Optic Disk Drusen in Ocular Hypertensive Patients: A Case Series and review of the literature

Optic disc drusen (ODD) are acellular deposits that likely occur due to impaired axonal transport and metabolism, though a pathogenesis that has not been fully elucidated.^{1, 2} ODD occur anterior to the lamina cribrosa and can be evident on the surface of the optic disc or deeper within the tissue, where imaging is necessary for diagnosis.² In studies using histologic analysis in post-mortem eyes, ODD have been reported in up to 2.4% of eyes^{3, 4}, though ODD may be observed in up to 14.6% of normal-appearing eyes using enhanced-depth imaging (EDI) optical coherence tomography (OCT) of the optic disc.⁵

The presence of ODD can be benign or result in structural and functional changes to the optic disc including slowly progressive visual field (VF) loss^{1, 2} as well as peripapillary retinal nerve fiber layer (pRNFL) or ganglion cell – inner plexiform layer (GCIPL) thinning.^{6, 7} The VF, pRNFL, and GCIPL progression patterns may be similar to what is seen in glaucomatous optic neuropathy (GON) creating a diagnostic dilemma.^{2, 6, 8, 9} Additionally, ODD obscures the clinical assessment of the optic nerve cup, which is often seen as a “cupless disc”.¹⁰ Since the principal defining feature of GON is neuroretinal rim thinning and enlargement of the optic nerve cup, establishing a diagnosis of GON in the presence of ODD, which typically prevents a discrete designation of the cup and neuroretinal rim,^{2, 8, 11, 12} is a diagnostic and therapeutic challenge where a diagnosis of GON could either be delayed or unnecessarily be made.^{13, 14} There is currently no widely accepted treatment for ODD with progressive changes to the pRNFL or VF loss. Intraocular pressure (IOP) lowering agents have been proposed as a therapeutic option.^{9, 15, 16} However, there is ongoing debate with data questioning the efficacy of IOP reduction for ODD patients, particularly with an IOP within a normal range.^{15, 17} In order to select a patient population with ODD and the leading risk-factor for GON, elevated IOP, we present a case series of patients with co-existing ODD and ocular hypertension to determine whether treatment of IOP slowed progression of optic neuropathy as assessed by VF or OCT analysis. In addition, we present a review of the literature on ODD and IOP.

Methods

Six consecutive cases evaluated at Mayo Clinic were retrospectively reviewed that had a documented history of ocular hypertension and ODD with baseline glaucoma testing that included Humphrey 24–2 Swedish Interactive Thresholding Algorithm (SITA), Cirrus pRNFL and GCIPL analysis, and optic disc photos with at least one set of follow-up tests. Prior glaucoma testing from outside institutions were used when available. Ocular hypertension was defined as a current or past IOP measurement of > 21 mmHg. Each case is described briefly, emphasizing the characteristics of ODD and how their presence can interfere with GON diagnosis and monitoring. Information included IOP measurements from the visit where ODD were first suspected or identified, central corneal thickness (CCT), refraction, cup to disc ratio (CDR), and imaging studies obtained. Progression and management information was included.

Articles from PubMed were identified using one or more of the following keywords: optic disc drusen, optic nerve head drusen, intraocular pressure, ocular hypertension, or glaucoma. Any study with two or more patients with ODD and a described association with IOP, ocular hypertension, or GON was included.

Results

Patient Demographics summary

Two males and four females with an age range of 32–78 years were enrolled in the study. Mean follow-up was 40 months with a range of 10 to 118 months. One of the six patients was observed without IOP-lowering medication and the remaining five patients were treated with a combination of topical eyedrop therapy, selective laser trabeculoplasty (SLT), or surgical intervention. Of the 10 eyes in the 5 treated patients, the average IOP reduction was 40.3% (Table).

Table 1. Patient demographics and management characteristics.

Age and sex are presented for each case in addition to diagnosis type, maximum IOP (IOPmax), central corneal thickness (CCT), treated IOP (most recent IOP), treatment, follow-up duration, and progression features.

