Monday, February 8, 2010

Neuroprotection in Glaucoma

 Main Entry: glau•co•ma (From Merriam-Webster)
Function: noun
Etymology: Latin, cataract, from Greek glaukōma, from glaukoun to have a cataract,from glaukos
Date: 1885
: a disease of the eye marked by increased pressure within the eyeball that can result in damage to the optic disk and gradual loss of vision

Now glaucoma is considered a primary optic neuropathy where ocular hypertension alone is not sufficient or necessary for development or progression

New concepts in treatmentPreserve neuronal tissue by interfering with injury and death pathways
 Provide a therapeutic regimen, independent of IOP, for slowing or preventing death of neurons and maintaining their function
 Amyotrophic lateral sclerosis:
 Riluzole
 Alzheimer disease:
 Memantine

What works










Therapeutic Options
 Supplement neurotrophic factors
– Exogenous BDNF effect temporary
– Need to upregulate receptors (AAV)
– Encapsulated cell intraocular implants (phase I clinical trials)
 Peptomimetic ligands
– More specific, longer lasting than neurotrophic factors




 Glutamate
– Main excitatory neurotransmitter in CNS and retina
– Released in pre-synaptic terminals throughout retina and binds to a variety of receptors (including NMDA type)
– Excessive expression is neurotoxic
– Chronic NMDA intravitreal injection causes glaucoma-like histology changes in animal retina
Increased glutamate in vitreous of gluacoma patients? (author of this study discredited)





Therapeutic Options
 Memantine
– Only currently available clnical glutamate modifier
– 1960s by Eli Lilly
– NMDA-receptor antagonist
– Uncompetitive open-channel blocker
 inhibits receptor activity when glutamate is at super-physiologic levels
 Immune deficient mice
– reduced neuronal survival after neuronal insult
 MS

- Copaxone



“protective” autoimmune T cells create a neuroprotective environment



 Mitochondrial dysfunction shown to occur in experimental glaucoma



 External stress can trigger mitochondrial dysfunction which can lead to production of ROS which cause cell death at neurotoxic levels
Significant increase in levels of ROS and lipd peroxides in experimental glaucoma eyes along with changes in activities of antioxidant enzymes




Other Therapeutic Options
 Vitamin E
– Improved visual fields?
– Long term studies less convincing
 Extract Gingko biloba
– Increase survival of RGCs in experimental glaucoma
– Interfere w/ glutamatergic NMDA receptor
– Mode of action not fully understood


Glaucoma and neuroprotection

Background
For the past 30 years, neuroscientists have sought to use neuroprotection -- the therapeutic paradigm directed at slowing or preventing death of diseased neuronal tissue to preserve and maintain physiologic function -- to treat central nervous system diseases. But success has been fleeting: Numerous pharmacologic neuroprotective agents that were initially investigated in the laboratory have almost invariably failed to translate to the clinic. Indeed, only memantine for Alzheimer disease[1] and riluzole for amyotrophic lateral sclerosis[2] have demonstrated improved outcomes. In the case of glaucoma, research into neuroprotection for glaucoma has suffered a number of setbacks. Still, preliminary findings continue to suggest that there may be a role for neuroprotection in the treatment of glaucoma, and research is ongoing.

Rationale for Neuroprotection to Treat Glaucoma
Glaucoma is currently recognized to be a multifactorial, progressive, neurodegenerative disorder.[3] It is characterized by the acquired death of retina ganglion cells (RGC) and loss of their axons as well as optic nerve atrophy and loss of neurons in the lateral geniculate nucleus and the visual cortex. In primary open-angle glaucoma, intraocular pressure (IOP) is the most important risk factor for glaucoma onset and progression. It is currently the only risk factor amenable to modification by the clinician. However, there are limitations to treating IOP exclusively, including:

•Most patients with elevated IOP never develop glaucoma;
•Many glaucoma patients do not have a statically elevated pressure (ie, low-tension glaucoma); and
•There are many patients who continue to progress with controlled low IOP.
These observations suggest that IOP-independent mechanisms contribute to disease onset and progression, and indeed, in vitro studies of RGC and animal models of optic nerve injury and elevated IOP have examined such mechanisms, particularly RGC death by apoptosis (a form of cell suicide in which the cell actively participates in its own demise).[4,5] RGCs undergo apoptosis when they are disconnected from their axon or when their axon is disconnected from its intracranial target. The steps involved in apoptosis of RGCs occur over hours or days, which offers a window of opportunity in which neuroprotective agents might work.

