The=20 Importance of IOP in Glaucoma

Archana=20 Gupta, Sheetal Totala, Prateep Vyas,=20 Glaucoma=20 Department

Shri=20 Ganapati Netralaya, Jalna

Glaucoma=20 is a major cause of blindness throughout the world. Between 67 million & 105 = million=20 people are estimated to have glaucoma worldwide¹. The concepts & definition = of=20 glaucoma have evolved in the past 100 years, but they still remain=20 imprecise. The word = glaucoma=20 originally meant =91Clouded=92 in Greek: it was originally used = to mean=20 increased IOP associated corneal edema. =20 Today, it does not refer to a single disease entity but to a = group of=20 disease that differ in their clinical presentation, pathophysiology = &=20 treatment.²

Currently,=20 glaucoma can be defined as a multifactorial optic neuropathy with a=20 characteristic loss of optic nerve fibers presenting as classical optic = nerve=20 head features & visual field changes which may or may not be = associated with=20 elevated IOP & angle anomalies in the presence or absence of any = cause for=20 the disease. Contrary to = the=20 earlier belief when IOP was considered to be the sole factor in the = causation of=20 glaucoma, the role of intraocular pressure in the current definition is = only one=20 of the multiple factors responsible for the disease. The current and evolving = hypothesis=20 states that in glaucoma, the impact of nerve damaging factors is = amplified by=20 the level of IOP.

The=20 ultimate goal of glaucoma therapy to delay, stop and sometimes reverse = the=20 damage to the optic nerve and =20 Ganglion Cell loss = caused by=20 the glaucomatous process². The only way to do this at present = is to=20 control the IOP.

An=20 English oculist, W. Mackenzie first suggested the role of increased IOP = in=20 glaucoma in 1835¹. = For=20 150 years physicians have prescribed ocular hypotensive agents for their = glaucoma patients, even before they understood why the drugs=20 worked¹.

The=20 goal of⁼glaucoma=20 treatment is to preserve the visual field of patients and prevent the = loss of=20 visual field that is=20 associated with the = disease. In a=20 study by neurophysiologist Lars Furen, it was estimated that humans lose = approximately 5000 axons per year in the normal ageing process even if = glaucoma=20 is not present³.

Appropriate therapy of glaucoma = should=20 achieve 3 targets⁴: =20

Decrease=20 of IOP
Enhancement=20 of outflow facility=20
Neuroprotection=20

Threshold=20 pressure is the IOP below which the rate of the retinal ganglion cell = loss is no=20 greater than the spontaneous rate caused by ageing³.

IOP=20 & Glaucoma in the present context

The=20 correlation between Intra ocular pressure and Visual field defect has = been=20 recognized for over 20 years¹. Considering the intra ocular = pressure=20 as a primary = variable Glaucoma can be = classified as=20

High-tension=20 glaucoma (IOP> 21mm of Hg)=20
Normal=20 Tension Glaucoma (IOP < 21mm of Hg)=20
Ocular=20 Hypertension

High=20 Tension Glaucoma

This=20 group encompasses various glaucomas with an intraocular pressure > = 21mm of=20 Hg, classical visual field changes and disc changes. From various epidemiological = studies,=20 the prevalence of glaucoma is known to increase with higher intraocular=20 pressure.

In a=20 population based prevalence survey of more than 5000 individuals aged 40 = and=20 over in Baltimore , participants who had a screening intraocular = pressure=20 greater than 30 mm of Hg. were over 38 times more likely to have = glaucoma (as=20 defined in the study) = than=20 individuals with an intraocular pressure below 15 mm of = Hg^1,5. The Australian Blue Mountain = Eye Study=20 found the odds ratio of developing glaucoma was 4 to 7 times higher in = patients=20 with a screening intraocular pressure of greater than 21mm of Hg than in = patients with lower intraocular pressures, and the odds of developing = glaucoma=20 were 2 to 8 times higher in patients with intraocular pressure asymmetry = between=20 left and right eyes of greater than 3mm of Hg than in patients with = smaller=20 intraocular pressure asymmetry¹. So the level of intraocular = pressure is=20 directly related to the likelihood of glaucoma. High-tension glaucoma can be = categorized=20 as: -