Case	Sex	Age	Diagnosis	IOPmax	CCT	Most Recent IOP	Treatment	Follow-up (Months)	Progression
1	M	41	OAG	Right – 29	595	14	IOP lowering drops bilaterally	10	Initial progression. No progression post final IOP lowering treatment either eye.
				Left – 26	583	16
2	F	32	OHT	Right – 27	611	25	Observation	30	No progression either eye.
				Left – 27	608	25
3	M	83	OAG	Right – 28	543	12	Right – SLT x1 with 3 IOP lowering drops.	54	Initial progression. No progression post final IOP lowering treatment either eye.
				Left – 28	553	9	Left – SLT x1 and IOP lowering drops followed by Trabeculectomy
4	F	78	PXE	Right – 34	574	22	Right – 3 IOP lowering medications and SLT.	118	Initial progression. No progression post final IOP lowering treatment either eye.
				Left – 24	587	18	Left – 1 IOP lowering drop initiated later in course.
5	F	69	OAG	Right – 32	520	10	Right – IOP lowering drops and SLT followed by trabeculectomy.	21	Initial progression. No progression post final IOP lowering treatment either eye.
				Left – 35	518	13	Left – IOP lowering drops and SLT followed by trabeculectomy.
6	F	44	PD	Right – 25	613	18	IOP lowering drops bilaterally	11	No progression either eye.
				Left – 25	600	15

Abbreviations: M = male, F = female, IOPmax = maximum intraocular pressure, CCT = central corneal thickness, IOP = intraocular pressure, SLT = selective laser trabeculoplasty, OAG = open angle glaucoma, OHT = ocular hypertension, PXE = pseudoexfoliation glaucoma, PD = pigment dispersion glaucoma

Case 1

A 41-year-old white male with a history of myopia treated with laser-assisted in situ keratomileusis (LASIK) was referred to the glaucoma service for ocular hypertension. Unmedicated Tmax was 29 mmHg in the right eye and 26 mmHg in the left eye. Post-LASIK CCT was 595μ in the right and 583μ in left. The patient had residual myopia, with −1.50 diopters sphere bilaterally, though the pre-operative refractive error was unknown. CDRs were 0.2 in the right and 0.1 in the left. Structurally elevated optic discs without papilledema were noted bilaterally and a tilted optic disk was also noted in the left. Baseline VF testing showed no deficits. OCT pRNFL analysis showed thinning superiorly in the right, and diffuse thinning in the left eye, which had progressed compared to baseline testing two years prior. GCIPL analysis showed no thinning in all sectors. B scan ultrasonography revealed hyperechoic signal at both optic discs consistent with ODD. Given co-existing ocular hypertension, ODD, and progression by OCT pRNFL, treatment was recommended and subsequently initiated for this patient using aqueous suppression in both eyes. At 10 months follow-up, there was no further progression after treatment was initiated by OCT pRNFL, GCIPL, or VF in either eye (Table).

Case 2

A 32-year-old white female was evaluated for ocular hypertension. Baseline examination revealed an unmedicated IOP of 27 mmHg in both eyes. CCT was 611μ in the right and 608μ in the left. The patient was myopic with −2.75 diopters of sphere bilaterally. Cup to disk ratios 0.1 in both eyes and pseudopapilledema was seen bilaterally. Baseline VF analysis showed an early inferior arcuate defect on the right and no defects on the left. OCT pRNFL demonstrated a superior thinning bilaterally. GCIPL analysis showed mild thinning in the superior sector of the left eye. B-scan ultrasonography and EDI OCT analysis were obtained and revealed bilateral ODD. Given concurrent ocular hypertension and ODD but without evidence of progression and thicker than average corneas, the patient was offered treatment with a topical glaucoma medication versus observation with a recommendation to observe given thicker CCT and the patient’s apprehension to a commitment to treatment.. Over 30 months of follow-up, no progression by VF or OCT pRNFL and GCIPL was noted.

