Monitoring MacTel: Why BCVA does not tell the whole story

Best-corrected visual acuity (BCVA) is the most used end point in retinal clinical trials. Although BCVA works well for quantifying visual disease burden in retinal conditions that primarily affect the central fovea, it can fail to capture visual disturbances experienced by patients with conditions whose pathology primarily or initially affects the parafoveal region.

There is no clear association between structural changes in the macula on optical coherence tomography (OCT) and BCVA. Many structural changes that can be observed with OCT, such as intraretinal cystoid spaces and disruption of the ellipsoid layers, are thought to be associated with reduced BCVA, but there is no direct relationship.¹ As such, the use of BCVA in the absence of measures that could capture other visual disturbances may contribute to underdiagnosis or misdiagnosis of diseases with primarily parafoveal pathology and may complicate the tracking of progression in these conditions.

Symptoms beyond the reach of BCVA

One disease that exemplifies the failure of BCVA to capture relevant visual disturbances is macular telangiectasia type 2 (MacTel). MacTel is a bilateral, neurodegenerative disease in which Müller glial cells, which help maintain the blood-retinal barrier and sustain photoreceptors, become dysfunctional, causing photoreceptor atrophy and visual loss.²

Although MacTel may eventually progress to the central fovea, initial changes are typically temporal to the foveal center.³ This is one reason that patients with MacTel may go years with no or only minimal decreases in BCVA,² but can still be markedly symptomatic with complaints of decreased reading ability and metamorphopsia.⁴

One way I have seen this manifest in patients with MacTel is that they may not have trouble when viewing a single isolated letter at a time, as they would when reading a chart, but if you ask them to view a whole word, suddenly portions of the letters are missing. This can make reading extremely difficult, and the mismatch between a patient’s daily experience and being told by their doctor that their vision is fine can be frustrating and disheartening.

MacTel has historically been considered a rare disease, but it is increasingly being recognized as underdiagnosed.⁵ In my practice, which is academic and primarily referral-based, I see 1 or 2 cases of MacTel a month, and often these patients are coming for a second or third opinion. They may even have been misdiagnosed and treated for a different condition.

Although BCVA alone is often inadequate for appropriately capturing disease progression in MacTel, the use of imaging can provide vital insights for this condition. It is critical to learn the imaging changes characteristic of this disease to ensure accurate diagnosis and effective monitoring of patients.

Structural monitoring

The current gold standard imaging modality for diagnosing MacTel is OCT, which allows for the measurement of key changes that have been used to classify MacTel, such as the presence of hyperreflective lesions and ellipsoid zone (EZ) loss.⁶ EZ loss is particularly crucial, as it can serve as a surrogate for photoreceptor loss.⁷ EZ loss is visible on OCT as a discontinuity in the third hyperreflective outer retinal line and as hyporeflective cavities in the inner and outer retina; as noted above, these changes typically start in the temporal region before progressing to the central fovea and, later, the nasal macula.³

In the past, fluorescein angiography (FA) was considered the gold standard for imaging of MacTel. Characteristic changes in MacTel that are observable on FA include telangiectatic capillaries in the parafoveal region, blunted right-angled venules, and leakage. In recent years, I have been favoring OCT and OCT-angiography (OCT-A) over FA. OCT-A is especially useful for monitoring for choroidal neovascularization (CNV), a rare but serious potential complication of MacTel. If CNV does occur, it can be treated with anti-VEGF agents, but these therapies have not shown efficacy in the nonproliferative form of MacTel.²

Functional monitoring

The biggest gap in monitoring of MacTel is the lack of a functional measure of noncentral visual acuity that is repeatable, reproducible, and can be performed quickly in a clinical setting. Although microperimetry has been used to assess visual function in MacTel,² the time and complexity involved make it too onerous for routine clinical use. Similarly, reading speed has been used as a functional measure in research studying MacTel, but is still uncommonly employed in clinical practice and may be confounded by variables such as socioeconomic or educational status.⁸

In the absence of an ideal tool for monitoring vision function, it is important to remember that a standardized, validated measure is not the only way to gain relevant clinical information. Monitoring for changes using OCT and OCT-A and discussing symptoms with the patient can provide a wealth of information on disease state and progression.

Conclusion

Although there is still much to learn, there is a heightened urgency to educate peers and patients about the nature of MacTel, ensuring that treatment reaches eligible individuals before significant disease progression occurs.

Sumit Sharma, MD

E: [email protected]

Sharma is a retina and uveitis specialist at Cole Eye Institute and serves as vice chair for the Integrated Surgical Institute and medical director for information technology at Cleveland Clinic in Cleveland, Ohio. Sharma reports consulting fees from 4DMT, AbbVie, Alimera Sciences (now ANI Pharmaceuticals Inc), Apellis Pharmaceuticals, Astellas, Bausch + Lomb, Clearside Biomedical, EyePoint Pharmaceuticals, Harrow, Genentech/Roche, Kodiak Sciences, Merck, Regeneron, REGENXBIO, Ripple Therapeutics, Volk, and Zeiss, with contracted research support from Acelyrin, Gilead Sciences, Genentech/Roche, Ionis Pharmaceuticals, Kodiak Sciences, and Santen.

References

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