoms of retinal detachment or eye diseases such as glaucoma. III. Definition of Disease Glaucoma Slowly progressive, insidious optic neuropathy, usually associated with chronic elevation of intraocular pressure. group of eye disorders characterized by progressive optic nerve damage in which an important part is a relative increase in intraocular pressure (IOP) Two main types of glaucoma o Open-angle glaucoma is a syndrome of optic nerve damage associated with an open anterior chamber angle and an elevated or sometimes average intraocular pressure (IOP) o Angle-closure glaucoma is glaucoma associated with a physically obstructed anterior chamber angle, which may be chronic or, rarely, acute Glaucomas are further subdivided into primary (cause of outflow resistance or angle closure is unknown) and secondary (outflow resistance results from a known disorder), accounting for > 20 adult types. IV. Epidemiology Glaucoma is the 2nd leading cause of irreversible blindness in the world. Globally, there are an estimated 60 million people with glaucomatous optic neuropathy and an estimated 8.4 million people who are blind as the result of glaucoma. The highest prevalence of open-angle glaucoma occurs in Africans, and the highest prevalence of angleclosure glaucoma occurs in the Inuit. In the Philippines, glaucoma is the 3rd leading cause of blindness in both eyes and is the leading cause of irreversible blindness of both eyes. Risk Factors Primary Open Angle o Older age, positive family history, black race, thinner central corneal thickness, systemic hypertension, diabetes, and myopia. o Strong Association 1. Raised intraocular pressure 2. Increasing age, particularly after 50 years 3. African descent 4. Positive family history of glaucoma (first-degree relative, particularly if sibling) o Moderate association 1. Myopia 2. Diabetes mellitus o Weak association 1. Migraine 2. Systemic hypertension 3. Vasospasm Primary Angle Closure o Family history, advanced age, and ethnicity; risk is higher among people of Asian and Inuit ethnicity and lower among people of European and African ethnicity. o Shallow anterior chamber depth, associated with: 1. Female gender 2. Increasing age 3. Asian (particularly chinese) origin o Shor globe axial length

Medication

Comprehensive Eye Evaluation

II.

Definition of Terms In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin Chronic (long-term) lung disease that inflames and narrows the airways. It causes recurring periods of wheezing (a whistling sound when you breathe), chest tightness, shortness of breath, and coughing. A condition in which the arteries have persistently elevated blood pressure. Metformin is used to treat type 2 diabetes. It is in a class of drugs called biguanides. Metformin helps to control the amount of glucose (sugar) in your blood decreases the amount of glucose you absorb from your food and the amount of glucose made by your liver. It also increases your body's response to insulin. Albuterol is in a class of medications called bronchodilators. It works by relaxing and opening air passages to the lungs to make breathing easier. It is used to prevent and treat wheezing, shortness of breath, coughing, and chest tightness caused by lung diseases such as asthma and chronic obstructive pulmonary disease ACE inhibitor used to treat high blood pressure (hypertension), congestive heart failure, and to improve survival after a heart attack. Intraocular pressure Pressure caused by the fluid inside the eye that helps maintain the shape of the eye. Method indirectly measures the IOP by gauging how much force it takes to flatten the cornea over a fixed surface area. Eye examination to look at the front part of your eye (anterior chamber) between the cornea and the iris. Process of measuring the thickness of the cornea. Examination of the back part of the eye (fundus), which includes the retina, optic

Type II Diabetes Asthma

V.

Hypertension Metformin

Albuterol

Lisinopril IOP

Applanation Tonometry Gonioscopic Examination Pachymetry Opthalmoscopy

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o Environmental factors 1. Seasonal variation 2. Extreme temperatures 3. Prolonged periods indoors in a dark environment In contrast, deficits of the more proximal visual pathways (ie, from the lateral geniculate nucleus to the occipital lobe) involve quadrants or hemispheres of the visual field; thus, deficits do not cross the vertical meridian