Case 3

An 83-year-old white male with a prior diagnosis of open angle glaucoma with pre-treatment maximum IOP of 28 mmHg bilaterally years prior was referred for continued VF and pRNFL progression despite IOP-lowering treatment. On presentation to our service, IOP was 14 mmHg in the right and 15 mmHg in the left on 4 topical glaucoma medications in each eye. The left eye also had a history of SLT. CCT was 543μ in the right and 553μ in the left. The patient was pseudophakic with mild residual myopia bilaterally. CDRs were 0.2 in the right and 0.1 in the left. Tilting of the optic disk was noted on the left. VF testing was full on the right and the left revealed a dense inferior arcuate defect threatening fixation that had been slowly progressive over time. OCT pRNFL demonstrated thinning superiorly in the right that was slowly progressive and diffuse thinning in the left that was near the floor. OCT GCIPL showed thinning superiorly and nasally in the right and diffuse thinning in the left. A B scan was scan was obtained given minimal cupping and progression of optic neuropathy in a glaucomatous pattern, which revealed ODD bilaterally. Given progression in both eyes, treatment was recommended. SLT was performed in the right eye and a trabeculectomy with mitomycin C was performed in the left. Post treatment IOP in the right eye was low teens on glaucoma medications and high single digits in the left eye. No further progression was observed 54 months from intervention.

Case 4

A 78-year-old white female with pseudoexfoliation syndrome with an IOP of 34 mmHg in the right and 14 mmHg in the left was referred to our department for concerns of persistently elevated IOP. CCT was 574μ in the right and 587μ in the left. Mild hyperopia was noted bilaterally and pseudoexfoliation of the anterior lens capsule was noted in the right. CDR was 0.1 bilaterally. Structurally elevated discs without papilledema were observed bilaterally. Buried ODD were suspected and subsequently confirmed on OCT. Baseline visual fields demonstrated inferior arcuate defects with unreliable testing. . OCT pRNFL revealed thinning superiorly and inferiorly in both eyes. GCIPL analysis demonstrated diffuse thinning in the right and thinning of the superotemporal sector in the left. Given ODD and ocular hypertension with IOP in the 30s in the right eye and with the additional risk factor of pseudoexfoliation, treatment was initiated with a prostaglandin, and was shortly followed by aqueous suppression and SLT in the right eye. Subsequent OCT pRNFL testing showed progression so a third drop was added for further IOP reduction. Since then, testing has been stable with over 77 months of additional follow-up. The left eye eventually showed IOP elevation of 24 and progression by OCT pRNFL, so a prostaglandin analog was added. Since that time, OCT pRNFL has remained stable for an additional 77 months of follow-up. The patient was followed with testing for a total of 118 months.

Case 5

A 69-year-old white female was referred with a diagnosis of open angle glaucoma with IOP in the mid-30s bilaterally, progression by OCT pRNFL in both eyes, and progression by VF in the left locally. On presentation to our service, IOP was 32 mmHg in the right and 35 mmHg in the left, and the patient was intolerant to all topical medications. CCT was 520μ in the right and 518μ in the left. The patient was mildly hyperopic bilaterally. CDR was 0.1 bilaterally. VF testing showed no notable defects in the right and a superior acuate and dense inferior arcuate threatening fixation in the left. OCT pRNFL had thinning inferiorly on the right and diffuse thinning on the left and progression on locally obtained studies was observed. GCIPL analysis was within normal limits in the right and showed thinning of the superior and temporal sectors in the left. Since the visual field and OCT pRNFL was out of proportion to the degree of cupping, a B-scan was obtained which revealed bilateral ODD. Given IOP in the 30s bilaterally and progression by OCT pRNFL and VF, treatment was recommended. The patient was completely drop intolerant and initially underwent SLT in both eyes without significant response and ultimately went on to require trabeculectomy bilaterally. Post trabeculectomy, IOP has been low teens bilaterally without further evidence of progression over 21 months follow-up.

