Incipient NAION vs Classic NAION with Vision Loss

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doi:10.62055/88951569Ck

ABSTRACT

BACKGROUND

Non-arteritic anterior ischemic optic neuropathy (NAION) is an optic nerve disorder believed to be caused by ischemia of the optic nerve head. The most common presentation is a sudden monocular painless vision loss that presents upon awakening. A less documented and understood entity, incipient NAION is characterized by optic neuropathy with clinical features similar to classic NAION but without vision loss. Incipient NAION may resolve or progress to classic NAION with vision loss.

CASE REPORTS

Presented are two cases of incipient NAION. In each case the patient had multiple risk factors for NAION. In one case, risk factors were not mitigated, and the patient progressed to classic NAION with vision loss, and in the other case, risk factors were effectively mitigated with resolution of the optic neuropathy.

CONCLUSION

Incipient NAION has a distinct clinical entity from classic NAION. Additional research and studies are necessary to determine whether incipient and classical NAION are separate disease entities or merely different stages of progression within one. The difficulty in this lies within the disease itself, whereby a patient with classical NAION typically presents with symptoms of vision loss upon awakening, but with incipient NAION there is no vision loss. Therefore, it is only by happenstance that optic disc edema is discovered in a routine exam when there are no associated symptoms. It stands to reason that incipient NAION may very well be its own disease and there is just not enough data to support the definition. Primary eye care providers have a significant role in monitoring individuals with incipient NAION and co-managing with primary care providers (PCPs) to aggressively manage the systemic risk factors of NAION before converting to classical NAION.

Keywords: Incipient nonarteritic anterior ischemic optic neuropathy, classic nonarteritic anterior ischemic optic neuropathy, disc at risk, nocturnal hypotension, obstructive sleep apnea, visual field, OCT analysis

INTRODUCTION

Non-arteritic ischemic optic neuropathy (NAION) is the most common acute optic nerve disease of adults over 50 years of age.¹ The median age for diagnosis of NAION is approximately 62 years and less than 11% of patients are 45 years or younger.^2,3 The US population incidence is 2 to 12 cases per 100,000 over the age of 50, with 6,000 new cases each year.^1,3,6 White individuals appear to be at significantly higher risk suggesting possible genetic predisposition.^1,2 It typically presents with sudden monocular, painless, altitudinal visual field loss upon awakening. If present, optic disc edema (ODE) can be diffuse or localized to the superior or inferior optic nerve head (ONH). Visual acuity (VA) can vary from 20/20 to no light perception (NLP).  Risk factors for NAION include a small optic disc and cup (“disc at risk”), advanced age, nocturnal hypotension, smoking, systemic arterial hypertension, diabetes mellitus, hyperhomocysteinemia, obstructive sleep apnea (OSA), vasospasm, hypercoagulable states, optic disc drusen, some ocular and non-ocular surgeries, atherosclerosis, migraine, and the use of certain vasoactive medications.^3,4,5,6,7,12

CASE REPORT 1 

A 45-year-old Hispanic male who had four months previously been diagnosed with NAION in his left eye presented for follow-up with no new complaints.  The visual acuity was 20/20 in each eye.  The left eye had a mild afferent pupillary defect (APD) along with superior optic nerve atrophy with a corresponding inferior altitudinal visual field loss. On fundus examination, a new finding was swelling at the inferior aspect of the right optic nerve head (Figure 1). Visual function in the right eye was normal; visual acuity of 20/20, normal color vision tested with Ishihara color plates, and visual fields measured with automated perimetry demonstrated a full visual field in the right eye. The left eye had an inferior visual field loss due to previous NAION. The retinal nerve fiber layer (RNFL) measured with OCT demonstrated a thicker (corresponding to swelling) RNFL inferior in the right eye and thinner