- =20 Early=20 manifest glaucoma,

- =20 Moderate=20 glaucoma and

- =20 Advanced=20 glaucoma

Early=20 Manifest Glaucoma

May be=20 defined as an intraocular pressure of > 22mm of Hg but less than 30mm = of Hg,=20 a visual field with a MD of less than -4dB and disc changes. The Early Manifest Glaucoma = Trial was=20 designed to evaluate the effectiveness of reducing intraocular pressure = in=20 early, previously untreated Open Angle Glaucoma^1,6,7. Participants were randomized = in two=20 groups =96 129 eyes received treatment in the form of Argon Laser = Trabeculectomy +=20 Betaxolol and 129 eyes received no treatment. Investigators reported a=20 significantly lower rate of progression of perimetric damage in patients = in whom=20 intraocular pressure was reduced by a mean of 25 % (5.1mm of Hg) with = Betaxolol=20 drops and Argon Laser Trabeculectomy (45 %) compared to those untreated = (62=20 %). Time to onset of such = progress,=20 was also delayed- median 66 months in the untreated group vs. a median = 48 months=20 in the observed cohort. = For every=20 1mm drop in intraocular pressure, a 10 % reduction of the risk of = glaucomatous=20 progress was observed. = This study=20 strengthened the current standard clinical management of glaucoma as = progress=20 was found to be significantly and substantially lower in the initially = treated=20 patients. =

Moderate=20 Glaucoma

In=20 patients with moderate glaucoma the objective is to lower the = intraocular=20 pressure to an appropriate level as determined by the treating = clinician. It is essential to follow up = and=20 document the disc and visual field to ensure stability over time. If the = disease=20 is found to be progressing the target intraocular pressure is to be = reset=20 further lower down. =20

Advanced=20 Primary Open Angle Glaucoma:

The=20 Advanced Glaucoma Intervention Study^1,8,9,10is one of the = most widely cited long-term = studies of=20 glaucoma progression & its relationship to intraocular = pressure. Participants included patients = with=20 definite glaucomatous visual field abnormalities and an inadequate = response to=20 maximally tolerated medical therapy.

789 eyes of 591 patients = were=20 randomized to sequentially undergo either Trabeculectomy =96 ALT- = Trabeculectomy=20 or ALT-Trabeculectomy- Trabeculectomy and additional medication as=20 necessary. They measured=20 intraocular pressures every 6 months for upto 8 years following surgery = to=20 reduce intraocular pressure. = The=20 study concluded that eyes with an intraocular pressure less than 18 mm = of Hg on=20 100 % visits experienced a low visual field progression close to=20 zero.

= Eyes with=20 less than 18 mm Hg intraocular pressure on 50 % visits estimated a = worsening of=20 visual field by 0.63 units of Visual field score. Although, the average = change in=20 the visual field was close to zero in the former group, a proportion of = the eyes=20 did experience worsening despite having intraocular pressure thought to = be safe.=20 In the predictive analysis, the mean visual field loss from baseline = measured in=20 eyes with a mean intraocular pressure between 14 and 17.5 mm of Hg over = the=20 first 3 visits was 3 times that of mean intraocular pressure less than = 14 mm of=20 Hg on these visits. =

The=20 clinical implication of the study are profound - intraocular pressure = levels=20 that are often considered adequate goals of treatment (near 17mm of Hg) = were=20 associated with more progressive visual field loss than were lower = intraocular=20 pressure levels. =20

Normal=20 Tension Glaucoma

The=20 term refers to typical glaucomatous optic disc changes and visual field = loss in=20 eyes that have a so called normal intraocular pressure, open angles, and = the=20 absence of any contributing ocular or specific systemic = disorders².=20 Involving 230 patients at 24 centers in the Collaborative Normal Tension = Glaucoma Study, participants were randomized to intraocular pressure = lowering=20 treatment or no treatment^1,11,12. The follow-up examinations = were=20 scheduled every 3 months during year 1 and every 6 months thereafter for = upto 8=20 years. Intraocular = pressure=20 reduction by 30 % reduced the risk of progressive visual field loss. = Even for=20 glaucoma patients with normal intraocular pressure a progression rate of = 26.5 %=20 in the treated group and 12 % in the untreated group was noted.=20

So in=20 conclusion, treatment is beneficial, the goal should be to reduce = intraocular=20 pressure by approximately 30=20 %.