Case 6

A 44-year-old white female with a history of ocular hypertension and pigment dispersion syndrome was referred to our service for further evaluation. On presentation, examination revealed diffuse iris transillumination defects bilaterally consistent with the prior diagnosis of pigment dispersion syndrome. IOP was 25 mmHg bilaterally, unmedicated. CCT was 613μ in the right and 600μ in the left. Myopia was present with −11.0 and −9.25 in the right and left, respectively. CDR was 0.0 bilaterally. VF analysis showed no defects in either eye. OCT pRNLF revealed thinning inferiorly in both eyes. GCIPL analysis showed diffuse thinning bilaterally. With crowding of the optic disks noted, a B-scan and EDI OCT was obtained and revealed ODD bilaterally. Given concurrent ocular hypertension and ODD with the additional risk factor of pigment dispersion syndrome in a young myopic patient, treatment was recommended. Following initiation of treatment with a prostaglandin analogue, IOP was lowered 25% and no further progression has been noted over 11 months follow-up.

Conclusions

ODD is a condition that causes progressive VF loss in some patients, and there is no currently accepted treatment strategy to reduce the risk of further progression. Identification of risk factors may allow for novel treatment strategies in hopes of reducing VF progression. Non-modifiable risk factors including ODD height and volume, measured by delineation on EDI OCT and B-scan, have been associated with VF abnormalities.^{11, 18, 19} Modifiable risk factors amendable to treatment, including IOP, with topical medications, laser, or surgical intervention has been controversial and was the subject of a recent Point Counter-Point in the Journal of Neuro-Ophthalmology.²⁰ Rationale for treating progressive VF loss with IOP lowering medications in ODD is largely secondary to the difficulty in excluding a co-existing GON or the possibility of a shared pathophysiological mechanism between ODD and GON.

Herein we present a cohort of patients with co-existing ODD and ocular hypertension. In our series of 6 patients, 2 patients showed no progression in either eye and 4 patients showed progression in both eyes. 5 patients were ultimately treated with IOP-lowering treatment. Of the 4 patients that showed evidence of progression in the setting of ocular hypertension, no further progression was observed after the final IOP lowering treatment (i.e. the time at which the target IOP was reached). This series of patients is presented to highlight the co-existence of ocular hypertension with ODD and suggests that treatment of ocular hypertension in a patient with ODD is a reasonable therapeutic option to reduce the risk of progression by VF or OCT pRNFL.

Relatively few reports are available in the medical literature studying patients with concurrent ODD and ocular hypertension. Descriptions of this rare patient population are mostly limited to the level of individual case reports²¹ or series^{13, 14}. Larger studies have also included a cohort of patients with co-existing ocular hypertension and ODD on subgroup analysis.^{15, 17} One series in the 1980s described 5 patients with co-existing pigment dispersion syndrome and ODD. Though not all patients had elevated IOP, treatment of IOP in the setting of progression of VF deficits and or optic disc changes was recommended.¹⁴ Another series of two patients detailed treatment of ocular hypertension in the setting of ODD with topical medications and/or laser intervention, which discussed the utility of using OCT pRNFL to help analyze progression when cup features are obscured by ODD.¹³ A larger study included 13 patients with coexisting ODD and ocular hypertension found that VF loss was more likely in eyes with ODD and coexisting ocular hypertension.¹⁵ Another report found a higher incidence of positive family history of glaucoma in patients with ODD, though specific IOP or progression data was not presented.²²

In the absence of definite ocular hypertension, IOP reduction as a treatment for ODD is also particularly controversial. In a retrospective study of 36 ODD patients that did not include patients with ocular hypertension, higher IOP was associated with greater VF and pRNFL loss.⁹ Furthermore, in a study of 34 patients with ODD, IOP reduction with topical aqueous suppression was associated with decreased progression by visual field and pRNFL thickness.¹⁶ On the contrary, in one study of 47 eyes, IOP was not associated with progression of VF deficits in patients with ODD, though patients with ocular hypertension were excluded from the study.¹⁸ Additionally, in a retrospective chart review that included 146 patients but excluded patients on IOP-lowering therapy, higher IOP was not associated with greater rates of progression by VF testing or OCT pRNFL. Of note, the 8 eyes with ocular hypertension included in this study did not have worse perimetric mean deviation as assessed by VF testing.¹⁷