(consistent with atrophic changes) RNFL superior in the left eye. The patient denied pain on eye movement, headache, or other neurological or systemic symptoms.  In addition to the previously diagnosed NAION OS, the patient’s medical history included hypertension, hyperlipidemia, gastroesophageal reflux disease (GERD), anxiety, obesity, prediabetes, and untreated obstructive sleep apnea (OSA). The patient denied symptoms consistent with arteritic ischemic optic neuropathy (AAION). His active medications included fluoxetine Hcl 20 mg for anxiety, lisinopril 40 mg for hypertension, ranitidine Hcl 150 mg for GERD and diet-controlled prediabetes.  A STAT erythrocyte sedimentation rate (ESR), C-reactive protein test (CRP) and complete blood count (CBC) were ordered.  The patient was advised that there appeared to be incipient NAION in his right eye.  The patient’s PCP was consulted with advice to monitor cardiovascular risk factors, for nocturnal hypotension and obstructive sleep apnea (OSA). Nine days later, the patient reported losing vision above fixation in the right eye with no change to the left. Uncorrected central VA remained 20/20 in each eye. There were new petechial hemorrhages at the inferior disc margin OD and an increase in optic nerve swelling. The increased optic nerve swelling was quantified using OCT (see Figure 2 for baseline and nine day later OCT measurements). Visual field testing showed a new superior altitudinal depression OD and a stable inferior altitudinal loss OS (see Figure 3 for comparison of right eye visual fields taken at baseline and nine days later). The patient was diagnosed with acute phase classic NAION OD and stable atrophic phase NAION OS. The patient was monitored closely over the next weeks as the right eye went through the acute phase of NAION with progressively increasing optic nerve swelling followed by the stable atrophic phase.

Figure 1. The right optic nerve (left) has inferior swelling . The left optic nerve (right) has pallor superior due to previous diagnosis of NAION.

Figure 2. OCT RNFL demonstrating increased inferior swelling of the right optic nerve from baseline (left) to nine days later (right). The left optic nerve has atrophic RNFL superior which is stable.

Figure 3. HVF 30-2 right eye gray scale taken at baseline (left) and nine days later (right). The patient was initially diagnosed with “incipient” NAION that converted to “classic” NAION.

CASE REPORT 2 

A 71-year-old Hispanic female presented to the clinic for her annual exam.  She had no new complaints and was using 5% lifitegrast ophthalmic solution eye drops for the treatment of Sjogren’s related dry eye. Her medical history included pre-hypertension, hypothyroidism, hyperlipidemia, obesity, vitamin-D deficiency, hypokalemia, hematuria, osteopenia, GERD, B-12 deficiency, OSA, rheumatoid arthritis, Sjogren’s syndrome, and postherpetic neuralgia.  Her best corrected VA was 20/20 OD, and 20/30 OS. IOP was 14 mmHg OD and 14 mmHg OS with Goldmann applanation tonometry. Preliminary test findings were unremarkable. Upon slit lamp examination, she had mild corneal punctate staining of the left eye, worse than the right. A dilated fundus exam revealed a C/D of 0.1mm OD and swollen OS ONH with no discernable cup, and no peripapillary or retinal hemorrhages noted (Figure 4). OCT RNFL showed a normal RNFLof the right eye and diffusely thicker RNFL of the left, consistent with swelling. A baseline Humphrey visual field analysis using a central 24-2 Size III threshold target revealed only a few scattered non-specific, shallow points of inferior depression OD and OS, which was not consistent with classic NAION. She had normal color vision tested with Ishihara color plates.  When questioned about her OSA treatment compliance, she reported that she used her CPAP mask sporadically. The initial tentative diagnosis was unspecified optic disc edema OS. The patient was educated on her systemic arterial health and advised to be more compliant with her CPAP and medications and to monitor her blood pressure with her PCP. Diagnostic testing that was ordered included CBC, ESR, HCT, platelets, CRP, bartonella antibodies, RPR, toxoplasmosis IgG titers, and an MRI with and without contrast of her brain and orbits. All the patient’s hematological and radiological testing came back normal. The patient was followed for the next 18 months, and she experienced slow resolution of the left optic disc swelling. The RNFL returned to a much more normal thickness and the observable optic disc swelling had resolved (see Figure 5 for OCT at baseline and 18 months later). Her vision remained stable. During this time, she became compliant with the use of CPAP for OSA and was compliant with her medications.  The patient exhibited all the hallmark signs of incipient NAION OS, as there was no loss of vision or visual field defects attributed to her ODE. Furthermore, her edematous ONH totally resolved without reason to believe it was caused by an underlying health condition, and her compliance to mitigating factors assumedly helped in total resolution. Today the patient is back on a regular annual schedule for primary eye care or PRN for symptoms related to her dry eye syndrome.