VII. Signs and Symptoms Primary Open Angle o Early symptoms are uncommon. Usually, the patient becomes aware of visual field loss only when optic nerve atrophy is marked; the typically asymmetric deficits contribute to delay in recognition. However, some patients have complaints, such as missing stairs if their inferior visual field has been lost, noticing portions of words missing when reading, or having difficulty with driving earlier in the course of the disease. o Examination findings include an unobstructed open angle on gonioscopy and characteristic optic nerve appearance and visual field defects. IOP may be normal or high but is almost always higher in the eye with more optic nerve damage. Primary Angle Closure o Patients have severe ocular pain and redness, decreased vision, colored halos around lights, headache, nausea, and vomiting. The systemic complaints may be so severe that patients are misdiagnosed as having a neurologic or GI problem. Examination typically reveals conjunctival hyperemia, a hazy cornea, a fixed mid-dilated pupil, and anterior chamber inflammation. Vision is decreased. IOP is usually 40 to 80 mm Hg. The optic nerve is difficult to visualize because of corneal edema, and visual field testing is not done because of discomfort. Optic nerve appearance: The optic nerve head (ie, disk) is normally a slightly vertically elongated circle with a centrally located depression called the cup. The neurosensory rim is the tissue between the margin of the cup and the edge of the disk and is composed of the ganglion cell axons from the retina. Characteristic optic nerve changes include VI.

Anatomy and Physiology

The eye is broadly divided into the anterior and posterior segments. The anterior segment begins at the limbus and consists of the cornea, anterior and posterior chambers (not to be confused with anterior and posterior segments), pupil, iris, lens, zonules, and ciliary body. The posterior segment lies posterior to the anterior segment and consists of the vitreous chamber, retina, choroid, sclera, optic disc, and ON. The trabecular meshwork and Schlemms canal are part of the limbus, a transition al structure between the sclera and cornea. The uvea is the vascular middle layer of the eye, consisting of the iris and ciliary body in the anterior segment and the choroid in the posterior segment. The anterior segment is further divided into anterior and posterior chambers by the lens-iris diaphragm. The anterior chamber is defined by the iris (forms the floor) and cornea (forms the roof).The trabecular meshwork is positioned at the point where the cornea and iris meet, and forms the apex of the anterior chamber angle of the eye. The trabecular meshwork is a sievelike structure that filters and controls the flow of aqueous humor (AH) from the anterior chamber into Schlemms canal, ultimately leading to the bloodstream. The posterior chamber is bordered laterally by the ciliary processes. The lens surface forms the floor and the posterior surface of the iris forms the roof of the chamber. Aqueous Humor Hydrodynamics AH functions to maintain the global shape of the eye; supply nourishment to the avascular lens, cornea, and trabecular meshwork; and remove metabolic waste. AH also participates in immunologic responses, contributes to the optical system by providing a transparent refractive medium between lens and cornea, and facilitates some ocular distribution of drugs. 5 AH is derived from plasma within the capillary network of the ciliary processes and is continually secreted into the posterior chamber at a rate of approximately 2.7 L per minute in healthy individuals. 6 The entire chamber content is replaced every 100 minutes to 2 hours. From the posterior chamber, AH flows through the pupil into the anterior chamber to exit the eye via conventional and unconventional pathways. The conventional pathway accounts for the majority of outflow and refers to AH coursing through the trabecular meshwork and the canal of Schlemm, ultimately draining into the systemic circulation. In unconventional pathways, AH seeps through tissues rather than flowing through the usual channels and vessels. The most common unconventional pathway is the uveoscleral pathway in which AH drains from the base of the ciliary muscle, through tissues in and around the uvea, and eventually into the sclera.5 Intraocular Pressure IOP refers to the pressure generated by flow of AH against resistance within ocular structures. IOP, maintained at about 15 mmHg in healthy individuals, is determined by a delicate balance between the rates of AH entering (inflow) and leaving (outflow) the eye. Whereas inflow is dependent upon rate of production of AH, outflow is regulated by resistance to aqueous drainage.7 Any condition that alters the equilibrium between inflow and outflow of AH may result in abnormal IOP levels. Resistance to outflow is usually responsible for elevated IOP, but other factors may contribute. 5 Aqueous humour secretion and drainage Intraocular pressure is regulated by a balance between the secretion and drainage of aqueous humour. This fluid is secreted posterior to the iris by the ciliary body and then flows anteriorly to the anterior chamber. Aqueous humour provides nutrients

Increased cup:disk ratio (including an increasing ratio over time) Thinning of the neurosensory rim Pitting or notching of the rim Nerve fiber layer hemorrhage that crosses the disk margin (ie, Drance hemorrhage or splinter hemorrhages) Vertical elongation of the cup Quick angulations in the course of the exiting blood vessels

Thinning of the neurosensory rim over time alone can be diagnostic of glaucoma regardless of the IOP or visual field. However, most initial diagnoses of glaucoma involve some visual field change. Visual field defects: Visual field changes caused by lesions of the optic nerve include

Nasal step defects (which do not cross the horizontal meridianan imaginary horizontal line between the upper and lower parts of the visual field) Arcuate (arc-shaped) scotomata extending nasally from the blind spot Temporal wedge defects Paracentral scotomata

