NIGHT VISION DISTURBANCES (NVDs) constitute a challenging array of quality-of-vision problems that eyecare providers encounter all too commonly. The current range of tools at our disposal includes some tried-and-true options, but even more exciting technologies are on the horizon.

In this article, I’ll provide a deeper dive into NVDs, as well as the options available and under study.

Defining NVDs

NVDs (also known as dim light disturbances) describe a decrease in the quality of vision secondary to glare disability, with decreased contrast sensitivity and consequential image degradation.¹ The three most common visual disturbances described include glare, ghosting, and starbursts.¹ Most often, NVDs affect patients with complex corneas, such as those with keratoconus, anterior-basement membrane dystrophy, previous refractive surgery (radial keratotomy, photorefractive keratotomy [PRK], LASIK), pterygium, Salzmann’s nodular degeneration, ocular surface disease, and ectasia.

In a 2017 study, investigators found that glare decreased several aspects of nighttime driving performance. The overall driving performance score was significantly reduced by intermittent glare; notably, pedestrian detection decreased by 38% in the presence of intermittent glare.²

Treatment Considerations

Treatment first involves knowing what is causing the NVD. In certain scenarios, such as a patient with ocular surface disease, diligently treating the surface may reduce or eliminate the symptoms. Other considerations for treatment include contact lenses, spectacle lenses, and surgical options. Rigid gas permeable and/or specialty contact lenses can be utilized to try to minimize visual disturbances in patients with irregular corneas. In certain cases of corneal dystrophies or other corneal pathology, phototherapeutic keratectomy may help to alleviate the disturbances.

Another consideration to reduce the effects of NVDs is making the pupil smaller, thus blocking unfocused or peripheral aberrant rays of light and selectively allowing for the passage of more centrally focused rays.^3,4 This goal can be most commonly accomplished using pharmaceutical agents.

Medications on the market and being studied include pilocarpine, brimonidine, diluted aceclidine, and phentolamine.

Pilocarpine is a muscarinic parasympathomimetic drug causing miosis by acting on the iris sphincter muscle, and ciliary muscle. Available in various concentrations, the drug has existed for decades. Depending on the concentration, miosis of the pupil can vary. Extreme miosis can lead to a decrease in distance visual acuity, negating the benefits of reducing NVDs. The most common ocular side effects include accommodative spasm and frontal headaches.

Brimonidine stimulates prejunctional alpha-2 agonist receptors and reduces norepinephrine release, inhibiting pupil dilation by decreasing the activity of the dilator muscle. Brimonidine at concentrations of 0.025%, 0.15%, and 0.2% has been associated with miosis and reduction in halos under scotopic conditions in post-LASIK patients.^5,6 A study using brimonidine tartrate 0.15% ophthalmic solution in patients with complaints of night-vision difficulties after laser refractive surgery improved low-contrast visual acuity (LCVA) and resulted in decreased night-vision difficulties.⁷ The most common side effects that limit its use include tachyphylaxis to miosis, rebound mydriasis, and follicular conjunctivitis.

Aceclidine is an acetylcholine receptor agonist that causes miosis by acting on the iris sphincter muscle with an absence of ciliary muscle activity. A study of 0.016% and 0.032% dilute aceclidine investigated patients who had undergone myopic or hyperopic LASIK or PRK and were beyond 6 months postoperatively. They had stable nighttime vision complaints lasting at least 3 months. The study found a statistically significant reduction in halos, double vision, and wavefront aberrations. In addition, the study found a 2.5 mm mean reduction in pupil diameter under scotopic conditions between 30 minutes and 5 hours following instillation. The most common adverse effects were conjunctival hyperemia and burning at instillation.⁸

Phentolamine Clinical Trials

Phentolamine ophthalmic solution 0.75% (Nyxol, Ocuphire Pharma) is a nonselective alpha-adrenergic antagonist that inhibits the contraction of the smooth muscle of the iris, thus acting on the iris dilator muscle. Currently in clinical trials, the drug is being tested for various indications, including NVDs, reversal of mydriasis, and presbyopia. The medication is showing a duration of action of 24 hours when dosed at 1 drop once daily in the evening.⁹