Ongoing Research Into Neuroprotection for Glaucoma
The randomized clinical trial is the gold standard by which neuroprotection will ultimately be assessed in glaucoma. To date, no randomized clinical trial has demonstrated a clear benefit for neuroprotection, although in vitro cell models and in vivo models of optic nerve injury have suggested a benefit.[6,7] There are a number of potential reasons for these discrepancies, including:

•An animal model cannot properly simulate human disease;
•The pathophysiology of human disease is intrinsically different from that in animals; and
•There is more variability in patients than in laboratory animals.
Furthermore, a RGC culture cannot reflect the complicated pathophysiology of the human disease. Laboratory glaucoma models induce elevated IOP in young healthy homogeneous animals with early open-label administration of the test agent; assessment of neuroprotection is most commonly performed by postmortem counting of RGC. In contrast, patients with glaucoma are heterogeneous, can be on many ocular and systemic medications, have comorbidities, and may not have control of physiologic parameters. In addition, the stage of the human disease process and the intraocular concentration of the intervention are unknown. However, despite these difficulties, research into neuroprotection is progressing. A few of the main avenues of exploration are discussed below.

Alpha-2-adrenergic Agonists
Laboratory studies have demonstrated that alpha-2-adrenergic agonists are neuroprotective in experimental cases of optic nerve injury, models of glaucoma, ischemia-induced injury, and photoreceptor degeneration.[8] In 1993, animal models of the alpha-2-adrenergic agonist dexmedetomidine showed it to be neuroprotective against focal cerebral ischemia.[9] With that background, brimonidine tartrate, a highly selective alpha-2-adrenergic agonist IOP-lowering agent,[10,11] was investigated for possible neuroprotective properties. Potential mechanisms for its neuroprotective effects included up-regulation of brain-derived neurotrophic factor in RGCs and the retina, activation of cell-survival signaling pathways and anti-apoptotic genes, and modulation of N-methyl-D-aspartate (NMDA) receptor function.[12-15] Animal and human studies have demonstrated the presence of alpha-2 receptors in the retina.[14,16,17] And systemic administration of brimonidine in rat models with ocular hypertension protected RGCs following partial crush injury to the rat optic nerve.[12,18-20] Still, clinical trials in nonglaucomatous diseases, such as nonarteritic anterior ischemic optic neuropathy, Leber hereditary optic neuropathy, and retinal dystrophies, have failed to show treatment benefit with alpha-2 agonist use.[8] Randomized, clinical trials are still needed to better understand what if any neuroprotective effect alpha-2-adrenergic agonists may have in eyes with glaucoma.

One study that may help elucidate the effects of brimonidine is the completed Low-pressure Glaucoma Treatment Study (LoGTS), a double-masked, randomized, multicenter clinical trial comparing the efficacy of medications with equal IOP-lowering efficacy (bilateral twice daily topical monotherapy with brimonidine tartrate 0.2% vs timolol maleate 0.5%[11,21]) in preventing or delaying visual field progression in patients with low-pressure (normal-tension) glaucoma. Although any separation between normal and abnormally elevated IOP is intrinsically arbitrary, population-based studies have demonstrated that low-pressure glaucoma represents 20% to 39% of patients with open-angle glaucoma in the United States and Europe.[22-24]

The LoGTS[25] includes 190 patients with untreated IOP of 21 mm Hg or lower, open iridocorneal angles, at least 2 reproducible visual fields with glaucomatous defects in at least 1 eye on automated perimetry with the location of the field defect consistent with the photographic appearance of the optic nerve head, and age 30 years or older. The main outcome measure is field progression, defined as the same 3 or more points with a negative slope equal or greater than -1 db/year at the P < 5% level, on 3 consecutive tests assessed by pointwise linear regression (PLR). Secondary outcome measures are field progression based on glaucoma change probability maps of pattern deviation and the 3-omitting method for PLR. This clinical trial on a selected glaucoma subset is completed and the outcome is under review.