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to the iris, lens, and cornea. It exits the eye into the venous circulation via the trabecular meshwork and independently through the uveoscleral outflow pathway. The optic nerve and inner retina Axons of retinal ganglion cells comprise the retinal nerve fibre layer, the innermost layer of the retina. The human optic nerve contains about one million nerve fibres (figure 2). These axons converge on the optic disc (also known as the optic nerve head) and form the optic nerve. The fibres exit the eye after traversing the lamina cribrosa, a series of perforated connective tissue sheets, and synapse in the lateral geniculate nucleus of the brain. The optic disc is about 15 mm in diameter and vertically oval. Its area varies up to sevenfold, and is largest in highly myopic individuals. The convergence of the axons forms a central depression in the disc, known as the cup. Most, but not all, optic nerves have a visible physiologic cup. The neuroretinal rim of the optic nerve head is pink and surrounds the cup. Trophic factors, including brain-derived neurotrophic factor, are retrogradely transported from the axonal terminals of retinal ganglion cells to their cell bodies in the inner retina, and are essential for the survival of the cells. Glutamate, a neurotransmitter, is normally present in low concentrations in the retina. Trophic factors also are transported via retinal ganglion cell axons in an anterograde fashion to the lateral geniculate nucleus. (From oxford) Anterior chamber angle extends from Schwalbes line (the termination of Descemets membrane on the peripheral cornea) posteriorly to the trabecular meshwork (TM), scleral spur, or ciliary body (depending on the angle configuration) where an acute angle is formed with the peripheral iris. Trabecular meshwork is a reticulated band of fibrocellular sheets, with a triangular cross-section and base toward the scleral spur. Schlemms canal is a circumferential septate drain with an inner wall of endothelium containing giant vacuoles and an outer wall obliquely punctuated by collector channels that drain into the episcleral veins. Scleral spur is a firm fibrous projection from the sclera, with Schlemms canal at its base and the longitudinal portion of the ciliary muscle inserting into its posterior surface. Ciliary body comprises the ciliary muscle and ciliary epithelium, arranged anatomically as the pars plana and pars plicata (containing the ciliary processes). Contraction of the ciliary muscle permits accommodation and increases trabecular outflow. The ciliary epithelium is a cuboidal bilayer arranged apex to apex with numerous gap junctions. The inner layer is nonpigmented, with high metabolic activity, and posteriorly is continuous with the neural retina. The outer layer is pigmented and posteriorly is continuous with the RPE. Trabecular (conventional) routeMost aqueous humor leaves the eye by this passive, pressure-sensitive route. Around 75% of outflow resistance is due to the trabecular mesh- work itself, the major component being the outermost (juxtacanalicular) portion of the trabecular meshwork. This comprises several layers of endothelial cells embedded in ground substance that appears to act as a filter, which is continually cleaned by endothelial cell phagocytosis. Further transport into Schlemms canal is achieved via pressure-dependent transcellular channels (seen as giant vacuoles of fluid crossing the endothe- lium) and paracellular pores. Aqueous is then transported via collector channels to the episcleral veins and on to the general venous circulation. Uveoscleral (unconventional) route The aqueous passes across the iris root and ciliary body into the supra- ciliary and suprachoroidal spaces from where it escapes via the choroidal circulation. Intraocular pressure (IOP) Flow in = Flow out = C (IOP Pv) + U where C is the pressure-sensitive outflow facility (via trabecular mesh- work), U is the pressure-independent outflow (via uveoscleral route), and Pv is the episcleral venous pressure. Typical values are as follows: Flow in =C (IOP Pv) +U 2.5 L/min = 0.3 L/min/mmHg (16 9 mmHg) + 0.4 L/min Variation in IOP Within the population Based on population studies, normal IOP is generally taken to be mean IOP (16 mmHg) 2 SD (2 x 2.5 mmHg), i.e., a range of 1121 mmHg. However, there is a positive skew to this distribution. Within the individual Mean diurnal variation is approximately 5 mmHg in normal patients but may fluctuate from 10 to 15 mmHg in primary openangle glaucoma (POAG). In most individuals, IOP tends to peak early morning upon awak- ening. Pulse pressure, respiration, extremes of blood pressure, and season also have an effect on IOP variation. VIII. Pathophysiology While the trabecular route is the major outflow, the uveoscleral contribu- tion may be as much as 30%. The outflow capacity through the trabec- ular route and uveoscleral route varies and has been demonstrated to decrease with age.