However,=20 factors besides intraocular pressure contributed to visual field damage = since 12=20 % of treated patients still developed further visual field loss despite=20 achieving intraocular pressure 30% below baseline.

Ocular=20 Hypertension (OH)

Ocular=20 hypertension may be defined as an intraocular pressure 21mm of Hg or = greater,=20 normal visual fields, normal optic discs, open angles, and absence of = any ocular=20 or systemic disorders contributing to the elevated intraocular=20 pressures².

A lower=20 intraocular pressure prevents or delays the onset of visual field loss = and optic=20 disc damage in individuals with ocular hypertension as shown in the = Ocular=20 Hypertension Treatment Study^1,13,14. A total of 1636 = participants=20 with no evidence of glaucomatous damage and aged 40-80 years and with an = intraocular pressure between 24 and 32mm of Hg in one eye and 21mm and = 32mm of=20 Hg in the other eye were randomized to either observation or treatment = with=20 commercially available ocular hypotensive medications. The goal in the=20 medication group was to reduce the intraocular pressure by 20% or more = and to=20 reach an intraocular pressure of 24mm of Hg or less. After 60 months, = the=20 treated group achieved a 22.5% mean reduction of intraocular pressure, = compared=20 with a 4.0% reduction in the treated group. The cumulative probability = of=20 developing primary open angle glaucoma was 4.4% in the treated group as = compared=20 to 9.5% in the observation group. The massive Ocular Hypertension = Treatment=20 Study database also afforded the opportunity to determine some = demographic and=20 clinical factors associated with conversion to glaucoma from simple = Ocular=20 Hypertension.

The companion paper to the = primary Ocular=20 Hypertension Treatment Study publication revealed that older age, larger = cup=20 disc (C/D ratio), greater pattern standard deviation (PSD), higher = intraocular=20 pressure and thinner central corneal thickness (CCT) appear to be good=20 predictors for the development of glaucoma in patients with ocular=20 hypertension¹⁵.

The=20 strength of CCT as a predictor for the conversion to glaucoma over the = range of=20 IOP values and cup disc ratios suggests that measurement of CCT showed = be an=20 essential element to the standard work-up of patients with ocular=20 hypertension^1,15.

The=20 question of when to treat ocular hypertensives is still a matter of = debate. Tilting the balance towards = treatment is=20 the presence of risk factors like black race, high myopia, and age more = than 65=20 years, a family history of primary open angle glaucoma, thinner corneas = and the=20 presence of systemic risk factors like diabetes mellitus and systemic=20 hypertension associated with ocular hypertension. Although the = guidelines of=20 when to treat in a case of ocular hypertension are controversial, most=20 clinicians would treat in case of:

=D8 =20 IOP=20 > 30mm of Hg =AE Every=20 case should be treated

=D8 =20 IOP=20 >25mm of Hg with a risk factor

=D8 =20 IOP=20 >21 mm of Hg with vein occlusion in the other eye. =

Besides=20 other patients needing liberal approach include

=D8 =20 One=20 eyed patients

=D8 =20 Young=20 patients

=D8 =20 Patients=20 opting for treatment

The=20 importance of diurnal variation:

Intraocular=20 pressure in an individual fluctuates throughout the day and night.=20

A=20 single IOP measurement in ophthalmologist=92s office may or may not = reflect what=20 the IOP is at other times of day or night, and certainly not what its = highest=20 value during the day may be.

It is=20 well documented that range of daily fluctuations in IOP is greater in = patients=20 with glaucoma than in normal individuals.^=
17

There=20 is some evidence that suggests there is a correlation between mean IOP = and=20 diurnal fluctuation ; with higher IOP having greater range of diurnal=20 variation.¹⁷

In=20 2000, Asrani et al published ¹⁶a study in which they looked = at a=20 group of patient with glaucoma who had had diurnal pressure curves = plotted using=20 the Zeimer self tonometer and then had been followed up for a number of = years. A=20 majority of these patients had progression of their visual field defects = during=20 this follow up period. A retrospective analysis was then performed, and = it was=20 found that the range of initial daily IOP variation was more predictive = of risk=20 of visual field loss progression than was the mean or peak IOP.=20

