Which of the following eye disorders is caused by an elevated intraocular pressure IOP )?

Ocular Hypertension: High Pressure Without Glaucoma

Approximately 3-6 million Americans and 4-7% of people above the age of 40 years old have elevated IOP without evidence of glaucomatous optic nerve damage. Normal IOP ranges from 10-21 mmHg with a mean of 16 mmHg. Therefore an IOP of greater than 21 classifies an eye as being ocular hypertensive. This increased pressure may result from decreased aqueous drainage, increased aqueous production, or could be that eye’s normal, as IOP is measured on a bell curve. Patients with ocular hypertension (OHTN) do not experience any pressure sensation or blurred vision. OHTN is not accompanied by cupping of the optic disc, VF defects, thinning of the RNFL, or RGC loss, as this would denote glaucoma, not OHTN. Therefore, patients with high IOP in the absence of glaucomatous damage are referred to as having OHTN or being glaucoma suspects. 

As no established standard of care existed for OHTN patients, the Ocular Hypertension Treatment Study (OHTS) was designed to evaluate the efficacy and benefits of initiating IOP lowering treatment to delay or prevent the onset of glaucoma. OHTS found that 5 years later the cumulative probability of glaucoma development for patients taking IOP lowering medication was only 4.4% and 9.5% in the untreated observation group. The OHTS results do not suggest that all patients with elevated IOP should be treated with ocular hypotensive medication and the researchers admit adverse effects of prolonged and indefinite medication use may exist, especially regarding financial and quality of life burden. Importantly, this study also identified risk factors for glaucoma, which were mentioned previously.

Notably, ONLY 9.5% of untreated OHTN patients developed glaucoma within 5 years. OHTS identified pertinent risk factors increasing the likelihood of OHTN patients eventually developing glaucoma. From the OHTS results, and similar studies, one can gather that ocular hypertension alone is not a sufficient or necessary factor for glaucoma development. Additionally, untreated OHTN patients have less than a 10% chance of developing glaucoma 5 years later. Said differently, over 90% of untreated OHTN patients will not proceed to develop glaucoma within 5 years. Such findings clearly demonstrate that while high IOP may raise the risk of glaucoma development and progression, high IOP alone does not warrant treatment with ocular hypotensive medication. Furthermore, 4.4% of the OHTN patients successfully treated with IOP lowering medication STILL developed glaucoma within 5 years. Moreover, the majority of major glaucoma studies (Advanced Glaucoma Intervention Study, Collaborative Normal Tension Glaucoma Study, Collaborative Initial Glaucoma Treatment Study, Early Manifest Glaucoma Trial) all demonstrate glaucoma progression despite significantly lowering IOP. These well-established outcomes indicate that glaucoma is far more complicated and multifaceted than elevated or fluctuating IOP alone.

Likewise, new research indicates there is no compelling evidence that postoperative transient IOP spikes in healthy eyes threaten optic nerve health and warrant treatment. The cessation of unnecessary IOP lowering treatments lessens clinician workload, decreases cost of medication for patients, reduces patient visits, and minimizes potential clinical and subclinical medication side effects.

THE ROLE OF THE VASCULAR SYSTEM IN GLAUCOMA INITIATION AND PROGRESSION

Eye care practitioners evaluate glaucoma progression based on both structural and functional metrics. Structural measurements are obtained using optical coherence tomography (OCT) technology calculating the thickness of the axons surrounding the ONH. Guided progression analysis (GPA) software analyzes data over time to quantify the rate of change while plotting these results on a graph. This graph depicts the current rate of progression and even predicts further progression over time. Functional progression is determined by field of vision loss estimated through automated perimetry and compared with previous values. These data sets indicate if progression is “possible”, “likely”, or “confirmed”.

Once progression is confirmed - a “target IOP” is determined using current IOP, percentage of desired IOP reduction, and degree of structural and functional loss. As current medicinal and surgical glaucoma treatments currently only focus on IOP lowering, a “target IOP” is formulated for each patient. Although studies validate that lowering IOP lessens the rate of glaucoma progression, these studies also confirmed that glaucoma frequently progresses despite achieving this “target IOP”. Such evidence implies factors other than IOP contribute to glaucoma progression.

A VASCULOPATHIC VIEW OF GLAUCOMA

While elevated IOP is an established risk factor for progression, perhaps a more significant risk factor is low ocular blood flow or ocular perfusion pressure (OPP). OPP is defined as the difference between arterial blood pressure and IOP. Therefore, both a high IOP and a low BP will lessen OPP potentially instigating ischemic damage to the retina and optic nerve. Research indicates that patients with low OPP have a considerably higher risk of glaucoma progression compared to patients with high OPP. Also, progression is associated with fluctuations in OPP from inconsistent BP or IOP. Nocturnal BP is normally lower due to diurnal patterns, however studies confirm progressive glaucomatous VF loss occurs in cases of exaggerated nocturnal BP drop.

