Role of oral acetazolamide in refractory glaucomatous deep cup-related maculopathy.

A 39-year-old man, a known case of primary open-angle glaucoma on treatment, presented with defective central vision in the left eye. On examination, his intraocular pressure (IOP) was 26 mmHg in the right eye and 30 mmHg in the left eye with best-corrected visual acuity of 6/12 in each eye. Fundus examination showed glaucomatous optic neuropathy in both eyes and macular thickening in the left eye. Optical coherence tomography of the left eye showed macular detachment with peripapillary retinoschisis and a hyporeflective tract connecting schitic retina and the deep cup in the absence of an optic disc pit. A diagnosis of glaucomatous deep cup maculopathy (DCM) was made in the left eye, which persisted despite well-controlled IOP and peripapillary laser photocoagulation. The addition of oral acetazolamide (250 mg twice daily) to his regimen resulted in prompt resolution of maculopathy. Glaucomatous DCM is relatively rare, and its primary management is adequate IOP control with antiglaucoma medications. Including oral acetazolamide in the antiglaucoma regimen can help in faster resolution of maculopathy due to its additional effect on retinal pigment epithelial pump induction and stabilization of the pressure gradient. Copyright:

Introduction

Congenital anomalies of optic nerve head (ONH) such as optic disc pit (ODP), optic disc colobomas, and morning glory syndrome are well known to cause peripapillary retinoschisis.[1] Up to 25%–75% of cases of temporal ODP are associated with macular involvement causing intraretinal and subretinal fluid accumulation with visual deterioration termed as ODP maculopathy.[1] Similar maculopathy has been described, though rarely, with acquired optic disk cup enlargement in glaucoma.[23]

Like ODP maculopathy, management options described for glaucomatous deep cup-related maculopathy (DCM) include observation, control of intraocular pressure (IOP), peripapillary barrage laser, and pars plana vitrectomy (PPV).[234] However, owing to the rarity and limited literature, there is a lack of clear treatment protocol for the same. We report a case of refractory glaucomatous DCM despite well-controlled IOP and peripapillary laser photocoagulation, showing rapid resolution following oral acetazolamide.

Case Report

A 39-year-old man, a known case of primary open-angle glaucoma for 1 year, presented with defective central vision in the left eye for 3 months. His antiglaucoma medications included topical timolol (0.5%) and brimonidine (0.2%) twice daily for both eyes; however, he was using medications irregularly for the past 6 months. On examination, his IOP was 26 mmHg in the right eye and 30 mmHg in the left eye. His best-corrected visual acuity (BCVA) in each eye was 6/12. Anterior segment examination was normal in both eyes. Fundus examination of the right eye was normal except for the optic cup-to-disc ratio of 0.7. The left eye showed the cup-to-disc ratio of 0.9 with macular thickening [Figure 1a]. Optical coherence tomography (OCT) of the left eye showed macular detachment with intraretinal schitic cavities prominent in the peripapillary area [Figure 1b]. Careful evaluation of radial OCT scans of the optic disc showed a hyporeflective tract connecting schitic retina and the deep cup; however, no evidence of ODP was seen [Figure 1c]. Fundus fluorescein angiography and indocyanine angiography showed normal angiographic features except blocked fluorescence in the area of subretinal fluid [Figure 2]. A diagnosis of primary open-angle glaucoma with glaucomatous optic neuropathy in both eyes and glaucomatous DCM in the left eye was made. Topical brinzolamide was added to his antiglaucoma regimen, and he was advised to use all medications regularly as prescribed.

Figure 1

(a) Fundus photograph showing advanced optic disc cupping (black arrows) with serous macular detachment (white arrows); (b and c) OCT showing serous macular detachment and retinal schisis with a tract (white arrow) connecting schitic retina to the disc cup. OCT: Optical coherence tomography

Figure 2

Fluorescein angiography and indocyanine green angiography showing no abnormalities except blocked fluorescence due to macular detachment

One month later, his IOP was reduced to 14 and 15 mmHg in the right and the left eye, respectively, and the same medications were continued. Repeat OCT after 2 months showed persisting maculopathy with signs of chronicity, including photoreceptor outer segment elongation and disruptions in the left eye, despite well-controlled IOP [Figure 3a]. At this stage, temporal peripapillary laser photocoagulation was done in the left eye. Three-month postlaser, BCVA of the left eye worsened to 6/18 with OCT showing persisting macular schisis and fluid despite the closure of connecting tract due to laser-induced rating of perceived exertion (RPE)-outer retinal scarring [Figure 3b]. Oral acetazolamide (250 mg twice daily) was added to his regimen, which caused further reduction in IOP to 13 mmHg in both eyes. One month after starting oral acetazolamide, OCT of the left eye showed decreasing maculopathy [Figure 3c] with BCVA improving to 6/12. The patient was continued with the same medications, and OCT after another month showed complete resolution of macular detachment, disrupted ellipsoid zone, and few residual intraretinal schitic spaces [Figure 3d]. Oral acetazolamide was stopped after 3 months. Visual acuity and OCT picture remained stable for the next 6 months of follow-up.