Memantine Glaucoma Clinical Trial
Excitotoxicity through excessive glutamate and stimulation of its receptors, including the NMDA receptor, is reported to be important in a number of neurodegenerative diseases.[26] Elevated levels of glutamate were reported in the vitreous in humans and monkeys with glaucoma.[27] Memantine, an NMDA open-channel receptor antagonist, was shown to have neuroprotective properties in a monkey glaucoma model,[28,29] and a randomized trial was undertaken. The trial -- which included all types of open-angle and chronic angle-closure post-iris surgery patients, including those with prior filtration surgery -- investigated 2 oral doses of memantine vs an arm of oral placebo in glaucoma patients with controlled IOP. The treating physician had total control of patient management, including IOP-lowering medications, to perform angle laser or filtration surgery, or to perform cataract removal. Each of the 2 parallel arms had 1100 patients from sites worldwide that were followed for at least 4 years. The main outcome measure was visual field progression from full threshold examinations performed every 6 months.

Unfortunately, the trial results have not been published. Neither of the parallel arms met the primary outcome measure according to a press release[30]; memantine did not show benefit in preserving visual function. Despite this setback, it is too early to abandon memantine or the neuroprotective approach. The press release indicated that memantine demonstrated a statistically significant benefit from the high dose compared with the low dose. Reports from the trial should produce important information related to glaucoma management as well as possible insights into the design of future neuroprotective glaucoma trials. It is possible that the results were at least partially affected by the fact that glaucoma subjects in this trial had diverse types of glaucoma and IOP-lowering treatments at baseline as well as during the study. Also, the assessment of visual field progression used standards from the 1990s.

Nerve Growth Factor
Growth factors are a heterogeneous group of endogenous proteins secreted by the body to control the growth, division, maturation, and proliferation of various cells and tissues. Nerve growth factor (NGF) was discovered by Rita Levi-Montalcini and Stanley Cohen in the late 1950s from salivary gland isolates to induce the differentiation and survival of particular target neurons. Like the majority of growth factors, with the exception of erythropoietin and colony-stimulating factor for anemia treatment, NGF has not evolved into a proven and approved clinical application.

Lambiase and colleagues[31] studied the intravitreal administration of NGF in experimental models of RGC degeneration and found the protein to be effective. An apparently unique feature of NGF was its ability to penetrate to the retina when administered topically, in spite of its being a large protein with a molecular weight of 30,000. In a recent publication, Lambiase and colleagues[32] reported survival of RGC in a rat glaucoma model receiving topical NGF 4 times daily for 7 weeks. They also treated 3 patients with advanced glaucoma with a murine topical NGF for 3 months and reported improvement in visual acuity, contrast sensitivity, perimetry, and electrophysiological functions. It should be stressed that no conclusions may be drawn from this small, short-term, open-label clinical study.

Considerations for Future Approaches to Glaucoma Neuroprotection Trials
As neuroprotection research moves forward in glaucoma, there are a number of approaches that can be taken in new trials that may help to better assess the feasibility of this approach. It will be important to ensure that randomized trials include a well-defined and homogenous glaucoma population. This should include patients with one defined glaucoma diagnosis, baseline moderate disease stage (level of optic nerve and visual field damage), IOP limits, and glaucoma treatments, as well as outcome measures that include the currently available visual field and structure (optic nerve and retinal nerve fiber) measurements. Evolving imaging methods should also be examined and if possible incorporated into studies. These may include the use of noninvasive in vivo real-time and reproducible imaging of RGC potentially through fluorescently labeled annexin V and fluorescent ophthalmoscopy[33,34] and magnetic resonance imaging (MRI) to, among other uses, visualize the lateral geniculate nucleus and assess shrinkage of visual structures along the geniculo-cortical pathway.[35,36] Finally, other strategies may include the use of prolonged methods of drug delivery, such as sub-Tenons and intraocular injection devices. As new trials are designed and implemented, a better understanding of the potential for neuroprotection in glaucoma should evolve.

Refrence:
MedscapeCME Ophthalmology/Neuroprotection and Glaucoma/Theodore Krupin, MD/01/29/2010

Tuesday, August 4, 2009

DDLS- A new approach to optic disc assesment

Glaucoma is defined a s an optic neuropathy charactearised by typical, progressive disc damage and visual field loss. The diagnosis of glaucoma is based on several factors that include identifying risk factors such elevation of intraocular pressure, race, age, family history and central corneal thickness, detecting optic nerve damage, documenting visual field defects and examining the anterior chanber angle.