The Thessaloniki Eye Study demonstrated increased cupping and decreased ONH rim area in non-glaucomatous patients taking anti-hypertensive medication whose diastolic BP fell below 90 mmHg overnight. Similarly, a BP drop of 10% or more in glaucoma patients with well-managed hypertension was connected with structural ONH damage and progressive VF loss. Also, the magnitude of OPP fluctuations is correlated with glaucoma severity in NTG patients.

New vascular imaging methods demonstrate reduced ocular blood flow (OBF) in glaucoma patients, especially in cases of progression despite normal IOP. Moreover, glaucoma progression can even be forecasted by diminished OBF rates. Fluctuations of ocular blood flow are particularly damaging and may be a more significant measurement for progression than baseline OBF measurements.

HOW THE EYE AND BRAIN COMPENSATE FOR REDUCED OCULAR BLOOD FLOW

The intrinsic capability of vascular autoregulation serves to continuously provide oxygen and nutrients despite any metabolic or pressure irregularities. The importance of autoregulation lies in the ability to maintain constant ocular blood flow despite (OBF) inconsistent ocular perfusion pressure (OPP). The autoregulatory response alters OBF in response to variations in OPP. Though elevated IOP results in decreased OPP, normal autoregulation enables microvascular consistency thus preventing ischemic damage. However, the ONH becomes vulnerable to OPP fluctuations if autoregulation is compromised or its regulatory range is surpassed. Such autoregulation impairment is one potential vasculopathic mechanism for the risk and progression of GON despite relatively normal IOP and BP fluctuations. Though OPP may decrease as a result of high IOP or low BP, research has not clearly demonstrated which, if either, is more injurious to the ONH. However, research suggests this autoregulation system better regulates low OPP induced by high IOP than that of low choroidal BP, suggesting that low blood pressure may play a more significant role than high IOP in GON. Also, in glaucoma patients with both normal and elevated IOP, studies reveal lower BP and greater nocturnal BP variation.

While the ONH blood supply through the parapapillary choroid can normally autoregulate to maintain a constant OPP, significant changes in BP or IOP may exceed the autoregulation ability. When either the range of autoregulation is exceeded or autoregulation function is impaired, the ONH is at risk for ischemic injury. Studies also indicate dysregulation or even non-regulation of ocular vasculature in glaucoma patients. Such dysregulation or non-regulation poses a substantial threat to the ONH with normal BP and IOP fluctuations, let alone abnormal fluctuations. Moreover, loss of autoregulatory function may further predispose an ONH to GON when subjected to high IOP or low BP.

Some researchers believe systemic primary vascular dysregulation (PVD) is the source of ocular vascular dysfunction triggering GON. While some optic neuropathies are caused by hypoxia, the fluctuations in OBF triggering oxidative stress may contribute to glaucoma risk and progression. PVD commonly results in stiff and irregular retinal vessels, increased retinal venous pressure, impaired neuro-coupling, and decreased autoregulation capacity, all of which increase glaucoma risk and progression. 

Evidence now exists that when vascular autoregulation is compromised, even normal BP and IOP fluctuation may lead to inconsistent OPP and subsequent ischemic ONH damage.  For this reason, primary vascular dysregulation is a substantial risk factor for GON as it is associated with impaired autoregulation, low nocturnal BP, and increased retinal venous pressure – each of which can cause GON independently. It is reasonable to assume that reduced OBF from dysfunctional autoregulation may play a significant role in GON risk and progression. Furthermore, research findings suggest proper autoregulatory responses are altered or missing with glaucoma. These daily and repetitive ischemic events suggest a potential vascular mechanism in glaucoma, especially NTG. Despite this, vascular etiology in glaucoma is rarely considered amongst eye care professionals, even in NTG eyes with vasculopathic risk factors. 

This evidence strongly suggests that elevated IOP alone does not cause GON, but rather diminished ocular blood flow, which is exacerbated by elevated IOP and reduced BP. While a vascular autoregulation system exists, PVD may limit or abolish this regulation capability leading to reduced OBF and subsequent ONH ischemic damage. Similarly, autoregulation capabilities may be exceeded in cases of elevated IOP, low BP, or OPP fluctuation. For these reasons, glaucoma progression is not resultant from high IOP or low BP alone, but in conjunction with decreased OPP resulting in ONH ischemia, axonal loss, and RGC death. This may explain why cardiovascular disease, hypertension, and diabetes are risk factors for glaucoma progression. Such evidence is biologically plausible and suggestive of a vasculopathic mechanism for progression.

Which of the following eye disorders is caused by an elevated intraocular pressure IOP?

What happens when IOP is increased?

What disorder is characterized by increased pressure in the eye?

What pathology is caused by increased intraocular pressure?