Figure 4 . Color fundus photo shows a normal fundus of the right eye (left) while the optic nerve of the left eye (right) appears swollen with blurred margins and no discernable cup without any retinal or peripapillary hemorrhages.

Figure 5. Cirrus OCT demonstrating swollen RNFL of the left eye at baseline (left) with resolution of RNFL swelling at 18 months (right).

DISCUSSION

Non-arteritic anterior ischemic optic neuropathy is the second most common optic neuropathy with approximately 6000 new diagnoses per year in the United States.^5,6 Classic NAION can be diagnosed if a patient has diffuse or sectoral swelling of the optic nerve head, RAPD, objective and/or sudden subjective vision loss in the affected eye upon awakening, and no ocular, orbital, neurologic, or systemic disorders contributing to the ODE and visual impairment. Spontaneously-resolved ODE can also be used as a good indicator of classical NAION as in the later stages of ONH atrophy resulting from persistent edema.^3,5,6,7  Less is known about incipient NAION which presents with disc edema similar to classic NAION but with normal vision. There is debate as to whether incipient NAION is its own clinical entity or a variant of classic NAION.

The first case presented with optic disc swelling as described in incipient NAION but converted to classic NAION with vision loss in nine days. The second case is consistent with incipient NAION, whereby disc edema of the left eye was present with no vision loss reported or measured. A study conducted by Hayreh and Zimmerman proposed the following criterion to diagnose an incipient NAION: (1) the presence of localized optic disc edema, (2) no subjective or objective visual loss attributed to classic NAION, with the exception that some eyes have enlarged blind spots on visual field perimetry corresponding to the edematous nerve, (3) ocular, orbital, neurologic, hematologic, and systemic evaluation showing no other possible cause for an asymptomatic edematous optic nerve.^7,8  Optic disc edema can present secondary to various conditions including optic neuritis, optic disc vasculitis, posterior uveitis, neuroretinitis, central vein occlusion, ocular hypotony, vitreous traction syndrome, orbital compressive lesion, Leber’s hereditary optic neuropathy, pseudopapilledema, optic nerve lesions, or, most commonly, elevated intracranial pressure.⁷ According to Hayreh, et al., differential diagnosis of other causes of asymptomatic ODE from incipient NAION is relatively straight-forward by means of appropriate diagnostic testing ruling out potential etiologies other than incipient NAION. Orbital diseases are ruled out by the absence of proptosis, tenderness, pain, ocular motility abnormalities, and if indicated, orbital echography. Neurologic disorders can be ruled out by neuroimaging and lumbar puncture. Hematologic testing can rule out inflammatory or infectious systemic diseases, while other conditions can be ruled out with biomicroscopy, dilated fundoscopy, intravenous fluorescence angiography, etc. Thus, incipient NAION is a diagnosis of exclusion.^7,8