Examining the optic nerve head is crucial both for diagnosing glaucomatous damage and managing patients with glaucoma or suspected to have glaucoma. Previous studies examining subjective assesments of the cup to disc ratio have demonstrated a low level of interoberserver, and even intraobserver agreement.

Since Armaly described cup to disc ratio as a method of optic nerve head(ONH) classification in 1969, it became the most commonly used method of ONH assesment. However, the disadvantage of this method leads to a lot of confusion on documenting glaucomatous optic disc considering the effect of optic nerve size and the focal rim loss, etc.

The Disc Damage Likelihood Scale (DDLS) is a method of assesment of the optic nerve developed by Professor George Spaeth, Wills Eye Hospital. The DDLS was designed in an attempt to provide a more accurate and valid method for defining glaucomatous optic nerve damage.

Henderer JD et al did a study on DDLS and concluded that DDLS had higher sensitivity and specificity for detecting glaucomatous changes versus cup to disc ratio. In another study he showd that inter and inra observer agreement for DDLS is greater than the Armaly cup to disc ratio.

The DDLS Step by Step as described by Prof. Spaeth:

Step 1
Dilate the eyes if necessary. The pupils must be sufficiently large to allow a clear view of the fundus.

Step 2
Get an idea of both of the patients optic nerves by a brief examination with a strong plus lens (eg. +66.00 D) using the slit lamp. Determine the vertical size of the discs. For example, if you use a +66.00D lens, the graticule on the slit lamp from Haag-Streit AG (Koniz, Switzerland) with indicate the size in millimeters. Multiply this figure by 0.9 for a +60.00D lens or by 1.3 for a +90.00 D lens.

Step3
Choose one of the patients eye to concentrate on first. With a direct ophthalmoscope, examine the optic disc for an area where its outer edge is clearly distinguished from other ocular tissue such a sclera. Then, determine the full circuference of the outer edge.

Step4.
Define the inside edge of the neuroretinal rim(outer edge of the cup) by direct ophthalmoscopy. Estimate the rim to disc ratio by comparing the with of the neuroretinal rim with that of the disc diameter on the same axis. Perform this comparison at several clock positions. If the rim to disc ratio is different at various parts of the rim, note the area at which the rim is narrowest and calculate the rim to dic ratio there.

Step 5
Draw the shape of the optic disc. When sketching the neuroretinal rims inner edge, indicate clear demarcation with a thick line and less clear demarcation with a thin or hatched line. Note the course of blood vessels that help determine the rims width and any pertinent features of the disc(eg. notches, pallor, hemorrhage etc.)

Step 6
Determine the DDLS by using your drawing of the disc, the narrowest rim to disc ratio, the size of the disc, and the DDLS nomogram (figure 1). If the nerve is smaller or larger than average, you must adjust the DDLS score appropiately. An easy method is to stage the nerve as if it were of averaage size and then increase the stagae by one if the nereve is small or decrease the stage by one if it is large. Note the DDLS score in the patients chart.

Step 7
Repeat steps 3 to 6 for the patients other eye.


Staging is done as follows:














The Glaucoma graph is a simple way of explaining patients about the progress of disease.






The single best indicator that the glaucomatous process is or was present is the existence of glaucomatous damage. Every other prognostic factor is indirect. The only indication that glaucomatous process is continuing is continuing damage. DDLS is the best way to asses whether the damage is present and whether the damage is continuing.