Because=20 functional damage from a high intraocular pressure is exponential, even=20 transient elevations in intraocular pressure may cause significant = glaucomatous=20 damage. Patients who have periodic or sporadic pressure spikes can lose = visual=20 field due to cumulative effects. An important goal of therapy therefore = should=20 be to prevent transient intraocular pressure elevations and achieve a = low stable=20 intraocular pressure throughout the day and night.=20 ¹⁷

When=20 evaluating the most at risk patients, the clinician should attempt to = measure=20 intraocular pressure at several points during the day. If multiple = diurnal=20 measurements are not possible, it is preferable to select therapies with = a more=20 consistent 24 hr intraocular pressure control in clinical=20 studies.

The=20 Target Pressure

The=20 discussion till now indicates that past efforts to lower intraocular = pressure in=20 the =91normal=92 range of = 21 mm Hg or=20 lower may be inadequate and that =93control=94 really means an = intraocular=20 of less than 15mm or 16mm of Hg especially in advanced=20 glaucoma².

Target=20 pressure may be defined as a pressure, rather a range of intraocular = pressure=20 levels within which the progression of glaucoma and visual field loss = will be to=20 delayed or halted. The goal should be to lower the intraocular pressure = is a=20 level that is =91safe=92 for that particular eye. Because individuals = vary in their=20 susceptibility to IOP independent damage, there is no =91Safe=92 = intraocular=20 pressure that can be guaranteed to prevent further glaucomatous=20 damage². The optic nerve that has already been damaged = appears to be=20 more susceptible to pressure mediated injury, so patients with advanced=20 glaucomatous neuropathy may require very low target pressure to halt the = disease.

In=20 determining the appropriate target pressure for an individual, the=20 ophthalmologist must take into account several major = factors^1,2,4:=20 the IOP level at which the nerve damage occurred, the extent & rate = of=20 progression of glaucomatous damage , if known ; the presence of other = risk=20 factors for glaucoma ; & the patients =20 age , expected = life span,=20 & medical history. =20

Specific=20 IOP ranges may be recommended as a starting point. The AAO guidelines=20 suggest¹.

=D8 =20 For=20 patients with mild damage (optic disc cupping but no visual field loss), = the=20 initial target pressure should be 20-30% below base = line.

=D8 =20 For=20 patients with advanced damage, the target pressure range may be a = reduction of=20 40 % or more from baseline. =20

=D8 =20 For=20 patients with NTG a 30% reduction is recommended.

A=20 target intraocular pressure that is appropriate when you first see a = patient may=20 not be a safe pressure 10 years later when he /she may have developed = systemic=20 hypertension, diabetes or some other condition, that may affect the = persons=20 susceptibility to glaucomatous progression. The clinician should = always=20 revaluate each glaucoma patient at regular intervals to determine if the = target=20 intraocular pressure originally selected is still valid. =

Because=20 of individual variability in susceptibility to damage of optic = nerve, combined vigilance for = progression using=20 automated static perimetry and optic nerve stereophotography is = necessary to=20 determine whether individual patients will progress at initial target = IOP.=20 Visual fields and optic nerve photos should be monitored for the signs = of change=20 and IOP should be lowered to additional 15% if progression=20 detected.

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Application=20 of clinical trials in developing countries

All the=20 major clinical trials like Collaborative Normal Tension Glaucoma study, = Ocular=20 Hypertension treatment study, Advanced glaucoma intervention Study, = Early=20 manifest glaucoma Treatment study =20 have shown beneficial effect of IOP reduction in patients with = glaucoma.=20 How do we apply these trials to developing countries? It can be done = based on=20 the concept of NNT i.e. number needed to treat.^{18 =}For=20 example, NNT for representative patient recruited in OHTS is 20. = That means we need to treat 20 = patients with=20 ocular hypertension for 5 years to prevent one from progressing to early = POAG.=20 Functional defects occurred only in 50% patients in OHTS and at best we = prevent=20 occurrence of early glaucoma, not blindness. Also there is high cost of = the=20 treatment involved. Hence we should search for subgroups at high risk. = In ocular=20 hypertension, with IOP >25.75 mm Hg and CCT <556um, the risk of=20 progression is 3 times higher. NNT for prevention of progression of = early=20 glaucoma is 5 to 6. because progression is usually slow and bilateral = blindness=20 is relatively low, developing countries should concentrate on cases at = higher=20 risk.

