The Brain-Eye Axis: Understanding Neurodegenerative Overlaps

Classically, glaucoma has been categorized as an ocular neurodegenerative disease, whereby increased IOP, axonal compression, and reduced blood flow lead to retinal ganglion cell (RGC) death and visual field (VF) defects.¹ The most frequently diagnosed condition of the optic nerve and the second leading cause of blindness, glaucoma is common, heterogenous, and, at times, misdiagnosed.² Many patients diagnosed with glaucoma, preperimetric glaucoma, or normal-tension glaucoma may actually have another optic neuropathy, neurodegenerative disease, or a structural anomaly or artifact on testing, leading the clinician awry and delaying the true diagnosis of the underlying condition. Thus, it is imperative to recognize the neurodegenerative overlaps.

THE CENTRAL NERVOUS SYSTEM: A REVIEW

The optic nerve originates from the diencephalon of the forebrain, making it a part of the central nervous system (CNS).³ Functionally and pathophysiologically, the eye and brain operate as an integrated neurological system, with the retina containing many of the same neural cell types found in the brain.⁴ The retina is composed of three primary neuronal layers: photoreceptors, bipolar cells, and RGCs.

Emerging evidence suggests that glaucoma may involve trans-synaptic degeneration, in which apoptosis of RGCs propagates anterogradely along the optic nerve to the lateral geniculate nucleus and primary visual cortex, consistent with CNS neurodegeneration.⁵ Given the bidirectional connectivity of the visual pathway, central neurologic conditions may also cause retrograde and/or anterograde degeneration, resulting in optic nerve pallor, retinal nerve fiber layer (RNFL) thinning, ganglion cell layer (GCL) loss, and VF loss that can mimic glaucomatous changes.⁶

GLAUCOMA MASQUERADERS AND CLINICAL RED FLAGS

Glaucoma masqueraders are conditions that may present with optic nerve or VF changes that may look glaucomatous but have a different pathophysiology and vary in progression, treatment response, and VF defects (Table). Because glaucoma presents with widespread patterns of RGC loss and progressive cupping, many other optic neuropathies can look similar in their early stages, particularly with normal-tension glaucoma.

In most glaucomatous cases, especially primary open-angle glaucoma, the RNFL thinning has a predilection for inferior, inferotemporal, superior, and superotemporal portions of the optic nerve and is slowly progressive. Due to the neuroanatomic division of the superior and inferior RNFL by the horizontal raphe in the eye, glaucomatous VF defects should correspond with the RNFL defect on OCT imaging and respect the horizontal midline.⁷ The cupping should be gradual and proceed optic disc pallor. Non-glaucomatous optic neuropathies—including compressive, inflammatory, demyelinating, ischemic, hereditary, mitochondrial, toxic, nutritional, and neurodegenerative etiologies—have notable differences in presentation that should alert the clinician to their etiology.

NEURODEGENERATIVE DISEASE AND THE EYE

A hallmark of any neurodegenerative disease is the progressive loss of neurons and their synapses.

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS that causes t-cell mediated neuroinflammation that results in demyelination and axonal damage. When MS affects the optic nerve through optic neuritis, there is an acute phase where RNFL thickness increases. After the acute phase, there is a progressive decrease in RNFL thickness over the next 2 to 6 months that stabilizes from 7 to 12 months and tends to affect the temporal RNFL sector more than other areas.^8-10 While it is intuitive that patients with a history of optic neuritis will have RNFL and GCL thinning, studies also show that patients with MS who do not have a history of optic neuritis still have significant peripapillary RNFL thinning and atrophy of the macular GCL and inner plexiform layer (IPL) compared with controls, albeit to a lesser extent than eyes with optic neuritis, suggestive of ocular neurodegeneration from the generalized CNS disease.^11,12

In Alzheimer disease (AD), an accumulation of beta-amyloid plaques and tau protein tangles disrupt cellular communication and axonal transport, leading to a neuroinflammatory response that causes neuronal cell death. Beta-amyloid plaques and tau protein tangles can deposit in the retinal IPL and outer plexiform layer,¹³ leading to microglial cell activation and RGC loss.¹⁴ Compared with healthy controls, patients with mild cognitive impairment and AD have significantly reduced RNFL thickness, particularly in the superior and inferior sector, although not as reduced as those with glaucoma, making this type of degeneration difficult to differentiate from glaucoma.¹⁵

Parkinson disease (PD) is caused by early death of dopaminergic neurons in the substantia nigra, leading to dopamine deficiency in the basal ganglia and progressive neurodegeneration. Retinal dopaminergic neurons (amacrine cells) are present in the IPL, GCL, outer plexiform layer, and outer segments of photoreceptors. Subsequently, PD is associated with diffuse RNFL thinning and macular volume loss. OCT findings often align with disease duration and severity and often correspond with impaired contrast sensitivity.¹⁶

Other neurodegenerative diseases such as Huntington disease and amyotrophic lateral sclerosis have also been associated with RNFL and GCL/IPL thinning, strengthening the concept that the retina/optic nerve mirrors CNS neurodegeneration across diverse diseases.^17,18

OPTIC NERVE APPEARANCE AND VISUAL FIELD CHANGES

Optic nerve and macular GCL/IPL changes in neurodegenerative disease can resemble glaucomatous cupping, leading to misdiagnosis. However, several distinguishing features may help differentiate central pathology from glaucoma.

In neurodegenerative optic neuropathies, the optic disc typically shows pallor greater than cupping, reflecting widespread axonal loss without the characteristic sectoral loss seen in glaucoma. Some conditions, such as MS, will show temporal pallor/RNFL loss more than other sectors due to preferential damage to the papillomacular bundle, which is less common in early glaucoma.^19-22 Due to diffuse RNFL/GCL loss, patients with neurodegenerative optic neuropathy will have significant contrast sensitivity loss, color vision loss, and visual acuity loss earlier in their disease state, while these findings are more common in later-stage glaucoma.

VF testing provides a functional perspective on neurodegeneration along the afferent visual pathway. Because the visual pathway spans the retina, optic nerve, chiasm, optic tracts, thalamus, and cortex, degeneration anywhere along this network can alter VF performance. Unlike glaucoma, which tends to produce arcuate and nasal step defects, many neurodegenerative diseases such as AD/PD present with generalized depression or a central/cecocentral scotoma or VF defect that respects the vertical midline, appears inconsistent with the disc/RNFL appearance, or fluctuates with disease activity.

Due to abnormalities in fixational stability and cognitive processing difficulties from their neurodegenerative disease, these patients may have inconsistent, variable, or unreliable VFs, as their disease influences their ability to take the test; thus, repeat testing is indicated. While it has been posited that there is an increased prevalence of primary open-angle glaucoma in patients with PD/AD, many of these patients have similar optic nerve cupping and glaucomatous-like VF defects but normal IOP—leading us to question if it is truly glaucoma or central neurodegenerative optic neuropathy.²³

APPROACH IT FROM MULTIPLE ANGLES

As our understanding of the brain-eye axis continues to grow, so too will our understanding of how glaucoma can influence CNS neurodegeneration and how CNS neurodegeneration can influence the eye. The eye will play an increasingly important role in the early detection and monitoring of neurodegeneration. However, given the significant neurodegenerative overlaps, a multimodal approach (eg, combining OCT, VF testing, oculomotor evaluation, contrast sensitivity, fundus evaluation, and a brief neurologic history) may significantly increase our diagnostic accuracy. By recognizing these patterns, optometrists can detect neurologic disease earlier, avoid mislabeling central pathology as glaucoma, and facilitate timely referral and intervention.