There are multiple studies investigating 0.75% phentolamine ophthalmic solution for use in NVDs. In a phase 2 clinical trial, mean pupil diameter of phentolamine ophthalmic solution subjects decreased by 1.3 mm. A meaningful improvement of mean contrast sensitivity with glare occurred, as well as improvements in the numbers of letters read for mesopic and photopic high-contrast visual acuity and LCVA.¹⁰

In the phase 3 LYNX-1 trial evaluating 0.75% phentolamine eye drops for NVD, 145 study participants who experienced vision impairment under dim light conditions were randomized to receive either 0.75% phentolamine or placebo, self-administered in each eye daily at or close to bedtime. Thirteen percent of the 0.75% phentolamine-treated subjects gained 15 or more letters of mesopic low contrast distance visual acuity (mLCVA) at day 8, compared to 3% in the placebo group. At day 15, 21% of subjects in the 0.75% phentolamine-treated group gained 15 or more letters of mLCVA compared to 3% of the placebo group. Other results of the study revealed that 0.75% phentolamine-treated subjects gained 10 or more letters of mLCVA at day 8 with 41% vs 22% placebo and at day 15 with 44% vs 23%.¹¹

As far as safety, no serious adverse events were reported in the study. Eighty-four percent of adverse events were graded as mild with no significant differences in conjunctiva hyperemia, vital signs, or intraocular pressure following treatment.¹¹

Presbyopia Use and Possibilities

Pilocarpine 1.25% HCL ophthalmic solution (Vuity, Allergan/AbbVie) was approved in October 2021 by the FDA for once-daily dosing for the treatment of presbyopia. Recently, the FDA approved a twice-daily dosing option for pilocarpine 1.25% in adults with presbyopia. A second dose may be administered 3 to 6 hours after the first dose, which may extend the duration of efficacy for up to 9 hours. The phase 3 VIRGO trial randomized patients to receive one drop in each eye twice daily, with each dose administered 6 hours apart for 14 days vs placebo. The primary endpoint of subjects gaining 3 lines or more in mesopic, high-contrast, binocular, distance-corrected near visual acuity (DCNVA) with no more than a 5-letter loss in low light-corrected distance visual acuity at day 14, hour 9, was met in 35.1% of subjects vs 7.8% in the placebo group.¹²

Aceclidine is being investigated in 2 different formulations to treat presbyopia: aceclidine 1.75% alone (LNZ100, Lenz Therapeutics) and aceclidine 1.75% plus brimonidine (LNZ101, Lenz Therapeutics). In the INSIGHT phase 2 clinical trial, both formulations achieved a 3-line or greater improvement in near visual acuity, without losing 1 line or more in distance visual acuity at 1 hour in 71% and 56% of treated subjects, respectively. In addition, both formulations maintained a 3-line or greater improvement compared to vehicle for all time points including the last measured at 10 hours in 37% and 48%, respectively. The average pupil size was 1.5 mm to 2.0 mm for 10 hours with both formulations. Phase 3 clinical trials are currently under way.¹³

Phentolamine 0.75% is being investigated for use for presbyopia. In the VEGA-1 phase 2 multicenter placebo-controlled trial, 29% of subjects who used 0.75% phentolamine as a standalone medication had a ≥3-line improvement in DCNVA, without loss of 5 letters or more in best-corrected distance visual acuity compared to 12% in the placebo group. At 12 hours postdose, 53% of subjects achieved ≥2-line gain in DCNVA.