Conclusion:=20

In the=20 current scenario of changing concepts of glaucoma diagnosis and = management,=20 after many rounds of debate about its significance, IOP still remains an = important risk factor and the sole variable that can be controlled among = a host=20 of probable mechanisms.

References

Goldberg=20 I: Relationship between Intraocular Pressure and Preservation of = visual field=20 in Glaucoma. Surv Ophthalmol 48 (Supp 1): S3-7, = 2003.=20

Stamper=20 R L, Leiberman MF, Drake M V: Becker and Schaffer=92s Diagnosis and = Therapy of=20 Glaucomas. Seventh edition: 2-9; 414-429,1999. =

Brubaker=20 R F: Three Targets of Glaucoma Therapy. Ocular Surgery News: 3, = September 15,=20 2002.

Brubaker=20 R F: Introduction: Three Targets for Glaucoma Management. Surv = Ophthalmol 48=20 (Supp 1): S1-2, 2003.

Kass=20 M A, Heur DK, Higginbotham D J et al: The Ocular Hypertension = Treatment Study;=20 A randomized trial determines that topical hypotensive medication = delays or=20 prevents the onset of Primary Open Angle Glaucoma. Arch Ophthalmol = 120:=20 701-713, June 2002.

Leske=20 C, Heijl A, Hyman L et al: Early Manifest Glaucoma Trial; Design and = Baseline=20 Data. Ophthalmology 106: 2144-2153, Nov 1999. =

Heijl=20 A, Leske M C, Bengtsson B et al: Reduction of Intraocular Pressure and = Glaucoma Progression; Results from the early manifest Glaucoma trial. = Arch=20 Ophthalmol 120: 1268-1372, Oct 2002.

The=20 Advanced Glaucoma Intervention Study Investigators: Advanced Glaucoma=20 Intervention Study 2. Ophthalmology 101: 1445-1455, Aug=20 1994.

The=20 AGIS Investigators: The Advanced Glaucoma Intervention Study (AGIS): = 7. The=20 relationship between control of Intraocular Pressure and Visual Field=20 deterioration. Am J Ophthalmol 130: 429-439, Oct = 2000=20

Beck=20 A D: Review of recent publications of the Advanced Glaucoma = Intervention=20 Study. Curr Opin Ophthalmol 14: 83-85, 2003. =

Collaborative=20 Normal Tension Study Group: The Effectiveness of Intraocular Pressure=20 Reduction in the Treatment of Normal- Tension Glaucoma. Am J Opthalmol = 126:=20 498-505, Oct 1998.

Anderson=20 D R: Collaborative Normal Tension Glaucoma Study. Curr Opin Ophthalmol = 14:=20 86-90, 2003.

Kass=20 M A, Heuer D K, Higginbotham E J: The Ocular Hypertension Treatment = Study; A=20 randomized Trial Determines that Topical Ocular Hypotensive medication = delays=20 or prevents the onset of Primary Open Angle Glaucoma. Arch Ophthalmol = 120:=20 701-713, June 2002.

Lee B=20 L, Wilson M R: Ocular Hypotension Treatment Study (OHTS) commentary. = Curr Opin=20 Ophthalmol 14: 74-77, 2003.

Gordon=20 M O, Beiser J A, Brandt J D et al: The Ocular Hypertension Treatment = Study:=20 Baseline Factors that Predict the onset of Primary Open Angle = Glaucoma. Arch=20 Ophthalmol 120: 714-720, June 2002.

16.Asrani=20 S.; Zeimer Wilensky J et al; large diurnal fluctuations in Intraocular = pressure=20 are an independent risk factor in patients with glaucoma. J. Glaucoma = 2000, 9,=20 134-142

Curr=20 Opin Ophthalmol 15, 90-92; 2004; the role of diurnal pressure = measurements in=20 the management of open angle glaucoma

Curr.=20 Opin Ophthalmol,15: 125-131, April 2004; glaucoma management in = developing=20 countries.