Acute ischemia during the development of an incipient NAION has a wide range of severity. Evidence suggests that in incipient NAION subclinical ischemia (or hypoxia) produces only axoplasmic flow stasis without causing infarction of tissue and no impairment of transmission of visual impulses. This is well demonstrated in a case of elevated intracranial pressure causing papilledema where there is typically no detectable interruption of axonal transmission. Alternatively, severe ischemia usually results in infarction of the optic nerve, as in arteritic AION, which often leads to permanent vision loss.^7,9,14 It is important to note that acute ischemia of the optic nerve does not always end in infarction and complete loss of vision. There are multiple case reports of incipient NAION that progress to classic NAION. Hayreh and Zimmerman reported that 25% of patients with incipient NAION progressed to classic NAION after a median of 5.8 weeks, and 20% of patients developed classic NAION after resolution of the optic disc edema.^7,8 The proposed theory of progression explains that swollen axons expand in a restricted space, as in a “disc at risk,” a tight Bruch’s membrane opening, or a small scleral canal, and compress the capillaries lying in between axons. It is believed that subclinical ischemia leads to compression of these low-pressure capillaries and reduction of blood flow. Prolonged ischemia leads to a vicious cycle of swelling of axons and further axoplasmic flow stasis that can potentially result in infarcted tissue and permanent visual loss. Compressed capillaries lead to an increase in vascular resistance, requiring higher levels of blood pressure to maintain adequate blood perfusion. If blood pressure falls below a critical level during an arterial hypotensive event (as in nocturnal hypotension), this may be the final result, where an incipient NAION progresses to classic NAION. Nevertheless, other factors such as sleep apnea, defective autoregulation and vasculopathic changes from arterial hypertension, diabetes, and atherosclerosis may individually or collectively contribute to an incipient NAION and progression to classic NAION.^3,4,5,6,7 It should be stated that contrary to the highly prevalent misconception that an absent or small cup is the primary factor for the development of incipient or classic NAION, it is now regarded as a secondary contributing factor, after the process of NAION (axonal swelling) has started ⁷. There have been studies suggesting certain vasoactive medications such as phosphodiesterase type-5 inhibitors (PDE-5i) have contributed to cases of NAION, but other studies conclude that the incidence of patients taking PDE-5i compared to control groups is not statistically significant.^5,11 Amiodarone and sumatriptan have also been associated with NAION.^5,10 Sumatriptan, commonly prescribed to treat migraine headaches, is a serotonin 1 (5-HT1) receptor agonist known to cause non-coronary vasospastic reactions which can lead to infarction.

CONCLUSION

Incipient NAION has a distinct clinical presentation from classic NAION, yet there has only been one comprehensive study on the disease.^7,13 It is possible that incipient NAION may very well be its own disease and there just is not enough data to support the definition.⁷ Additional research and studies are necessary to determine whether incipient and classical NAION are separate disease entities or merely different stages of progression within one. It is only then that an effective treatment can be developed to prevent future incidence of vision loss due to conversion to classical NAION. The difficulty in this lies within the disease itself, whereby a patient with classic NAION typically presents with symptoms upon awakening, but it is only by happenstance that ODE in incipient NAION is discovered at a routine visit when there are no associated symptoms. It is rare that the clinician is fortunate enough to observe the evolution of a disease before it becomes symptomatic, since it is the onset of symptoms that normally brings the patient to the physician.¹⁵ It must be considered as a top differential in those who previously had classic NAION, as well as in those with high risk factors for NAION. To reduce the chances of progression from incipient to classic NAION, precautions should be taken to reduce the risk factors immediately. Although it is the most common acute optic nerve disease in individuals over 50 years of age, there is no effective treatment for NAION. However, there were four presumed incipient NAION cases from Singapore and two Chinese patients that were treated with brimonidine eye drops that did not progress to full-blown NAION.¹³ Brimonidine, in initial treatment for incipient NAION, may offer some benefit. Primary eye care providers have a significant role in monitoring individuals with incipient NAION and co-managing with PCPs to aggressively manage the systemic risk factors before converting to classical NAION.