When 0.75% phentolamine was combined with low-dose 0.4% pilocarpine, 61% of subjects achieved a ≥3-line improvement in DCNVA without losing 5 letters or more in BCDVA. At 12 hours postdose, 79% of subjects achieved a ≥2-line gain in DCNVA.¹⁴

It’s exciting to have options and considerations to help patients who suffer from NVDs. These options will improve patients’ ability to function well at night and enhance overall quality of life. ■

References

1. Rosen ES. Night vision disturbance. J Cataract Refract Surg. 2005;31(2):247-249.
2. Kimlin JA, Black AA, Wood JM. Nighttime driving in older adults: effects of glare and association with mesopic visual function. Invest Ophthalmol Vis Sci. 2017;58(5):2796-2803.
3. Bidgoli S, Alio JL. Night vision disturbances following refractive surgery: causes, prevention, and treatment. In: Alio JL, Azar DT, eds. Management of Complications in Refractive Surgery. Springer; 2017:163-174.
4. Martínez CE, Applegate RA, Klyce SD, McDonald MB, Medina JP, Howland HC. Effect of pupillary dilation on corneal optical aberrations after photorefractive keratectomy. Arch Ophthalmol. 1998;116(8):1053-1062.
5. Lee JH, You YS, Choe CM, Lee ES. Efficacy of brimonidine tartrate 0.2% ophthalmic solution in reducing halos after laser in situ keratomileusis. J Cataract Refract Surg. 2008;34(6):963-967.
6. Nejad M, Lin SR, Hwang LH, Landig M, Al-Hashimi S, Bartlett JD. Effect of over-the-counter brimonidine tartrate 0.025% ophthalmic solution on pupil size in healthy adults. Graefes Arch Clin Exp Ophthalmol. 2021;259(11):3333-3338.
7. Randazzo R, Nizzola F, Rossetti L, Orzalesi N, Vinciguerra P. Pharmacological management of night vision disturbances after refractive surgery Results of a randomized clinical trial. J Cataract Refract Surg. 2005;31(9):1764-1772.
8. Edwards JD, Burka JM, Bower KS, Stutzman RD, Sediq DA, Rabin JC. Effect of brimonidine tartrate 0.15% on night-vision difficulty and contrast testing after refractive surgery. J Cataract Refract Surg. 2008;34(9):1538-1541.
9. Safety and Efficacy of Nyxol With Pilocarpine Eye Drops in Subjects With Presbyopia. ClinicalTrials.gov . June 22, 2022. Accessed May 3, 2023. https://clinicaltrials.gov/ct2/show/NCT04675151
10. Pepose J, Brigell M, Lazar E, et al. A randomized phase 2 clinical trial of phentolamine mesylate eye drops in patients with severe night vision disturbances. BMC Ophthalmol. 2022;22(1):402.
11. Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) in Subjects With Dim Light Vision Disturbances. ClinicalTrials.gov . May 23, 2022. Accessed May 3, 2023. https://clinicaltrials.gov/ct2/show/NCT04638660
12. Kannarr S, El-Harazi SM, Moshirfar M, et al. Safety And Efficacy of Twice-Daily Pilocarpine HCl In Presbyopia: The Virgo Phase 3, Randomized, Double-Masked, Controlled Study. Am J Ophthalmol. 2023 May 4:S0002-9394(23)00195-2. doi: 10.1016/j.ajo.2023.05.008. Epub ahead of print. PMID: 37149245.
13. Press release. LENZ Therapeutics Announces Positive Topline Data from Phase 2 INSIGHT Trial of LNZ100 and LNZ101 to Treat Presbyopia: https://www.businesswire.com/news/home/20221018005258/en/LENZ-Therapeutics-Announces-Positive-Topline-Data-from-Phase-2-INSIGHT-Trial-of-LNZ100-and-LNZ101-to-Treat-Presbyopia .
14. Katz J, Lazar E, Kolli A, et al. VEGA-1: Phentolamine Ophthalmic Solution as a Single Agent Improves Distance-Corrected Near Visual Acuity in Patients with Presbyopia. Investigative Ophthalmology & Visual Science June 2022, Vol. 63, 1813-F0429.

Dr. Schweitzer specializes in advanced glaucoma, refractive surgical clinical care, and anterior-segment pathology at Vance Thompson Vision, Sioux Falls, SD. He received his professional training and Doctor of Optometry degree from Pacific University College of Optometry in Forest Grove, OR.

Disclosures
Dr. Schweitzer is a consultant for Ocuphire Pharma and Allergan.