Figure 3

(a) OCT showing persisting maculopathy at 2 months of IOP control; (b) OCT at 3-month postlaser showing outer retinal scar and persisting maculopathy; (c) OCT at 1 month after starting oral acetazolamide showing significantly reduced macular detachment with residual schisis and ellipsoid zone defects; (d) One month later, OCT showing completely resolved macular detachment with photoreceptor reorganization and minimal residual schisis. OCT: Optical coherence tomography; IOB: Intraocular pressure

Discussion

Glaucoma-associated peripapillary retinoschisis, seen in about 6% of patients, often go unnoticed in routine clinical practice as patients remain asymptomatic.[5] Glaucomatous DCM is a rare but symptomatic condition presenting with defective central field of vision. With the advancement and frequent use of imaging modalities such as spectral-domain OCT, more cases are being reported recently. However, other conditions mimicking macular schisis such as juvenile X-linked retinoschisis, ODP-maculopathy, chronic central serous chorioretinopathy, cystoid macular edema (CME), epiretinal membrane, and vitreomacular traction should be ruled out carefully before confirming the diagnosis of glaucomatous maculopathy.[6] It should be suspected in patients with large optic cups, a convex elevation of the macula, no other retinal or choroidal pathology, and normal fluorescein angiography results.[2] With all these findings, our case was diagnosed with glaucomatous DCM.

The pathogenesis of glaucomatous DCM is not precisely known. Various plausible factors proposed include prolonged IOP elevation, IOP fluctuation, and structural defect in the neural rim of the optic disk.[678] Hollander et al. suggested that in advanced optic nerve cupping, a prolonged IOP elevation may lead to ruptures in the internal limiting membrane (ILM) and the formation of micropores in the retinal nerve fiber layer causing the seepage of liquid vitreous into the neurosensory retina and consequently causing retinoschisis.[7] Another hypothesis suggests the role of acute IOP fluctuations causing small changes in axial length and inducing vitreomacular traction leading to macular schisis.[6] Acquired ONH pit, a deep localized excavation of the neural rim with a sharp depression and loss of the normal laminar architecture of the lamina cribrosa has also been suggested to cause maculopathy.[8] In our case, OCT showed a hyporeflective tract at the level of OPL extending from the temporal disc margin to the peripapillary retinoschisis, which gives evidence to the origin of fluid to be from an occult ANOP, driven by the pressure gradient across lamina cribrosa. Irrespective of the exact pathomechanism, the splitting of neurosensory retinal layers appears as the primary outcome with serous macular detachment being the secondary result.

As per Investigating Glaucoma Progression Study, the peripapillary retinoschisis without any macular involvement is mostly asymptomatic and does not require any treatment other than adequate IOP control.[5] However, cases with maculopathy need more aggressive treatment. An adequate control of IOP may be the primary aim during the management of such cases, which is known to cause the resolution of peripapillary and macular schisis.[46] Peripapillary temporal barrage laser has also been described to manage glaucomatous DCM.[4] RPE-outer retinal scarring induced by laser photocoagulation causes the closure of micropores or ANOP tract and hence the resolution of maculopathy with preservation of the central field of vision.[3]

In our case, maculopathy persisted despite well-controlled IOP and peripapillary temporal laser. However, the addition of oral acetazolamide resulted in prompt resolution of maculopathy. Oral and topical carbonic anhydrase inhibitors (CAIs) are reported to enhance the fluid transport function of RPE pump, especially for CME in inherited disorders such as retinitis pigmentosa and juvenile retinoschisis.[9] Oral acetazolamide has higher potency in reducing macular edema compared to topical CAIs.[9] However, there is no previous report of using CAIs for DCM. The dramatic response after starting acetazolamide in our case could be explained with its additional advantages over other antiglaucoma drugs, including topical CAIs. Oral acetazolamide also reduces the fluctuation of pressure gradient between IOP and intracranial pressure across lamina cribrosa, due to its systemic effect.[9] However, the use of oral acetazolamide should be aimed for the prompt resolution of macular detachment and hence central scotoma in this subset of patients with advanced glaucomatous deep cupping and compromised peripheral fields.

With successful outcomes in ODP maculopathy, PPV with ILM peeling with or without gas tamponade has been attempted for DCM with the rationale of removing peripapillary vitreous traction.[24] However, PPV in eyes with advanced glaucomatous cupping carries the risk of causing “wipe-out” of the residual central field of vision leading to vision loss.[10] Even mild-to-moderate intraoperative or postoperative fluctuations in IOP can result in damage to the advanced glaucomatous optic nerve fibers in these eyes. In addition, PPV with ILM peeling carries a risk of foveal deroofing and formation of full-thickness macular holes in 36% of eyes.[4] Therefore, unlike ODP maculopathy, PPV may be reserved as the last resort in the management of glaucomatous DCM, considering the risk of residual central field wipe-out with IOP fluctuations.

To conclude, glaucomatous DCM is a relatively rare but an important entity for ophthalmologists to recognize. Adequate IOP control with antiglaucoma medications should be the first line of the management. Inclusion of oral acetazolamide in the antiglaucoma regimen can help in the accentuated resolution of maculopathy due to its additional effect on RPE pump induction and the stabilization of pressure gradient. Laser and surgical treatment may be reserved for the refractory cases considering the risks and benefits. Although being a single case report is the limitation in proposing the treatment protocol for glaucomatous DCM, this first report of using systemic CAI in this rare entity highlights the need for further studies to formulate a treatment protocol.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.