The general oder of examination is to look at the right optic nerve first, and then the left optic nerve, getting the rough assesment as to the DDLS. The important factors that need to be considered are

1. The diameter of the optic disc
2. The width of the neuroretinal rim
3.Valid definition of the outer edge of the disc and the outer edge of the cup using direct ophthalmoscope
4. Definition of internal edge of the neuroretinal rim, that is the outer edge of the cup
5. Drawing of the disc
6. Caliculating the Disc Damage Likelihood Score
7. The size of the dics needs to be taken into consideration during scoring [ small <1.5mm,>2.omm in vertical diameter]
8. The two important factors considered during staging are, the narrowest width of the rim and extent of absence of neuroretinal rim

Uses of DDLS:

1. It is used in the diagnosis of glaucoma
Discs with a DDLS of 5 or more are not healthy. Such discs are not necessarily glaucomatous, but they are virtually always pathologic.
A DDLS so stege 1 would be extremely rare in a patient who had glaucoma.
THe DDLS has a lower positive predictive value when the score is 2. Stage 2 disc could be a deterioration from stage 1 or stage 2 could be entirely normal for that person

2. DDLS can be used as a way to categorize the severity of the condition
Visual field loss does not develop until patients deteriorate to stage 4 of the DDLS. Patients who do not have visual field loss usually do not have visual symptomatology from glaucoma. DDLS stages 1,2 or 3 does not damage the person functionally. We can wait and watch in these patients. At the other end of the spectrum, DDLS stages 5,6, 7, or 8, the conditon has declared itself by showing certain damage in the visual field.

3. DDLS can be used as a method of monitoring the course of glaucoma

There are some associated signs which are of highest predictive value in indicating that the changes are actually glaucomatous.

Aquired pit of the optic nerve - Pathognomonic
Absence of neuroretina rim ina focal area - Highly suggestive
especially inferotempora or superotemporal
Notch in the rim - Highly suggestive
Documented progressive narrowing of - Highly suggestive
a rim/width ratio for more that 1 stage
Hemorrhage across the rim - Moderate value
Asymmetry of DDLD between 2 eyes - Moderate value

Summary:

The Disc Damage Likelihood Scale provides a quantitative method of assessing the glaucomatous optic nerve damage. Combining DDLS with other information like patients symptoms and patients risk factors helps in establishing the rate of change in patients condition; this information assists in assuring that the patients treatment is rational and effective.

Thursday, July 23, 2009

New definition of glaucoma

Glaucoma is defined as a condition with intraocular pressure(IOP) >20 mm/Hg or IOP asymmetry between fellow eyes >2 with one or all of the following features.

1) A definite notch in the neuroretinal rim (a defect of at least 1 disc unit for a circumferential extent of less than 2 clock hours), or
2) Absence of neuroretinal rim not due to optic neuritis, anterior ischemic optic neuropathy, giant cell arteritis or other known cause, or
3) A difference in C/D ratio of >2, or
4) A difference in DDLS >1 which cannot be explained by anisometropia or other nonglaucomatous reason.

Note that this disc change must fit with a definite visual field defect, that is,
1) At least 3 contiguous points depressed by at least 5 dB,
2) A pattern of loss corresponding to a nerve fiber bundle type of defect.

Monday, July 20, 2009

What are the types of Glaucoma?

There are several different types of glaucoma depending on the mechanism of the disease process. They are as follows.

1. Primary Open-Angle Glaucoma
2. Acute Angle Closure Glaucoma
3. Chronic Angle Closure Glaucoma
4. Inflammatory Open-Angle Glaucoma
5. Pigmentary Glaucoma
6. Pseudoexfoliation Glaucoma
7. Phacolytic Glaucoma
8. Phacomorphic Glaucoma
9. Lens-Particle Glaucoma
10. Angle Recession Glaucoma
11. Steroid responsive Glaucoma
12. Neovascular Glaucoma
13. Postoperative Glaucoma
14. Malignant Glaucoma( Aqueous Misdirection Syndrome)
15. Glaucomatocyclitic Crisis( Posner Schlossman Syndrome)
16. Plateau Iris Syndrome
17. Iridocorneal Endothelial Syndrome
18. Ocular Hypertension
19. Normal Tension Glaucoma
20. Glaucoma Suspect

What is glaucoma

Glaucoma is a group of conditions in which the tissues of the eye become damaged by intraocular pressure that is higher than the eye can tolerate. The most characteristic and specific type of damage occurs to the optic nerve. The retinal ganglions cells become damaged, as a result of which the nerve becomes atrophic in characteristic ways and vision is lost in characteristic ways. The most traditional way of defining the visual loss in glaucoma relates to changes in the visual field which are most characteristically in the nasal portion of the filed, but can involve the entire visual field when the optic atrophy becomes marked. The disease is quite strongly asymmetric, one optic nerve being affected more than the other.