REFERENCES

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2. Johnson, L., Arnold, A. (1994). Incidence of Nonarteritic Anterior Ischemic Optic Neuropathy: Population-Based Study In The State Of Missouri And Los Angeles County, California. Journal of Neuro-Ophthalmology 14(1): 38-44
3. Miller, N. R., & Arnold, A. C. (2014). Current Concepts In The Diagnosis, Pathogenesis And Management Of Nonarteritic Anterior Ischaemic Optic Neuropathy. Eye, 29(1), 65–79. doi: 10.1038/eye.2014.144
4. Archer, E. L., & Pepin, S. (2013). Obstructive Sleep Apnea And Nonarteritic Anterior Ischemic Optic Neuropathy: Evidence For An Association. Journal of Clinical Sleep Medicine, 09(06), 613–618. doi:10.5664/jcsm.2766
5. Berry, S., Lin, W., Sadaka, A., & Lee, A. (2017). Nonarteritic Anterior Ischemic Optic Neuropathy: Cause, Effect, And Management. Eye and Brain, Volume 9, 23–28. https://doi.org/10.2147/eb.s125311
6. Shir Yen, W., Yathavan, S., Ramli, M. A., Siu Wan, F., & Che Hamzah, J. (2021b). Bilateral Sequential Non-arteritic Anterior Ischemic Optic Neuropathy (NAION). Cureus. doi: 10.7759/cureus.19408
7. Hayreh, S. S., & Zimmerman, M. B. (2007). Incipient Nonarteritic Anterior Ischemic Optic Neuropathy. Ophthalmology, 114(9), 1763–1772. doi: 10.1016/j.ophtha.2006.11.035
8. Eshtiaghi, A., & Micieli, J. A. (2021). Incipient Non-Arteritic Anterior Ischemic Optic Neuropathy In A Patient With Metastatic Small-Cell Lung Cancer. Case Reports in Ophthalmology, 12(2), 513–518. doi: 10.1159/000516573
9. Levin, L. A. (1996). Apoptosis Of Retinal Ganglion Cells In Anterior Ischemic Optic Neuropathy. Archives of Ophthalmology, 114(4), 488. doi: 10.1001/archopht.1996.01100130484027
10. Chiari, M., Manzoni, G. C., & Geijn, E. J. (1994). Ischemic Optic Neuropathy After Sumatriptan In A Migraine With Aura Patient. Headache: The Journal of Head and Face Pain, 34(4), 237–238. https://doi.org/10.1111/j.1526-4610.1994.hed3404237_2.x
11. Liu, B., Zhu, L., Zhong, J., Zeng, G., & Deng, T. (2018). The Association Between Phosphodiesterase Type 5 Inhibitor Use And Risk Of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review And Meta-Analysis. Sexual Medicine, 6(3), 185–192. doi: 10.1016/j.esxm.2018.03.001
12. Hufdhi, R. Chandra, A., Bolognian, F., Rushdi, H., Aldhafeeri, A., Altorok, N. (2022). Acute, Painless Monocular Vision Loss: Non-arteritic Ischemic Optic Neuropathy Associated With Untreated Obstructive Sleep Apnea, Uncontrolled Type 2 Diabetes Mellitus, Essential Hypertension, and Hyperlipidemia: A Case Report. Cureus 14(7): e26687. doi: 10.7759/cureus.26687
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15. Hayreh, S. (1981). Anterior Ischemic Optic Neuropathy V. Optic Disc Edema An Early Sign. Arch Ophthalmol 99, 1030-1040

Joey Kalec, OD

Central Texas Veterans Health Care System | Austin, TX

Dr. Kalec graduated from the University of Houston College of Optometry in 2022. The next year he completed a residency in primary care with an emphasis in ocular disease at the Valley Coastal Bend VA in Harlingen/McAllen, Texas. He is currently a staff optometrist with the Central Texas Veterans Health Care System in Austin, Texas. A veteran himself, Dr Kalec was deployed during Operation Enduring Freedom and Operation Iraqi Freedom while serving aboard ship in the United States Navy, until his Honorable discharge in 2005.

Michael Wingard, OD, ABCMO, FAAO

VA Texas Valley Coastal Bend Health Care System | McAllen, TX

VA Residency Coordinator at VA Texas Valley Coastal Bend Health Care System, McAllen and Harlingen, Texas.

Celina Villarreal, OD, FAAO, Diplomate of the ABO

Central Texas Veteran Affairs Health Care System(CTVHCS) | Waco, TX

Graduate of the University of Houston College of Optometry, Magna Cum Laude with over 20 years of experience as an Optometric Glaucoma Specialist with an emphasis in diabetic, glaucoma, and specialty contact lens optometric eye care. Currently working as Supervisor Optometrist at VA Texas Valley Coastal Bend Health Care System and serves as an adjunct professor for the University of Texas Health Science Center Long School of Medicine.

Hyoung I. Lho OD

Central Texas Veteran Affairs Health Care System(CTVHCS) | Waco, TX

Graduated from Pennsylvania College of Optometry at Salus University. Currently at Veterans Affairs as staff optometrist in Waco, Texas. Adjunct faculty at Rosenberg College of Optometry and New England College of Optometry.