Shared pathophysiological mechanisms may contribute to both ODD and GON. Therefore, IOP related stresses whether related to mechanical, metabolic, or vascular stress may contribute to progression of ODD. Ocular perfusion pressure (OPP) describes perfusion of the retina as a difference in pressure between the central retinal artery and central retinal vein. Since IOP and central retinal venous pressure are similar conditions and since the mean brachial artery blood pressure is similar to the central retinal artery pressure, OPP is generally estimated as a function of mean arterial pressure and IOP.²³ Diminished OPP may be a shared pathophysiological mechanism with GON^{24, 25} and ODD.^{26, 27} Alternatively, elevated retinal ganglion cell susceptibility to damage by increased mechanical stress and impairing axonal transport at a given IOP is a potential mechanism of GON.^28–30 ODD are suspected to arise from impaired axonal transport and metabolism of the retinal ganglion cells.^{1, 2} Therefore, impairment of axonal transport and mechanical stress may be an additional shared pathophysiological mechanism. Though different conditions, both ODD and GON may both show a pressure-dependent loss of retinal ganglion cells by shared mechanisms and may, therefore, respond to IOP-lowering treatment in a similar fashion.

Though ocular hypertension is a significant risk factor for GON, not all ocular hypertensive patients will develop VF or structural changes consistent with GON over time. While lowering IOP medically or surgically in patients with ocular hypertension decreases the risk of progression into GON, there is a subset of patients where ocular hypertension seems to never result in GON.^{31, 32} It is possible that a similar phenomenon may be observed in patients with concurrent ODD and ocular hypertension where some patients may benefit from IOP reduction while others are more resistant to progressive optic disc changes consistent with ODD or GON, which was seen in our case series. Furthermore, many patients with GON will have no history of IOP higher than the upper limit of normal (21 mmHg). These patients have a diagnosis of normal or low-tension glaucoma (LTG). In some populations, LTG is the most common type of open angle glaucoma.³³ Therefore, it is possible that patients with progressive ODD without elevated IOP are progressing by an LTG-type mechanism. In this case, the hypothesis would be that it is a predominantly GON-driven process, whether high tension or LTG, that drives the progression seen in ODD that is simply masked at the neuroretinal rim by the presence of ODD.

There are limitations to this study inherent to the retrospective and descriptive nature of a case series. First, though one of the larger case series available in the medical literature on the subject,^13–15 our study was limited by a small sample size. Second, in some of the cases, a limited number of serial glaucoma tests were available limiting the detection of progression and potential treatment effects over a long period of time. However, the primary goal of this case series was to present characteristics in this relatively rare subset of patients with simultaneously co-existing ODD and ocular hypertension where glaucoma monitoring and management is challenging rather than providing evidence supporting a definitive cause-effect relationship.

Establishing a concurrent diagnosis of ODD and GON is both challenging and controversial.^{13, 15} With current diagnostic modalities, it may not be possible to distinguish with certainty progressive ODD versus progressive GON in the setting of ODD. Cupping in the setting of ODD has been suggested as a rare occurrence¹⁴ but this may be dependent on the location of the ODD. Further work is needed to elucidate the mechanisms of optic neuropathy progression in patients with ODD. Since IOP appears to be a risk factor, particularly in ocular hypertensive patients, it needs to be determined whether a potential shared mechanisms between ODD and GON exists or whether a predominantly GON process is occurring and the definitive diagnosis is masked by the appearance of the optic disc. Our case series of 6 patients with co-existing ODD and ocular hypertension with two-thirds showing progression that was halted with IOP lowering interventions suggest there is a GON component in some of these patients. Though progression inferences are limited given the duration of follow-up for some cases, 2 patients did not show progression despite being ocular hypertensive, which suggests that the process is multifactorial and not all patients require treatment. In the setting of progressive optic neuropathy, treatment of IOP, particularly for ocular hypertensive patients, is a reasonable therapeutic option. Though determining the origin of optic neuropathy in ocular hypertensive patients with ODD can be a challenge, we believe having a low threshold for initiating IOP-lowering treatment is warranted at this this time.

Abbreviations

ODD

Optic Disk Drusen

IOP

Intraocular pressure

GON

Glaucomatous optic neuropathy

OCT

Optical coherence tomography

EDI

Enhanced-depth imaging

VF

Visual field

RNFL

Retinal nerve fiber layer