Physiology Aqueous production Aqueous humor is a clear, colorless, plasma-like balanced salt solution pro- duced by the ciliary body. It is a structurally supportive medium providing nutrients to the lens and cornea. It differs from plasma in having lower glucose (80% of plasma levels), low protein (assuming an intact blood aqueous barrier), and high ascorbate. It is formed at around 2.5 L/min by a combination of active secre- tion (70%), ultrafiltration (20%), and osmosis (10%). Active secretion is complex, involving the maintenance of a transepithelial potential by the Na +K+ pump, ion transport by symports and antiports (including the important Na +/K+/2Cl symport), calcium- and voltage-gated ion channels, and carbonic anhydrase. Aqueous outflow

Elevated intraocular pressure - the prime factor?

[CASE DISCUSSION GLAUCOMA] 4

Until recently it was believed that elevated IOP plays a major role in RGC apoptosis and it is also true that reduction of elevated IOP often helps in slowing down the progression of degenerative changes in glaucoma. However, among glaucoma patients only one-third to half of all glaucoma patients have elevated IOP at the initial stages. On an average, 30-40% of patients with glaucomatous visual field defects are being diagnosed as having normal tension glaucoma (NTG) in peripheral clinics. Therefore, elevated IOP is now believed to be an important but not the only factor responsible for optic nerve damage. Elevated IOP often results from alterations in aqueous humor dynamics due to changes in trabecular meshwork leading to impaired drainage of aqueous. The trabecular meshwork has been shown to exhibit cytoskeletal changes in cells, altered cellularity[23,24] and changes in extracellular matrix (ECM). Several investigators have studied the association of RGC loss and elevated IOP. A significant positive correlation has been observed between change in IOP and RGC death in glaucomatous rats. A positive correlation has also been observed between the level and duration of elevated IOP and RGC axon loss. Loss of half of the ganglion cells takes place during the initial two to three months of IOP elevation. RGC death in experimental glaucoma has been shown to occur by the process of apoptosis and IOP elevation can directly induce RGC death by apoptosis. Results of a number of experiments suggest that RGC death after exposure to elevated IOP takes place in two phases. The first phase lasts for about three weeks, with loss of approximately 12% RGCs per week. This is believed to be followed by a second slower phase of neuronal loss. The primary mechanism of neuronal loss in the initial phase is apoptosis while in the second phase neuronal loss is due to toxic effects of the primary degenerating neurons in addition to continuing exposure to elevated IOP. Neuronal loss in glaucoma by apoptosis The characteristic change in the optic nerve head in glaucoma is a cupping of the optic disc where ganglion cell axons have been lost. The death of the axons is associated with a loss of ganglion cell bodies in the retina and ganglion cell axon terminals in the dorsal lateral geniculate body. Death of RGCs in glaucomatous human eyes and experimental animal models of glaucoma takes place by apoptosis,[6,7] which is also the means of eliminating 50% of the RGCs during normal developmental organization of the visual pathway.[8] Apoptosis is a process of programmed cell death in the absence of inflammation, characterized by DNA fragmentation, chromosome clumping, cell shrinkage and membrane blebbing.[9] Nuclear damage is followed by breaking down of the cell into multiple membrane-bound vesicles which are engulfed by neighboring cells. Some researchers have suggested preferential loss of larger ganglion cells in the retina belonging to parasol and midget cell classes[4,1012] but this issue still remains debatable.[13] Although there are compelling evidences showing apoptosis as the primary and early mechanism of ganglion cell death in glaucoma, necrosis is also a contributory mechanism in the late phase, evidence to which was observed in rats subjected to optic nerve transection.[14] Peripheral anterior synechiae (scarring) and adhesions may be visible between the cornea and the iris. Peripheral anterior synechiae may destroy the trabecular meshwork, and adhesions may cause permanent dilation of the iris. Glaucoma flecks (also known as glaukomflecken) are spots on the lens of the eye. Glaucoma flecks may be seen if an acute attack of angle closure has occurred in the past.

X.

Management

Surgery: Surgery for primary open-angle and normal-pressure glaucoma includes laser trabeculoplasty, a guarded filtration procedure, and possibly procedures that create only a partial-thickness drainage pathway. Argon laser trabeculoplasty (ALT) may be the initial treatment for patients who do not respond to or who cannot tolerate drug therapy. Laser energy is applied to either 180 or 360 of the trabecular meshwork to improve the drainage of aqueous humor. Within 2 to 5 yr, about 50% of patients require additional drug therapy or surgery because of insufficient IOP control. Selective laser trabeculoplasty (SLT) uses a pulsed double-frequency neodymium:yttrium-aluminum-garnet laser. SLT and ALT are equally effective initially, but SLT may have greater effectiveness in subsequent treatments. SLT may also be considered for initial treatment. A guarded filtration procedure is the most commonly used filtration procedure. A hole is made in the limbal sclera (trabeculectomy), which is covered by a partial-thickness scleral flap that controls egress of aqueous from the eye to the subconjunctival space, forming a filtration bleb. Adverse effects of glaucoma filtration surgery include acceleration of cataract growth, pressures that are too low, and transient accumulation of fluid in the choroidal space (ie, choroidal effusion) during the perioperative period. Patients with trabeculectomies are at increased risk of bacterial endophthalmitis and should be instructed to report any symptoms or signs of bleb infection (blebitis) or endophthalmitis (eg, worsening vision, conjunctival hyperemia, pain) immediately. In partial thickness procedures, the fistula or drainage pathway created between the anterior chamber and subconjunctival space is only partial thickness. In the ab interno approach (an approach from inside the eye), a device is used to bypass the trabecular meshwork, creating direct communication between the anterior chamber and collecting channels. No bleb is formed.

IX.

Diagnosis Gonioscopy is performed to check the drainage angle of your eye; to do so, a special contact lens is placed on the eye. This test is important to determine if the angles are open, narrowed or closed, and to rule out any other conditions that could cause elevated IOP. Tonometry is a method used to measure the pressure inside the eye. Eye pressure is measured in millimetres of mercury (mm Hg). Normal eye pressure ranges from 10-21 mm Hg. In a case of acute angle-closure glaucoma, IOP may be as high as 40-80 mm Hg. Biomicroscopy is a technique to examine the front of your eyes and uses a special microscope called a slit lamp. This examination may reveal a poorly reactive pupil, a shallow anterior chamber, corneal swelling, redness around the iris, and inflammation. Ophthalmoscopy is used to examine the optic nerves for any damage or abnormalities; this may require dilation of the pupils to ensure an adequate examination of the optic nerves. In an acute attack of angleclosure glaucoma, this test may reveal a swollen optic nerve. If episodes of angle-closure glaucoma have been chronic (long term), this test may reveal excavation of the optic disk, which is a depression in the front surface of the optic nerve.

The ab externo approach (an approach from outside the eye), including viscocanalostomy, deep sclerectomy, and canaloplasty, involves a deep dissection of greater than > 98% thickness of the scleral passage, leaving a window of Descemet membrane and/or the inner wall of the Schlemm canal and trabecular meshwork. The canal is dilated by using a viscoelastic solution (in viscocanalostomy) or a microcatheter (in canaloplasty). Deep sclerectomy generally relies on the formation of a conjunctival bleb. Although these procedures are still under study, they do appear to be safer but less effective than trabeculectomy. Most commonly prescribed eyedrops include:

Prostaglandins. Doctors often prescribe prostaglandins to treat open-angle glaucoma. These eyedrops increase the outflow of the fluid in your eye (aqueous humor) and reduce pressure in your eye. Examples include latanoprost (Xalatan) and

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bimatoprost (Lumigan). Possible side effects include mild reddening and stinging of the eyes and darkening of the iris, changes in the pigment of the eyelid skin and blurred vision.

Beta blockers. These reduce the production of fluid in your eye and pressure in your eye (intraocular pressure). Examples include timolol (Betimol, Timoptic) and betaxolol (Betoptic). Possible side effects include difficulty breathing, slowed heart rate, lower blood pressure, impotence and fatigue. If you have lung or heart conditions, medications other than beta blockers may be recommended because beta blockers may worsen breathing problems. Alpha-adrenergic agonists. These medications reduce the production of aqueous humor and increase outflow of the fluid in your eye. Examples include apraclonidine (Iopidine) and brimonidine (Alphagan). Possible side effects include irregular heart rate, high blood pressure, fatigue, red, itchy or swollen eyes, and dry mouth. Carbonic anhydrase inhibitors. These are rarely used, but these medications may reduce the production of fluid in your eye. Examples include dorzolamide (Trusopt) and brinzolamide (Azopt). Possible side effects include frequent urination and a tingling sensation in the fingers and toes. Miotic or cholinergic agents. These also increase the outflow of fluid in your eye. Examples include pilocarpine (Isopto Carpine) and carbachol (Isopto Carbachol). Possible side effects include smaller pupils, blurred or dim vision, or nearsightedness. Combined medications. Sometimes doctors may prescribe a combined medication, such as a beta blocker and alpha adrenergic agonist, or a beta blocker and carbonic anhydrase inhibitor.